Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.Cl.[F:14][C:15]([F:26])([F:25])[C:16]1[N:20]2[CH2:21][CH2:22][NH:23][CH2:24][C:19]2=[N:18][N:17]=1.C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([N:23]1[CH2:22][CH2:21][N:20]3[C:16]([C:15]([F:26])([F:14])[F:25])=[N:17][N:18]=[C:19]3[CH2:24]1)=[N:3][N:4]=[CH:5]2
Reactant: FC(F)(F)c1nnc2n1CCNC2
Reactant: Clc1ccc2c(Cl)nncc2c1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1nnc2n1CCN(c1nncc3cc(Cl)ccc13)C2

Procedure:
The title compound was prepared according to the method described in Example 19, using 1,6-dichlorophthalazine (400 mg, 2010 μmol), 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (Balsells, et. al. Org. Lett., 7:1039-1042 (2005), 689 mg, 3015 μmol) and N,N-diisopropylethylamine (702 μl, 4019 μmol) in NMP (5 mL). MS (ESI, pos. ion) m/z: 355 (M+1).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:10][N:11]1[C:16](=[O:17])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[Cl:26])=[CH:14][N:13]([CH2:27][C:28]2[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:31]=[CH:30][C:29]=2[F:38])[C:12]1=[O:39])=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:8][C@H:9]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:10][N:11]1[C:16](=[O:17])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[Cl:26])=[CH:14][N:13]([CH2:27][C:28]2[C:33]([C:34]([F:36])([F:35])[F:37])=[CH:32][CH:31]=[CH:30][C:29]=2[F:38])[C:12]1=[O:39]
Reactant: COc1cccc(-c2cn(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c3ccccc3)c2=O)c1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(-c2cn(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](N)c3ccccc3)c2=O)c1Cl
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 95.6 %

Procedure:
Compound 7g (2.7 g, 4.2 mmol) was dissolved in dichloromethane (10 mL), TFA (14 mL, 175 mmol) was added, and the mixture was stirred at room temperature for 4.5 hours. After concentration, the residue was taken up in DCM and saturated aqueous NaHCO3 was added. The aq. layer was extracted with DCM. Combined organic extracts were dried over Na2SO4 and concentrated to give compound 7h (2.2 g, 96%). MS (CI) m/z 548.0, 550.0 (MH+).
Reaction SMILES: BrC[C:3]1([O:25][CH3:26])[CH:11]=[C:10]2[C:6](=[C:7]([C:23]#[N:24])[CH:8]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[N:9]2[CH2:12][CH3:13])[CH:5]=[CH:4]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.Cl[CH2:34]CCl>>[CH2:12]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([CH2:34][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[C:3]([O:25][CH3:26])[CH:11]=2)[C:7]([C:23]#[N:24])=[C:8]1[C:14]1[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=1)[CH3:13]
Reactant: CCN1C2=CC(CBr)(OC)C=CC2=C(C#N)C1c1ccc([N+](=O)[O-])cc1
Reactant: ClCCCl
Reactant: C1COCCN1
Product: CCn1c(-c2ccc([N+](=O)[O-])cc2)c(C#N)c2cc(CN3CCOCC3)c(OC)cc21
Yield: 44 %

Procedure:
Crude 6-bromomethyl-1-ethyl-6-methoxy-2-(4-nitro-phenyl)-1H-indole-3-carbonitrile (0.3 mmol) was heated with morpholine (150 μL, 1.75 mmol) and DCE (1.0 mL) at 90° C. overnight. The reaction mixture was then partitioned between H2O and EtOAc. The organic layer was dried and concentrated. Purification by silica gel chromatography (50-100%, EtOAc/CH2Cl2), followed by trituration with 1/1 hexane/acetone yielded 1-ethyl-6-methoxy-5-morpholin-4-ylmethyl-2-(4-nitrophenyl)-1H-indole-3-carbonitrile (57 mg, 44% overall yield) as a yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][CH2:8][C@H:9]([C@@H:11]1[CH:15]=[CH:14][CH2:13][O:12]1)[OH:10].[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.ClCCl>O.O1CCCC1>[O:12]1[CH2:13][CH:14]=[CH:15][C@H:11]1[C@H:9]([OH:10])[CH2:8][NH:7][C:24](=[O:25])[O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NC[C@@H](O)[C@@H]1C=CCO1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC[C@@H](O)[C@@H]1C=CCO1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 80 %

