Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:25]=[CH:24][C:6]([O:7][CH2:8][CH2:9][CH2:10][O:11][N:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+]>CO.[Cl-].[Na+].O>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][O:11][N:12]=[CH:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([CH3:21])([CH3:23])[CH3:22])=[CH:18][CH:19]=2)=[CH:24][CH:25]=1
Reactant: CC(C)(C)c1ccc(C=NOCCCOc2ccc(C=O)cc2)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1ccc(C=NOCCCOc2ccc(CO)cc2)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 4-tert-butyl-benzaldehyde O-[3-(4-formyl-phenoxy)-propyl]-oxime (1.303 g, 3.84 mmol) in methanol (30 mL) was added sodium borohydride (0.201 g, 5.31 mmol) and the reaction was allowed to stir for 20 minutes. It was then poured slowly into brine and extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 4-tert-butyl-benzaldehyde O-[3-(4-hydroxymethyl-phenoxy)-propyl]-oxime which was used without further purification. To a solution of 4-tert-butyl-benzaldehyde O-[3-(4-hydroxymethyl-phenoxy)-propyl]-oxime in methylene chloride (30 mL) was added phosphorus tribromide (0.400 mL, 4.25 mmol) and the reaction was stirred at room temperature for 30 minutes. It was then poured slowly over ice and extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 4-tert-butyl-benzaldehyde O-[3-(4-bromomethyl-phenoxy)-propyl]-oxime (˜0.8 g) which was used without further purification. To a solution of 4-tert-butyl-benzaldehyde O-[3-(4-bromomethyl-phenoxy)-propyl]-oxime (−0.8 g) in tetrahydrofuran (25 mL) was added tetrabutylammonium cyanide (0.650 g, 2.42 mmol) and the reaction was allowed to stir at room temperature overnight. It was then poured into brine and extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate/hexanes (10/90 to 15/85) to give {4-[3-(4-tert-butyl-benzylideneaminooxy)-propoxy]-phenyl}-acetonitrile (0.607 g, 45% over 3 steps) as a colorless oil. 1H NMR (300 MHz, CDCl3); δ 8.08 (s, 1H), 7.52 (d, 2H), 7.40 (d, 2H), 7.22 (d, 2H), 6.92 (d, 2H), 4.35 (t, 2H), 4.10 (t, 2H), 3.68 (s, 2H), 2.21 (m, 2H), 1.34 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:22](O)=[O:23])[C:7]([C:10]2[C:11](C(O)=O)=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2].O.Cl>O1CCCC1>[OH:23][CH2:22][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=1[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1-c1ccc([N+](=O)[O-])cc1C(=O)O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(-c2ccc([N+](=O)[O-])cc2CO)cc1
Reaction time: 19 h

Procedure:
3.6 g (10.83 mmol) 4,4′-Dinitro-1,1′-biphenyl-2,2′-dicarboxylic acid are dissolved in 25 ml tetrahydrofuran and added dropwise in a the course of 1 hours to 65 ml (65.02 mmol) of a borane-tetrahydrofuran complex 1.0 M solution in tetrahydrofuran. After 19 hours at 25° C., 50 ml water are carefully added. After 1 h the solution is acidified to pH=1-2 with 10 ml 1N HCl solution and allowed to stirred for 30 min. The reaction mixture is then partitioned between ethyl acetate and water; the organic phase is washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. The residue, 4.2 g of 2,2′-bis(hydroxymethyl-4,4′-Dinitro 1,1′-biphenyl as white powder is used without further purification.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[N:19]([CH3:30])[C:20](=[O:29])[C:21]5[CH:27]=[CH:26][NH:25][C:24](=[O:28])[C:22]=5[N:23]=4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].S(C1C=CC(C)=CC=1)(O[CH2:41][CH2:42][F:43])(=O)=O>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[N:19]([CH3:30])[C:20](=[O:29])[C:21]5[CH:27]=[CH:26][N:25]([CH2:41][CH2:42][F:43])[C:24](=[O:28])[C:22]=5[N:23]=4)=[CH:14][CH:13]=3)[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Reactant: Cn1c(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)nc2c(=O)[nH]ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)nc2c(=O)n(CCF)ccc2c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 3.7 %

