Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:19][N:18]([C:28]3[CH2:32][CH2:31][C:30](=[O:33])[CH:29]=3)[CH2:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Br:36]Br>C(Cl)Cl.O>[F:10][C:9]([F:11])([F:12])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:20]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH2:19][N:18]([C:28]3[CH2:32][CH2:31][C:30](=[O:33])[C:29]=3[Br:36])[CH2:17]2)[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:8]=1
Reactant: C[C@@H](O[C@H]1CN(C2=CC(=O)CC2)C[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: BrBr
Solvent: O
Solvent: ClCCl
Product: C[C@@H](O[C@H]1CN(C2=C(Br)C(=O)CC2)C[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In a round bottomed flask, 150 mg (0.299 mmol) 3-[(3R,4S)-3-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-4-(4-fluorophenyl)pyrrolidin-1-yl]cyclopent-2-en-1-one (Example 3, step F) was dissolved in methylene chloride (5 mL) under nitrogen atmosphere and cooled to 0° C. To this solution was added a solution of 300 mg (1.877 mmol) bromine in methylene chloride (5 mL). The resulting solution was stirred for 0.25 hr at 0° C. then was quenched by the addition of sat. aq. Na2SO3 until a clear solution resulted. The mixture was diluted with 5 mL water then extracted with methylene chloride (3×5 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and the solvent removed under vacuum. The resulting oil was purified by prep TLC on silica gel eluting with methylene chloride/methanol (95/5) to afford the title compound and a small amount of the less polar 2,2-dibromo compound. Monobromide, 1H-NMR (CD3OD): δ: 1.44 (d, 3H), 2.48 (br. s, 2H), 2.87 (m, 2H), 3.43 (m, 1H), 3.66 (m, 1H), 4.0-4.22 (m, 2H), 4.70-4.83 (m, 2H), 6.98 (t, 2H), 7.18 (dd, 2H), 7.70 (s, 2H), 7.83 (s, 1H)ppm. MS: 580.0 and 582 (MH+) observed. Dibromide, 1H-NMR (CD3OD): δ: 1.46 (d, 3H), 2.82 (d, 1H), 3.24 (dd, 1H), 3.38-4.85 (m, 7H), 5.35, 5.36 (2s, 1H), 7.00 (m, 2H), 7.20 (m, 2H), 7.67-7.87 (m, 3H)ppm. MS: 657.9, 659.9 and 661.9 (MH+) observed.
Reaction SMILES: [C:1]1([CH:7]([NH:9][C:10](=[O:12])[CH3:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][O:14]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH:13]([C:4]1[CH:5]=[CH:6][C:1]([CH:7]([NH:9][C:10](=[O:12])[CH3:11])[CH3:8])=[CH:2][CH:3]=1)=[O:14]
Reactant: COC(Cl)Cl
Reactant: CC(=O)NC(C)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)NC(C)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of N-(1-phenylethyl)acetamide (5.0 g) in dichloromethane (100 ml) was added dropwise titanium tetrachloride (16.7 ml) at below 5° C. over 30 min. Thereto was added dropwise a solution of dichloromethyl methyl ether (14.1 ml) in dichloromethane (30 ml) solution at below 5° C. over 30 min. The mixture was stirred at 25° C. for 3 hr, at room temperature for 12 hr, and then at 25° C. for 3 hr, and poured into ice water (800 ml) and extracted with ethyl acetate. The extract was washed successively with a saturated sodium hydrogencarbonate solution (500 ml) and saturated brine (500 ml), and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (elution solvent; hexane:ethyl acetate=1:3) to give the title compound (0.35 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH2:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1.Cl.O([NH2:18])C.N1C=CC=CC=1>CO.Cl.[Pd]>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([NH2:18])[CH2:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: CON
Reactant: CC1(C)CC(=O)c2ccc(F)cc2O1
Agent: [Pd]
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CC1(C)CC(N)c2ccc(F)cc2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 65A (415 mg, 2.14 mmol) in methanol (12 mL) was added methoxylamine hydrochloride (0.179 g, 2.14 mmol) and pyridine (0.87 mL, 10.8 mmol). The mixture was stirred overnight at room temperature and was then evaporated in vacuo. The residue was partitioned between ethyl acetate and H2O, and the organic layer was dried over Na2SO4 and was evaporated in vacuo. The residue thus obtained was dissolved in methanol (8 mL) and was hydrogenated (balloon) over 10% Pd-C in the presence of 4 drops of concentrated HCl overnight at room temperature. The catalyst was filtered off (Celite), and the filtrate was evaporated in vacuo. The residue was taken up in ether (20 mL) and was extracted with 1N HCl (3×10 mL). These acidic extracts were then basified to pH 10 with 2N NaOH and were extracted with ethyl acetate (3×10 mL). Drying over Na2SO4, followed by evaporation in vacuo, yielded Example 65B, 158 mg (48%). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.56 (m, 1H), 6.66 (m, 1H), 6.48 (m, 1H), 3.81 (m, 1H), 2.02 (m, 2H), 1.35 (s, 3H), 1.20 (s, 3H). MS (ESI) m/z 196 (M+H).
