Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[C:2]([C:6]1[N:7]=[C:8]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=2)[C:17]([O:19]C)=[O:18])[S:9][CH:10]=1)([CH3:5])([CH3:4])[CH3:3].[ClH:24]>CO>[ClH:24].[C:2]([C:6]1[N:7]=[C:8]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=2)[C:17]([OH:19])=[O:18])[S:9][CH:10]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cccc(OCCc2nc(C(C)(C)C)cs2)c1
Agent: Br
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1csc(CCOc2cccc(C(=O)O)c2)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A mixture of methyl 3-[2-(4-tert-butyl-2-thiazolyl)ethoxy]benzoate hydrobromide (102 mg, 0.25 mmol), methanol (1 ml) and 6 N hydrochloric acid (0.5 ml) was stirred at 60° C. for 2 hours, 6 N hydrochloric acid (1 ml) was added, and the mixture was and stirred at 110° C. for 2 hours. The reaction solution was cooled and concentrated under reduced pressure. The resulting solid material was collected by filtration and washed with acetonitrile and diethyl ether in that order to give 3-[2-(4-tert-butyl-2-thiazolyl)ethoxy]benzoic acid hydrochloride (69 mg, 0.20 mmol, 80%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[OH:12])[CH3:2].Cl>CO.[Pd]>[NH2:9][C:7]1[CH:6]=[CH:5][C:4]([OH:12])=[C:3]([CH2:1][CH3:2])[CH:8]=1
Reactant: CCc1cc([N+](=O)[O-])ccc1O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCc1cc(N)ccc1O
Yield: 122.1 %

Procedure:
A solution of 2-ethyl-4-nitro-phenol (3.34 g, 20.00 mmol) in MeOH (40 ml) and aqueous 1M HCl (20 ml, 20.00 mmol) was hydrogenated in the presence of 10% Pd/C (0.33 g) for 4 h. After removal of the catalyst the reaction was evaporated and suspended in CH2Cl2 and a small amount of MeOH, dried (Na2SO4) and evaporated to give 3.35 g (96%) of 4-amino-2-ethyl-phenol.HCl, MS: 138 (MH+), MP: 239-240° C., dec.
Reaction SMILES: [C:1]([NH:9][CH:10]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@H:11]([S:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH:12]=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][C:32]([CH3:58])([O:34][C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][C@@H:42]([C:44]([N:46]1[CH2:57][CH2:56][CH2:55][C@H:47]1[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[O:45])[NH2:43])=[O:36])[CH3:33].C(O)C.C([BH3-])#N.[Na+]>O1CCCC1>[C:1]([NH:9][C@@H:10]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH:11]([S:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[CH2:12][NH:43][C@H:42]([C:44]([N:46]1[CH2:57][CH2:56][CH2:55][C@H:47]1[C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49])=[O:45])[CH2:41][CH2:40][CH2:39][CH2:38][NH:37][C:35]([O:34][C:32]([CH3:58])([CH3:31])[CH3:33])=[O:36])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reactant: COc1ccc(CS[C@H](C=O)C(Cc2ccccc2)NC(=O)c2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(CSC(CN[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)OC(C)(C)C)[C@H](Cc2ccccc2)NC(=O)c2ccccc2)cc1
Reaction time: 2 h