Procedure:
2-{4-[(1-Cyclobutylpiperidin-4-yl)oxy]phenyl}-3-methyl-3,7-dihydropyrido[3,4-d]pyrimidine-4,8-dione (24 mg, 0.06 mmol) and potassium carbonate (33 mg, 0.24 mmol) were stirred in DMF (0.5 mL) at room temperature, then 2-fluoroethyl tosylate (40 mg, 0.18 mmol) was dropwise added thereto and stirred at room temperature for 20 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline water in that order, and the organic layer was dried with magnesium sulfate. The solvent was evaporated off, and the residue was purified through silica gel thin-layer chromatography (chloroform/methanol=9/1) to obtain the intended compound (1.0 mg, 4%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([S:10][CH3:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH2:12](SSCC)C>>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH3:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCSSCC
Reactant: CSc1ccc(Cl)c(C#N)c1
Product: CCSc1ccc(Cl)c(C#N)c1

Procedure:
The subtitle compound was prepared by the method of example 5 step iv) using the product from step i) and diethyldisulphide. Yield 2.50 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([N:14]=[C:15]([Cl:17])[N:16]=3)[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:21][CH2:20]1>>[Cl:17][C:15]1[N:16]=[C:9]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:28]4[CH2:27][CH2:26][CH:25]([N:22]5[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]5)[CH2:30][CH2:29]4)=[CH:3][CH:4]=3)=[CH:13][CH:12]=[CH:11][N:10]2[N:14]=1
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: Clc1nc2c(-c3ccc(Br)cc3)cccn2n1
Product: CN1CCN(C2CCN(c3ccc(-c4cccn5nc(Cl)nc45)cc3)CC2)CC1

Procedure:
206 a) 2-Chloro-8-{4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-(4-bromo-phenyl)-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (100.0 mg, 0.3241 mmol) and 1-methyl-4-piperidin-4-yl-piperazine (66.0 mg, 0.360 mmol) in a manner analogous to Example 2d. Product isolated as a pale yellow solid (0.023 g, 17%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.40 (d, J=6.7 Hz, 1H), 7.93 (d, J=8.0 Hz, 2H), 7.64 (d, J=7.4 Hz, 1H), 7.10 (t, J=6.8 Hz, 1H), 7.03 (d, J=8.3 Hz, 2H), 3.87 (d, J=12.5 Hz, 2H), 2.82 (t, J=12.6 Hz, 2H), 2.70-2.35 (m, 9H), 2.30 (s, 3H), 1.95 (d, J=11.9 Hz, 2H), 1.75-1.60 (m, 2H). MS=411 (MH)+. 206 b) [3-(4-Methyl-piperazin-1-yl)-phenyl]-(8-{4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine was prepared from 2-chloro-8-{4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-[1,2,4]triazolo[1,5-a]pyridine (23.0 mg, 0.0560 mmol) and 3-(4-methylpiperazin-1-yl)aniline (12.0 mg, 0.0627 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (5.0 mg, 0.0091 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow solid (0.014 g, 44%). MP=222-225° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.33 (d, J=6.6 Hz, 1H), 7.96 (d, J=8.3 Hz, 2H), 7.52 (d, J=7.7 Hz, 1H), 7.48 (s, 1H), 7.21 (t, J=7.6 Hz, 1H), 7.03 (d, J=7.9 Hz, 2H), 6.95-6.89 (m, 2H), 6.82 (s, 1H), 6.57 (d, J=8.4 Hz, 1H), 3.86 (d, J=13.2 Hz, 2H), 3.31-3.26 (m, 4H), 2.81 (t, J=12.2 Hz, 2H), 2.70-2.38 (m, 13H), 2.37 (s, 3H), 2.30 (s, 3H), 1.94 (d, J=11.6 Hz, 2H), 1.75-1.63 (m, 2H). MS=566 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([Cl:17])[N:3]=1.[NH3:18]>[Cu].CCO>[NH2:1][C:2]1[N:7]=[C:6]([NH2:18])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([Cl:17])[N:3]=1
Reactant: N
Reactant: Nc1nc(Cl)c(-c2ccc(Cl)cc2Cl)c(Cl)n1
Agent: [Cu]
Solvent: CCO
Product: Nc1nc(N)c(-c2ccc(Cl)cc2Cl)c(Cl)n1
Temperature: 180 °C
Yield: 25 %

Procedure:
A mixture of 2-amino-5-(2,4-dichlorophenyl)-4,6-dichloropyrimidine (0.5 g) (Example 32) EtOH saturated with ammonia (20 ml) and copper powder (0.05 g) was heated in an autoclave at 180° C. for 18 hours. The cooled reaction mixture was filtered, evaporated and the residue purified by flash column chromatography to give the title compound (0.12, 25%), mp. 219° C. Microanalysis:
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[N:23]([CH2:28][CH3:29])[N:24]=[C:25]([CH3:27])[CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])[CH:8]=2)[NH:3]1.[CH:30](OCC)=[O:31].[O-]CC.[Na+].Cl>C(O)C>[OH:31][CH:30]=[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[N:23]([CH2:28][CH3:29])[N:24]=[C:25]([CH3:27])[CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])[CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)CC(=O)N3)c1
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)C(=CO)C(=O)N3)c1
Temperature: 78 °C
Yield: 50.9 %