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][S:14]([O-:17])(=O)=[O:15])=[CH:8][CH:7]=1.[Na+].C1C=CC=CC=1>CN(C)C=O>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][S:14]([Cl:3])(=[O:17])=[O:15])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)([O-])CCc1ccc(Br)cc1
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)CCc1ccc(Br)cc1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
Thionyl chloride (1.51 mL, 20.8 mmol) was added dropwise at 0° C. to a suspension of sodium 2-(4-bromo-phenyl)-ethanesulfonate (4.33 g, 15.08 mmol) in a mixture of anhydrous benzene (50 mL) and N,N-dimethylformamide (1 mL). The reaction mixture was allowed to warm to room temperature and was then heated at 80° C. for 18 hours. The reaction mixture was cooled to room temperature and filtered through a pad of Celite. The solids were washed with benzene and the combined filtrates were concentrated in vacuo. The residue was taken up in hexane (30 mL) and the resulting suspension was heated at 50° C. for 30 min. After cooling to room temperature, the formed precipitate was collected by filtration to give 4.06 g (95% yield) of the title compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][C:16]#[CH:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])CCC.[CH3:23][O:24][CH2:25][O:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31](=[O:48])[C:32]([C:38]3[CH:43]=[CH:42][C:41]([O:44][CH2:45][O:46][CH3:47])=[CH:40][CH:39]=3)([CH3:37])[CH2:33][S:34]2)=[CH:29][CH:28]=1.[Cl-].[NH4+]>O1CCCC1>[Si:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][C:16]#[C:17][C:31]1([OH:48])[C:30]2[C:35](=[CH:36][C:27]([O:26][CH2:25][O:24][CH3:23])=[CH:28][CH:29]=2)[S:34][CH2:33][C:32]1([C:38]1[CH:39]=[CH:40][C:41]([O:44][CH2:45][O:46][CH3:47])=[CH:42][CH:43]=1)[CH3:37])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: C#CCOCCOCCO[Si](C)(C)C(C)(C)C
Reactant: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2=O)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2(O)C#CCOCCOCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
To a solution of 9-(t-butyldimethylsilyloxy)-4,7-dioxa-1-nonyne (1.03 g, 4.01 mmol) in dry tetrahydrofuran (10 ml) was added dropwise -n-butyl lithium (2.3 ml, 3.74 mmol, 1.63 mole/l in tetrahydrofuran) at −78° C., which was then stirred at −20° C. for 1 hour. Then, to this reaction mixture was added 7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methylthiochroman-4-one (1.0 g, 2.67 mmol) dissolved in tetrahydrofuran (10 ml) at the same temperature for 30 min, and the resulting mixture was stirred at −10° C. (for 24 hours. After the reaction was completed, saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (n-hexane:ethyl acetate=4:1) to give the title compound (1.15 g, yield: 68%) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([F:12])[CH:11]=1)[C:6](O)=[O:7])#[N:2].S(Cl)([Cl:15])=O>>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([F:12])[CH:11]=1)[C:6]([Cl:15])=[O:7])#[N:2]
Reactant: N#Cc1cc(F)cc(C(=O)O)c1
Reactant: O=S(Cl)Cl
Product: N#Cc1cc(F)cc(C(=O)Cl)c1

Procedure:
1.65 g (10.0 mmol) 3-cyano-5-fluorobenzoic acid were boiled for 2 h with 7.27 mL (100 mmol) thionyl chloride with stirring. The reaction mixture was evaporated to dryness i. vac. and coevaporated twice with toluene. The residue was reacted further as the crude product.
