Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:14]2[CH:13]=[C:12]([C:15]3[C:20]4[O:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[C:19]=4[CH:18]=[CH:17][CH:16]=3)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C([Li])(CC)C.C1CCCCC1.C(O[B:44]1[O:48][C:47]([CH3:50])([CH3:49])[C:46]([CH3:52])([CH3:51])[O:45]1)(C)C>C1COCC1>[CH3:1][C:2]1([CH3:28])[C:14]2[CH:13]=[C:12]([C:15]3[C:20]4[O:21][C:22]5[C:27]([B:44]6[O:48][C:47]([CH3:50])([CH3:49])[C:46]([CH3:52])([CH3:51])[O:45]6)=[CH:26][CH:25]=[CH:24][C:23]=5[C:19]=4[CH:18]=[CH:17][CH:16]=3)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: CC1(C)c2ccccc2-c2ccc(-c3cccc4c3oc3ccccc34)cc21
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC1(C)c2ccccc2-c2ccc(-c3cccc4c3oc3c(B5OC(C)(C)C(C)(C)O5)cccc34)cc21
Temperature: -78 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
Into a solution of 4-(9,9-dimethyl-9H-fluoren-2-yl)dibenzo[b,d]furan (11.55 g, 32.0 mmol) and THF (200 ml), a solution of sec-butyllithium 1.4 M in cyclohexane (30.9 ml, 43.3 mmol) at −78° C. was slowly added. The resulting mixture was stirred at −78° C. for 2 hours before adding 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.81 ml, 48.1 mmol) by syringe. The reaction solution was allowed to gradually warm to room temperature and stirred for 14 h. The reaction was quenched with methanol (MeOH) and the solvent was removed in vacuo. The residue was dissolved in DCM and washed with water and brine. The organic layer was dried over sodium sulfate, then filtered, before the solvent was evaporated. The crude product was purified by column chromatography on silica gel with a heptane/DCM/EtOAc (75/20/5 to 40/50/10, v/v/v) eluent and recrystallization from toluene yielded 2-(6-(9,9-dimethyl-9H-fluoren-2-yl)dibenzo[b,d]furan-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13.1 g, 84%) as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:16][CH2:17][CH:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:30])[F:31])=[CH:24][CH:23]=3)[CH2:19][CH2:20]2)=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: FC(F)(F)Oc1ccc(OC2CCN(c3ccc(OCc4ccccc4)cc3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(N2CCC(Oc3ccc(OC(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Yield: 101.7 %

Procedure:
After 1-(4-Benzyloxyphenyl)-4-[4-(Trifluoromethoxy)phenoxy]piperidine (20.0 g) and ethyl alcohol (200 mL) was mixed and then (50% wet) 5 w/w % palladium on carbon (1 g) was added. The resulting mixture was stirred under 4 atms of atmosphere of hydrogen at 60-61° C. for 3 hr. The reaction mixture was then cooled to room temperature and was filtered to remove the catalyst followed by concentration in vacuo to give 16.2 g (99.5% yield) of an ivory crystal target compound.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][O:7][C:8](=[NH:10])[NH2:9].[OH-].[Ca+2].[OH-].[C:14]([CH:17]1[CH2:22][CH2:21][O:20][C:18]1=[O:19])(=O)[CH3:15]>O.C(O)C>[CH3:6][O:7][C:8]1[NH:9][C:18](=[O:19])[C:17]([CH2:22][CH2:21][OH:20])=[C:14]([CH3:15])[N:10]=1
Reactant: COC(=N)N
Reactant: CC(=O)C1CCOC1=O
Agent: O=S(=O)(O)O
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1nc(C)c(CCO)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of O-methylisourea hydrogen sulfate (17.2 g, 0.1 mol) in water (90 ml) was added calcium hydroxide (8.14 g, 0.11 mol) followed by a solution of 2-acetylbutyrolactone (10.7 ml, 0.1 mol) in ethanol (70 ml). The mixture was stirred at room temperature for two days, filtered and washed with ethanol. The filtrate was concentrated in vaccuum and purified by flash chromatografy (dichloromethane/methanol=95/5). Yield 2.6 g (14%) of a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:21])=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][C:6]1[C:7]([O:16][CH3:17])=[CH:8][C:9]([F:15])=[C:10]([CH:14]=1)[C:11](O)=[O:12].S(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([F:21])=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][C:6]1[C:7]([O:16][CH3:17])=[CH:8][C:9]([F:15])=[C:10]([CH:14]=1)[C:11]([Cl:24])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(F)c(C(=O)O)cc1Cc1cccc(Cl)c1F
Solvent: Cc1ccccc1
Product: COc1cc(F)c(C(=O)Cl)cc1Cc1cccc(Cl)c1F
Temperature: 25 °C

