Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:13][CH2:12][N:11]([C:14](=[O:17])[CH2:15][CH3:16])[CH2:10]1.[N+:18]([O-])([OH:20])=[O:19].S(=O)(=O)(O)O.[OH-].[Na+]>[N+](C)([O-])=O.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:18]([O-:20])=[O:19])=[CH:5][C:4]=1[CH:9]1[CH2:13][CH2:12][N:11]([C:14](=[O:17])[CH2:15][CH3:16])[CH2:10]1
Reactant: CCC(=O)N1CCC(c2ccccc2OC)C1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C[N+](=O)[O-]
Solvent: O
Product: CCC(=O)N1CCC(c2cc([N+](=O)[O-])ccc2OC)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.8 %

Procedure:
1-[3-(2-Methoxy-phenyl)-pyrrolidin-1-yl]-propan-1-one (0.7 g; 3 mmol) were dissolved in 10 ml of nitromethane. At −5° C. to −10° C., a mixture of 0.290 g nitric acid, 0.5 g water and 5.52 g sulphuric acid were added within 25 minutes, and the reaction mixture was stirred for another 1 h at low temperature and 16 h at room temperature. Ice was added, the reaction mixture was adjusted to alkaline pH with 50% aqueous NaOH, and the aqueous phase was extracted twice with diethylether. The organic layers were combined, dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure to yield 0.85 g of the desired product as a mixture of isomers and small amounts of the dinitro derivative which was used in the next reaction without further purification.
Reaction SMILES: Cl[Si:2]([C:5]1[CH2:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([CH3:4])[CH3:3].[CH:14]1([Na])[CH:18]=[CH:17][CH:16]=[CH:15]1.O>C(OCC)C.O1CCCC1>[CH:14]1([Si:2]([C:5]2[CH2:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)([CH3:3])[CH3:4])[CH:18]=[CH:17][CH:16]=[CH:15]1
Reactant: [Na]C1C=CC=C1
Reactant: C[Si](C)(Cl)C1=Cc2ccccc2C1
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[Si](C)(C1=Cc2ccccc2C1)C1C=CC=C1
Temperature: 0 °C
Reaction time: 15 h
Yield: 45.8 %

Procedure:
Chloro-2-indenyldimethylsilane (4.6 g, 0.022 mol.) from Example 1 was dissolved in 20 ml of diethyl ether. The solution was cooled to 0° C., and a solution of cyclopentadienylsodium (1.94 g, 0.022 mol.) in 20 ml of tetrahydrofuran was added dropwise. The mixture was stirred for 15 hours at 25° C. 50 ml of water were then added, and the organic phase was washed with water again and dried over Na2SO4. After removal of the solvents under an oil pump vacuum, the light-yellow oil that remained was purified by means of column chromatography. The solvent was removed to yield 2.4 g (46%) of cyclopentadienyl-2-indenyl-dimethylsilane in the form of a colorless oil.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[OH:11])([CH3:3])[CH3:2].[NH2:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17](F)[C:14]=1[C:15]#[N:16]>>[NH2:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([O:11][C@@H:5]2[CH2:6][C@H:7]([CH3:10])[CH2:8][CH2:9][C@H:4]2[CH:1]([CH3:3])[CH3:2])[C:14]=1[C:15]#[N:16]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Reactant: N#Cc1c(N)cccc1F
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1Oc1cccc(N)c1C#N

Procedure:
Prepared as in Example 22b from (1R,2S,5R)-2-isopropyl-5-methylcyclohexanol and 2-amino-6-fluorobenzonitrile as a white solid (51%). MS 273 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Mg]Cl)(C)C.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C1COCC1.O>[CH3:20][S:21]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: Brc1cccnc1
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cccnc1
Reaction time: 2 h

