Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:41])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][CH:30]=[C:31]([O:32][C:33]([C:36](OCC)=[O:37])([CH3:35])[CH3:34])[C:19]=4[CH2:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:41])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][CH:30]=[C:31]([O:32][C:33]([CH3:34])([CH3:35])[CH2:36][OH:37])[C:19]=4[CH2:18]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Oc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(CO)Oc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Yield: 94.9 %

Procedure:
To a solution of product of example 138 (500 mg) in methanol (5 ml) was added sodium borohydride (330 mg), and the mixture was heated to reflux for 1 hour. The mixture was distilled off under reduced pressure. Water and ethyl acetate were added to the residue, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography eluting with chloroform-methanol (10:1) to give the titled compound (440 mg).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Br:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](OC)=[O:17])=[CH:12][CH:11]=1>C1COCC1>[Br:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(CCBr)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(CCBr)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 90.7 %

Procedure:
To a suspension of LiAlH4 (4.5 mmol; 0.172 g) in anhydrous THF (5.0 ml) cooled to 0° C. was added dropwise a solution of methyl 4-(2-bromoethyl)benzenecarboxylate (1.0 g; 4.1 mmol) in anhydrous THF (10.0 ml). The reaction mixture was stirred for 5 minutes at room temperature and, after adding ice, was filtered through a Büchner filter. The solvent was removed under reduced pressure and the residue was extracted with ethyl acetate (3×100 ml). The combined organic phases were washed with saturated NaCl solution, dried over sodium sulfate and evaporated under reduced pressure. 800 mg (82.6%) of pure product were thus obtained as an oil.
Reaction SMILES: [OH:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH:7]([CH3:20])[C:6]=2[NH:5][C:4](=[O:21])[CH:3]=1>CCOCC>[OH:1][C:2]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][CH:7]([CH3:20])[C:6]=2[NH:5][C:4](=[O:21])[CH:3]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCc2c(O)cc(=O)[nH]c21
Solvent: CCOCC
Product: CC1CNCCc2c(O)cc(=O)[nH]c21
Temperature: 25 °C
Reaction time: 10 h
Yield: 109 %

Procedure:
HCI (2 N in Et2O, 5 ml) was added dropwise to a stirred solution of tert-butyl 4-hydroxy-9-methyl-2-oxo-1,2,5,6,8,9-hexahydro-7H-pyrido[2,3-d]azepine-7-carboxylate (250 mg, 850 μmol). After 10 h of stirring at room temperature, the reaction was quenched with sat. aq. NaHCO3 and extracted with DCM. The organic layer was dried and concentrated in vacuo to provide 180 mg (92%) of 4-hydroxy-9-methyl-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one. 1H-NMR (DMSO-d6) δ 13.20 (br s, 2H), 12.93 (br s, 2H), 10.02 (br s, 1H), 9.41 (br s, 1H), 6.65 (s, 1H), 3.51 (br s, 1H), 3.32 (m, 2H), 3.15 (m, 2H), 2.95 (m, 1 H), 2.85 (m, 1 H), 1.39 (d, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].Cl.[NH2:13][C@@H:14]([C:19]([NH2:21])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17].CCN(C(C)C)C(C)C.O>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[C:3]([C:4]#[N:5])=[CH:6][C:7]([F:11])=[C:8]([NH:13][C@H:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:19]([NH2:21])=[O:20])[CH:9]=1
Reactant: N#Cc1cc(F)c(F)cc1Br
Reactant: CC(C)C[C@@H](N)C(N)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](Nc1cc(Br)c(C#N)cc1F)C(N)=O
Yield: 53.3 %

