Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:9]1[CH:14]=[C:13]([CH2:15][C@H:16]2[C:19](=[O:20])[NH:18][C@@H:17]2[C:21]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[O:22])[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:41]1COCC1.[Si](C=[N+]=[N-])(C)(C)C.C(OCC)(=O)C>CO>[C:1]([O:5][C:6]([N:8]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:9]1[CH:14]=[C:13]([CH2:15][C@H:16]2[C:19](=[O:20])[NH:18][C@@H:17]2[C:21]([N:23]([S:24]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH3:41])=[O:22])[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cc(C[C@H]2C(=O)N[C@@H]2C(=O)NS(=O)(=O)c2ccc(F)cc2)ccn1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C(=O)[C@H]1NC(=O)[C@@H]1Cc1ccnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1)S(=O)(=O)c1ccc(F)cc1
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a solution of 98 (18 mg, 1.0 eq.) in MeOH: THF (1 mL: 300 uL) was added 2.0M TMSCHN2 in hexanes (266 uL, 17 eq.). After 15 minutes, TLC showed complete conversion of starting material. The reaction was poured into ethyl acetate and then washed with 0.2N HCl, 1N NaHCO3 and brine. The organic layer was then dried over sodium sulfate and concentrated in vacuo. The product was then purified via reverse phase HPLC (C18, acetonitrile/water with 0.1% TFA) to yield 99 (11.9 mg, 65%) as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=O)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.ClC(N(C)C)=C(C)C.[CH3:22][N:23]1[C:31]2([CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24]1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:34]3[CH2:35][CH2:36][C:31]4([C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:24][N:23]4[CH3:22])[CH2:32][CH2:33]3)=[O:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1c[nH]c2cc(Cl)ccc12
Reactant: CN1Cc2ccccc2C12CCNCC2
Agent: CC(C)=C(Cl)N(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1Cc2ccccc2C12CCN(C(=O)c1c[nH]c3cc(Cl)ccc13)CC2
Reaction time: 1 h
Yield: 29 %

Procedure:
To a solution of 0.040 g (0.20 mmol) 6-chloro-1H-indole-3-carboxylic acid in 3 ml dichloromethane were added 0.03 ml (0.22 mmol) 1-chloro-N,N,2-trimethyl-propenylamine at room temperature. After stirring for 1 h the reaction mixture was concentrated in vacuo. The residue was redissolved in 2 ml dry N,N-dimethylformamide. A solution of 0.041 g (0.20 mmol) 2-methyl-2,3-dihydrospiro[isoindole-1,4′-piperidine] and 0.043 ml (0.31 mmol) triethylamine in 1 ml dry N,N-dimethylformamide was added at room temperature. After stirring for 2 h the reaction mixture was quenched with 1 M aqueous sodium hydroxide solution (30 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with water (2×30 ml) and brine (1×30 ml), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (n-heptane/ethyl acetate) to give the title compound (0.022 g, 23%) as an off-white solid with a purity of approx. 83% by LC-MS.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29](=[O:36])[CH2:30][C:31]([O:33]CC)=O)([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:38]O.[OH-].[Na+].Cl>O.CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29]3[O:36][N:38]=[C:31]([OH:33])[CH:30]=3)([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: CCOC(=O)CC(=O)C[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(CC)CC)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)N1C(=O)[C@@](C)(Cc2cc(O)no2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To an ice-cooled slurry of 65 mg (0.12 mmol) of ethyl 4-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)-3-oxobutanoate (Example 79, Step B) in water (2 mL) was added 53.5 mg (0.77 mmol) of hydroxylamine hydrochloride and 62 mg (1.55 mmol) of sodium hydroxide. After 5 min, THF (1 mL) and MeOH (1 mL) were added. The resulting cloudy light yellow solution was stirred at 0° C. for 20 min, then was warmed to room temperature and stirred for an additional 6 h. The reaction was acidified by dropwise addition of conc. HCl until strongly acidic, then was diluted with water and extracted with EtOAc (4×). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by reversed phase prep. HPLC (Sunfire™ Prep C18 OBD 10 μm column (Waters, Milford, Mass.), gradient elution of 55% MeCN in water to 85% MeCN in water over a 30 min period, where both solvents contain 0.1% TFA) provided the title compound as a white solid.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[CH3:11]C(C)([O-])C.[K+].IC>C1COCC1.O>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH3:11])[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: Ic1n[nH]c2ncccc12
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CI
Product: Cn1nc(I)c2cccnc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 30.8 %