Procedure:
A mixture of (S)-β-(benzoylamino)-α-[[(4-methoxyphenyl)methyl]thio]-benzenebutanal (isomer A) (0.59 g. 1.40 mmole), 1-[N6 -[(1,1-dimethylethoxy)carbonyl]-L-lysyl]-L-proline, 1,1-dimethylethyl ester (1.55 g., 3.88 mmole), and crushed 3 A° molecular sieves (2.0 g.) in tetrahydrofuran (5 ml.) and absolute ethanol (5 ml.) is stirred at room temperature under argon. After stirring for 2 hours, sodium cyanoborohydride (0.27 g., 3 eq.) is added and stirring continued for 18 hours. The reaction mixture is filtered through Celite to remove the sieves. The filtrate is then diluted with ethyl acetate and washed with water, 1N hydrochloric acid (twice), 1N sodium bicarbonate, and brine. After drying over anhydrous MgSO4, the solvent is removed at reduced pressure to give the desired product, a mixture of diastereomers, as a pale yellow oil. TLC (silica gel, benzene:acetone 4:1) isomer A at Rf =0.31, and isomer B at Rf =0.15. Repeated chromatography (flash, silica gel LPS-1; chloroform:methanol, 98:2; hexane-acetone, 65:35; benzene:acetone, 4:1; ethyl acetate:hexane, 6:4; ethyl acetate:hexane, 6:4) gives 0.41 g. of 1-[N-[(3S)-3-(benzoylamino)-2-[[(4-methoxyphenyl)methyl]thio]-4-phenylbutyl]-N6 -[(1,1-dimethylethoxy)carbonyl]-L-lysyl]-L-proline, 1,1-dimethylethyl ester (isomer A) as a colorless oil.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[C:26](Cl)=[O:27]>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[C:26]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:27]
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Product: CCOC(=NC(=O)c1ccc(OC)c(OC)c1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and 3,4-dimethoxybenzoyl chloride, there is obtained ethyl N-(3,4-dimethoxybenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a solid, mass spectrum m/e: M+ 430 (12), 401 (5), 194 (100), 165 (42);
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][C:19]1[CH:23]=[CH:22][S:21][C:20]=1[C:24](O)=[O:25]>>[CH3:18][C:19]1[CH:23]=[CH:22][S:21][C:20]=1[C:24]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:25]
Reactant: Cc1ccsc1C(=O)O
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: Cc1ccsc1C(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 90.5 %

Procedure:
Beginning with 7.0 mg (0.03 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 12.8 mg (0.09 mMol) 3-methyl-2-thienoic acid, 9.6 mg (90%) of the title compound were recovered.
Reaction SMILES: Cl[C:2](=[N:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=1)[C:3](=[O:5])[CH3:4].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1.C(N(CC)CC)C>C(O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:2](=[N:6][NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[C:3](=[O:5])[CH3:4])=[CH:18][CH:17]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CC(=O)C(Cl)=NNc1cccc(C)c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)C(=NNc1cccc(C)c1)Sc1ccc(Cl)cc1
Yield: 87.6 %