Procedure:
A solution of 2-bromo-4,5-difluorobenzonitrile (218 mg, 1.00 mmol), D-leucine amide hydrochloride (185 mg, 1.10 mmol) and DIEA (0.600 mL, 3.45 mmol) in DMSO (3 mL) was stirred at 120 C for 18 h. Water and EtOAc were added. The organic phase was separated, washed with water, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column, eluted with 0-50% EtOAc in hexane to give (R)-2-(5-bromo-4-cyano-2-fluorophenylamino)-4-methylpentanamide (175 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][C@@H:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:4][CH:3]=1.[F-].[Cs+].O1[CH2:24][CH2:23]OCC1>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:4][C:5]1[C:23]2[C:24](=[CH:10][CH:9]=[C:14]([C:2]3[N:7]=[N:6][C:5]([O:8][C@@H:9]4[CH:14]5[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]5)[CH2:10]4)=[CH:4][CH:3]=3)[CH:13]=2)[NH:7][N:6]=1
Reactant: Clc1ccc(O[C@H]2CN3CCC2CC3)nn1
Reactant: C1COCCO1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cs+]
Solvent: CCOC(C)=O
Product: Cc1n[nH]c2ccc(-c3ccc(O[C@H]4CN5CCC4CC5)nn3)cc12

Procedure:
The product of Example 9A (120 mg, 0.5 mmol) was coupled with the product of Example 20A (278 mg, 0.7 mmol) under the catalysis of by Pd2(dba)3 (Aldrich, 24 mg, 0.025 mmol) and (tBu3P)2 Pd (Strem Chemicals, 26 mg, 0.05 mmol) with CsF (Strem Chemicals, 152 mg, 1 mmol) in dioxane (10 ml) at 80° C. under N2 for 16 hours. After the reaction went to completion, it was diluted with EtOAc (50 mL) and washed with brine (2×10 mL). The organic solution was concentrated under vacuum and the residue was treated with TFA (1 mL) in CH2Cl2 (5 mL) at ambient temperature for 2 hours. It was then concentrated. The title product was purified by preparative HPLC (Xterra™, column, Xterra RP-18 5 μm, 30×100 mm. Eluting Solvent, MeCN/H2O (NH4HCO3, 0.1 M, pH=10) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (68 mg, 41%). 1H NMR (MeOH-D4, 300 MHz) 1.50-1.66 (m, 1H) 1.70-1.94 (m, 2H) 2.01-2.15 (m, 1H) 2.29-2.37 (m, 1H) 2.62 (s, 3H) 2.81-3.04 (m, 5H) 3.44-3.56 (m, 1H) 5.28-5.36 (m, 1H) 7.28 (d, J=9.2 Hz, 1H) 7.59 (d, J=8.8 Hz, 1H) 8.05 (dd, J=8.8, 1.4 Hz, 1H) 8.16 (d, J=9.2 Hz, 1H) 8.31 (s, 1H) ppm. MS (DCI/NH3) m/z 336 (M+H)+.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O>CC(O)=O>[CH3:24][O:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH:15]=[C:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][C:5]2[C:14]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: COc1cccc(C(O)C2c3ccccc3Cc3ccccc32)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1cccc(C=C2c3ccccc3Cc3ccccc32)c1
Temperature: 0 °C
Yield: 123.7 %

Procedure:
Add 4. 1 g (13 mmol) of (9,10-dihydro-anthracen-9-yl)-(3-methoxy-phenyl)-methanol to HOAc (75 mL) containing sulfuric acid (2 mL). Reflux for 2 h and pour into 1.2L ice water. Extract the product into EtOAc and wash with dilute NaOH. Dry (MgSO4) the organic solution, and concentrate to give 4.8 g dark oil. Purify on the ISCO using EtOAc/hexane to give 1.12 g (29%) title compound as a colorless oil. HPLC shows >95% purity. 1H NMR (CDCl3) δ3.87 (s, 2H), 3.92 (s, 3H), 6.89-7.47 (m, 13H); MS (CI) 298 (M).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Mg].[CH3:15][Si:16]([CH3:25])([CH3:24])[C:17]1[O:21][CH:20]=[C:19]([CH:22]=[O:23])[CH:18]=1>O1CCCC1>[OH:23][CH:22]([C:19]1[CH:18]=[C:17]([Si:16]([CH3:25])([CH3:24])[CH3:15])[O:21][CH:20]=1)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH3:2]
Reactant: C[Si](C)(C)c1cc(C=O)co1
Reactant: CCCCCCCCCCCCBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Reaction time: 0.5 h