Procedure:
2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-amide (1.12 g, 2.89 mmol) and ethyl formate (0.700 mL, 8.67 mmol) were dissolved in anhydrous ethanol (5.78 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (5.40 mL, 14.50 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale orange precipitate. The suspension was filtered yielding an orange solid as the pure product (0.609 g, 1.47 mmol, 57%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[C:53]([C:57]([F:60])([F:59])[F:58])[CH:52]=1)[C:12]1[C:17](=[O:18])[N:16]2[C@H:19]([C:34](N(C(OC(C)(C)C)=O)C3C=CC=CC=3)=[O:35])[CH2:20][C@:21]([CH2:23][C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])([CH3:22])[C:15]2=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OO.[Li+].[OH-].[O-:65]S([O-])=O.[Na+].[Na+].Cl>O.C1COCC1>[CH2:1]([O:8][C:9]([N:11]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[C:53]([C:57]([F:60])([F:58])[F:59])[CH:52]=1)[C:12]1[C:17](=[O:18])[N:16]2[C@H:19]([C:34]([OH:35])=[O:65])[CH2:20][C@:21]([CH2:23][C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:25])([CH3:22])[C:15]2=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S([O-])[O-]
Reactant: CC(C)(C)OC(=O)N(C(=O)[C@@H]1C[C@@](C)(CC(=O)OCc2ccccc2)c2ncc(N(Cc3cccc(C(F)(F)F)c3)C(=O)OCc3ccccc3)c(=O)n21)c1ccccc1
Agent: Cl
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@]1(CC(=O)OCc2ccccc2)C[C@@H](C(=O)O)n2c1ncc(N(Cc1cccc(C(F)(F)F)c1)C(=O)OCc1ccccc1)c2=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 124.6 %

Procedure:
To a solution of 117d (537 mg, 0.651 mmol) in 4:1 THF/H20 at 0° C., were added 30% H2O2 (0.295 mL, 2.604 mmol) and 1M LiOH (1.107 mL, 1.107 mmol). The mixture was stirred at 0° C. for 2 h, then a solution of Na2SO3 (140 mg, 1.107 mmol) in 1 mL H2O was added dropwise. The mixture was poured into 0.5 M HCl and the product was extracted with EtOAc. The organic was washed with brine, dried (Na2SO4), and concentrated to afford 527 mg of 117e, which was contaminated with BocNHPh. The mixture was used as is in the following step. MS(ESI) 650.3 (M+H+); 648.3 (M−H+).
Reaction SMILES: FC(F)(F)[C:3]([N:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])C)=O.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21]([OH:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1>CO>[S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)([OH:24])(=[O:23])=[O:22].[CH3:3][NH:5][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12]
Reactant: C=CCCCCN(C)C(=O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: C=CCCCCNC

