Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[O:2]([CH2:10][CH2:11][CH2:12]Br)[Si:3]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH2:14]1[O:48][C:17]2=[CH:18][C:19]3[C:32]4[N:31]([CH3:33])[CH:30](OCC)[C:29]5[C:24](=[CH:25][CH:26]=[C:27]([O:45][CH3:46])[C:28]=5[O:37][CH2:38][C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[C:23]=4[CH:22]=[CH:21][C:20]=3[CH:47]=[C:16]2[O:15]1.[Cl-].[NH4+]>O1CCCC1.II.BrCCBr>[CH2:14]1[O:48][C:17]2=[CH:18][C:19]3[C:32]4[N:31]([CH3:33])[CH:30]([CH2:12][CH2:11][CH2:10][O:2][Si:3]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4])[C:29]5[C:24](=[CH:25][CH:26]=[C:27]([O:45][CH3:46])[C:28]=5[O:37][CH2:38][C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[C:23]=4[CH:22]=[CH:21][C:20]=3[CH:47]=[C:16]2[O:15]1
Reactant: CCOC1c2c(ccc(OC)c2OCc2ccccc2)-c2ccc3cc4c(cc3c2N1C)OCO4
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COc1ccc2c(c1OCc1ccccc1)C(CCCO[Si](C)(C)C(C)(C)C)N(C)c1c-2ccc2cc3c(cc12)OCO3
Temperature: 25 °C
Yield: 85.2 %

Procedure:
In a dry flask, a piece of magnesium (0.468 g, 19.3 mmols) was charged, and tetrahydrofuran (15 mL) was added thereto. A solution of 3-(t-butyldimethylsiloxy)propyl bromide (2.36 g, 9.63 mmols) in tetrahydrofuran (15 mL), iodine (a few pieces) and 1,2-dibromoethane (a few drops) were added portionwise to the mixture. The resulting mixture was stirred at room temperature for an hour. A solution of 2,3-(methylenedioxy)-5-methyl-6-ethoxy-7-benzyloxy-8-methoxy-5,6-dihydrobenzo[c]phenanthridine (1.01 g, 2,2 mmols) in tetrahydrofuran (10 mL) was added to the resulting solution followed by stirring at room temperature for 2 hours. A saturated ammonium chloride aqueous solution was added to the reaction mixture followed by extracting with ethyl acetate. The organic layer was separated, washed with saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. After sodium sulfate was removed by filtration, the solvent was distilled off in vacuo. The resulting residue was purified by silica gel column chromatography (eluted with 33-66% methylene chloride-hexane) to give 2,3-(methylenedioxy)-5-methyl-6-[3-(t-butyldimethylsiloxy)propyl]-7-benzyloxy-8-methoxy-5,6-dihydrobenzo[c]phenanthridine (1.12 g, yield 96%) as colorless amorphous solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[C@@H:10]([CH3:18])[CH2:9]1)=O)(C)(C)C.[ClH:19]>ClCCl.C(OCC)C>[ClH:19].[CH3:17][S:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]1[CH3:18])(=[O:15])=[O:16]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1S(C)(=O)=O
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@H]1CNCCN1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of (S)-4-methanesulfonyl-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (924 mg) in dichloromethane (20 mL) at 0° C. was added dropwise HCl (6.65 mL of a 2 M solution in diethyl ether). The reaction mixture was stirred at room temperature for 2 h. The precipitate formed was then collected by filtration and dried to afford (S)-1-methanesulfonyl-2-methyl-piperazine hydrochloride salt as a white solid (583 mg, 82%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](Cl)=[O:39])=[CH:33][CH:32]=1>C(Cl)Cl>[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=2)=[O:39])=[CH:33][CH:32]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: FC(F)(F)c1ccc(C2NCCc3ccccc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Cc1ccc(F)cc1)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1