Procedure:
A mixture of 1-bromododecane (2.97 g, 11.9 mmol) and magnesium turnings (300 mg, 12.5 mmol) in tetrahydrofuran (20 ml) was refluxed under argon for 30 minutes. On cooling, a solution of 5-trimethylsilyl-3-furaldehyde (1g, 5.9 mmol) in tetrahydrofuran (THF) (2 ml) was added. After 30 min., the reaction mixture was quenched with saturated ammonium chloride. Extraction (ethyl ether), drying (magnesium sulfate) and evaporation afforded an oil, which was purified by flash chromatography on silica using 15% ethyl ether/hexane. Fractions with Rf of about 0.25 on evaporation gave the title alcohol as a pale yellow oil, which solified into a colorless solid on storage at -20°.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]2[C:15](=[O:16])[O:14][C:12](=[O:13])[C:9]2=[N:10][CH:11]=1.[NH2:17][C:18]([CH3:25])([CH:22]([CH3:24])[CH3:23])[C:19]([NH2:21])=[O:20]>O1CCCC1>[C:19]([C:18]([NH:17][C:12]([C:9]1[N:10]=[CH:11][C:6]([CH:2]2[O:3][CH2:4][CH2:5][O:1]2)=[CH:7][C:8]=1[C:15]([OH:14])=[O:16])=[O:13])([CH3:25])[CH:22]([CH3:24])[CH3:23])(=[O:20])[NH2:21]
Reactant: O=C1OC(=O)c2ncc(C3OCCO3)cc21
Reactant: CC(C)C(C)(N)C(N)=O
Solvent: C1CCOC1
Product: CC(C)C(C)(NC(=O)c1ncc(C2OCCO2)cc1C(=O)O)C(N)=O
Yield: 128.1 %

Procedure:
A solution of 5-(1,3-dioxolan-2-yl)-2,3-pyridinedicarboxylic anhydride (2.64 g, 0.012 mol) and 2-amino-2,3-dimethylbutyramide (1.55 g, 0.012 mol) in tetrahydrofuran is stirred for 2 days at room temperature. The reaction mixture is concentrated in vacuo to give the title compound as an orange oil (5.4 g, 100%), identified by NMR spectra analysis.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[NH:12][CH:11]=[N:10][C:9]=3[N:8]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[C:6]2=[O:7])[CH2:3][CH2:2]1.[N+:20]([O-])([OH:22])=[O:21]>C(O)(=O)C>[CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[NH:12][C:11]([N+:20]([O-:22])=[O:21])=[N:10][C:9]=3[N:8]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[C:6]2=[O:7])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])O
Reactant: O=c1c2[nH]cnc2n(CC2CC2)c(=O)n1CC1CC1
Solvent: CC(=O)O
Product: O=c1c2[nH]c([N+](=O)[O-])nc2n(CC2CC2)c(=O)n1CC1CC1
Temperature: 5 °C
Reaction time: 1 h
Yield: 52.6 %

