Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@H:8]([C:10](=[O:35])[NH:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:17](=[O:28])[N:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:19][C:20]=2[N:21]=1)[CH3:9])(C)(C)C.[ClH:38]>>[ClH:38].[CH3:6][NH:7][C@@H:8]([CH3:9])[C:10]([NH:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:17](=[O:28])[N:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:19][C:20]=2[N:21]=1)=[O:35]
Reactant: C[C@@H](C(=O)Nc1ccc2c(n1)CN(c1ccccc1)C(=O)N2c1ccccc1)N(C)C(=O)OC(C)(C)C
Agent: Cl
Product: CN[C@@H](C)C(=O)Nc1ccc2c(n1)CN(c1ccccc1)C(=O)N2c1ccccc1

Procedure:
Methyl-[(S)-1-(2-oxo-1,3-diphenyl-1,2,3,4-tetrahydro-pyrido[3,2-d]pyrimidin-6-ylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (35 mg, 0.07 mmol) was treated with HCl according to the General procedure 3 to afford the title compound (28 mg). 1H NMR (400 MHz, Me-d3-OD): 7.91 (1H, d), 7.64-7.38 (9H, m), 7.38-7.28 (1H, m), 6.70 (1H, d), 5.03 (2H, s), 4.01 (1H, q), 2.74 (3H, s), 1.62 (3H, d). MS: [M+H]+=402.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:17]([O:19][CH3:20])=[O:18])[CH:14](C)[CH3:15])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.CN[C@H](C(O)=O)C[CH2:26][S:27]C>>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:17]([O:19][CH3:20])=[O:18])[CH2:14][CH2:15][S:27][CH3:26])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CN[C@@H](CCSC)C(=O)O
Reactant: COC(=O)[C@@H](NC(=O)Cc1cc(F)cc(F)c1)C(C)C
Agent: Cl
Product: COC(=O)[C@H](CCSC)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
A method similar to that used for the preparation of (107a) was used except that methyl-L-methionine hydrochloride (214 mg) was used instead of methyl-L-valinate hydrochloride to afford the desired product (300 mg). 1H NMR (300 MHz, CDCl3) δ 1.178 (t, 3H, J=7 Hz), 1.93 (m, 2H), 2.02 (s, 3H), 2.51 (m, 2H), 3.53 (s, 2H), 4.38 (m, 1H), 7.07 (m, 3H), 8.54 (d, 1H, J=8 Hz). LC/MS: 2.28 min.
Reaction SMILES: Cl[CH2:2][P:3](=[O:6])([CH3:5])[CH3:4].[CH2:7]([O:9][P:10]([O:14]CC)[O:11][CH2:12][CH3:13])[CH3:8]>>[CH2:7]([O:9][P:10]([CH2:2][P:3]([CH3:5])([CH3:4])=[O:6])(=[O:14])[O:11][CH2:12][CH3:13])[CH3:8]
Reactant: CCOP(OCC)OCC
Reactant: CP(C)(=O)CCl
Product: CCOP(=O)(CP(C)(C)=O)OCC
Reaction time: 1.5 h
Yield: 68 %

Procedure:
252 g of chloromethyl-dimethylphosphine oxide are heated to 140° to 150° C. under an atmosphere of nitrogen and 480 g of triethylphosphite are added dropwise in the course of 4 hours. Stirring is continued for a further 1.5 hours at the temperature indicated, 98 g of ethyl chloride (76% of theoretical) being collected in a cold trap connected downstream of the apparatus. The mixture is then incipiently distilled at 0.6 mm Hg until the internal temperature reaches 148° C., with distillate passing over at a temperature of 135° C. This gives 309 g of the ester, having a solidification point of 59°-60° C. (yield: 68 percent of theoretical). The product can be employed for further reactions in the form of the crude product; further purification can be effected by distillation (boiling point at 0.4 mm Hg: 140° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:19]2[C@H:9]3[CH2:10][CH2:11][C@@:12]4([CH3:18])[C@H:16]([C@@H:8]3[CH2:7][CH2:6][C:5]=2[CH:4]=1)[CH2:15][CH2:14][C:13]4=[O:17].C([O-])(=O)C.[Na+].S(=O)(=O)(O)O>CO.ClCCl.[Pt]>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:19]2[C:9]3=[CH:10][CH2:11][C@@:12]4([CH3:18])[C@H:16]([C@@H:8]3[CH2:7][CH2:6][C:5]=2[CH:4]=1)[CH2:15][CH2:14][C:13]4=[O:17]
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Pt]
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2c(c1)CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 83.9 %