Procedure:
To a solution of 3-bromopyridine (20 g, 127 mmol) in THF (200 ml) at room temperature is added a solution of 2M isopropylmagnesium chloride in THF (64 ml, 127 mmol). The resulting mixture is stirred for 2 hours, treated with triethylamine (20 ml), immediately followed by methanesulfonylchloride (10 ml, 127 mmol) and the resulting mixture stirred for 18 hours at room temperature. The mixture is diluted with water (200 ml) and extracted with EtOAc (3×100 ml). The mixture is concentrated in vacuo and purified on Silica gel (eluting with 50/50 Hexane/EtOAc). 1H-NMR (CDCl3) δ: 9.17 (s, 1H), 8.90 (d, 1H), 8.25 (dd, 1H), 7.55 (m, 1H), 3.12 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[C:9]1[N:10]=[C:11]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][C@@H:21]2[CH3:26])[C:12]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][C:13]=2[N:14]=1)[NH2:5].[CH2:27]([N:29]=[C:30]=[O:31])[CH3:28]>>[CH2:27]([NH:29][C:30]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([C:9]2[N:10]=[C:11]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][C@@H:21]3[CH3:26])[C:12]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][C:13]=3[N:14]=2)=[C:2]([F:1])[CH:3]=1)=[O:31])[CH3:28]
Reactant: CCN=C=O
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(N)cc2F)nc2c1CCN(C)C2
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C)C3)c(F)c1
Yield: 6 %

Procedure:
Method as example 85 using (S)-3-fluoro-4-(7-methyl-4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)aniline and ethyl isocynate as starting materials. The solvent was removed in vacuo and purified by prep HPLC (low pH) yielding the title compound (4.3 mg, 0.01 mmol, 6%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[NH:14][C:15]([NH2:24])=[C:16]2[C:20]([N:21]=1)=[N:19][C:18]([O:22][CH3:23])=[N:17]2)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][CH2:28][CH2:29]Br.[NH:31]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][CH2:29][N:31]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: BrCCCCBr
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: C1CCCNCC1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCN3CCCCCC3)c2n1

Procedure:
Prepared similarly to Intermediate 20 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate, 1,4-dibromobutane and hexahydro-1H-azepine.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][C:6]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([F:17])[CH:11]=1)=S.[NH2:24][C:25]1[NH:29][N:28]=[C:27]([C:30]([F:33])([F:32])[F:31])[CH:26]=1.Cl.C(N=C=NCCCN(C)C)C>C1COCC1.O.C(OC(C)C)(=O)C>[Cl:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH2:4][NH:5]/[C:6](/[NH:24][C:25]1[NH:29][N:28]=[C:27]([C:30]([F:33])([F:32])[F:31])[CH:26]=1)=[N:8]/[C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([F:17])[CH:11]=1
Reactant: Nc1cc(C(F)(F)F)n[nH]1
Reactant: O=C(NC(=S)NCc1ccc(F)cc1Cl)c1ccc(F)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)OC(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=C(/N=C(/NCc1ccc(F)cc1Cl)Nc1cc(C(F)(F)F)n[nH]1)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.3 %