Reaction SMILES: [CH2:1]([N:3]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[N+:20]([O-])=O)[C:4](=[O:11])[CH2:5][C:6](OCC)=[O:7])[CH3:2].[O-]CC.[Na+]>[C].[Pd].C(O)C>[CH2:1]([N:3]1[C:4](=[O:11])[CH2:5][C:6](=[O:7])[NH:20][C:13]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:12]1=2)[CH3:2]
Reactant: CCOC(=O)CC(=O)N(CC)c1cc(OC)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCN1C(=O)CC(=O)Nc2ccc(OC)cc21
Temperature: 25 °C
Yield: 49.7 %

Procedure:
Palladium carbon (10%, 1.1 g) was added to an ethanol solution (250 ml) of ethyl N-ethyl-N-(5-methoxy-2-nitrophenyl)malonamate (21.05 g, 67.8 mmol), and cooled in an ice water bath. Catalytic reduction was conducted at about room temperature. Celite filtration was conducted to remove the catalyst, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (THF) (200 ml). Sodium ethoxide (6.9 g, 102 mmol) was added thereto, and then heating was conducted under reflux for 15 minutes. The reaction mixture was cooled to room temperature, and the precipitated insoluble matter was collected by filtration. The filtrate was concentrated under reduced pressure. Water was added to the residue and the collected insoluble matter, and the mixture was neutralized with hydrochloric acid. Extraction with ethyl acetate was then performed. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethanol to thereby obtain 7.9 g (yield: 50%) of 1-ethyl-8-methoxy-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione as a white powder. The mother liquor was then concentrated, and the residue was purified using a silica gel flash column (n-hexane:ethyl acetate=1:1→0:1) to thereby obtain 2.9 g of object compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]3[CH:31]=[N:32][C:33]([C:40]([OH:43])([CH3:42])[CH3:41])=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=3)=[O:28])=[C:22]([F:44])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10]CC1C=CC(OC)=CC=1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4]1[C:9](=[O:10])[NH:8][CH:7]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]3[CH:31]=[N:32][C:33]([C:40]([OH:43])([CH3:41])[CH3:42])=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:35]=3)=[O:28])=[C:22]([F:44])[CH:21]=2)[CH:5]=1)[CH3:2]
Reactant: CCOc1cc(-c2ccc(CC(=O)Nc3cnc(C(C)(C)O)c(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Agent: [Pd]
Solvent: CO
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cnc(C(C)(C)O)c(C(F)(F)F)c3)c(F)c2)c[nH]c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 9.6 %

Procedure:
To a mixture of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(6-(2-hydroxypropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide (70 mg, 0.114 mmol) in MeOH (10 mL) was added Pd/C (7 mg, 0.066 mmol). The mixture was stirred under a H2 atmosphere at 25° C. for 16 h. Then the reaction residue was filtered and concentrated. The crude material was purified by preparative HPLC (MeCN/H2O as eluants, basic condition) to yield a white solid of 2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(6-(2-hydroxypropan-2-yl)-5-(trifluoromethyl)pyridine-3-yl)acetamide (5.71 mg, 0.011 mmol, 10.9% yield): 1H NMR (400 