Procedure:
To a stirred solution of 3-iodo-1H-pyrazolo[3,4-b]pyridine (3.5 g, 14.3 mmol) in THF (70 mL) at 0° C. was added potassium tert-butoxide (1.92 g, 17.1 mmol) and the reaction mixture stirred at 0° C. for 1 h. Iodomethane (2.43 g, 1.07 mL, 17.1 mmol) was added drop-wise, then the mixture was warmed to rt. After 6 h the mixture was diluted with water, extracted with dichloromethane, then the combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. Purification by chromatography (silica, 20-60% ethyl acetate in hexanes) gave 3-iodo-1-methyl-1H-pyrazolo[3,4-b]pyridine (1.14 g, 4.4 mmol, 31%) as an off-white solid. MS (M+H)+=260.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:32]([F:33])=[C:31]([NH2:34])[C:9]2[C:10](=[O:30])[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[C:16]([F:29])[CH:15]=3)[O:13][C:8]=2[C:7]=1[F:35])(=O)C.[OH-].[Na+].O>CO>[NH2:34][C:31]1[C:9]2[C:10](=[O:30])[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][CH2:23][CH2:24][N:25]([CH3:26])[CH3:27])=[C:16]([F:29])[CH:15]=3)[O:13][C:8]=2[C:7]([F:35])=[C:6]([CH2:5][OH:4])[C:32]=1[F:33]
Reactant: CC(=O)OCc1c(F)c(N)c2c(=O)cc(-c3ccc(NC(=O)CCCN(C)C)c(F)c3)oc2c1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)CCCC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)c(CO)c(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
To a suspension of 1j (363 mg, 0.739 mmol) in methanol (36 mL) was added 1 mol/L sodium hydroxide (4 mL), and the mixture was stirred at room temperature for 20 minutes. Water was added thereto and the crystals precipitated were collected by filtration. Purification by silica gel column chromatography gave a free base of 1k (299 mg, 69%), which was converted into a hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:24])[CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1>CN(C(OC)OC)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:24])[C:10]([N:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:15][CH2:16]1)=[CH:10][N:11]([CH3:16])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)c2ccc(Cl)cc2Cl)CC1
Agent: COC(OC)N(C)C
Product: CN(C)C=C(C(=O)c1ccc(Cl)cc1Cl)N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
1 mmol of tert-butyl 4-[2-(2,4-dichlorophenyl)-2-oxoethyl]piperazinecarboxylate was heated to 80° C. in neat N,N-dimethylformamidedimethyl acetal for six hours. The reaction mixture was concentrated in vacuo and purified by trituration with diethyl ether to obtain tert-butyl 4-{2-(2,4-dichlorophenyl)-1-[(dimethylamino)methylene]-2-oxo-ethyl}piperazinecarboxylate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[NH:10]2)=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2].[H-].[Na+].[Cl:35][CH2:36][S:37](Cl)(=[O:39])=[O:38]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[N:10]2[S:37]([CH2:36][Cl:35])(=[O:39])=[O:38])=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2]
Reactant: O=S(=O)(Cl)CCl
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(S(=O)(=O)CCl)C(=O)N1c1cccc(C(F)(F)F)c1
Yield: 69.2 %