Procedure:
1,3-Di-cyclopropylmethyl xanthine (20 g, 0.076 mol) was dissolved in acetic acid (33 ml) and then treated with concentrated nitric acid (13.2 g) at 87° C. After 1 hour, the mixture was cooled to 5° C. and the resulting yellow precipitate filtered off. The yellow crystals were dissolved in dichloromethane and washed with water. The separated organic layer was then dried over anhydrous sodium sulphate and concentrated in vacuo. The product crystallized from the concentrate to yield a yellow crystalline product yield 12.2 g, (56.5%), m.pt. 207° C. (with decomposition).
Reaction SMILES: C([O:5][C:6]([C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:38])[N:12]2[C:17]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[C:27]([F:33])[C:26]=2[F:34])[C:20]([O:35][CH3:36])=[CH:19][C:18]=1[Cl:37])=O)CCC.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Cl:37][C:18]1[CH:19]=[C:20]([O:35][CH3:36])[C:21]([O:23][CH2:24][C:25]2[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[C:27]([F:33])[C:26]=2[F:34])=[CH:22][C:17]=1[N:12]1[C:11](=[O:38])[NH:10][C:9]2[C:13]1=[N:14][CH:15]=[N:16][C:8]=2[CH2:6][OH:5]
Reactant: CCCCOC(=O)c1ncnc2c1[nH]c(=O)n2-c1cc(OCc2c(OC)ccc(F)c2F)c(OC)cc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: COc1cc(Cl)c(-n2c(=O)[nH]c3c(CO)ncnc32)cc1OCc1c(OC)ccc(F)c1F
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
To a solution of 6-(n-butoxycarbonyl)-9-[2-chloro-5-(2,3-difluoro-6-methoxy-benzyloxy)-4-methoxyphenyl]-7,9-dihydro-8H-purin-8-one (0.82 g) in tetrahydrofuran (25 mL) was added diisobutylaluminium hydride (0.93 mol/L n-hexane solution, 4.03 mL) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 3 hours. To the reaction mixture was added 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate) to give the title compound (0.6 g).
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][N:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:7][CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)C.[OH-].[Na+].Cl>CCO.CCOC(C)=O>[CH2:17]([O:16][C:14]([N:6]([CH2:5][C:4]([OH:19])=[O:3])[CH2:7][CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:15])[CH3:18]
Reactant: CCOC(=O)CN(CCc1cccs1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)N(CCc1cccs1)CC(=O)O
Reaction time: 8 h

Procedure:
The crude material from step (a) (165 mmol, ˜47 g) was dissolved in EtOH (700 mL) and treated with 600 mL of 1 M NaOH. After stirring overnight, the reaction was acidified with concentrated HCl to pH-1. The crude reaction was diluted with EtOAc (400 mL) and washed with water. The water was back-extracted with EtOAc. The combined organic extracts were washed with water (2×) and dried over MgSO4. Concentration and evaporation from toluene (2×) gave the sub-title product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.[Cl:11]Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:11])=[N:7][OH:8])=[CH:4][CH:3]=1
Reactant: ON=Cc1ccc(Cl)cc1
Reactant: ClCl
Solvent: ClC(Cl)Cl
Product: ON=C(Cl)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 16.75 g of 4-chlorobenzaldoxime in 155 ml of chloroform was cooled to 5°. Chlorine gas was passed slowly through the solution until no more was absorbed; a blue-green color developed and the temperature slowly increased to 20°. The mixture was stirred for 1 hour at 5°, then heated under reflux for half an hour. The mixture was cooled to room temperature, then the solvent was evaporated under reduced pressure to give a white solid. The solid was collected and dried in a vacuum desiccator in a refrigerator at 5° to give 20.4 g of 4-chlorobenzohydroximoyl chloride, m.p. 81°-85°.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][C:16]=1[CH3:24].O[N:26]=[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][C:36]([F:39])([F:38])[F:37])[NH2:28].CCN(C(C)C)C(C)C>>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:23][N:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][C:36]([F:37])([F:38])[F:39])[N:26]=2)=[CH:17][C:16]=1[CH3:24]
Reactant: NC(=NO)c1ccccc1OC(F)(F)F
Reactant: COc1ccccc1-c1ccc(C(=O)O)cc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc(-c2nc(-c3ccccc3OC(F)(F)F)no2)cc1C