Procedure:
A solution of sodium carbonate (12.26 g, 115.7 mmol) in water (80 mL) was added whilst stirring to a solution of (R)-2-amino-1-((S)-2,5-dihydrofuran-2-yl)ethanol (assumed to be 55 mmol) in tetrahydrofuran (100 mL). The mixture was cooled to 0° C. then benzylchloroformate (9.69 mL, 68.87 mmol) was added. The mixture was stirred at 0° C. for 45 minutes, then dichloromethane (400 mL) and water (400 mL) added. The organic phase was separated and the aqueous reextracted with dichloromethane (2×400 mL). The organic layer was washed with brine (400 mL), then dried (Na2SO4), filtered and reduced in vacuo to leave a residue. Flash chromatography over silica, eluting with ethyl acetate:heptane mixtures 0:100 to 65:35 gave alcohol (18) (11.58 g, 80%) as a pale yellow oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][N:24]=[CH:23][C:22]=1[Cl:28].[CH3:31][N:32]([CH3:38])[CH2:33][CH2:34][CH2:35][NH:36][CH3:37]>>[Cl:28][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([Cl:27])[C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:36]([CH2:35][CH2:34][CH2:33][N:32]([CH3:38])[CH3:31])[CH3:37])[C:10]([O:29][CH3:30])=[CH:11][CH:12]=2)[NH:17][C:16](=[O:19])[CH:15]=1
Reactant: CNCCCN(C)C
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCCl
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCN(C)CCCN(C)C

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 4) and N1,N1,N3-trimethylpropane-1,3-diamine following the procedure outlined in Example 18, Step 2 (modifications: 40° C., 24 h then 60° C., 4 h). 1H NMR (400 MHz, DMSO-d6, bis HCl salt): δ 10.78-10.62 (br, 2H), 10.33 (s, 1H), 9.17 (s, 1H), 8.81 (s, 2H), 8.00 (d, 1H), 7.15 (d, 1H), 4.93 (s, 1H), 4.01 (t, 2H), 3.94 (s, 3H), 3.25-2.95 (m, 6H), 2.76-2.70 (m, 9H), 2.13 (m, 2H), 1.80 (m, 2H), 1.73 (m, 2H), 1.47 (m, 2H), 1.37 (m, 2H); MS (ESI): 550.5.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8](=[O:27])[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=1)=[C:10]([CH2:17][CH3:18])[NH:11]2.Cl[C:30](OC(=O)C)([F:32])[F:31]>>[CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:27][CH:30]([F:32])[F:31])=[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([Br:26])=[CH:24][CH:25]=1)[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: CC(=O)OC(F)(F)Cl
Reactant: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(Br)cc1
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(Br)cc1

Procedure:
The title compound was prepared by the method of Preparation 1d using [3-(4-bromobenzyl)-2-ethyl-8-fluoro-4-oxo-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester and acetic acid chlorodifluoromethyl ester.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[C:9]([NH:13][C:14]([NH2:16])=[O:15])([CH3:12])([CH3:11])[CH3:10].O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:9]([NH:13][C:14]([NH:16][C:1]1[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH:2]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)NC(N)=O
Reactant: O=C1CCCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C)NC(=O)NC1=CC(=O)CCC1
Yield: 66.7 %