Procedure:
5-(3-Chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoic acid (10 g) was suspended in toluene (50 ml) with stirring at room temperature, thionyl chloride (4.57 g) was added dropwise at 65-75° C., and the mixture was stirred for 1.5 hr. After cooling, the solvent was concentrated under reduced pressure, toluene (50 ml) was added to the residue, and the mixture was concentrated again under reduced pressure. The residue was dissolved in toluene (20 ml) to give a solution of 5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl chloride in toluene. This was identified as the title compound by HPLC.
Reaction SMILES: FC(F)(F)[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[N:7]([CH:15]([CH3:17])[CH3:16])[CH:6]=1)=[O:4].[OH-:20].[Na+]>>[F:14][C:10]1[CH:9]=[C:8]2[C:13]([C:5]([C:3]([OH:4])=[O:20])=[CH:6][N:7]2[CH:15]([CH3:17])[CH3:16])=[CH:12][CH:11]=1
Reactant: [OH-]
Reactant: CC(C)n1cc(C(=O)C(F)(F)F)c2ccc(F)cc21
Agent: [Na+]
Product: CC(C)n1cc(C(=O)O)c2ccc(F)cc21
Temperature: 25 °C
Yield: 96 %

Procedure:
A solution of 2,2,2-trifluoro-1-(6-fluoro-1-isopropyl-1H-indol-3-yl)-ethanone (1.65 g, 6.04 mmol) in a 20% aqueous sodium hydroxide solution (25 mL) was heated at 110° C. for 18 h. At this time, the reaction was cooled to 25° C., partitioned between water (50 mL) and ethyl acetate (50 mL), and treated with a 1N aqueous hydrochloric acid solution (50 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 6-fluoro-1-isopropyl-1H-indole-3-carboxylic acid (1.29 g, 96%) as a yellow solid: mp 177-180° C.; EI-HRMS m/e calcd for C12H12FNO2 (M+) 221.0852, found 221.0850.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]#[C:17][CH2:18][CH2:19]O)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.C(N(CC)CC)C.[B-](F)(F)(F)[F:29].CCN([S+](F)F)CC.C([O-])(O)=O.[Na+]>ClCCl>[F:29][CH2:19][CH2:18][C:17]#[C:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[N:8]=[CH:9]2
Reactant: OCCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Reactant: F[B-](F)(F)F
Agent: CCN(CC)[S+](F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: FCCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.9 %

Procedure:
To a solution of 4-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-yn-1-ol (1.0 g, 3.7 mmol; Intermediate 20) in dry dichloromethane (25 mL), was added triethylamine.3HF (1.2 g, 7.4 mmol). XtalFluor-E (1.2 g, 5.5 mmol) was then added. The resulting solution was stirred at room temperature for 30 minutes. Upon completion, the reaction solution was neutralized by slow addition of saturated NaHCO3 (10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0-20% EtOAc in petroleum ether) affording the title compound (100 mg). 1H NMR (400 MHz, DMSO-d6): δ 8.12 (s, 1H), 7.88 (s, 1H), 7.73 (d, 1H), 7.42 (dd, 1H), 5.86 (dd, 1H), 4.60 (dt, 2H), 3.88 (m, 1H), 3.78-3.71 (m, 1H), 2.89 (dt, 2H), 2.48-2.34 (m, 1H), 2.06-1.95 (m, 2H), 1.78-1.72 (m, 1H), 1.58 (m, 2H); LCMS: 273 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH3:19][C:20]1[CH:33]=[CH:32][C:23]([C:24]([NH:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)=[O:25])=[CH:22][C:21]=1B1OC(C)(C)C(C)(C)O1>>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:17]=[CH:18][C:2]([C:21]3[CH:22]=[C:23]([C:24](=[O:25])[NH:26][C:27]4[S:28][CH:29]=[CH:30][N:31]=4)[CH:32]=[CH:33][C:20]=3[CH3:19])=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: COc1ccc(NC(=O)c2ccc(Cl)nc2)cc1
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1B1OC(C)(C)C(C)(C)O1
Product: COc1ccc(NC(=O)c2ccc(-c3cc(C(=O)Nc4nccs4)ccc3C)nc2)cc1