Procedure:
To a solution of 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (100 mg, 0.36 mmol, example 9 (step 3) and DIEA (63 μL, 0.36 mmol) in DCM (2 mL) was added 4-fluorophenylacetyl chloride (62 μL, 0.36 mmol). The resulting mixture was reacted under the same conditions as described for example 10 give the title compound as a white oil. MS (ESI, positive ion) m/z: 414 (M+H).
Reaction SMILES: C(O)(=O)C.[N+:5]([C:8]1[CH:9]=[CH:10][C:11]2[S:15][N:14]=[C:13]([O:16][CH2:17][C:18]#[N:19])[C:12]=2[CH:20]=1)([O-])=O>[Fe].C(OCC)(=O)C>[NH2:5][C:8]1[CH:9]=[CH:10][C:11]2[S:15][N:14]=[C:13]([O:16][CH2:17][C:18]#[N:19])[C:12]=2[CH:20]=1
Reactant: N#CCOc1nsc2ccc([N+](=O)[O-])cc12
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: N#CCOc1nsc2ccc(N)cc12
Temperature: 50 °C

Procedure:
A mixture of iron powder (13.0 g, 0.233 mol) in a 5% acetic acid solution (65.0 mL) is heated to 50° C., treated portionwise with a mixture of [(5-nitro-1,2-benzisothiazol-3-yl)oxy]acetonitrile (11.0 g, 0.047 mol), acetic acid (100 mL) and ethyl acetate (65.0 mL), refluxed for two hours, cooled to 40° C., and filtered to remove solids. The phases are separated and the aqueous phase is extracted with ethyl acetate. The organic phase and the organic extracts are combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title product as an oil which is identified by NMR spectral analysis.
Reaction SMILES: Cl[C:2]1[C:3](F)=[CH:4][C:5](F)=[C:6]([CH:14]=1)[C:7](NS(C)(=O)=O)=[O:8].[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]>>[C:6]12([CH2:7][O:8][C:19]3[C:18]([Cl:17])=[CH:32][C:22]([C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24])=[C:21]([F:33])[CH:20]=3)[CH2:5][CH:4]3[CH2:5][CH:6]([CH2:14][CH:2]([CH2:3]3)[CH2:14]1)[CH2:7]2
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide (as prepared in Example 31), the title compound was obtained as a colorless solid (0.25 g, 38%): 1H NMR (300 MHz, DMSO-d6) δ 11.77 (s, 1H), 7.72 (d, J=7.45 Hz 1H), 7.22 (d, J=12.3 Hz, 1H), 3.72 (s, 2H), 2.87 (s, 6H), 1.99 (br, 3H), 1.75-1.64 (m, 12H); MS (ES−) m/z 443.1, 445.1 (M−1).
Reaction SMILES: [NH:1]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:2]([C:4]([NH:6][C@H:7]([C:9]([OH:11])=[O:10])[CH3:8])=[O:5])[CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO.O.CN(C=O)C>[NH:1]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[C@H:2]([C:4]([NH:6][C@H:7]([C:9]([O:11][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:10])[CH3:8])=[O:5])[CH3:3]
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1

Procedure:
Boc-Ala-Ala-OH (7.23 g, 27.8 mmol) was dissolved in a mixture of 200 ml MeOH and 20 ml H2O. Cs2CO3 solution (20% aqueous) was added until the pH reached 7.0 (~30 ml) and the resultant neutral solution evaporated to dryness. The residue was re-evaporated twice with DMF (150 ml) and the gelatenous solid that remained was stirred in 120 ml DMF with benzyl bromide (7.2 g, 42 mmol) for 15 hours. The solvent was then removed by evaporation and the residue treated with 500 ml water. The product precipitated as an oil which gradually solidified on standing. It was taken up in EtOAc (400 ml), washed with H2O (3 times), dried (Na2SO4), and evaporated to a syrup which on treatment with petroleum ether began to crystallize. The product was recrystallized from EtOAc and petroleum ether to yield, 7.2 g (73.8%); mp 71°-73° (lit. mp 73°-74° ; D. A. Laufer et al., J. Amer. Chem. Soc., 90, 2696 (1968)).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[OH-].[Na+].[I:13]I>O1CCOCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:13])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2cn[nH]c2c1
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Brc1ccc2c(I)n[nH]c2c1
Reaction time: 1 h