Procedure:
To a solution of 11.2 g of 1,3-cyclohexanedione in 250 ml of benzene is added 11.6 g tert-butylurea and 100 mg of p-toluenesulfonic acid. The solution is heated at reflux under nitrogen with water removal for three hours. At the end of this period the solution is cooled and the precipitated product removed by filtration. The precipitate is recrystallized from acetonitrile to give 14 g of 1-tert-butyl-3-(3-oxo-1-cyclohexene-1-yl)urea, m.p. 223°-225° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1.[C:17](OCC)(OCC)(OCC)[CH3:18]>C(OC(=O)C)(=O)C>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([N:8]2[C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[N:1]=[C:17]2[CH3:18])=[CH:10][CH:11]=1)#[N:16]
Reactant: N#Cc1ccc(Nc2ccncc2N)cc1
Reactant: CCOC(C)(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: Cc1nc2cnccc2n1-c1ccc(C#N)cc1

Procedure:
A mixture of 3-amino-4-[N-(4-cyanophenyl)amino]pyridine (see part (b)) (9.31 g, 44.3 mmol), triethyl orthoacetate (40 ml) and acetic anhydride (30 ml) was heated at reflux for 2 hours under nitrogen, cooled, then concentrated under reduced pressure. The brown residue was dissolved in 1M hydrochloric acid and washed with ethyl acetate (200 ml). The aqueous layer was rendered basic with saturated aqueous ammonia and extracted with dichloromethane (3×200 ml). The combined extracts were washed with water, dried (MgSO4) and concentrated to give the title compound (6.5 g), as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][C:16]([F:21])([F:20])[CH2:15]2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH3:22][S:23]([NH2:26])(=[O:25])=[O:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl.CCOC(C)=O>[Cl:1][C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][C:16]([F:21])([F:20])[CH2:15]2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:26][S:23]([CH3:22])(=[O:25])=[O:24])=[O:8]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cc(Cl)c(OCC2CCCC(F)(F)C2)cc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(OCC2CCCC(F)(F)C2)cc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of the product from step 3, methanesulfonamide (32 mg), HBTU (86 mg), and DIPEA (0.18 mL) in dichloromethane (1.7 mL) was stirred at rt for 16 hr. Diluted with EtOAc, the contents were washed with 1:4 mixture of 1M HCl and 1M NaH2PO4 (2×) and brine, and dried (Na2SO4). The crude was purified with HPLC. LCMS (Method D): RT=5.35 min, m/z: 400.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 12.08 (s, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.14 (d, J=12.3 Hz, 1H), 4.13-3.98 (m, 2H), 3.13 (s, 3H), 2.18 (s, 1H), 2.04 (s, 2H), 1.90-1.56 (m, 4H), 1.55-1.39 (m, 1H), 1.19 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([N+:35]([O-])=O)=[C:7]([NH:9][C:10]2[N:15]=[C:14]3[N:16]([C@@H:27]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)[CH3:28])[C:17](=[O:26])[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:13]3=[CH:12][CH:11]=2)[CH:8]=1)#[N:2].[O-]S(S([O-])=O)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C1COCC1.O.C(OCC)(=O)C>[NH2:35][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][C:7]=1[NH:9][C:10]1[N:15]=[C:14]2[N:16]([C@@H:27]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[CH3:28])[C:17](=[O:26])[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[C:13]2=[CH:12][CH:11]=1
Reactant: C[C@H](c1cccnc1)n1c(=O)n(C(=O)OC(C)(C)C)c2ccc(Nc3cc(C#N)ccc3[N+](=O)[O-])nc21
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H](c1cccnc1)n1c(=O)n(C(=O)OC(C)(C)C)c2ccc(Nc3cc(C#N)ccc3N)nc21