MHz, CD3OD) δ 8.90 (s, 1H), 8.48 (s, 1H), 7.48-7.43 (m, 1H), 7.40-7.32 (m, 3H), 7.26 (d, J 2.01 Hz, 1H), 4.15 (m, 2H), 3.86 (s, 2H), 1.62 (s, 6H), 1.49 (t, J=7.03 Hz, 3H); ES-LCMS m/z 494.2 (M+H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[CH2:10][CH:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])O[N:7]=1.C[OH:20]>O=[Pt]=O>[C:14]([O:13][C:11](=[O:12])[CH2:9][CH2:10][CH:6]1[CH2:5][CH:4]([OH:20])[C:3](=[O:2])[NH:7]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)CCC1=NOC(C(=O)OC(C)(C)C)C1
Reactant: CO
Agent: O=[Pt]=O
Product: CC(C)(C)OC(=O)CCC1CC(O)C(=O)N1

Procedure:
A suspension of 40 g of 4,5-dihydro-5-t-butoxycarbonyl-3-isoxazole-propanoic acid methyl ester and 2.0 g of PtO2 /C in 400 ml of methanol is placed under a hydrogen atmosphere with agitation. After H2 absorption is complete, the solution is filtered and the solvent removed under reduced pressure to give an oil. The oil is triturated with anhydrous diethyl ether to yield 4-hydroxy-5-oxo-2-pyrrolidinepropanoic acid t-butyl ester as a white solid with mp 94°-95° C. NMR (CDCl3) and 6.83 (s, 1H, 4.42 (m, 1H), 3.93 (s, 1H), 3.70 (m, 1H), 2.78-1.66 (m, 6H), 1.47 (s, 9H). IR (KBr) 3320, 2980, 1732, 1705, 1456, 1417, 1353, 1368, 1295, 1260, 1214.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[C:8](=O)([O-])[NH2:9].Cl[CH2:13][CH2:14]Cl>>[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[NH:9]1[CH2:8][CH2:14][CH2:13][CH2:1]1
Reactant: ClCCCl
Reactant: NC(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: C1CCNC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
TFA (250 μL, 3.24 mmol) was added to a solution of carbamate J5a in DCE (1 mL) and the reaction was stirred at rt for 1.5 hr. The reaction was concentrated under a stream of nitrogen to provide a TFA salt of pyrrolidine J5b (45 mg). LC-MS retention time 2.928 min; m/z 525.32 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([C@@H:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:30][CH2:31][CH2:32][C:33](Cl)=[O:34]>C1COCC1.C(OCC)(=O)C>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:33](=[O:34])[CH2:32][CH2:31][Cl:30])[CH2:25]3)[N:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)[C:22]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2[C@@H]1CCCNC1
Reactant: O=C(Cl)CCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2[C@@H]1CCCN(C(=O)CCCl)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
To a solution of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (6) (0.40 g, 1.04 mmol) and TEA (0.29 mL, 2.08 mmol) in THF (15 mL) cooled to 0° C. was added 3-chloropropanoyl chloride (0.132 g, 2.08 mmol). After stirring 1 hr at 0° C., the reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL). The organic layer was dried (MgSO4), filtered and concentrated to collect 0.49 g of a white solid. The white solid was subjected to flash chromatography (5% MeOH/EtOAc) to provide 0.31 g (62%) of (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-3-chloropropan-1-one (9) as a white solid. 1H NMR (300 MHz, DMSO) δ 8.25 (s, 1H), 7.64 (d, 2H, J=8.5 Hz), 7.40 (m, 2H), 7.20-7.00 (m, 7H), 4.60 (m, 1H), 4.12-3.10 (m, 6H), 2.94-1.60 (m, 6H).