Procedure:
N-((2-Chloro-4-fluorobenzyl)carbamothioyl)-3,4-difluorobenzamide (98.0 g, 273 mmol) and 5-amino-3-trifluoromethylpyrazole (41.3 g, 273 mmol) were dissolved in THF (546 mL). N1-((Ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (57.6 g, 300 mmol) was added and the reaction was stirred at room temperature for 1 h and then heated to 40° C. for 15 h. The crude mixture was diluted with water (500 mL) and isopropyl acetate (500 mL). The organic layer was washed with brine (500 mL), dried over sodium sulfate, and concentrated. The residue was diluted with isopropyl acetate (1.3 L) and heated to 65° C. for 1 hour. The solution was allowed to cool to room temperature, filtered and the filtrate was concentrated. The residue was heated to 70° C. in acetonitrile (900 mL) and then allowed to cool to room temperature. The resulting suspension was filtered, rinsed with acetonitrile (200 mL) and dried in vacuo at 60° C. to afford 55 g (43%) of (Z)—N-(((2-chloro-4-fluorobenzyl)amino)((3-(trifluoromethyl)-1H-pyrazol-5-yl)amino)methylene)-3,4-difluorobenzamide as a white solid. 1HNMR (400 MHz, MeOH-d4) δ 7.95 (bs, 2H), 7.50 (t, 1H, J=7.2 Hz), 7.26 (m, 2H), 7.06 (t, 1H, J=7.5 Hz), 6.56 (s, 1H), 4.84 (s, 2H).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[C:28]3[CH2:30][NH:31][CH2:32][CH2:33][C:27]3=[N:26][C:25]=2[NH:34][CH:35]([CH3:37])[CH3:36])[CH2:20][CH2:19]1)[C:12]#[N:13].C(N(CC)CC)C.[CH3:45][N:46]([CH3:50])[C:47](Cl)=[O:48]>C(Cl)Cl>[C:12]([C:11]1[CH:14]=[CH:15][C:16]([O:17][CH:18]2[CH2:19][CH2:20][N:21]([C:24]3[N:29]=[C:28]4[CH2:30][N:31]([C:47]([N:46]([CH3:50])[CH3:45])=[O:48])[CH2:32][CH2:33][C:27]4=[N:26][C:25]=3[NH:34][CH:35]([CH3:37])[CH3:36])[CH2:22][CH2:23]2)=[C:9]([F:8])[CH:10]=1)#[N:13].[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(C#N)cc3F)CC1)CNCC2
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(C#N)cc3F)CC1)CN(C(=O)N(C)C)CC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-fluoro-4-((1-(2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)benzonitrile TFA salt (20.7 mg, 0.039 mmol) and triethylamine (0.017 mL, 0.118 mmol) in DCM (0.5 mL) was added dimethylcarbamoyl chloride (7.3 μL, 0.079 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min and then concentrated via rotary evaporation. The crude material was diluted with DMSO, filtered, rinsed with DMSO, and purified by HPLC Method B, with the exception that a Waters XSelect® CSH C18, 5 μm, ID 4.6×50 mm was used, using a 30% to 70% ACN gradient to give the title compound as a TFA salt (11.6 mg, 49.4%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.26 (m, 6H), 1.87-1.96 (m, 2H), 2.08-2.16 (m, 2H), 2.81-2.99 (m, 6H), 3.25-3.42 (m, 3H), 3.65-3.71 (m, 1H), 4.12-4.19 (m, 2H), 4.25-4.31 (m, 1H), 4.82-4.88 (m, 1H), 5.89 (d, J=8.3 Hz, 1H), 7.50 (t, J=8.6 Hz, 1H), 7.66-7.71 (m, 1H), 7.87 (dd, J=11.4, 2.0 Hz, 1H), 9.96 (br s, 1H); ESI-MS m/z [M+H]+ 482.5.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH3:14])=[O:12])[NH:6]2.[C:15](OC(=O)C)(=[O:17])[CH3:16]>CN(C)C1C=CN=CC=1>[C:15]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH3:14])=[O:12])[NH:6]2)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc2c(O)cccc2[nH]1
Agent: CN(C)c1ccncc1
Product: COC(=O)c1cc2c(OC(C)=O)cccc2[nH]1
Temperature: 80 °C