Procedure:
Analogously to the preparation of Example 27, (4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (100 mg, 217 μmol; Example 6), sodium hydride (60%, 11.3 mg, 282 μmol) and chloromethanesulfonyl chloride (42 mg, 282 μmol) were reacted with one another for 3 h. This gave the title compound as a colorless solid (86 mg, 69% of theory).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[CH:9][CH:8]=[C:7]([F:18])[CH:6]=2)[CH3:2].Br[CH2:20][CH2:21][CH2:22][S:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C(OCC)(=O)C>[CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH2:20][CH2:21][CH2:22][S:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:14][CH2:13]1)=[CH:9][CH:8]=[C:7]([F:18])[CH:6]=2)[CH3:2]
Reactant: Fc1ccc(SCCCBr)cc1
Reactant: CCc1[nH]c2cc(F)ccc2c1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1[nH]c2cc(F)ccc2c1C1CCN(CCCSc2ccc(F)cc2)CC1
Temperature: 100 °C

Procedure:
A mixture of 2-ethyl-6-fluoro-3-piperidin-4-yl-1H-indole (0.9 g), 1-(3-Bromo-propylsulfanyl)-4-fluoro-benzene (1.0 g), potassium iodide (20 mg) and potassium carbonate (0.7 g) in DMF (10 ml) is heated at 100° C. for 3 h, and allowed to cool to rt overnight. Ethyl acetate (50 ml) and water (25 ml) are added and the organic phase is washed with water, dried and concentrated in vacuo. The crude product is purified by flash chromatography (95:5 CH2Cl2:MeOH) and its hydrochloride salt is prepared by reaction in acetone with the appropriate amount of ethereal HCl giving, after recrystallisation from ether, 1.1 g pure product (70%) as white crystals.
Reaction SMILES: ClC1C(N(C(=O)COS(C)(=O)=O)C)=CC=C(Cl)C=1CO[C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.NC1C=C(C2C=CC(C(N(C)C)=O)=CC=2)C=CC=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH3:16][C:13]1[CH:12]=[CH:11][C:10]2[C:15](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:14]=1
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)COS(C)(=O)=O)c3Cl)c2n1
Agent: CN(C)C(=O)c1ccc(-c2cccc(N)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2ccccc2n1
Temperature: 60 °C
Reaction time: 12 h
Yield: 92.1 %

Procedure:
A mixture of 8-[2,6-dichloro-3-(N-methanesulfonyloxyacetyl-N-methylamino)benzyloxy]-2-methylquinoline (110 mg), 4-(3-aminophenyl)-N,N-dimethylbenzamide (60.2 mg) and potassium carbonate (94.2 mg) in N,N -dimethylformamide (1 ml) was stirred for 12 hours at 60° C., and ethyl acetate and water were added thereto. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform:methanol=20:1, V/V) to give 8-[2,6-dichloro-3-methylamino]benzyloxy]-2-methylquinoline (30 mg) as colorless amorphous.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]=[O:28])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:30]1[CH:31]=[N:32][CH:33]=[C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=2)[CH:35]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:28])[C:30]4[CH:31]=[N:32][CH:33]=[C:34]([C:36]5[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:44])([F:45])[F:43])[CH:37]=5)[CH:35]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: FC(F)(F)c1cccc(-c2cncc(Br)c2)c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C=O)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cncc(-c5cccc(C(F)(F)F)c5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 19, Step 1, using 1-[4′-(4-formyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-5-(3-trifluoromethyl-phenyl)-pyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.O>[CH2:11]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4-aminobenzoic acid (10 g, 73 mmol) in tetrahydrofuran (200 ml) was added benzaldehyde (9.63 ml, 95 mmol), acetic acid (4.9 ml, 91.3 mmol) followed by sodium triacetoxyborohydride (31 g, 146 mmol) and the reaction was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (200 ml) and extracted with dichloromethane (2×200 ml). The organics were combined, washed with brine, dried over magnesium sulfate and then concentrated in vacuo. The residue was purified by flash chromatography (SiO2) eluting with diethylether/dichloromethane (1:4) to afford the title compound as an off white solid (4.74 g, 28% yield). HPLC retention time 5.32 min. Mass spectrum (ES+) m/z 228 (M+H).