Procedure:
At room temperature, compound 31a (71.88 g, 1 eq.) and p-toluene sulfonic acid (74.4 g, 1.2 eq.) were dissolved in MeOH (640 mL). The reaction mixture was refluxed for 7 days. The solvent was then removed under vacuum, and the residue was recrystallized in acetone. The product was isolated by filtration, dried over P2O5 to give compound 32a as a white powder in 76% yield.
Reaction SMILES: [NH2:1][CH:2]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:32])([F:31])[CH:28]([F:30])[F:29])[CH:21]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=1)[OH:4].[C:33]1([C:44](O)=[O:45])[CH:34]=[CH:35][CH:36]=[C:37]2[CH2:43][CH2:42][CH2:41][CH:40]=[CH:39][C:38]=12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[CH2:12]([O:11][C:7]1[CH:6]=[C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:44]([C:33]2[CH:34]=[CH:35][CH:36]=[C:37]3[CH2:43][CH2:42][CH2:41][CH:40]=[CH:39][C:38]=23)=[O:45])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:31])([F:32])[CH:28]([F:29])[F:30])[CH:21]=2)[CH:10]=[CH:9][CH:8]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(OCc2ccccc2)c1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(OCc2ccccc2)c1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(3-(benzyloxy)phenyl)-3-(3-((1,1,2,2-tetrafluoroethyl)oxy)-phenyl)-1-propanol (405 mg, 0.90 mmol) in acetonitrile (30 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (170 mg, 0.90 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (259 mg, 1.35 mmol) and 1-hydroxybenzotriazole hydrate (138 mg, 0.90 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-1:1). Recrystallization from ethyl acetate-hexane gave the objective substance (407 mg, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:14]3[CH:15]=[C:16]([C:19]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)([C:21]4[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=4)O)[CH:17]=[CH:18][C:13]=3[N:12]3[N:34]=[N:35][N:36]=[C:11]3[CH2:10][S:9]2)[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:39])=O>>[Cl:39][C:19]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)([C:21]1[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=1)[C:16]1[CH:17]=[CH:18][C:13]2[N:12]3[N:34]=[N:35][N:36]=[C:11]3[CH2:10][S:9][CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:14]=2[CH:15]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)SCc1nnnn1-2
Product: Cn1cncc1C(Cl)(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)SCc1nnnn1-2
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A mixture of 6-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-4 H,6H-tetrazolo[1,5-a][4,1]benzothiazepine-8-methanol (described in Example B15b) (0.0032 mol) in thionyl chloride (40 ml) was stirred at room temperature for 30 min and at 40° C. for 1 hour. The solvent was evaporated till dryness. The product was used without further purification, yielding (quant.) of 8-[chloro(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-6-(3-chlorophenyl)-4H,6H-tetrazolo[1,5-a ][4,1]benzothiazepine.
Reaction SMILES: Cl[C:2]1[C:3]2[S:20][C:19]([NH2:21])=[N:18][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:7]=1.Cl.[NH2:23][CH:24]([CH2:27][O:28][CH3:29])[CH2:25][OH:26]>>[NH2:21][C:19]1[S:20][C:3]2[C:2]([NH:23][CH:24]([CH2:27][O:28][CH3:29])[CH2:25][OH:26])=[N:7][C:6]([S:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=3[F:17])=[N:5][C:4]=2[N:18]=1
Reactant: COCC(N)CO
Reactant: Nc1nc2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Agent: Cl
Product: COCC(CO)Nc1nc(SCc2cccc(F)c2F)nc2nc(N)sc12

Procedure:
Prepared by the method of example 12 step a) using the product of example 4 step b) and the product of example 40 step a).
Reaction SMILES: O[CH:2]([C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].S(Cl)([Cl:16])=O>ClCCl>[Cl:16][CH:2]([C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1cc2ccccc2cn1
Solvent: ClCCl
Product: CC(Cl)c1cc2ccccc2cn1
Temperature: 0 °C
Reaction time: 3 h
Yield: 95.4 %

Procedure:
3-(1-Hydroxyethyl)-isoquinoline (1.32 g, 7.6 mmole) is dissolved in 20 ml dichloromethane in a 100 ml one neck round bottom flask under nitrogen. The solution is cooled to 0° C., is treated dropwise with thionyl chloride (835 μl, 11.4 mmole), and is stirred 3 h at 0° C. followed by 1 h at room temperature. The mixture is recooled to 0° C., is quenched with 50 ml saturated sodium bicarbonate, and the layers are separated. The aqueous layer is extracted with 3×25 ml dichloromethane and the combined organics are dried over potassium carbonate. The dried organics are concentrated in vacuo to a pale amber oil. The crude material is chromatographed over 60 g silica gel (230-400 mesh), eluting with 20% acetone/hexane, while collecting 9 ml fractions. Fractions 17-26 are combined and concentrated to afford 1.39 g (95%) of 3-(1-chloroethyl)-isoquinoline as a yellow oil.
Reaction SMILES: C(OC([N:11]1[CH2:25][CH:24]([O:26][CH2:27][O:28][CH3:29])[CH2:23][C@H:12]1[C:13]([NH:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:14])=O)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:29][O:28][CH2:27][O:26][CH:24]1[CH2:25][NH:11][C@H:12]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:14])[CH2:23]1
Reactant: COCOC1C[C@@H](C(=O)NCC2CCCCC2)N(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: COCOC1CN[C@H](C(=O)NCC2CCCCC2)C1
Reaction time: 3 h
Yield: 105.2 %

