Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[C:16]2[C:11](=[C:12]([C:17]3[S:18][C:19]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[C:24]([C:32]#[N:33])[CH:23]=4)=[N:20][N:21]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:35]>O1CCOCC1.C(OCC)C>[ClH:35].[NH2:7][C@@H:8]1[C:16]2[C:11](=[C:12]([C:17]3[S:18][C:19]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[C:24]([CH:23]=4)[C:32]#[N:33])=[N:20][N:21]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1
Reactant: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4NC(=O)OC(C)(C)C)s2)cc1C#N
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4N)s2)cc1C#N
Temperature: 55 °C
Reaction time: 2.5 h
Yield: 96 %

Procedure:
Prepared using General Procedure 5. To a stirred solution of (S)-tert-butyl(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate (1.1 g, 2.3 mmol) in 1,4-dioxane (10 mL) was added 4N HCl solution of in 1,4-dioxane (10 mL). The reaction mixture was stirred at 55° C. for 2.5 h. Upon cooling to 0° C., the reaction mixture was diluted with diethyl ether (100 mL) and the resulting solid was filtered and dried to afford 980 mg (96%) of (S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 4 as off-white solid. LCMS-ESI (m/z) calculated for C21H20N4OS, 376.1; found 377.1 (M+H). tR=2.35 min. 1H NMR (400 MHz, DMSO) δ 8.64-8.51 (m, 3H), 8.41 (d, J=2.3 Hz, 1H), 8.32 (dd, J=8.9, 2.4 Hz, 1H), 7.99 (d, J=7.4 Hz, 1H), 7.84 (d, J=7.6 Hz, 1H), 7.59-7.49 (m, 2H), 4.95 (dt, J=12.2, 6.1 Hz, 1H), 4.84 (s, 1H), 3.54-3.32 (m, 1H), 3.30-3.15 (m, 1H), 2.65-2.53 (m, 1H), 2.12 (ddd, J=13.9, 5.6, 3.0 Hz, 1H), 1.37 (dd, J=10.4, 6.1 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 166.61, 166.11, 161.5, 143.05, 141.73, 134.16, 133.45, 129.74, 128.26, 127.84, 126.47, 122.33, 115.79, 115.2, 102.53, 72.43, 54.75, 31.48, 30.12, 21.74. Chiral HPLC: (S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 4 was eluted using 30% EtOH in hexanes plus 0.1% DEA: 99.0% ee, tR=34.2 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=O)=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:12][C:11]2=[O:17])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2)N1
Reactant: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCCn2ccnn2)c(C=C2C(=O)Nc3cccc(-c4cccc(Cl)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 54.1 %

Procedure:
To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-(1,2,3]triazol-1-yl-ethyl)-amide (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(3-chlorophenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (64 mg, 54%).
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[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:35][C:36]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[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[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:37]5[CH:38]=[CH:39][CH:40]=[C:41]([F:42])[C:36]=5[Cl:35])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Reactant: OB(O)c1cccc(F)c1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cccc(F)c5Cl)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2-chloro-3-fluoro-phenylboronic acid. (1,1′-Bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used in place of tetrakis(triphenylphosphine)palladium(0).
Reaction SMILES: [OH:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:8]([Mg]Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[NH4+]>ClCCl.O=[Mn]=O>[CH2:8]([CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][N:2]1[OH:1])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ON1CCCCC1
Reactant: Cl[Mg]Cc1ccccc1
Agent: O=[Mn]=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: ON1CCCCC1Cc1ccccc1
Reaction time: 1 h
Yield: 32.6 %

Procedure:
Activated MnO2 (1.29 g, 14.8 mmol) was added to a solution of N-hydroxypiperidine (0.50 g, 4.95 mmol) in dichloromethane (25 mL) at 0° C. and the mixture was stirred for 1 h. The reaction mixture was filtered through a pad of Celite™ and Na2SO4. The filtrate was added dropwise to a solution of benzylmagnesium chloride (2.0 M in tetrahydrofuran, 4.95 mL, 9.90 mmol) at −10° C. The reaction mixture was stirred at 0° C. for 0.5 h and then saturated aqueous ammonium chloride solution (25 mL) and dichloromethane (25 mL) were added. The aqueous phase was separated and extracted with dichloromethane (2×30 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The crude product was subjected to flash chromatography on SiO2 eluting with 60% diethyl ether in hexanes to give the title compound (0.309 g, 33%) as a white crystalline solid.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.O.C([O-])([O-])=O.[Na+].[Na+].[CH3:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][N:18]=1>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:7]1[C:2]([C:20]2[CH:19]=[N:18][C:17]([CH3:16])=[CH:22][CH:21]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccnc1Cl
Reactant: Cc1ccc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2ncccc2Cl)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.2 %