Procedure:
A solution of 6-bromo-1H-indazole (10 g, 50.8 mmol, commercially available) in dioxane (200 ml) was treated with 3N aqueous NaOH (100 ml). The vigorously stirred mixture was treated with iodine (27.1 g, 107 mmol), added portionwise over 5 minutes then stirred for 60 minutes. The reaction was quenched with 200 ml of 20% citric acid solution, followed by 160 ml of saturated NaHSO3 solution, then partitioned between ethyl acetate and water. The organic extract was dried with MgSO4 and concentrated to a solid which was triturated with ether and pentane to afford the title compound.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[CH:9][CH:10]=2)[C:5]([OH:20])=[C:4]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])[N:3]=1.[C:28]([Cu])#[N:29].C(Cl)Cl>CN(C=O)C>[C:28]([C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[CH:9][CH:10]=2)[C:5]([OH:20])=[C:4]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])[N:3]=1)#[N:29]
Reactant: CCCCOC(=O)c1nc(Br)c2ccc(Oc3ccccc3C)cc2c1O
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccccc3C)cc2c1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Butyl 1-bromo-4-hydroxy-6-(o-tolyloxy)isoquinoline-3-carb oxylate (130 mg, 0.30 mmol) and CuCN (54 mg, 0.61 mmol) were suspended in DMF (1.2 mL). The resulting mixture was heated to reflux for 40 minutes and then cooled to room temperature. The reaction crude was poured into CH2Cl2 (30 mL) and stirred vigorously for 10 minutes at room temperature. The resulting suspension was filtered through a pad of celite and the filtrate was washed with H2O and brine sequentially. The organic layer was dried over MgSO4, concentrated, and purified by flash chromatography (0-30% EtOAc/hexanes) to give the title compound in 65 mg. MS: (−) m/z 375.29 (M−1).
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:25])[CH2:20][NH:21]C(C)C)=[CH:15][CH:14]=2)=[CH:9]1.[CH2:26]([N:33]=[C:34]=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[S:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:25])[CH2:20][NH:21][C:34]([NH:33][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:35])=[CH:15][CH:14]=2)=[CH:9]1
Reactant: O=C=NCc1ccccc1
Reactant: CC(C)NCC(C)c1ccc(-c2ccsc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(CNC(=O)NCc1ccccc1)c1ccc(-c2ccsc2)cc1

Procedure:
The title compound was prepared from 2-(4-(3-thienyl)phenyl)propyl-2-propyl amine trifluoroacetate (prepared in example 1) and benzyl isocyanate in a manner analogous to the procedure described in Example 1.
Reaction SMILES: C[O:2][C:3](=O)[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1.[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30][NH2:31]>CO>[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30][NH:31][C:3](=[O:2])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1
Reactant: CN(C)CCN
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Solvent: CO
Product: CN(C)CCNC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1

Procedure:
A solution of 4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.5 g) in methanol (75 mL) was treated with N,N-dimethylethylenediamine (0.2 mL) and the mixture was refluxed for 18 hours. The solvents were removed by evaporation and the residue was purified by HPLC (ethyl acetate-methanol-triethylamine; 95:5:2) followed by crystallization from ethyl acetate-hexane to give 0.28 g of N-[2-(dimethylamino)ethyl]-4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzeneacetamide as a colorless solid, mp 102°-104° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([F:14])([F:13])[F:12])[C:5]([CH:8]([OH:10])[CH3:9])=[N:6][CH:7]=1>C1COCC1.O=[Mn]=O>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([F:14])([F:12])[F:13])[C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1
Reactant: CC(O)c1ncc(Br)cc1C(F)(F)F
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: CC(=O)c1ncc(Br)cc1C(F)(F)F