Procedure:
A solution of 3.0 grams of 3-methoxy-13β-methylgona-1,3,5(10)-trien-17-one and 0.66 gram of sodium acetate in 60 milliliters of methanol and 20 milliliters of dichloromethane was electroyzed between the same platinum electrodes as specified in Example 1 while a potential of 1.7 volts (measured at the anode against a standard saturated calomel electrode) was maintained between the electrodes. At the completion of the electrolysis, which was established by thin-layer chromatography, the solution was made slightly acid by adding sulfuric acid thereto and it was allowed to stand at room temperature for a period between 20 and 30 minutes. Thereafter the dichloromethane was distilled and the product was crystallized from the remaining methanolic solution. In this manner, 2.5 grams of 3-methoxy-13β-methylgona-1,3,5(10),9(11)-tetraen- 17-one having a melting point of 142°- 145° C. was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[NH:7][C:6]=2[CH:16]=1.[Cl:17][CH2:18][CH2:19][C:20](Cl)=[O:21].[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:17][CH2:18][CH2:19][C:20]([N:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH2:10][CH2:11][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:16][C:6]1=2)=[O:21]
Reactant: O=C(Cl)CCCl
Reactant: Clc1ccc2c(c1)Nc1ccccc1CC2
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(CCCl)N1c2ccccc2CCc2ccc(Cl)cc21
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
3-Chloro-10,11-dihydro-5H-dibenz[b,f]azepine (3.82 g, 16.6 mmol) was dissolved in toluene (20 ml). A solution of 3-chloropropionylchloride (2.53 g, 19.9 mmol) in toluene was added dropwise, and the resulting mixture was heated to 95° C. and stirred at that temperature for 30 minutes. The mixture was stirred overnight at room temperature. Further 3-chloropropionylchloride (2.53 g, 19.9 mmol) was added and the mixture was stirred at 95° C. for 1.5 h. After cooling, 0.2 M sodium hydroxide (10 ml) was added, and the phases were separated. The organic phase was diluted with more toluene (50 ml); and washed with first 0.2 M sodium hydroxide (6×10 ml) and then with more 0.2 M sodium hydroxide (3×20 ml) until the aqueous phase was alkaline. The organic phase was washed with water (3×15 ml), brine (25 ml), and dried (MgSO4). Evaporation in vacuo afforded 5.23 g (98%) of crude 3-chloro-1-(3-chloro-10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propanone as an oil. This was further purified by addition of a mixture of heptane and ethyl acetate (1:1). This afforded 3.14 g (59%) of the product as a solid.
Reaction SMILES: [CH2:1](Br)[CH:2]([CH3:4])[CH3:3].Cl[SiH:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH2:9][CH2:8]1>>[CH2:1]([Si@H:7]1[CH2:8][CH2:9][C@H:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:27])[F:28])=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)[CH2:11][CH2:12]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CBr
Reactant: FC(F)Oc1ccc(-c2ccc(C3CC[SiH](Cl)CC3)cc2)cc1
Product: CC(C)C[Si@H]1CC[C@H](c2ccc(-c3ccc(OC(F)F)cc3)cc2)CC1

Procedure:
Preparation was conducted in the same manner as in Example 1 except for the fact that isobutyl bromide was used instead of n-propylbromide and that 4'-(4-chloro-4-silacyclohexyl)-4-difluoromethoxybiphenyl was used instead of 4'-(4-chloro-4-silacyclohexyl)-4-fluorobiphenyl.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](O)(=[O:33])[CH2:28][CH2:29][C:30]([OH:32])=[O:31].CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:27](=[O:33])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCC(=O)O
Reactant: O=S(=O)(CCN1CC[C@H](Cc2ccccc2)[C@H](O)C1)c1ccc(O)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: O=C(O)CCC(=O)Oc1ccc(S(=O)(=O)CCN2CC[C@H](Cc3ccccc3)[C@H](O)C2)cc1
Yield: 7.9 %

Procedure:
To a solution of 1.0 g (2.66 mmol) (3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenol in 25 ml CH2Cl2 were added 320 mg (3.2 mmol) succinic acid and 390 mg (3.2 mmol) dimethylaminopyridine and the reaction mixture was refluxed for 20 hours. The reaction mixture was concentrated to 10 ml and was purified by chromatography over silica gel to give 100 mg (0.21 mmol, 7.4%) succinic acid mono-{(3S,4S)-4-[2-(4-benzyl -3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl} ester as colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[F:24][C:25]([F:38])([F:37])[CH:26]1[CH2:31][CH2:30][CH:29](OS(C)(=O)=O)[CH2:28][CH2:27]1.ClCCl>CC(O)(C)C.CC(=O)CC>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH:29]3[CH2:30][CH2:31][CH:26]([C:25]([F:38])([F:37])[F:24])[CH2:27][CH2:28]3)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)ccc21
Reactant: CS(=O)(=O)OC1CCC(C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc(OC3CCC(C(F)(F)F)CC3)ccc21
Temperature: 100 °C
Yield: 37.1 %