Procedure:
The reaction of 2.88 g (0.0136 mol)of 1-chloro-1-[(3-methylphenyl)hydrazono]-2-propanone with 2.10 g of 4-chlorothiophenol and 2.04 ml of triethyl amine in 35 ml of ethanol as Example 11 yielded 3.8 g of 1-[(4-chlorophenyl)thio]-1-[(3-methylphenyl)hydrazono]-2-propanone, mp 112°-114° C.
Reaction SMILES: Cl.[CH2:2]([NH:5][C:6]([CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][N:9]1[C:17](=[O:33])[C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([O:25]COC)=[CH:20][C:19]=1[O:29]COC)=[O:7])[CH:3]=[CH2:4].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:2]([NH:5][C:6]([CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][N:9]1[C:17](=[O:33])[C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([OH:25])=[CH:20][C:19]=1[OH:29])=[O:7])[CH:3]=[CH2:4]
Reactant: C=CCNC(=O)C1c2ccccc2CN1C(=O)c1cc(Cl)c(OCOC)cc1OCOC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCNC(=O)C1c2ccccc2CN1C(=O)c1cc(Cl)c(O)cc1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Hydrogen chloride (4 mL, 16 mmol; 4 M in dioxane) was added to a solution of N-allyl-2-[5-chloro-2,4-bis(methoxymethoxy)benzoyl]isoindoline-1-carboxamide (392 mg, 0.85 mmol) in DCM (5 mL). The reaction was stirred at room temperature for 12 hours. The reaction mixture was neutralized with saturated NaHCO3 (aq) and then extracted with EtOAc (2×50 mL). The combined organic layers were dried, filtered, and evaporated to give the desired final product as the parent compound (N-allyl-2-(5-chloro-2,4-dihydroxybenzoyl)isoindoline-1-carboxamide) as a white solid (221 mg, 69.7% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.57 (d, J=79.33 Hz, 2 H), 4.65-4.93 (m, 1 H), 4.97-5.19 (m, 1 H), 5.42-5.70 (m, 1 H), 5.68-5.95 (m, 1 H), 6.40-6.71 (m, 1 H), 6.92 (s, 1 H), 7.15-7.67 (m, 4 H), 8.28 (s, 1 H), 10.06 (s, 1 H), 10.40 (s, 1 H). Anal. Calcd for C19H17ClN2O4: C, 61.21; H, 4.60; N, 7.51. Found: C, 61.02; H, 4.63; N, 7.36.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].Br[CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C)P(N(C)C)(N(C)C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(C)Oc1ccc(OCc2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
To 20.0 g of p-(benzyloxy)phenol in 80 ml of dry hexamethylphosphoramide is added 5.4 g of sodium methoxide. The mixture is stirred 10 minutes and 18.1 g of ethyl 2-bromopropionate is added (exotherm). After 15 minutes the mixture is heated on a steam bath for 16 hours. The mixture is poured onto ice, extracted with ether, the ether extracts washed with water, dried over magnesium sulfate and concentrated in vacuo to give off-white crystals, mp 36°-44° C. Two recrystallizations from ethanol give off-white crystals, mp 46°-49° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH2:35][OH:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:36][CH2:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][NH:29][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:27])([F:28])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: NCCOCCCO
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCOCCCO)ccc21
Yield: 83.1 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(3-hydroxy-propoxy)-ethyl]-amide (85 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (82 mg), 3-(2-amino-ethoxy)-propan-1-ol (48 mg), HBTU (91 mg), and DIEA (52 uL). LC/MS: m/z 510.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[CH2:20][OH:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].CI.[C:26](=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[CH2:20][O:21][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(CO)c2cccc(OCc3ccccc3)c2n1
Reactant: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: CN(C)C=O
Product: COCc1cc(C)nc2c(OCc3ccccc3)cccc12
Reaction time: 0.25 h

Procedure:
To a solution of 8-benzyloxy-4-hydroxymethyl-2-methylquinoline (148 mg) in N,N-dimethylformamide (1.5 ml) was added sodium hydroxide (60% in oil, 23.3 mg) under ice-cooling, and the mixture was stirred for 15 minutes at the same temperature. To the mixture was added methyl iodide (82.7 mg) under ice-cooling, and the mixture was stirred for 15 minutes at the same temperature and then overnight at ambient temperature. To the mixture was added saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water twice, dired over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (Ethyl acetate:n-hexane=1:3, V/V) to give 8-benzyloxy-4-methoxymethyl-2-methylquinoline (123 mg) as pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:7][CH:6]([C:8]2[C:16]3[C:11](=[C:12]([C:24]([NH2:26])=[O:25])[CH:13]=[C:14]([C:17]4[CH:21]=[C:20]([CH:22]=O)[S:19][CH:18]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:5][CH2:4][S:3]1(=[O:28])=[O:27].[NH:30]1[CH2:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[N:30]1([CH2:22][C:20]2[S:19][CH:18]=[C:17]([C:14]3[CH:15]=[C:16]4[C:11](=[C:12]([C:24]([NH2:26])=[O:25])[CH:13]=3)[NH:10][CH:9]=[C:8]4[CH:6]3[CH2:5][CH2:4][S:3](=[O:28])(=[O:27])[C:2]([CH3:1])([CH3:29])[CH2:7]3)[CH:21]=2)[CH2:33][CH2:32][CH2:31]1
Reactant: CC1(C)CC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CCS1(=O)=O
Reactant: C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CC1(C)CC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCC5)c4)cc23)CCS1(=O)=O
Yield: 36.3 %