Procedure:
Methyl 4-hydroxyindole-2-carboxylate (0.5 g) and 4-dimethylaminopyridine (50 mg) were dissolved in acetic anhydride (5 ml) and heated at 80° C. for 3 hours. The reaction was allowed to cool overnight to precipitate white crystals, which were filtered and dried in vacuo (0.44 g, 72%); NMR δ(CD3SOCD3) 2.34 (s, 3H), 3.85 (s, 3H), 6.80 (d, 1H) 7.06 (s, 1H), 7.23 (t, 1H), 7.29-7.35 (m, 1H), 12.1 (bs, 1H); M/z (−) 232 (M−H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[NH2:33][C@H:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][C@H:35]1[OH:43]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:33][C@H:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][C@H:35]1[OH:43])=[O:31]
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)c(OC)c32)cc1OC
Reactant: O=C(Br)CBr
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Product: COc1ccc(CC2c3c(cc(OC)c(OC)c3OC)CCN2CC(=O)N[C@H]2c3ccccc3C[C@H]2O)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with (1S,2R)-1-amino-2-indanol
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][CH2:22][N:21]([S:24]([C:27]4[S:28][C:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[CH:30][CH:31]=4)(=[O:26])=[O:25])[C@@H:20]([C:38]([NH:40][O:41][CH:42]4[CH2:47][CH2:46][CH2:45][CH2:44][O:43]4)=[O:39])[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1>N1CCCCC1.CN(C=O)C>[C:32]1([C:29]2[S:28][C:27]([S:24]([N:21]3[CH2:22][CH2:23][NH:18][CH2:19][C@@H:20]3[C:38]([NH:40][O:41][CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)=[O:39])(=[O:25])=[O:26])=[CH:31][CH:30]=2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(NOC1CCCCO1)[C@H]1CN(C(=O)OCC2c3ccccc3-c3ccccc32)CCN1S(=O)(=O)c1ccc(-c2ccccc2)s1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: O=C(NOC1CCCCO1)[C@H]1CNCCN1S(=O)(=O)c1ccc(-c2ccccc2)s1
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
(2R)-4-(9-Fluorenylmethyloxycarbonyl)-1-(5-phenylthiophene-2-sulfonyl)-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (16.5 g) was dissolved in a solution (160 ml) of 20% piperidine in DMF at room temperature. After stirring for 30 minutes at said temperature, the solution was concentrated in vacuo. The residue was purified by SiO2 column chromatography (eluent: 1% MeOH in CHCl3, then 4% MeOH in CHCl3) to give 9.57 g of (2R)-1-(5-phenylthiophene-2-sulfonyl)-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide as an amorphous powder.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].Cl.[CH3:13][NH:14][CH:15]1[CH2:17][CH2:16]1.Cl.Cl.C[Si](C)(C)CCOC[N:26]1[C:30]2[N:31]=[CH:32][N:33]=[C:34]([C:35]3[CH:36]=[N:37][N:38]([C:40]4([CH2:44][C:45]#[N:46])[CH2:43][NH:42][CH2:41]4)[CH:39]=3)[C:29]=2[CH:28]=[CH:27]1>>[C:45]([CH2:44][C:40]1([N:38]2[CH:39]=[C:35]([C:34]3[C:29]4[CH:28]=[CH:27][NH:26][C:30]=4[N:31]=[CH:32][N:33]=3)[CH:36]=[N:37]2)[CH2:43][N:42]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([N:14]([CH:15]3[CH2:17][CH2:16]3)[CH3:13])=[O:8])=[CH:4][C:3]=2[F:11])[CH2:41]1)#[N:46]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: CNC1CC1
Agent: Cl
Product: CN(C(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)c(F)c1)C1CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 3, Step 1-3 starting from 4-bromo-3-fluorobenzoic acid, N-methylcyclopropanamine hydrochloride (J&W PharmLab: Cat. #20-0433S) and {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride. LCMS (M+H)+: m/z=471.2. 1H NMR (400 MHz, DMSO-D6): δ 12.83 (s, 1H), 9.17 (s, 1H), 8.91 (s, 1H), 8.60 (s, 1H), 7.85 (s, 1H), 7.33 (m, 3H), 6.71 (t, J=9.0 Hz, 1H), 4.66 (d, J=8.0 Hz, 2H), 4.41 (d, J=8.0 Hz, 2H), 3.79 (s, 2H), 2.97 (m, 1H), 2.93 (s, 3H), 0.59 (m, 2H), 0.42 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7]Br)([CH3:4])([CH3:3])[CH3:2].[C:10]12(O)[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2.[OH2:21]>[OH-].[K+].C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:9])[CH:7]([C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2)[OH:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: O
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C(O)C12CC3CC(CC(C3)C1)C2
Reaction time: 2 h

Procedure:
29.26 g (150 mmol) of bromoacetic acid-tert-butyl ester is added at 0° C. to 15.22 g (100 mmol) of 1-adamantanol in 300 ml of 50% aqueous potassium hydroxide solution, 200 ml of toluene, and it is vigorously and thoroughly stirred for 2 hours. It is poured onto 1500 ml of water and extracted 2 times with 300 ml of diethyl ether. The combined organic phases are dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: n-hexane/diethyl ether 20:1).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([OH:14])=O.C(=O)(OC)[O:16][C:17]1[CH:22]=[C:21]([NH2:23])[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:19][C:18]=1[C:28]([CH3:31])([CH3:30])[CH3:29].CC1OCCC1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.N1C=CC=CC=1.C[O-].[Na+].CO>>[C:24]([C:20]1[CH:19]=[C:18]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:17]([OH:16])=[CH:22][C:21]=1[NH:23][C:12]([C:3]1[C:2](=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)=[O:14])([CH3:27])([CH3:25])[CH3:26]
Reactant: COC(=O)Oc1cc(N)c(C(C)(C)C)cc1C(C)(C)C
Reactant: O=C(O)c1c[nH]c2ccccc2c1=O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Solvent: CC1CCCO1
Product: CC(C)(C)c1cc(C(C)(C)C)c(NC(=O)c2c[nH]c3ccccc3c2=O)cc1O
Reaction time: 8 h