Procedure:
A mixture of 5-hydroxy-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (0.33 g, 1.4 mmol), cesium carbonate (0.93 g, 2.8 mmol), and methanesulfonic acid 4-trifluoromethyl-cyclohexyl ester (0.70 g, 2.8 mmol) in t-BuOH (5 mL) and 2-butanone (2.5 mL) was heated in a sealed vial at 100° C. overnight. The mixture was treated with dichloromethane to form precipitate. The solid was filtered off and the filtrate was concentrated. The residue was treated with minimum of amount dichloromethane to form solid during 2 days. The solid was filtered and washed with ether to give desired product (200 mg, yield: 40%). ESI-MS: 408.20 (M+23)+.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[CH2:5][CH2:4]1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:2]([C@H:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[CH2:5][CH2:4]1)[CH3:1])(=[O:25])=[O:24]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CN[C@@H]1CCc2ccc(C(=O)OC)cc21
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)[C@H](N(C)S(=O)(=O)c1ccccc1Cl)CC2
Reaction time: 0.25 h
Yield: 89 %

Procedure:
TEA (864 μl, 6.23 mmol, 2.5 eq.) was added to a cooled (0° C.) solution of (R)-methyl 3-(methylamino)-2,3-dihydro-1H-indene-5-carboxylate (A-17) (2.49 mmol, 1.0 eq.) in methylene chloride (10 ml) and the reaction mixture was allowed to stir for 15 min. A solution of 2-chlorobenzene-1-sulfonyl chloride (407 μl, 2.99 mmol, 1.2 eq.) in methylene chloride (5 ml) was then added and the reaction mixture was stirred at RT for 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with methylene chloride (100 ml) and the organic layer was washed with water (50 ml) and brine (50 ml), and dried over anhydrous Na2SO4. The solvent was evaporated to afford the crude product which was purified by column chromatography (silica gel; 20% ethyl acetate/hexanes) to yield the desired compound as a white solid. Yield: 89% (840 mg, 2.216 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[C@H:10]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH:11][C:12]([N:14]([CH2:16][CH2:17][N:18](C(OC(C)(C)C)=O)[CH3:19])[CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:35]>C(OCC)(=O)C>[ClH:35].[CH2:1]([O:8][C:9](=[O:34])[C@H:10]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH:11][C:12]([N:14]([CH2:16][CH2:17][NH:18][CH3:19])[CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCN(C)C(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CNCCN(C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
N-[N-[2-(N-tert-Butoxycarbonyl-N-methylamino)ethyl]-N-methylaminocarbonyl]-L-phenylalanine benzyl ester (11 g was dissolved in a solution of 4M hydrogen chloride in ethyl acetate (200 ml) under ice-bath cooling. After being stirred at the same temperature for 30 minutes, the solution was concentrated in vacuo to give N-[N-[2-(N-methylamino)ethyl]-N-methylaminocarbonyl]-L-phenylalanine benzyl ester hydrochloride (10 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28](O)=[O:29])[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1.[CH3:31][O:32][CH2:33][CH2:34][NH2:35]>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([NH:35][CH2:34][CH2:33][O:32][CH3:31])=[O:29])[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)O)c4)c3cn2)c1Cl
Reactant: COCCN
Product: COCCNC(=O)Cn1cc(-c2n[nH]c3cc(-c4c(Cl)c(OC)cc(OC)c4Cl)ncc23)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 36, Step 2, starting from {4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}acetic acid and 2-Methoxyethylamine. LCMS (M+H)+=505.1/507.1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.CC1N=C([N+]([O-])=O)[C:14]([OH:20])=[CH:13]C=1.[H-].[Na+].ClCC(OC)=O>CS(C)=O>[CH3:9][C:4]1[CH:5]=[CH:6][C:7]2[O:8][CH2:13][C:14](=[O:20])[NH:1][C:2]=2[N:3]=1
Reactant: Cc1ccc(O)c([N+](=O)[O-])n1
Reactant: Cc1ccc(O)c(N)n1
Agent: COC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc2c(n1)NC(=O)CO2
Temperature: 100 °C