Procedure:
3-(2,2-Dimethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (30 mg, 0.070 mmol) was dissolved in dimethyl sulfoxide (1.5 mL) and put in a microwave vial. The mixture was stirred and 1-2 drops of acetic acid and azetidine (0.047 mL, 0.697 mmol) was added. The mixture was left stirring 30 minutes at 23° C., before adding sodium triacetoxyborohydride polymer bound (299 mg, 0.697 mmol). The vial was sealed using a silicon septum, and the mixture left stirring 16 h at 23° C. Based on LCMS only 60-70% of conversion was observed. The sodium triacetoxyborohydride polymer bound was removed by filtration. The crude product was purified by preparative HPLC(NH4OH buffer). The desired fractions were concentrated, giving 12 mg of the title compound.
Reaction SMILES: CO[C:3](=[O:18])[C:4]([C:6]1[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[S:11][CH2:10][CH2:9][N:8]3[CH:7]=1)=O.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28][C:29]([NH2:31])=[O:30])=[CH:20]1>>[C:6]1([C:4]2[C:3](=[O:18])[NH:31][C:29](=[O:30])[C:28]=2[C:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:19][CH:20]=2)[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[S:11][CH2:10][CH2:9][N:8]3[CH:7]=1
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)SCC2
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)SCC3)=C1c1c[nH]c2ccccc12

Procedure:
Beginning with (3,4-dihydro-5-thia-2a-aza-acenaphthylen-1-yl)oxoacetic acid methyl ester and (indol-3-yl)acetamide, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[OH:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:28](=[O:29])[CH2:27][C:24]3[CH:25]=[CH:26][C:21]([OH:20])=[CH:22][CH:23]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Product: O=C(Cc1ccc(O)cc1)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product of Example 86A and 2-(4-hydroxyphenyl)acetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.38-8.42 (m, 1H), 7.95-8.02 (m, 2H), 7.72-7.75 (m, 1H), 7.60-7.67 (m, 4H), 7.17-7.19 (m, 2H), 6.73-6.75 (m, 2H), 3.57 (s, 2H); MS (ESI−) M/Z 404 (M−H)−.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[O:14])[CH3:12])[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+].OS([O-])(=O)=O.[K+].CCOCC>O1CCOCC1>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:13]([N:11]([CH3:12])[C@H:8]2[CH2:7][CH2:6][C@H:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]2)=[O:14])=[CH:21][CH:20]=1
Reactant: COC(=O)[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(Cl)cc2)CC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](C(=O)O)CC1
Reaction time: 3 h

Procedure:
A solution of 1.1 g (3.37 mmol) of trans-4-[(4-chloro-phenoxycarbonyl)-methyl-amino]-cyclohexanecarboxylic acid methyl ester was dissolved in 25 mL of dioxane and treated at 0° C. with 6.7 mL (6.70 mmol, 2 eq) of aqueous 1M NaOH. After 3 h at RT, the reaction was poured into aqueous 10% KHSO4/Et2O (3×). The organic phases were washed with aqueous 10% NaCl solution and dried over Na2SO4 to give 0.97 g (92%) of trans-4-[(4-chloro-phenoxycarbonyl)-methyl-amino]-cyclohexanecarboxylic acid, MS: 310 (M−H−, 1Cl).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=4)[N:27]([CH2:35][CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[N:26]=3)=[CH:23][N:24]=[C:19]2[N:18](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=1)=[O:15])([CH3:12])[CH3:11])(C(C)(C)C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:34][C:30]1[CH:29]=[C:28]2[C:33]([C:25]([C:22]3[N:21]=[C:20]4[C:16]([C:14]([NH:13][C:10]([CH3:12])([CH3:11])[CH2:9][OH:8])=[O:15])=[CH:17][NH:18][C:19]4=[N:24][CH:23]=3)=[N:26][N:27]2[CH2:35][CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])=[CH:32][CH:31]=1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3nn(CCCS(C)(=O)=O)c4cc(F)ccc34)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CO)NC(=O)c1c[nH]c2ncc(-c3nn(CCCS(C)(=O)=O)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
To a stirred solution of N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-fluoro-1-(3-(methylsulfonyl)propyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (35 mg, 0.042 mmol) in DCM (2 mL) was added trifluoroacetic acid (1 mL) dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 h, then concentrated in vacuo. The residue obtained was dissolved in DCM, washed with NaHCO3 (aq.), and then the organic layer was concentrated and purified by prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; 25% acetonitrile/75% water (doped with 0.1% TFA, v/v) to 42% acetonitrile/58% water (doped with 0.1% TFA, v/v) over 9 min) to give 2-(6-fluoro-1-(3-(methylsulfonyl)propyl)-1H-indazol-3-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (10 mg, 50%) as a white solid. 1H NMR (300 MHz, DMSO): δ 12.81 (s, 1H), 9.10 (s, 1H), 8.63-8.58 (m, 1H), 8.37 (s, 1H), 7.90 (s, 1H), 7.71 (d, 1H, J=8.1 Hz), 7.16 (t, 1H, J=9.2 Hz), 5.08 (t, 1H, J=5.5 Hz), 4.62 (t, 2H, J=6.6 Hz), 3.60 (d, 2H, J=5.4 Hz), 3.18 (t, 2H, J=6.4 Hz), 2.96 (s, 3H), 2.32 (t, 2H, J=7.6 Hz), 1.43 (s, 6H). LC/MS: 489.2 [M+H]+, 487.0 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](O)=[N:6][CH:7]=1.P(Br)(Br)[Br:13].O>C1(C)C=CC=CC=1.CN(C=O)C>[Br:13][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Reactant: BrP(Br)Br
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(Br)cnc1Br
Temperature: 120 °C
Yield: 80 %