Procedure:
A solution of (R)-tert-butyl 5-(5-cyano-2-nitrophenylamino)-2-oxo-3-(1-(pyridin-3-yl)ethyl)-2,3-dihydroimidazo[4,5-b]pyridine-1-carboxylate (70) (100 mg) in THF (5 mL) was treated with an aqueous solution comprised of 0.5 g of Na2S2O4 and 0.25 g NaHCO3 in 5 mL of water. The mixture went quickly from a red color to a slightly yellow color, which indicated reduction of the nitro group. The mixture was diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated to provide the intermediate (R)-tert-butyl 5-(2-amino-5-cyanophenylamino)-2-oxo-3-(1-(pyridin-3-yl)ethyl)-2,3-dihydroimidazo[4,5-b]pyridine-1-carboxylate (71). The intermediate was dissolved in THF (5 mL), DMF (1 mL), and trimethylorthoformate (2 mL). The mixture was treated with 10 mg of p-toluenesulfonic acid and stirred for 20 h. The mixture was diluted with ethyl acetate and washed once with saturated sodium bicarbonate and twice with saturated NaCl solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated. Column chromatography (2% MeOH in methylene chloride) provided 57 mg tert-Butyl 5-(6-cyano-1H-benzo[d]imidazol-1-yl)-2-oxo-3-((R)-1-(pyridin-3-yl)ethyl)-2,3-dihydroimidazo[4,5-b]pyridine-1-carboxylate (72).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[O:7][C:8]3[C:9](=[C:11]([C:15]([OH:17])=O)[CH:12]=[CH:13][CH:14]=3)[N:10]=2)[N:3]=[CH:2]1.[ClH:18].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:42][CH:43]1[CH2:50][CH:49]2[N:51]([CH3:52])[CH:45]([CH2:46][CH2:47][CH2:48]2)[CH2:44]1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[ClH:18].[CH3:52][N:51]1[CH:45]2[CH2:46][CH2:47][CH2:48][CH:49]1[CH2:50][CH:43]([NH:42][C:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:8]3[O:7][C:6]([C:4]4[N:3]=[CH:2][S:1][CH:5]=4)=[N:10][C:9]=13)=[O:17])[CH2:44]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: O=C(O)c1cccc2oc(-c3cscn3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C2CCCC1CC(NC(=O)c1cccc3oc(-c4cscn4)nc13)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.7 %

Procedure:
A mixture of 2-(thiazol-4-yl)benzoxazole-4-carboxylic acid (60 mg, 0.24 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (92 mg, 0.48 mmol), 1-hydroxybenzotriazole (65 mg, 0.48 mmol) and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (68 mg, 0.30 mmol) in DMF (2 mL) was stirred at room temperature for 10 min, then triethylamine (0.10 mL, 0.73 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine (2×25 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) and recrystallization from acetonitrile to afford the desired product (51 mg, 56%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.14 (br s, 1H), 9.03 (d, J=2.0 Hz, 1H), 8.40 (d, J=2.0 Hz, 1H), 8.22 (dd, J=7.8, 1.0 Hz, 1H), 7.76 (dd, J=8.0, 0.9 Hz, 1H), 7.51 (t, J=7.9 Hz, 1H), 4.70-4.61 (m, 1H), 3.35-3.28 (m, 2H), 2.75-2.66 (m, 2H), 2.68 (s, 3H), 2.40-2.30 (m, 1H), 2.24-2.12 (m, 2H), 1.97-1.85 (m, 2H), 1.70-1.61 (m, 1H), 1.50-1.41 (m, 2H); MS (ESI+) m/z 383 (M+H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]([O:11][C:12]([N:14]1[CH2:20][CH2:19][C:18]2[C:21]([C:26]#[CH:27])=[C:22]([Cl:25])[CH:23]=[CH:24][C:17]=2[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>>[C:7]([O:11][C:12]([N:14]1[CH2:20][CH2:19][C:18]2[C:21]([C:26]#[C:27][C:2]3[S:3][CH:4]=[CH:5][N:6]=3)=[C:22]([Cl:25])[CH:23]=[CH:24][C:17]=2[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: C#Cc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: Brc1nccs1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(C#Cc3nccs3)c2CC1
Yield: 88.4 %