Procedure:
A solution of 2-amino-6-methyl-pyridin-3-ol (5.7 g, 46 mmol) (prepared by reduction of 6-methyl-2-nitro-pyridin-3-ol according to the procedure of J. Kaminski et al, [J. Med. Chem, 30 (11), 2031 (1987)1 in dimethylsulphoxide (60 ml) was treated with sodium hydride (44 mmol) under argon. After 0.25 hours methyl chloroacetate (4 mL, 5 g, 46 mmol) was added and the mixture heated at 100° C. for 3.5 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (10 mL), then partitioned between dichloromethane and water. The organic extracts were dried and evaporated and the residue was chromatographed eluting with 0-20% ethyl acetate in dichloromethane affording the product as a white crystalline solid (4.7 g, 62%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:27]1[N:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][N:28]=1>>[CH2:33]([C:30]1[CH:29]=[N:28][C:27]([N:23]2[CH2:24][CH2:25][CH:20]([C@@H:18]3[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH:7]=5)[CH:12]=[C:13]4[CH2:19]3)[CH2:21][CH2:22]2)=[N:32][CH:31]=1)[CH3:34]
Reactant: CCc1cnc(Cl)nc1
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCNCC2)C3)CC1
Product: CCc1cnc(N2CCC([C@H]3Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O3)CC2)nc1

Procedure:
The title compound is prepared from (R)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 39, the configuration of the stereocenter is arbitrarily assigned) and 2-chloro-5-ethylpyrimidine following a procedure analogous to that described in Example 1. LC (method 5): tR=0.87 min; Mass spectrum (ESI+): m/z=470 [M+H]+.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[N:7][N:6]=1>C(O)C>[CH:11]1[CH:12]=[CH:13][C:14]2[C:9](=[CH:8][N:7]=[N:6][C:5]=2[NH:2][NH2:3])[CH:10]=1
Reactant: Clc1nncc2ccccc12
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1nncc2ccccc12
Reaction time: 1 h

Procedure:
To a 2-L, 3-necked, round-bottom flask fitted with a temperature probe and condenser were charged 700 mL of ethanol and 7.6 mole equivalents (630 mL) of hydrazine hydrate, and the solution was cooled to <10° C. One (1) mole equivalent (280 g) of 1chlorophthalazine (solid) was added in portions at a rate to maintain the solution temperature at <20° C. The solution was stirred and heated to 60–70° C. After 1 hour at temperature, the hot solution was filtered to remove any insoluble by-products, and the filtrate was cooled to 0–5° C. A light yellow solid formed in the cold solution, and was isolated by filtration and washed with cold ethanol. The resulting product, hydralazine free base, was dried to constant mass and characterized. Typical yields were in the range 77–80%. The hydralazine thus obtained could be used in the next step without purification.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][CH:6]1[N:24]=[N+]=[N-])(=[O:3])[CH3:2].[H][H]>O=[Pt]=O.O1CCCC1>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][CH:6]1[NH2:24])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)OC[C@H]1OC(N=[N+]=[N-])[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=[Pt]=O
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1OC(N)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
4 g, that is, 11 mmol of the 2,3,4,6-tetra-O-acetylglucopyranosyl azide was added to 50 ml of dry tetrahydrofuran containing 200 mg of PtO2. The mixture was shaken under 40 psi of hydrogen for 2 hours, filtered, concentrated to dryness, to produce 2,3,4,6-tetra-O-acetylglucopyranosyl amine.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:20]([NH2:25])([CH2:23][CH3:24])([CH3:22])[CH3:21].O>C1(C)C=CC=CC=1>[CH3:21][C:20]([NH:25][S:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][Br:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])([CH3:22])[CH2:23][CH3:24]
Reactant: CCC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCC(C)(C)NS(=O)(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 8.5 %

Procedure:
To a solution of 10 g of 4-bromomethylbenzenesulfonyl chloride and 10 ml of triethylamine in 50 ml of toluene is added, dropwise at RT, a solution of 3.2 g of tert-amylamine in 10 ml of toluene, and the mixture is left stirring for 3 hours at RT. Water is then added to the reaction mixture and, after separation by settling, the organic phase is washed with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica, eluting with a DCM/heptane mixture (50/50; v/v). 1 g of the expected product is obtained after crystallization from iso ether, mp=100° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N+:2]=1[O-].P(Cl)(Cl)([Cl:14])=O>C(Cl)(Cl)Cl>[Cl:14][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: [O-][n+]1ccc2ccccc2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Clc1nccc2ccccc12
Temperature: 17.5 °C
Yield: 48.4 %