Procedure:
Dissolve 1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)ethanol (3.75 g, 0.01394 moles) in anhydrous THF (75 mL) and add MnO2 (12.1-24.2 g, 10 to 20 eq) at room temperature. Reflux the mixture under N2 atmosphere for 3 days. Cool the reaction mixture, filter through celite, wash the celite with THF (3×50 mL) and then concentrate under vacuum to afford the title compound as a colorless yellow oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[C:19]([C:23]1[O:27][N:26]=[C:25]([C:28](O)=[O:29])[CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>>[C:19]([C:23]1[O:27][N:26]=[C:25]([C:28]([NH:1][C@@H:2]([CH3:18])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=3)=[N:5]2)=[O:29])[CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CC(C)(C)c1cc(C(=O)O)no1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(C(C)(C)C)on1
Yield: 53.6 %

Procedure:
(S)-5-tert-butyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)isoxazole-3-carboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg, 0.69 mmol) and 5-tert-butylisoxazole-3-carboxylic acid (132 mg, 0.782 mmol). The product was purified by Flash-chromatography (reverse phase). Yield 53.6%. 1H-NMR (400 MHz; MeOD): δ 1.26 (d, 3H), 1.35 (s, 9H), 4.26-4.45 (m, 2H), 4.51-4.63 (m, 1H), 6.34 (s, 1H), 6.77 (d, 1H), 7.70 (d, 1H), 7.77 (dd, 1H), 7.87 (dd, 1H), 8.09 (dd, 1H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:13]=[C:14]([Cl:17])[C:15]=1F.O>C1C=CC=CC=1.C([Li])CCC.CCCCCC.C(OCC)C>[Cl:9][C:10]1[CH:11]=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:13]=[C:14]([Cl:17])[C:15]=1[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(I)cc1
Reactant: Fc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1
Yield: 85.1 %

Procedure:
To 5.7 g (26.1 mmol) of 4-iodotoluene in 30 ml of dry benzene, 17.0 ml of a n-butyllithium solution in hexane (1.60 mol/l) was added dropwise in a nitrogen stream at room temperature with stirring. After 2 hours of stirring at room temperature, 10 ml of 6.0 g (25.8 mmol) of 3,5-dichloro-4-fluorobenzotrifluoride in 10 ml of diethyl ether was added dropwise at 10° C. After another 12 hours of stirring at room temperature, the reaction mixture was poured into 100 ml of water for separation. The organic layer was washed with 50 ml of water twice and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 6.7 g of 4-(2,6-dichloro-4-trifluoromethylphenyl)toluene (yield 85.0%) as a colorless liquid.
Reaction SMILES: C([Si](C)(C)[N:6]1[C:14]2[CH:13]=[C:12]3[O:15][CH2:16][O:17][C:11]3=[CH:10][C:9]=2[CH:8]=[CH:7]1)(C)(C)C.Cl[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH:28]2[CH2:33][C:32]([CH3:35])([CH3:34])[NH:31][C:30]([CH3:37])([CH3:36])[CH2:29]2)[N:22]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[O:17]1[C:11]2=[CH:10][C:9]3[C:8]([C:25]4[CH:26]=[CH:21][N:22]=[C:23]([NH:27][CH:28]5[CH2:33][C:32]([CH3:35])([CH3:34])[NH:31][C:30]([CH3:37])([CH3:36])[CH2:29]5)[N:24]=4)=[CH:7][NH:6][C:14]=3[CH:13]=[C:12]2[O:15][CH2:16]1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: CC(C)(C)[Si](C)(C)n1ccc2cc3c(cc21)OCO3
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)CC(Nc2nccc(-c3c[nH]c4cc5c(cc34)OCO5)n2)CC(C)(C)N1

Procedure:
The title compound was prepared as described in Example 215, starting from 5-(tert-butyl-dimethyl-silanyl)-5H-[1,3]dioxolo[4,5-f]indole (prepared by TBDMS protection of 5H-[1,3]Dioxolo[4,5-f]indole) and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by in situ cleavage of the TBDMS protecting group with catalytic amounts of TBAF. Yield: 555 mg (87%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH:4]=[CH:5][CH2:6]Cl.[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]=2[N:22]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][N:18]([CH2:6][CH:5]=[CH:4][C:3]3[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=3[F:1])[CH2:19][CH2:20][C:21]=2[N:22]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: Fc1ccccc1C=CCCl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Nc1nc2c(s1)CCN(CC=Cc1ccccc1F)CC2
Yield: 36 %