Procedure:
Use a method similar to the General Procedure 8 to couple 2-bromo-thiazole (0.09 mL, 0.96 mmol) with 3-tert-butoxycarbonyl-7-chloro-6-ethynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (148 mg, 0.48 mmol). Purify by chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 4:1 gradient over 30 min) to give the desired intermediate (165 mg, 89%). MS (ES+) m/z: 389 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([OH:14])([CH3:13])[C:9]([F:12])([F:11])[F:10])[CH:5]=[N:6][CH:7]=1.CC1(C)C2[C:37](=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)[O:36][C:18]2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C[OH:58].C(N(CC)CC)C>C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:10][C:9]([F:12])([F:11])[C:8]([C:4]1[CH:3]=[C:2]([C:18]([O:36][CH3:37])=[O:58])[CH:7]=[N:6][CH:5]=1)([OH:14])[CH3:13]
Reactant: CC(O)(c1cncc(Br)c1)C(F)(F)F
Reactant: CO
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cncc(C(C)(O)C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of the title compound from Step A (0.170 g, 0.628 mmol), Pd(OAc)2 (2.8 mg, 0.013 mmol), Xantphos (0.015 g, 0.025 mmol), methanol (0.254 mL, 6.28 mmol), and triethylamine (8.96 mL, 1.25 mmol) was stirred under an atmosphere of carbon monoxide at 70° C. overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, filtered through Celite using ethyl acetate and concentrated under reduced pressure. Purification by column chromatography on silica gel (30% ethyl acetate in hexanes) provided the title compound: LCMS m/z 250.02 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 9.22 (s, 1 H), 9.00 (s, 1 H), 8.52 (s, 1 H), 3.98 (s, 3 H), 2.94 (br s, 1 H), 1.86 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:19].[Na+]>COCCOC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:11])=[O:19])=[CH:6][CH:7]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=C(CSc1ccc(Cl)cc1)c1ccccc1
Agent: [Na+]
Solvent: COCCOC
Product: O=C(CS(=O)c1ccc(Cl)cc1)c1ccccc1
Temperature: 40 °C

Procedure:
To a vigorously stirred solution of 199 g. (0.75 mole) of 4-chloro-2-(phenylthio)acetophenone in 2 liters of 1,2-dimethoxyethane (glyme) is added a solution of 175.5 g. (0.825 mole) of sodium periodate; the mixture is heated at 40°C for 7 days. The mixture is then filtered from the inorganic materials and the glyme distilled from the filtrate to give a slurry of crystals. These are filtered and this mixture of sulfoxide and starting material is separated from the inorganic contaminants by extraction into abs. ethanol. After filtration and concentration, the residue is dissolved in 1.5 liters of boiling hexane to give (after cooling and filtration) 91.8 g. of product, melting point 129°-130°C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[CH:8]=[C:9]([NH2:11])[CH:10]=1)=[O:4].[N-:20]=[N+:21]=[N-:22].[Na+].[CH3:24]C(O)=O>COC(OC)OC>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[CH:8]=[C:9]([N:11]2[CH:24]=[N:22][N:21]=[N:20]2)[CH:10]=1)=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(N)cc(-c2ccccc2OC)c1
Reactant: CC(=O)O
Agent: [Na+]
Solvent: COC(OC)OC
Product: COC(=O)c1cc(-c2ccccc2OC)cc(-n2cnnn2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 5-amino-2′-methoxy-biphenyl-3-carboxylic acid methyl ester (7.2 g, 28 mmol) in trimethoxymethane (22.8 mL) was added NaN3 (5.7 g) followed by HOAc (285 mL). The reaction mixture was stirred at room temperature for 30 minutes, then stirred at 100° C. for three hours, and then stirred at room temperature for 18 hours. The resulting mixture was partitioned between water and methylene chloride, and the combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure to give 8.6 g of 2′-methoxy-5-tetrazol-1-yl-biphenyl-3-carboxylic acid methyl ester, MS (M+H)=311.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:25][C:26]1[N:30]2[N:31]=[C:32](Cl)[CH:33]=[CH:34][C:29]2=[N:28][C:27]=1[C:36]([CH3:43])([CH3:42])[C:37]([O:39][CH2:40][CH3:41])=[O:38].C(=O)(O)[O-].[Na+]>>[ClH:25].[ClH:25].[Cl:25][C:26]1[N:30]2[N:31]=[C:32]([NH:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:10][CH2:11]3)[CH:33]=[CH:34][C:29]2=[N:28][C:27]=1[C:36]([CH3:42])([CH3:43])[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)C(C)(C)c1nc2ccc(Cl)nn2c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)C(C)(C)c1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2c1Cl
Product: Cl
Yield: 152.8 %