Procedure:
69.3 g of isoquinoline N-oxide (448 mmol) manufactured by Tokyo Chemical Industry Co., Ltd. and 225 ml of chloroform were introduced into a 1 L-three-neck flask dissolved therein. Then, 219.6 g (1,432 mmol) of phosphorous oxychloride was slowly added dropwise therein and stirred under ice-cooling while maintaining the inner temperature at 15 to 20° C. Thereafter, the mixture was heated and stirred under reflux for 3 hours. The reaction product was left to cool to room temperature, and the resulting product was poured into ice water. The mixture was extracted with ethyl acetate, and the organic layer was washed with water until it was neutral. The solvent was then dried under reduced pressure. The residue was purified using silica gel column chromatography (eluent: chloroform/hexane: 5/1) to yield 35.5 g of 1-chloroisoquinoline white crystals (44.9% yield).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].C([Li])CCC.[Br:17]C(Cl)(Cl)C(Br)(Cl)Cl.O>O1CCCC1>[Br:17][C:10]1[N:5]2[N:4]=[C:3]([CH2:1][CH3:2])[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: CCc1cc2ccccn2n1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc2cccc(Br)n2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
To a solution of 2-ethylpyrazolo[1,5-a]pyridine (80 mg) dissolved in tetrahydrofuran (1 mL) was added n-butyllithium (1.6M hexane solution: 0.58 mL) dropwise at −78° C. under a nitrogen stream, and the reaction mixture was further stirred for 30 minutes at the same temperature. A solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (196 mg) in tetrahydrofuran (0.5 mL) was added dropwise to the reaction mixture, and stirring was continued for 30 minutes. After raising the temperature to room temperature and adding water to the reaction mixture, extraction was performed with ethyl acetate and the organic extract was washed with water and brine. The obtained organic extract was dried over anhydrous magnesium sulfate and filtered, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography and the title compound (90 mg) was obtained as a light brown oil from the n-hexane:ethyl acetate (20:1) fraction.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:29]=[CH:28][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][C:17]=3[F:27])=[C:13](N)[CH:12]=2)=[O:10])=[CH:4][CH:3]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:29]=[CH:28][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][C:17]=3[F:27])=[CH:13][CH:12]=2)=[O:10])=[CH:31][CH:32]=1
Reactant: COC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2N)c(F)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(F)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
Isobutyl nitrile (0.060 ml, 0.51 mmol) was diluted with DMF (2 mL), placed under nitrogen and heated to 60° C. followed by the addition of methyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)-2-aminophenoxy)-3-fluorophenyl)acetate (93 mg, 0.20 mmol) in 500 μL of DMF. The reaction was stirred 30 minutes and then cooled. The reaction was diluted with ethyl acetate and washed with 2N HCl and saturated sodium bicarbonate. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was purified by silica gel chromatography, eluting with hexanes:ethyl acetate (2:1) to yield methyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-fluorophenyl)acetate (35 mg, 39% yield).
Reaction SMILES: C(OC([NH:11][C:12]([CH3:30])([CH3:29])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[C:24](N)[CH:25]=[CH:26][C:19]=2[NH:18][C:17]1=[O:28])=[O:14])=O)C1C=CC=CC=1.Cl.N([O-])=O.[Na+].[F:36][P-](F)(F)(F)(F)F.[H+]>O>[NH2:11][C:12]([CH3:30])([CH3:29])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[C:24]([F:36])[CH:25]=[CH:26][C:19]=2[NH:18][C:17]1=[O:28])=[O:14]
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2cc(N)ccc2NC1=O
Reactant: F[P-](F)(F)(F)(F)F
Agent: Cl
Agent: O=N[O-]
Agent: [H+]
Solvent: O
Product: CC(C)(N)C(=O)N[C@@H]1CCc2cc(F)ccc2NC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 256 mg (0.624 mmol) of 2-benzyloxycarbonylamino-2-methyl- N-[7-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]propanamide (Step C) in 1.2 mL of water was added 0.171 mL of concentrated hydrochloric acid. The resulting mixture was stirred until all the solids were dissolved then the solution was cooled to 0° C. To this solution was added a solution of 52 mg (0.75 mmol) of sodium nitrite in a minimal amount of water. After 30 minutes at 0° C., 0.156 mL (1.06 mmol) of 60 weight percent aqueous hexafluorophosphoric acid was added dropwise. Immediately a white precipitate formed. The solids were filtered and washed with ice cold water, then air dried. The resulting solid was dried under vacuum overnight.