Procedure:
4-Oxo-1,4-dihydroquinoline-3-carboxylic acid, 26, (1.0 eq) and 5-amino-2,4-di-tert-butylphenyl methyl carbonate, 32, (1.1 eq) were charged to a reactor. 2-MeTHF (4.0 vol, relative to the acid) was added followed by T3P® 50% solution in 2-MeTHF (1.7 eq). The T3P charged vessel was washed with 2-MeTHF (0.6 vol). Pyridine (2.0 eq) was then added, and the resulting suspension was heated to 47.5+/−5.0° C. and held at this temperature for 8 hours. A sample was taken and checked for completion by HPLC. Once complete, the resulting mixture was cooled to 20° C.+/−5° C. 2-MeTHF was added (12.5 vol) to dilute the mixture. The reaction mixture was washed with water (10.0 vol) 2 times and 2-MeTHF (16.5 vol) was charged to the reactor. This solution was charged with 30% w/w NaOMe/MeOH (1.7 equiv) to perform the methanolysis. The reaction was stirred at 25.0° C.+/−5.0° C. for no less than 1.0 hour, and checked for completion by HPLC. Once complete, the reaction was quenched with 1.2 N HCl/H2O (10.0 vol), and washed with 0.1 N HCl/H2O (10.0 vol). The organic solution was polish filtered to remove any particulates and placed in a second reactor.
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([N+:32]([O-])=O)[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:18][CH:19]3[CH2:27][CH:22]4[CH2:23][N:24]([CH3:26])[CH2:25][CH:21]4[CH2:20]3)=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.CN(C=O)C>[Pd].CO>[F:1][C:2]1[CH:31]=[C:30]([NH2:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:18][CH:19]3[CH2:20][CH:21]4[CH2:25][N:24]([CH3:26])[CH2:23][CH:22]4[CH2:27]3)=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCC1CC2CN(C)CC2C1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OCC1CC2CN(C)CC2C1

Procedure:
To a par hydrogenation reaction vessel was added 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(2-methyl-octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinoline (0.800 g, 1.6 mmol, 1.0 eq.), DMF (50 mil), EtoAc (50 ml), MeOH (50 ml), TEA (5 ml) and 10% Pd/C (200 mg). The vessel was placed on the par hydrogenator at 35 psi overnight. The Pd was filtered and the solvent removed to give 3-fluoro-4-[6-methoxy-7-(2-methyl-octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinolin-4-yloxy]-phenylamine as an off yellow solid (0.78 g, 99% yield). 1H NMR (400 MHz, CDCl3): 8.45 (d, 1H), 7.57 (s, 1H), 7.36 (s, 1H), 7.05 (t, 1H), 6.54 (m, 2H), 6.39 (d, 1H), 4.16 (d, 2H), 4.01 (s, 3H), 3.81 (m, 3H), 2.61 (m, 3H), 2.41 (m, 1H), 2.29 (s, 3H), 2.23 (m, 2H), 1.32 (m, 2H); MS (EI) for C25H28FN3O3: 438 (M+H+).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.Cl[C:13]1[CH:22]=[C:21](Cl)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.[CH3:24][NH:25][CH2:26][CH2:27][NH2:28].ClC1C=C(Cl)C2C(=CC=C(Cl)C=2)N=1.C(N)CN>>[CH3:24][NH:25][CH2:26][CH2:27][NH:28][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[C:13]([N:2]2[CH2:3][CH2:4][CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[CH2:1]2)[CH:22]=1
Reactant: Clc1cc(Cl)c2ccccc2n1
Reactant: CNCCN
Reactant: c1ccc2c(c1)CCCNC2
Agent: Clc1ccc2nc(Cl)cc(Cl)c2c1
Solvent: NCCN
Product: CNCCNc1cc(N2CCCc3ccccc3C2)nc2ccccc12