Procedure:
N-(4-Methoxyphenyl)-6-[2-methyl-5-(thiazol-2-ylcarbamoyl)-phenyl]-nicotinamide was prepared from 6-chloro-N-(4-methoxyphenyl)nicotinamide (Intermediate 2) and 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiazol-2-yl)-benzamide (Intermediate 11) using General Method B. LCMS: retention time 3.22 min, MH+ 445. NMR: δH [2H6]-DMSO 12.72,(1H, s), 10.40,(1H, s), 9.22,(1H, d), 8.44,(1H, dd), 8.24,(1H, s), 8.09,(1H, d), 7.87,(1H, d), 7.71, (2H, d), 7.58,(1H, d), 7.53,(1H, d), 7.30,(1H, d), 6.97,(2H, d), 3.76,(3H, s), 2.48, (3H, s).
Reaction SMILES: ClC(Cl)(F)F.F[O:7][C:8]([O:11]F)([F:10])[F:9].[Br:13][C:14]([F:18])=[C:15]([F:17])[F:16]>N#N>[Br:13][C:14]1([F:18])[C:15]([F:17])([F:16])[O:11][C:8]([F:10])([F:9])[O:7]1
Reactant: FC(F)=C(F)Br
Reactant: FOC(F)(F)OF
Agent: FC(F)(Cl)Cl
Agent: N#N
Product: FC1(F)OC(F)(F)C(F)(Br)O1
Temperature: -70 °C

Procedure:
Into a multineck glass reactor equipped with: magnetic entrainment mechanical stirrer, reflux cooler, thermocouple, inner plunging pipes for introducing the reagents, and maintained at a temperature of -70° C., there were simultaneously fed--after having introduced 75 ml of dichlorodifluoromethane--0.75 l of bis(fluoroxy)difluoromethane at a flowrate of 0.375 l/h diluted with N2 (0.5 l/h) and bromotrifluoroethylene (5.4 g/h) for 2 hours.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:15].[C:16](Cl)(=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20].N1C=CC=CC=1>C(#N)C>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:15][C:16](=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCC(=O)Cl
Reactant: Nc1ccc2oc3c(c2c1)CCCCC3
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCCC(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 49.6 %

Procedure:
Following the procedure of Example 1, 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (0.25 g, 1.2 mmol), valeryl chloride (0.16 mL, 1.4 mmol), and pyridine (0.30 mL, 3.7 mmol) in acetonitrile (15 mL) provided N-(7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-yl)pentanamide (0.17 g). MS (ESI) m/z 286([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:27]=1.[C:28](Cl)(=[O:31])[CH2:29][CH3:30]>CN(C)C(=O)C.C(=O)([O-])O.[Na+]>[CH3:26][C:22]1[N:21]=[C:20]([C:18]([NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([O:10][C:7]3[CH:8]=[CH:9][C:4]4[N:5]([CH:27]=[C:2]([NH:1][C:28](=[O:31])[CH2:29][CH3:30])[N:3]=4)[CH:6]=3)[CH:12]=2)=[O:19])[CH:25]=[CH:24][CH:23]=1
Reactant: CCC(=O)Cl
Reactant: Cc1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)cn4c3)c2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCC(=O)Nc1cn2cc(Oc3cccc(NC(=O)c4cccc(C)n4)c3)ccc2n1
Temperature: 25 °C
Reaction time: 10 h
Yield: 40.4 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}-6-methylpyridine-2-carboxamide (300 mg, 0.835 mmol) in N,N-dimethylacetamide (5 mL) was added propionyl chloride (72.6 μL, 0.836 mmol), and the mixture was stirred at room temperature for 10 hr. The reaction mixture was diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, 0%→100% ethyl acetate-hexane) to give the title compound (140 mg, 40%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:10][CH:9]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 13.9 g 4-(5-bromo-2-chloro-benzyl)-phenol in 140 mL dichloromethane is cooled in an ice bath. Then 7.54 g tert-butyldimethylsilylchlorid in 20 mL dichloromethane are added followed by 9.8 mL triethylamine and 0.5 g 4-dimethylaminopyridine. The solution is stirred for 16 h at ambient temperature and then diluted with 100 mL dichloromethane. The organic phase is washed twice with aqueous 1 M hydrochloric acid and once with aqueous sodium hydrogen carbonate solution and then dried over sodium sulfate. After the solvent has been removed, the residue is filtered through silica gel (cyclohexane/ethyl acetate 100:1).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:11])=[C:5]([CH3:10])[C:6]=1[C:7](Cl)=[O:8].[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:25])=[C:17]([CH:24]=1)[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:25][C:16]1[CH:15]=[CH:14][C:13]([NH:12][C:7]([C:6]2[C:5]([CH3:10])=[C:4]([CH3:11])[O:3][C:2]=2[CH3:1])=[O:8])=[CH:24][C:17]=1[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19]
Reactant: Cc1oc(C)c(C(=O)Cl)c1C
Reactant: CC(C)OC(=O)c1cc(N)ccc1Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1oc(C)c(C(=O)Nc2ccc(Cl)c(C(=O)OC(C)C)c2)c1C
Temperature: 60 °C
Yield: 42.6 %