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]1[C:9]2[S:10][CH:11]=[C:12]([CH3:13])[C:8]=2[S:7](=[O:15])(=[O:14])[N:6]=[CH:5]1.Cl>C(O)(C)C.O>[CH3:3][N:4]1[C:9]2[S:10][CH:11]=[C:12]([CH3:13])[C:8]=2[S:7](=[O:15])(=[O:14])[NH:6][CH2:5]1
Reactant: Cc1csc2c1S(=O)(=O)N=CN2C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Cc1csc2c1S(=O)(=O)NCN2C
Temperature: 50 °C

Procedure:
240 mg of sodium borohydride are added to 120 mg of the compound obtained in Step B above dissolved in 6 ml of isopropanol. The mixture is heated at 50° C. for 10 minutes. The solvent is removed under reduced pressure, then the residue that is obtained is taken up in 5 ml of water. The pH of the solution is adjusted to 4 by addition of 6N hydrochloric acid. The precipitate is collected by filtration, washed with water and dried.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[CH2:7][CH2:8][Br:9])([O-])=O>>[NH2:2][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[CH2:7][CH2:8][Br:9]
Reactant: O=[N+]([O-])c1ccccc1CCBr
Agent: Cl
Product: Nc1ccccc1CCBr

Procedure:
Stannous chloride and conc. hydrochloric acid are added to 2-nitrophenethyl bromide to obtain 2-aminophenethyl bromide and a cyclization of 2-aminophenethyl bromide is carried out to obtain the indolines (J. of the American Chemical Society Vol. 63, page 1563 (1941)).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]([C:15]2([C:18]3[CH:28]=[CH:27][C:21]4[O:22][C:23]([F:26])([F:25])[O:24][C:20]=4[CH:19]=3)[CH2:17][CH2:16]2)=[O:14])[N:3]=1.[CH3:29][O:30][C:31]1[N:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC>[F:25][C:23]1([F:26])[O:22][C:21]2[CH:27]=[CH:28][C:18]([C:15]3([C:13]([NH:12][C:4]4[N:3]=[C:2]([C:34]5[CH:35]=[N:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=5)[C:11]5[C:6]([CH:5]=4)=[CH:7][CH:8]=[CH:9][CH:10]=5)=[O:14])[CH2:17][CH2:16]3)=[CH:19][C:20]=2[O:24]1
Reactant: COc1ccc(B(O)O)cn1
Reactant: O=C(Nc1cc2ccccc2c(Br)n1)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc3ccccc23)cn1
Temperature: 120 °C
Yield: 71.5 %

Procedure:
N-(1-Bromoisoquinolin-3-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (268 mg, 0.600 mmol) was dissolved in 6 mL of 1,2-dimethoxyethane (DME) in a microwave reactor tube. 6-Methoxypyridin-3-ylboronic acid (119 mg, 0.780 mmol), 0.6 mL of an aqueous 2 M potassium carbonate solution, and tetrakis(triphenylphospine)palladium(0) (Pd(PPh3)4, 34.7 mg, 0.0300 mmol) were added and the reaction mixture was heated at 120° C. in a microwave reactor for 20 minutes. The resulting material was cooled to room temperature, filtered, and the layers were separated. The crude product was evaporated to dryness and then purified on silica gel utilizing a gradient of 0-50% ethyl acetate in hexanes to yield 1-(2,2-difluorobenzo-[d][1,3]dioxol-5-yl)-N-(1-(6-methoxypyridin-3-yl)isoquinolin-3-yl)cyclopropane-carboxamide (204 mg, 71%). ESI-MS m/z calc. 475.1. found; 476.3 (M+1)+ Retention time 2.31 minutes.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][NH:6][N:5]=[CH:4]1)[CH3:2].[CH2:8]([N:10]=[C:11]=[S:12])[CH3:9]>C(O)C>[CH2:8]([NH:10][C:11]([N:5]1[CH2:4][CH:3]([CH2:1][CH3:2])[CH:7]=[N:6]1)=[S:12])[CH3:9]
Reactant: CCN=C=S
Reactant: CCC1C=NNC1
Solvent: CCO
Product: CCNC(=S)N1CC(CC)C=N1
Yield: 1 %

Procedure:
2.68 g (1 mol equiv.) 4-Ethyl-4,5-dihydro-1H-pyrazole (synthesized as described in WO 2008/034863) and 3.11 mL (1.3 mol equiv.) ethyl isothiocyanate were added to 20 mL ethanol. The reaction mixture was refluxed overnight, silica gel was added and volatiles were removed under reduced pressure. Purification by flash chromatography on silica gel (Et2O:PA=1:3) afforded 1.80 g (36%) 4-ethyl-4,5-dihydro-pyrazole-1-carbothioic acid ethylamide. 1H NMR (400 MHz, CDCl3) δ 0.99 (t, J=7.5 Hz, 3H), 1.25 (t, J=7.2 Hz, 3H), 1.47-1.71 (m, 2H), 3.08-3.18 (m, 1H), 3.63-3.72 (m, 2H), 3.86 (dd, J=11.5, 7.1 Hz, 1H), 4.25 (t, J=11.5 Hz, 1H), 6.90 (d, J=1.5 Hz, 1H), 7.12 (br.s., 1H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=O)[N:11]=2)=[CH:6][C:3]=1[C:4]#[N:5].[NH2:18][C@@H:19]([CH2:23][OH:24])[CH:20]([CH3:22])[CH3:21].C(O)(=O)C.C([BH3-])#N>CO>[F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH:18][C@H:19]([CH:20]([CH3:22])[CH3:21])[CH2:23][OH:24])[N:11]=2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC(C)[C@@H](N)CO
Reactant: N#Cc1cc(-c2cccc(C=O)n2)ccc1F
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)[C@H](CO)NCc1cccc(-c2ccc(F)c(C#N)c2)n1
Reaction time: 2 h
Yield: 52.5 %

Procedure:
To a solution of 6-bromopicolinaldehyde (1.00 g, 5.38 mmol) in dioxane (30 mL) at ambient temperature was added 3-cyano-4-fluorophenylboronic acid (0.887 g, 5.38 mmol), 2M cesium carbonate (8.1 mL, 16.2 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.220 g, 0.269 mmol). The mixture was degassed (3× vacuum/purge N2), then heated at 80° C. overnight. The mixture was cooled, concentrated and partitioned between water and CH2Cl2. The organic layer was concentrated and purified by chromatography (30% ethyl acetate:hexanes) to provide 2-fluoro-5-(6-formylpyridin-2-yl)benzonitrile. To a solution of 2-fluoro-5-(6-formylpyridin-2-yl)benzonitrile (0.500 g, 2.21 mmol) in methanol (20 mL) at ambient temperature was added D-valinol (0.25 mL, 2.2 mmol), acetic acid (0.50 mL, 8.8 mmol) followed by MP-cyanoborohydride (2.49 mmol/g; 1.0 g). After 2 hours, the mixture was filtered, concentrated, and the residue partitioned between ether and 1M NaOH. The organic layer was concentrated and purified by chromatography to provide 362 mg (52%) of the title compound. MS (DCI+) m/z 314 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 8.62 (dd, J=6.3, 2.3 Hz, 1H), 8.52 (ddd, J=8.9, 5.3, 2.4 Hz, 1H), 7.97-7.84 (m, 2H), 7.66 (t, J=9.0 Hz, 1H), 7.49 (dd, J=7.4, 1.1 Hz, 1H), 3.92 (d, J=3.6 Hz, 2H), 3.52-3.43 (m, 1H), 2.40-2.22 (m, 2H), 1.93-1.76 (m, 1H), 0.89 (dd, J=9.5, 6.9 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].P(Cl)(Cl)(Cl)(Cl)Cl.CC1C([N+]([O-])=O)=C(C=CC=1)C(Cl)=O.O.[NH2:34][C:35]1[NH:39][N:38]=[N:37][N:36]=1>C1CCCCC1.O1CCCC1.O.C(Cl)Cl>[CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:34][C:35]1[NH:39][N:38]=[N:37][N:36]=1)=[O:6]
Reactant: Nc1nnn[nH]1
Reactant: Cc1cccc(C(=O)O)c1[N+](=O)[O-]
Agent: Cc1cccc(C(=O)Cl)c1[N+](=O)[O-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Solvent: C1CCCCC1
Product: Cc1cccc(C(=O)Nc2nnn[nH]2)c1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
The reaction of 50 g of 3-methyl-2-nitrobenzoic acid and 57.5 g of phosphorus pentachloride in 300 ml of cyclohexane gave, after treatment of the crude product with methylene chloride, 3-methyl-2-nitrobenzoyl chloride melting at about 81°-82° C. A solution of 53.1 g of this acid chloride and 50 ml of tetrahydrofuran was added to a warm solution of 55 g of 5-aminotetrazole monohydrate in 500 ml of tetrahydrofuran and 20 ml of water. The reaction was exothermic, a white precipitate formed and the mixture was allowed to stand for 4 hours. It was then diluted with water, the white precipitate was separated by filtration, washed with water and air dried to give 3-methyl-2-nitro-N-(1H-tetrazol-5-yl)benzamide melting at about 262°-263° C., with decomposition, after recrystallization from a mixture of dimethylformamide and water.