Procedure:
Prepared from 2-fluoro-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo-[5,4-d]azepine in chloroform. Yield: 36% of theory, Melting point: 96°-102° C. (ether).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23](=[O:35])CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[N:36]([C:39]1[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=1)=C=O>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23]([NH:36][C:39]3[CH:44]=[CH:43][C:42]([C:45]([F:46])([F:47])[F:48])=[CH:41][CH:40]=3)=[O:35])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Product: N#Cc1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3NC(=O)Nc3ccc(C(F)(F)F)cc3)C2)cc1

Procedure:
1-((1R,2R)-2-((S)-1-(4-Cyanophenyl)piperidin-3-ylamino)cyclohexyl)-3-(4-(trifluoromethyl)phenyl)urea was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (50 mg, 0.17 mmol) and 1-isocyanato-4-(trifluoromethyl)benzene (31.3 mg, 0.17 mmol) according to General Procedure G to give 18 mg (22.1%) of white solid. Anal. Calcd. for C26H30F3N5O m/z 458.2, found: 486.3 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 7.53 (d, J=8.8 Hz, 2H), 7.45 (d, J=8.6 Hz, 2H), 7.25 (d, J=9 Hz, 2H), 6.88 (d, J=9 Hz, 2H), 3.64 (m, 1H), 3.51 (m, 2H), 3.05 (m, 1H), 2.70 (m, 1H), 2.12 (m, 1H), 1.99 (m, 3H), 1.83 (m, 3H), 1.67 (m, 3H), 1.39 (m, 6H).
Reaction SMILES: C[O:2][C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]2[C:14](=[O:18])[NH:15][CH2:16][CH2:17][N:6]12)=O.[BH4-].[Li+].O.[H-]>O1CCCC1>[OH:2][CH2:3][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]2[C:14](=[O:18])[NH:15][CH2:16][CH2:17][N:6]12
Reactant: COC(=O)C1c2ccccc2C2C(=O)NCCN21
Agent: [BH4-]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1NCCN2C(CO)c3ccccc3C12
Yield: 55.3 %

Procedure:
A mixture of 1,2,3,4,6,10b-hexahydro-1-oxo-pyrazino[2,1-a]isoindole-6-carboxylic acid methyl ester (0.5 g, described in Example 24) and lithium borohydride (0.044 g) in tetrahydrofuran (25 ml) is refluxed for 18 hr. Water is carefully added to decompose the excess hydride and the tetrahydrofuran is evaporated. Water is added and the solution is continuously extracted with ethyl acetate for 18 hr. The extract is dried and evaporated to give 1,2,3,4,6,10b-hexahydro-6-hydroxymethylpyrazino[2,1-a]isoindol-1-one (0.245 g), nmr (CDCl3) δ2.8(s), 3.2(m), 3.75(m), 4.3(m), 4.9(m), 6.95(s) and 7.2(m).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[N:8][C:6]=2[N:7]=1.[NH2:19][CH3:20].CO.[BH4-].[Na+]>C1(C)C=CC=CC=1.C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][NH:19][CH3:20])=[N:8][C:6]=2[N:7]=1
Reactant: CN
Reactant: O=Cc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CO
Product: CNCc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Reaction time: 48 h

Procedure:
To 5-chloro-7-morpholinothiazolo[4,5-d]pyrimidine-2-carbaldehyde 43 in 50 mL Toluene and 50 mL THF was added 30 mL of NH2Me (40% in water) and the mixture stirred under N2 for two days. The mixture was concentrated in vacuo and redissolved in 50 mL THF and 50 mL MeOH followed by the portionwise addition of 1.6 g (4.0 eq) NaBH4 and the reaction mixture stirred overnight at room temperature. Complete reaction was confirmed by LCMS and the mixture was concentrated in vacuo and purified by flash chromatography (95/5% EtOAc/EtOH 20 min followed by a gradient up to 100% EtOH over 30 min more) to give 1-(5-chloro-7-morpholinothiazolo[4,5-d]pyrimidin-2-yl)-N-methylmethanamine 60.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:8][N:9]([CH2:11]CO)[CH3:10]>C1C2NC3C(=CC=CC=3)SC=2C=CC=1.O>[C:1]([O:6][CH2:7][CH2:8][N:9]([CH3:11])[CH3:10])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CN(C)CCO
Reactant: C=C(C)C(=O)OC
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: O
Product: C=C(C)C(=O)OCCN(C)C
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 90.8 %