Procedure:
Oxalyl chloride (126 μL; 1.49 mmol; 3 eq.), Intermediate 26 (120 mg; 0.5 mmol; 1 eq.), Intermediate 2 (109 mg; 0.5 mmol, 1 eq.) and DIEA (256 μL; 1.49 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography c-hexane/ethyl acetate, 95/5) afforded the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[N+](C1C=CC([N:26]([C:30]2[S:31][CH:32]=[C:33]([CH3:35])[N:34]=2)[C:27](=O)[O-:28])=CC=1)([O-])=O.CCN(CC)CC.CCOC(C)=O.O>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:27]([NH:26][C:30]3[S:31][CH:32]=[C:33]([CH3:35])[N:34]=3)=[O:28])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: Cc1csc(N(C(=O)[O-])c2ccc([N+](=O)[O-])cc2)n1
Reactant: Fc1ccc2c(c1)N(C1CCNCC1)CC2
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1csc(NC(=O)N2CCC(N3CCc4ccc(F)cc43)CC2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 6-fluoro-1-(piperidin-4-yl)indoline, prepared as in STEP 2 above (128 mg, 0.5 mmol) and 4-nitrophenyl(4-methylthiazol-2-yl)carbamate, prepared as in STEP 3 above (186 mg, 0.4 mmol, ca. 60% purity) in CH2Cl2 (3 mL) was added Et3N (0.28 mL, 2 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 h and was poured into EtOAc/H2O (20 mL/20 mL). The organic layer was dried (Na2SO4) and filtered. The solvent was removed by roto-evaporator and the resulting residue purified by silica gel chromatography using 40% EtOAc/hexane as the eluent to yield 4-(6-fluoroindolin-1-yl)-N-(4-methylthiazol-2-yl)piperidine-1-carboxamide as a white solid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].[OH:12][C:13]1[N:17]=[C:16]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[S:15][N:14]=1>O1CCCC1>[CH3:8][NH:9][C:10]([N:14]1[C:13](=[O:12])[N:17]=[C:16]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[S:15]1)=[O:11]
Reactant: Oc1nsc(OC2CCCCC2)n1
Reactant: CN=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)n1sc(OC2CCCCC2)nc1=O
Temperature: 20 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
1 ml of triethylamine and 6.7 g of methyl isocyanate were added to a solution of 14.01 g of 3-hydroxy-5-cyclohexyloxy-1,2,4-thiadiazole in 150 ml of tetrahydrofuran and the mixture was stirred for 2 hours at 20° C, treated with activated carbon, stirred and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was taken up in isopropyl ether. The mixture was vacuum filtered and the recovered crystals were dried to obtain 13.5 g of 2-(N-methylcarbamoyl)-5-cyclohexyloxy-1,2,4-thiadiazole-3-one melting at 121° C.
Reaction SMILES: [CH:1]([C:3]1[N:8]2[C:9](SCC)=[N:10][CH:11]=[C:7]2[CH:6]=[CH:5][CH:4]=1)=[O:2]>C(O)(C)C.[Ni]>[CH:1]([C:3]1[N:8]2[CH:9]=[N:10][CH:11]=[C:7]2[CH:6]=[CH:5][CH:4]=1)=[O:2]
Reactant: CCSc1ncc2cccc(C=O)n12
Agent: [Ni]
Solvent: CC(C)O
Product: O=Cc1cccc2cncn12

Procedure:
To a solution of 20 g of 5-formyl-3-ethylthioimidazo[1,5-a]pyridine in 200 ml of isopropanol is added approximately 15 g of Raney nickel. The reaction mixture is stirred and heated at reflux temperature for 16 hours. The catalyst is removed by filtration through celite. The filtrate is evaporated under reduced pressure to yield an oily residue. This is purified by column chromatography on silica gel using a mixture of diethyl ether and ethyl acetate (2:1) as eluent. Evaporation of the solvent under reduced pressure yields 5-formylimidazo[1,5-a]pyridine melting at 138°-140°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]2)[CH:5]=[C:4]([C:22]#[N:23])[CH:3]=1.Cl.[NH2:25][OH:26]>CO>[NH2:23][C:22](=[N:25][OH:26])[C:4]1[CH:3]=[C:2]([Cl:1])[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:18])[CH3:19])[CH2:12][CH2:13]2)[CH:5]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc(C#N)cc(Cl)n2)CC1
Reactant: NO
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(c2cc(C(N)=NO)cc(Cl)n2)CC1