Procedure:
A solution of 2,4,5-trimethyl-3-furancarbonyl chloride (7.8 g, 0.045 mole) in toluene (25 ml) was added to 1-methylethyl 5-amino-2-chlorobenzoate (10.6 g, 0.050 mole) and triethylamine (6 g) in toluene (25 ml). The mixture was warmed to 60° C. for about 1 hour,then washed in sequence with dilute hydrochloric acid, water, aqueous 5% sodium bicarbonate and water. The solution was dried with magnesium sulfate, filtered and evaporated. The residue was crystallized from toluene/petroleum ether to give 6.7 g of a pale yellow solid, m.p. 83°-85° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1Cl)([O-])=O.[S-:14][C:15]#[N:16].[NH4+].O>S1(CCCC1)(=O)=O>[NH2:16][C:15]1[S:14][C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N:1]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: Nc1nc2cc([N+](=O)[O-])ccc2s1
Temperature: 150 °C
Yield: 134.7 %

Procedure:
A suspension of 5.06 g of 2,4-dinitrochlorobenzene and 7.6 g of ammonium thiocyanate in 25 ml of sulpholane is heated, with stirring, to 150° C. and maintained at this temperature for 1.5 hours. The product is discharged into 300 ml of water, and the solid is filtered off with suction and washed with water. After drying, 6.57 g of crude 2-amino-5-nitrobenzothiazole are obtained. The identity was confirmed by TLC comparison (TLC=thin-layer chromatography) with authentic material.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[CH:7][N:6]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:19](=[O:21])[CH3:20])[N:6]=1
Reactant: CC(=O)Cl
Reactant: COC(=O)Cc1ncc2ccccn12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)Cc1nc(C(C)=O)c2ccccn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of imidazo[1,5-a]pyridin-3-yl-acetic acid methyl ester (1.38 g, 7.26 mmol) in CH2Cl2 (50 mL) was added to a suspension of AlCl3 (2.9 g, 21.77 mmol) in CH2Cl2 (115 mL) and the mixture was stirred at RT for 30 min under nitrogen atmosphere. Acetyl chloride (1.55 mL, 21.77 mmol) was subsequently added dropwise and the mixture was further stirred overnight. AlCl3 (1.94 g, 14.51 mmol) and 15 min later acetyl chloride (1.04 mL, 14.51 mmol) were added and stirring was continued overnight to complete the reaction. The reaction mixture was cooled with at 0° C. and carefully quenched by cautious addition of MeOH (35 mL). Solvents were evaporated under reduced pressure and the crude residue was purified by flash column chromatography on silica gel (eluent: CH2Cl2 to CH2Cl2/MeOH 94:6). TLC, Rf (CH2Cl2/MeOH 9:1)=0.60; MS (UPLC/MS): 233.1 [M+H]+, 255.1 [M+Na]+, 487.1 [2M+Na]+; tR (HPLC conditions f): 1.27 min.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]=[C:8]=[O:9])[CH:2]=1.[NH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[CH2:14][CH2:13]1.C(Cl)Cl>CCOCC>[NH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]([CH2:19][CH2:18][N:15]2[CH2:16][CH2:17][N:12]([NH:11][C:8]([NH:7][C:3]3[CH:2]=[C:1]([CH3:10])[CH:6]=[CH:5][CH:4]=3)=[O:9])[CH2:13][CH2:14]2)=[CH:21]1
Reactant: Cc1cccc(N=C=O)c1
Reactant: NN1CCN(CCc2c[nH]c3ccccc23)CC1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cccc(NC(=O)NN2CCN(CCc3c[nH]c4ccccc34)CC2)c1
Reaction time: 2 h