Procedure:
2.56 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 1.19 g of ethyl 2-[3,6-dichloroimidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate were stirred at 160° C. for 3 hours. After cooling, aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected and dissolved in 5 ml of ethyl acetate; 0.80 ml of a 4 N hydrogen chloride solution in ethyl acetate was added, followed by concentration. The residue was powdered by the addition of ether and dried to yield 1.33 g of the title compound.
Reaction SMILES: [F:1][C:2]([P:8](Cl)[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])([F:7])[C:3]([F:6])([F:5])[F:4].[CH2:17]([OH:19])[CH3:18]>CN(C)C1C=CN=CC=1.C(OCC)C>[F:1][C:2]([P:8]([C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[O:19][CH2:17][CH3:18])([F:7])[C:3]([F:6])([F:5])[F:4]
Reactant: CCO
Reactant: FC(F)(F)C(F)(F)P(Cl)C(F)(F)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Product: CCOP(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F

Procedure:
Bis(pentafluoroethyl)phosphinous acid chloride, (C2F5)2PCl, obtainable in accordance with Example 2, is added to a mixture of ethanol and 4-dimethylaminopyridine in diethyl ether at room temperature. The precipitated product 4-dimethylaminopyridinium chloride is separated off, and the solution comprises ethyl bis(pentafluoroethyl)phosphinite, (C2F5)2POC2H5.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.[N-:19]=[N+:20]=[N-:21].[Na+].CCN(C(C)C)C(C)C>CS(C)=O.C(OCC)(=O)C>[N:19]([CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)=[N+:20]=[N-:21]
Reactant: O=[N+]([O-])c1ccc(N2CCN(CCCl)CC2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1-(2-Chloroethyl)-4-(4-nitrophenyl)piperazine (1 g, 0.0033 mol) was dissolved in dimethylsulphoxide (30 mL) and sodium azide (0.34 g, 0.0052 mol) was added followed by Hunig's base (0.84 g, 0.0065 mol). The mixture was stirred at 80° C. overnight in a sealed tube, then diluted with ethyl acetate and washed with water, dried and evaporated to yield the title compound. LCMS: 90%, t=0.85 min, [MH+]=277.26.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:19])[CH:14]([NH2:18])[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:6])[CH3:5].[OH:21][C@@H:22]([CH:26]([CH3:28])[CH3:27])[C:23](O)=[O:24]>>[CH3:1][O:2][C:3](=[O:20])[C:4]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:19])[CH:14]([NH:18][C:23](=[O:24])[CH:22]([OH:21])[CH:26]([CH3:28])[CH3:27])[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:5])[CH3:6]
Reactant: CC(C)[C@H](O)C(=O)O
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)C(=O)OC)cn1
Product: CCCC(NC(=O)C(O)C(C)C)C(=O)Nc1cn(C(C)(C)C(=O)OC)cn1

Procedure:
2-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-2-methyl-propionic acid methyl ester was coupled with (S)-2-hydroxy-3-methyl-butyric acid to provide the title compound: C13 NMR (100 MHz, CDCl3) 13.8, 15.9, 19.1, 19.4, 26.1, 26.2, 32.1, 35.5, 52.6, 53.3, 61.2, 76.4, 106.1, 131.9, 137.5, 169.6, 172.6, 173.9; MS 383.2 m/z (M+1).