Procedure:
Into a flask equipped with a stirrer, a thermometer and a distilling column are charged 750.8 g of methyl methacrylate, 268.7 g of dimethylaminoethanol containing 0.5% by weight of moisture, and 6.0 g of phenothiazine as a polymerization inhibitor. The mixture is heated with stirring until it boils. The reaction mixture is refluxed until the temperature at the top of the column reaches 95° C., and the azeotropic mixture of methyl methacrylate and water is then distilled at a reflux ratio of 10:1. When the amount of the collected filtrate (methyl methacrylate, water and a small amount of methanol) reaches 55 g, the distillation is stopped. The reaction mixture is then cooled to 80° C. and 7.5 g of di-n-butyltin oxide is added. The resulting mixture is heated until it boils. The azeotropic mixture of the methanol formed and methyl methacrylate is refluxed for 20 minutes, and the reaction mixture is then reacted while part of the azeotropic mixture is withdrawn from the system at a reflux ratio of 15:1. During the reaction, the temperature at the top of the distilling column is kept at 65°-70° C. The esterification reaction is completed in 4.5 hours. The reaction mixture is distilled under reduced pressure as it is to obtain 430.1 g of dimethylaminoethyl methacrylate. This yield corresponds to 91.2% based on the starting dimethylaminoethanol.
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C:13](=[O:33])[C:14]1[C:19]([F:20])=[CH:18][C:17]([N:21]2[CH2:25][CH:24]([CH2:26][NH:27][C:28](=[O:30])[CH3:29])[O:23][C:22]2=[O:31])=[CH:16][C:15]=1[F:32])(C)(C)C>C(Cl)Cl>[C:28]([NH:27][CH2:26][CH:24]1[O:23][C:22](=[O:31])[N:21]([C:17]2[CH:16]=[C:15]([F:32])[C:14]([C:13]([OH:33])=[O:12])=[C:19]([F:20])[CH:18]=2)[CH2:25]1)(=[O:30])[CH3:29]
Reactant: CC(=O)NCC1CN(c2cc(F)c(C(=O)OC(C)(C)C)c(F)c2)C(=O)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)NCC1CN(c2cc(F)c(C(=O)O)c(F)c2)C(=O)O1
Reaction time: 1 h
Yield: 98.4 %

Procedure:
TFA (10 mL) is added with stirring to a solution of 4-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2,6-difluoro-benzoic acid tert-butyl ester (1.44 g, 3.88 mmol) in DCM (20 mL). The resulting solution is stirred for 1 h, and the volatiles removed under vacuum to afford 4-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2,6-difluoro-benzoic acid as a white solid (1.20 g). The acid intermediate is dissolved in dry t-BuOH (15 mL). Diphenylphosphoryl azide (1 mL, 4.65 mmol) and TEA (1.62 mL, 11.64 mmol) are added. The mixture is heated at reflux for 3 h and allowed to cool down to r.t. Solvent is removed under vacuum. The compund, N-[3-(4-tert-butoxycarbonylamino-3,5-difluoro-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide, is purified by silica gel column chromatography (eluent—EtOAc). The compound is dissolved in DCM (20 mL); and TFA (10 mL) is added. The reaction is stirred at r.t. for 1 h, and the volatiles are removed under vacuum. The crude aniline is purified by silica gel column chromatography (EtOAc) to afford the pure title compound. MS (m/z): 286 [M+H]+. 1H NMR (300 MHz, CDCl3) δ 2.16 (s, 3H), 3.73–3.74 (m, 2H), 3.90–3.96 (m, 1H), 4.26 (t, J=9.0 Hz, 1H), 4.93–5.01 (m, 1H), 7.32 (d, 8.7 Hz, 2H).