Procedure:
3.34 G of m-tolylisocyanate are added dropwise to a stirred solution of 6.13 g of 3-[2-(4-aminopiperazin-1-yl)ethyl]indole in 100 ml. of dry methyene chloride while maintaining the reaction temperature below 35° C. After 2 hours a fine precipitate appears, 50 ml. of ether are added and stirring is continued for 3 additional hours. More ether is added and the product is filtered and washed with ether. The solid product is recrystallized from an ethanol and water mixture to give white flakes, m.p. 186°-188°C. of 1-[1-(indol-3-ylethyl)piperazin-4-yl]-3-m-tolylurea.
Reaction SMILES: [NH2:1][C:2]1[N:6](/[CH:7]=[CH:8]/OCC)[N:5]=[CH:4][C:3]=1[CH3:12].Cl.C(OCC)(=O)C>O1CCCC1>[CH3:12][C:3]1[CH:4]=[N:5][N:6]2[CH:7]=[CH:8][NH:1][C:2]=12
Reactant: CCO/C=C/n1ncc(C)c1N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cnn2cc[nH]c12
Yield: 90.1 %

Procedure:
To a solution of 5-amino-4-methyl-1-[(E)-2-ethoxyvinyl]pyrazole (10.6 g) in tetrahydrofuran (212 ml) was added 4N hydrochloric acid, and the mixture was refluxed for 3 hours. The reaction mixture was adjusted to pH 8 under ice-cooling, thereto was added ethyl acetate (100 ml). The separated organic layer was dried over magnesium sulfate and evaporated in vacuo to give 7-methyl-1H-imidazo[1,2-b]pyrazole (6.92 g) as crystals. IR (Nujol) : 3100, 1620, 1500 cm-1
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH2:16][CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:12]3=[N:11][N:10]=2)[CH:6]=[CH:5][C:4]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1.[H-].[Na+].[Cl:31]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[Cl:31][C:17]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:15][CH2:14][N:13]2[C:9]([C:7]3[CH:6]=[CH:5][C:4]([N:23]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]4)=[C:3]([O:2][CH3:1])[N:8]=3)=[N:10][N:11]=[C:12]12
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)C1CCCn2c(-c3ccc(-n4cnc(C)c4)c(OC)n3)nnc21
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(Cl)CCCn2c(-c3ccc(-n4cnc(C)c4)c(OC)n3)nnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
Under a nitrogen atmosphere, to a mixture of ethyl 3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (3.1 g) in DMF (30 mL) was added sodium hydride (60%, 0.34 g) at 0° C., and the mixture was stirred at room temperature for 30 min. N-Chlorosuccinimide (1.14 g) was added to the reaction mixture at 0° C., and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, the mixture was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (1.9 g).
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:24])[C:11]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=2)([OH:16])[C:12]([F:15])([F:14])[F:13])=[C:6]([Cl:25])[CH:5]=1.[Li+].[OH-]>C1COCC1.CO>[Cl:25][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[CH:10]([CH3:24])[C:11]([C:17]1[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=1)([OH:16])[C:12]([F:15])([F:14])[F:13])[C:3]([OH:26])=[O:2]
Reactant: COC(=O)c1ccc(C(C)C(O)(c2ccnc(Cl)c2)C(F)(F)F)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(c1ccc(C(=O)O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Temperature: 65 °C
Reaction time: 2 h