Procedure:
TEA (0.24 ml, 1.78 mmol) was added to a solution of tert-butyl 1-(6-chloro-4-cyanopyridin-2-yl)piperidin-4-ylcarbamate (Intermediate 53, 0.4 g, 1.19 mmol) in MeOH (2 ml), followed by the addition of hydroxylamine hydrochloride (0.82 g, 1.19 mmol). The mixture was refluxed for 4 h, then the solvent was removed in vacuo to give the desired product. (410 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]([NH:12]/[N:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1)=[S:11].C(N(CC)CC)C.Cl[CH2:45][C:46](=[O:48])[CH3:47].O>CC(=O)CC>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:46]([CH3:47])([OH:48])[CH2:45][S:11]/[C:10]/1=[N:12]/[N:13]=[CH:14]\[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:35])([F:34])[F:36])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1
Reactant: Fc1cccc(F)c1NC(=S)N/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CC(=O)CCl
Solvent: CCC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(O)CS/C(=N/N=C\c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)N1c1c(F)cccc1F
Temperature: 80 °C
Reaction time: 15 h
Yield: 88.1 %

Procedure:
To a solution of (E)-N-(2,6-difluorophenyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (253 mg, 0.49 mmol) in butanone (4.9 mL) was added triethylamine (0.14 mL, 0.98 mmol) and chloroacetone (0.055 mL, 0.68 mmol), and the reaction was stirred at 80° C. for 15 hours. The mixture was allowed to cool to room temperature, transferred to a separatory funnel containing water (5 mL), and extracted twice with dichloromethane. The organic extracts were filtered through a phase separator, adsorbed onto silica gel, and purified by flash chromatography (0-20% ethyl acetate/B, where B=1:1 dichloromethane/hexanes) to afford the title compound as a yellow solid (248 mg, 88%): mp 105° C. (dec); 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.25-8.12 (m, 3H), 7.88-7.72 (m, 4H), 7.39 (d, J=8.5 Hz, 3H), 7.06 (td, J=8.9, 4.4 Hz, 2H), 3.58 (d, J=11.5 Hz, 1H), 3.37 (d, J=11.5 Hz, 1H), 3.24 (d, J=2.7 Hz, 1H), 1.59 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −58.02, −113.71, −115.83, −115.84; ESIMS m/z 576 (M+H)+.
Reaction SMILES: [CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13](I)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:17])(=[O:6])=[O:5])([CH3:3])[CH3:2].CS(C)=O.C(N(CC)CC)C.[C:29]1([C:35]#[CH:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CC#N.C([O-])(=O)C.[Pd+2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(=O)C.[Cu]I>[CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:36]#[C:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:17])(=[O:6])=[O:5])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(I)cc21
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)S(=O)(=O)n1c(N)nc2ccc(C#Cc3ccccc3)cc21
Temperature: 22.5 °C
Reaction time: 0.25 h

Procedure:
Under a nitrogen atmosphere, combine 1-isopropylsulfonyl-2-amino-6-iodo benzimidazole (400 g, 1.095 moles), bis(triphenylphosphine) palladium(II)acetate (32.8 g, 0.044 moles), and CuI (41.7 g, 0.219 moles), followed by DMSO (8.4 L) and triethylamine (317 g, 3.133 moles). Stir the resulting mixture at 20 to 25° C. for 15 minutes, followed by the addition of phenylacetylene (168 g, 1.645 moles) over 30 minutes giving a temperature rise to 34° C. Cool the reaction slowly to 20 to 25° C., and after 15 hours, quench an aliquot of the reaction into water and dilute with CH3CN for HPLC analysis. The HPLC chromatogram (Column:Zorbax SB-C8, 4.6×250 mm, 5 micron UV=218 nm, gradients acetonitrile/buffer) indicates complete consumption of the iodide with the production of two new less polar products (desired product and phenylacetylene dimer). Add water (4 L) to the reaction over 1 hour giving a temperature rise to 40° C., and a dark precipitate (mainly catalyst). Filter the reaction through a thin layer of Celite® (24 cm diameter) with no washing of the catalyst waste cake. Return the filtrate to the reactor and add an additional 4 L of water over 1 hour to give an ending temperature of 45° C., and a yellow slurry. Leave the mixture to cool overnight to 20 to 25° C. with stirring. Collect the solids by vacuum filtration, and wash with water (4 L). Dry the solids at 60° C. under vacuum to constant weight. Yield=319 g (86%) of light yellow granular solid. MS(ES+): m/z=340.2 (M+H)+