Procedure:
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5-tetrahydro-1H-2-benzazepine (commercial available), 2,4-dichloroquinoline (commercial available) and N-methyl-ethane-1,2-diamine (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine, 2,4,6-trichloroquinoline and ethane-1,2-diamine respectively. MS obsd. (ESI+) [(M+H)+] 347. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.42 (brs, 2 H), 7.88 (s, 1 H), 7.55 (d, J=6.4 Hz, 1 H), 7.47 (s, 2 H), 7.16-7.11 (m, 4 H), 6.01 (s, 1 H), 4.87 (s, 2 H), 4.14 (s, 2 H), 3.63 (s, 2 H), 3.20 (t, J=5.6 Hz, 2 H), 3.02 (s, 2 H), 2.67 (s, 3 H), 1.80 (s, 2 H).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[C:13]2[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([N:28]=[C:29]=[O:30])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>O1CCCC1>[CH2:20]([NH:28][C:29](=[O:30])[O:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH:9]2[CH2:10][CH2:11][CH2:12][N:8]2[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: Oc1cccc(C2CCCN2Cc2ccccc2)c1
Reactant: CCCCCCCCN=C=O
Solvent: C1CCOC1
Product: CCCCCCCCNC(=O)Oc1cccc(C2CCCN2Cc2ccccc2)c1
Reaction time: 17 h
Yield: 52 %

Procedure:
To a solution of 3-(1-phenylmethyl-2-pyrrolidinyl)phenol (0.06 g) in dry tetrahydrofuran (30 ml) was added octyl isocyanate (0.44 ml) at ambient temperature, under nitrogen. The reaction mixture was stirred for 17 hrs and filtered through a pad of celite. The filter cake was washed with ethyl acetate and the combined filtrates were concentrated. The residue was purified by flash column chromatography (silica gel, dichloromethane). The appropriate fractions were collected and concentrated to give 0.50 g (52%) of product. The analytical sample was prepared by flushing the product through alumina with ether.
Reaction SMILES: CO.S(C1C=CC(C)=CC=1)(O[CH:7]([CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:8])(=O)=O.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26].C(OCC)C>C(Cl)(Cl)Cl>[CH3:8][CH:7]([N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCNCC
Reactant: Cc1ccc(S(=O)(=O)OC(C)CCOc2ccccc2)cc1
Solvent: CCOCC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(C)CCOc1ccccc1
Yield: 77 %

Procedure:
To 60 ml of absolute methyl alcohol were added 10 g of 4-phenoxy-2-butyl tosylate and 9.62 g of diethylamine. The mixture was reacted in a sealed tube for one hour at 125° C. After the reaction solution was condensed under reduced pressure, 100 ml of diethyl ether was added into the solution, and then the solution was separated into the diethyl ether solution and 20% aqueous sodium hydroxide solution. The ether layer was dried over anhydrous sodium sulfate, and the ether was removed under reduced pressure therefrom. The residue thus obtained was subjected to an alumina-column chromatography using chloroform as the developing solvent to give 5.32 g of 1-methyl-3-phenoxypropyldiethylamine in a yield of 77%.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16](Cl)[N:15]=1)[CH3:7])([CH3:4])([CH3:3])[CH3:2].[O:21]1[CH2:25][CH2:24][C@H:23]([O:26][C:27]2[CH:28]=[C:29]([C@@H:33]([NH2:35])[CH3:34])[CH:30]=[CH:31][CH:32]=2)[CH2:22]1.CS(C)=O.CCN(C(C)C)C(C)C>O>[C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:35][C@H:33]([C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([O:26][C@H:23]3[CH2:24][CH2:25][O:21][CH2:22]3)[CH:28]=2)[CH3:34])[N:15]=1)[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1c1ccnc(Cl)n1
Reactant: C[C@H](N)c1cccc(O[C@H]2CCOC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: C[C@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)n1)c1cccc(O[C@H]2CCOC2)c1
Temperature: 110 °C

Procedure:
To a microwave vial with a stir bar was added (R)-4-((R)-1-tert-butoxyethyl)-3-(2-chloropyrimidin-4-yl)oxazolidin-2-one (43.6 mg, 0.145 mmol) and (S)-1-(3-((S)-tetrahydrofuran-3-yloxy)phenyl)ethanamine (25.1 mg, 0.121 mmol), followed by DMSO (605 uL) and DIEA (63.5 ul, 0.363 mmol). The vial was capped and the reaction mixture heated in a preheated oil bath at 110° C. for 21 hr. The mixture was diluted with water and extracted with EtOAc two times. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, concentrated and dried on house vacuum to afford crude (R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(3-((S)-tetrahydrofuran-3-yloxy)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one, as a brown solid film, (yield assumed quantitative). LCMS m/z 471.4 (M+H)+, Rt 0.85 min.