Procedure:
3-Chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-benzoic acid methyl ester (Example 135, 62 mg) in THF (1.5 mL) and MeOH (0.3 mL) was treated with 1M aqueous LiOH (0.228 mL) and stirred for 2 h at 65° C. (bath-temperature). The organic solvents were evaporated in vacuo and the residue was diluted with water (2 mL) and acidified with 1M aqueous HCl (0.3 mL). The precipitate was filtered and dried under high vacuum, leading to the title compound as white solid (54 mg). MS (m/e)=392.2 (M−H).
Reaction SMILES: O=S(Cl)Cl.[CH:5]1([NH:9][C:10]2([CH2:15]Cl)[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:8][CH2:7][CH2:6]1.ClCCN.[CH3:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[N:31]=[C:32]=[O:33]>>[CH:5]1([N:9]2[C:10]3([CH2:14][CH2:13][CH2:12][CH2:11]3)[CH2:15][O:33][C:32]2=[N:31][C:23]2[CH:24]=[CH:25][C:26]([N+:28]([O-:30])=[O:29])=[CH:27][C:22]=2[CH3:21])[CH2:8][CH2:7][CH2:6]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=O
Reactant: ClCC1(NC2CCC2)CCCC1
Agent: NCCCl
Solvent: O=S(Cl)Cl
Product: Cc1cc([N+](=O)[O-])ccc1N=C1OCC2(CCCC2)N1C1CCC1

Procedure:
1-Aminocyclopentanecarboxylic acid was converted to the methyl ester according to Method B1c, Step 1. The ester reduced to 1-hydroxymethylcyclopentanamine according to Method B1c, Step 2. The 2-hydroxyethylamine was reacted with cyclobutanone according to Method B4a, Step 1 to give 5-aza-12-oxadispiro[3.1.4.2]dodecane. The oxazolidine was reduced according to Method B4a, Step 2 to give 1-(cyclobutylamino)-1-(hydroxymethyl)cyclopentane. The substituted 2-hydroxyethylamine was reacted with SOCl2 according to Method B7b to 1-(cyclobutylamino)-1-(chloromethyl)cyclopentane. The 2-chloroethylamine was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C4a to afford 1-cyclobutyl-2-(2-methyl-4-nitrophenylimino)-3-oxa-1-azaspiro[4.4]nonane.
Reaction SMILES: [CH2:1]([N:3]1[C:8]([CH3:9])=[C:7]([C:10]#[N:11])[CH:6]([C:12]2[CH:17]=[CH:16][C:15](F)=[C:14]([C:19]#[N:20])[CH:13]=2)[C:5]([C:21]#[N:22])=[C:4]1[CH3:23])[CH3:2].O.[NH2:25][NH2:26]>C(O)CCC>[CH2:1]([N:3]1[C:8]([CH3:9])=[C:7]([C:10]#[N:11])[CH:6]([C:12]2[CH:13]=[C:14]3[C:15](=[CH:16][CH:17]=2)[NH:26][N:25]=[C:19]3[NH2:20])[C:5]([C:21]#[N:22])=[C:4]1[CH3:23])[CH3:2]
Reactant: NN
Reactant: CCN1C(C)=C(C#N)C(c2ccc(F)c(C#N)c2)C(C#N)=C1C
Solvent: CCCCO
Solvent: O
Product: CCN1C(C)=C(C#N)C(c2ccc3[nH]nc(N)c3c2)C(C#N)=C1C

Procedure:
A mixture of 1-ethyl-4-(3-cyano-4-fluorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarbonitrile (1 eq), from Synthetic Example 8, and hydrazine hydrate (110 eq) in n-butyl alcohol (75 mL) was kept at 80° C. for 5 hr. The mixture was cooled and concentrated. To the residue, sodium bicarbonate solution (sat.) was added and the mixture was extracted with ethyl acetate. The organic phases were combined, dried, and concentrated to afford 1-ethyl-4-(3-amino-1H-indazol-5-yl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarbonitrile (Cpd. No. 294, Table 7). 1H-NMR (400 MHz, DMSO-D6): δ=11.43 (s, 1H), 7.51 (s, 1H), 7.26 (d, 1H), 7.12 (d, 1H), 5.37 (s, 2H), 4.32 (s, 1H), 3.67 (q, 2H), 2.27 (s, 6H), 1.18 (t, 3H) ppm.