Procedure:
21.2 g of the obtained N-(1-benzyloxycarbonyl-4-methoxymethoxy-L-prolyl)-N-cyclohexylmethylamine was dissolved in 200 ml of ethanol. To the solution was added 2 g of 10% Pd-C. The mixture was subjected to hydrogenation for 3 hours. The catalyst was removed by filtration. The solvent in the filtrate was removed by distillation to obtain 14.9 g of N-(4-methoxymethoxy-L-prolyl)-N-cyclohexylmethylamine.
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[NH:21][CH2:20][CH2:19]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:21]2[C:22]3[C:18](=[CH:17][C:16]([Cl:15])=[CH:24][C:23]=3[Cl:25])[CH2:19][CH2:20]2)[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=1
Reactant: CCC(CC)n1cc(Cl)nc(Cl)c1=O
Reactant: Clc1cc(Cl)c2c(c1)CCN2
Product: CCC(CC)n1cc(Cl)nc(N2CCc3cc(Cl)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-(1-ethylpropyl)-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 168–170° C.; 1H NMR (300 MHz, CDCl3): δ 7.18 (d, J=1.8 Hz, 1 H), 7.11 (d, J=2.2 Hz, 1 H), 6.78 (s, 1 H), 4.82–4.78 (m, 1 H), 4.35 (t, J=7.9 Hz, 2 H), 3.14 (t, J=8.1 Hz, 2 H), 1.88–1.74 (m, 2 H), 1.70–1.60 (m, 2 H), 0.88 (t, J=7.5 Hz, 6 H); HRMS (ESI) calcd for C17H19N3OCl3 (M+H)+: 386.0594; found m/z 386.0614.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([N:12]([CH3:18])[CH2:13][CH2:14][C:15](O)=O)=[O:11].C(OC(=O)C)(=[O:21])C>>[CH3:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:15][CH2:14][C:13](=[O:21])[N:12]([CH3:18])[C:10]1=[O:11]
Reactant: Cc1cc(Cl)ccc1NC(=O)N(C)CCC(=O)O
Reactant: CC(=O)OC(C)=O
Product: Cc1cc(Cl)ccc1N1CCC(=O)N(C)C1=O
Yield: 24.1 %

Procedure:
At first, 8.0 g (0.03 moles) of N-(2-methyl-4-chlorophenylcarbamoyl)-N-methyl-β-alanine was added to 250 ml of acetic anhydride, and the mixture was refluxed with heating for 2.5 hours. Acetic anhydride was removed therefrom by distillation under reduced pressure, and precipitated crystals were recrystallized from 60 ml of ethyl acetate and 150 ml of n-hexane, whereby 1.8 g of the desired compound was obtained as crystals having a melting point of 120° to 127° C. (yield: 24.1%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9][CH:8]=1)=[O:5].[C:18]([C:20]1[CH:33]=[CH:32][C:23]([CH2:24][N:25]2[C:29]([CH:30]=O)=[CH:28][N:27]=[CH:26]2)=[CH:22][C:21]=1[F:34])#[N:19].C(N(CC)C(C)C)(C)C.[BH3-]C#N.[Na+]>CO.CC(O)=O>[C:18]([C:20]1[CH:33]=[CH:32][C:23]([CH2:24][N:25]2[C:29]([CH2:30][NH:2][CH2:3][C:4]([NH:6][C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=4)[CH:10]=[CH:9][CH:8]=3)=[O:5])=[CH:28][N:27]=[CH:26]2)=[CH:22][C:21]=1[F:34])#[N:19]
Reactant: NCC(=O)Nc1cccc2ccc(O)cc12
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1F
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: N#Cc1ccc(Cn2cncc2CNCC(=O)Nc2cccc3ccc(O)cc23)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Amino-N-(7-hydroxynaphthalen-1yl)acetamide hydrochloride, as described above in Step M, (90 mg, 0.36 mmol) and 1-(4-cyano-3-fluorobenzyl)-5-imidazolecarboxaldehyde, as described above in Step G, (82 mg, 0.36 mmol), were stirred in MeOH (2 mL) and was neutralized with N,N-diisopropylethylamine. Acetic acid was then added dropwise to adjust the mixture to ca. pH 5, as judged by wetted pH paper. The mixture was stirred for 1 hr at ambient temperature, then NaCNBH3 (25 mg, 0.40 mmol) was added, the solution was readjusted to ca. pH 5 by addition of AcOH, and stirring was continued for 18 hrs. The reaction was quenched with saturated aqueous Na2CO3 (2 mL) and most of the MeOH was removed under reduced pressure. The residual solution was partitioned between saturated aqueous Na2CO3 (10 mL) and CH2Cl2 (20 mL). The aqueous layer was extracted further with CH2Cl2 (3×20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of 1% to 6% MeOH-0.1% to 0.6% NH4OH—CH2Cl2 to yield the titled product.