Procedure:
To a solution of 0.5 g (3.6 mmol) 2,3-dichloropyridine in 20 mL 1,2-dimethoxyethane and 20 mL distilled water were added 2.2 g (21.1 mmol) Na2CO3, 0.41 g (3.0 mmol) 2-methylpyridine-5-boronic acid and 50 mg Pd(PPh3)4, followed by stirring for 18 hours in a heat flux condition. After being cooled to room temperature, the solution was 50% concentrated in a vacuum condition. The aqueous layer was washed with ethyl acetate. Thereafter, the organic layer was dried over magnesium sulfate and vacuum concentrated. The concentrate was separated using column chromatography (developing solvent: ethyl acetate/hexane=1/10) to produce 0.56 g of 3-chloro-2-(6-methylpyridin-3-yl)pyridine (yield 80%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[OH:13])([O-:3])=[O:2].[C:14](Cl)(=[O:18])[O:15][CH2:16][CH3:17]>N1C=CC=CC=1>[OH:13][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:9]([C:14]([O:15][CH2:16][CH3:17])=[O:18])[N:8]=1
Reactant: O=[N+]([O-])c1ccc2[nH]nc(O)c2c1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)n1nc(O)c2cc([N+](=O)[O-])ccc21
Temperature: 70 °C
Yield: 89.6 %

Procedure:
To a solution of 5-nitro-1H-indazol-3-ol (1.00 g, 5.60 mmol) in pyridine (6.0 mL) was added ethyl carbonochloridate (0.590 μL, 6.14 mmol) and the reaction mixture was heated to 70° C. After 3 hr the reaction mixture was cooled to RT and evaporated in vacuo. The residue was triturated with water (50 mL) to afford ethyl 3-hydroxy-5-nitro-1H-indazole-1-carboxylate as a yellow solid (1.26 g, 85%); Rt 1.70 min (Method 2, acidic); m/z 252 (M+H)+ (ES+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:31])[C@H:15]([NH:19][C:20]3[NH:24][N:23]=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]=3)[CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:32]NN>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:31])[C@H:15]([NH:19][C:20]3[N:24]([CH3:32])[N:23]=[C:22]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:21]=3)[CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)[C@@H](Nc1nc(-c2ccccc2)n[nH]1)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Reactant: CNN
Solvent: C1CCOC1
Product: CC(C)[C@@H](Nc1nc(-c2ccccc2)nn1C)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 47 %

Procedure:
(R)-1-(4-(4-Chlorophenyl)piperidin-1-yl)-3-methyl-2-(3-phenyl-1H-1,2,4-triazol-5-ylamino)butan-1-one (40 mg, 0.09 mmol) was dissolved in THF (0.5 mL) and then treated with MeNHNH2 (10 μL, excess). The reaction was stirred at rt. overnight. After this time, the THF was removed in vacuo and the remains were taken up in MeOH and then purified by preparative HPLC to give (R)-1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methyl-2-(1-methyl-3-phenyl-1H-1,2,4-triazol-5-ylamino)butan-1-one (18 mg, 47%) as a 90/10 mixture of N1—CH3/N2—CH3 isomers. MS found: 452 (M+H).
Reaction SMILES: C1(=O)[N:5]([CH:6]2[C:12](=[O:13])[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[O:8][CH2:7]2)C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][CH:6]1[C:12](=[O:13])[NH:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[O:8][CH2:7]1
Reactant: O=C1Nc2ccccc2OCC1N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: NC1COc2ccccc2NC1=O
Temperature: 25 °C

Procedure:
A suspension of 1.85 g of 3-phthalimido-2,3-dihydro-1,5-benzoxazepin-4(5H)-one in 60 ml of absolute ethanol is treated with 0.31 ml of hydrazine hydrate and the reaction mixture is heated to reflux for 1.5 hr. After cooling to room temperature, the solid is removed by filtration and the filtrate is concentrated in vacuo. The residue is dissolved in chloroform and filtered and concentrated a second time to afford 3-amino-2,3-dihydro-1,5-benzoxazepin-4(5H)-one; m.p. 65°-70°; NMR (CDCl3) δ 6.50-7.60 (m, 4), 3.60-5.30 (m, 3), 3.25 [d (broad), 1].
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].Br[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[N:17]=1>>[CH3:23][O:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:2]#[C:1][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:5][O:6][C:7]=2[CH3:8])[N:17]=1
Reactant: COc1cccc(Br)n1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Product: COc1cccc(C#Cc2c(-c3ccccc3)noc2C)n1
Yield: 67 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-bromo-6-methoxypyridine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 97 mg, 67%) which was obtained as a yellow oil. MS: m/e=291.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([N+:10]([O-])=O)[CH:3]=1.Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.O>CCO.[Pd]>[CH3:9][C:7]1[C:5]2[NH:6][C:14](=[O:16])[NH:10][C:4]=2[CH:3]=[C:2]([CH3:1])[CH:8]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(C)c(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c2[nH]c(=O)[nH]c2c1
Reaction time: 3 h

Procedure:
A mixture of 4,6-dimethyl-2-nitroaniline (10.0 g, 60.2 mmol) and 10% Pd/C (1.0 g) in EtOH (300 mL) was stirred under an atmosphere of hydrogen (ca. 1 atm) for 3 h, then filtered through a celite pad and concentrated in vacuo. The crude solid was dissolved in CH3CN (200 mL) and triphosgene (15.0 g, 50.5 mmol) was added. The mixture was stirred for 1 h, then H2O (200 mL) was added slowly and stirring was continued for 1 h. The precipitate was isolated by filtration and dried to give the title compound. MS: m/z=163 (M+1).