Procedure:
To a solution of 5-Bromo-3-nitro-pyridin-2-ol (10.0 g, 45.66 mmol) in 70 ml of toluene and 7 ml of DMF was added PBr3 (6.60 ml, 68.49 mmol) and the reaction mixture was heated at 120° C. for 20 min under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (100 mL) was added and extracted with ethyl acetate (3×200 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated to get the desired product (10.30 g, 80.03%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:11][CH2:10]1.Br.[OH-].[Na+]>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]1
Reactant: Cc1ccc(S(=O)(=O)N2CCN(c3cnc(C)cc3C)CC2)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1cc(C)c(N2CCNCC2)cn1
Temperature: 100 °C
Yield: 62.3 %

Procedure:
To 5-amino-2,4-dimethylpyridine (883 mg) were added N,N-diisopropylethylamine (2.1 mL) and N,N-bis(2-chloroethyl)-p-toluenesulfonamide (2.08 g), and the mixture was stirred with heating under reflux. After completion of the reaction, water was added to the reaction mixture, the mixture was extracted with chloroform, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give 1-(4,6-dimethylpyridin-3-yl)-4-(toluene-4-sulfonyl)piperazine (380 mg). The obtained 1-(4,6-dimethylpyridin-3-yl)-4-(toluene-4-sulfonyl)piperazine (380 mg) was dissolved in acetic acid (2 mL), 40% hydrobromic acid (2 mL) was added, and the mixture was stirred at 100° C. After completion of the reaction, the reaction mixture was neutralized with aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer to give the title compound (131 mg).
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]([CH3:19])[CH3:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]1=[O:20].FC(F)(F)C(O)=O>>[CH:17]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:7]([CH2:6][CH:2]=[O:1])[C:8](=[O:20])[CH:9]=[CH:10]2)([CH3:19])[CH3:18]
Reactant: CC(C)c1ccc2c(ccc(=O)n2CC2OCCO2)c1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc2c(ccc(=O)n2CC=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 0.42 g of 1-(1,3-dioxolan-2-ylmethyl)-6-isopropylquinolin-2(1H)-one, 4 mL of a 90% aqueous trifluoroacetic acid solution was added, and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and ethyl acetate and an aqueous saturated sodium hydrogen carbonate solution were added thereto. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 0.41 g of a pale yellow oily substance, (6-isopropyl-2-oxoquinolin-1(2H)-yl)acetaldehyde.
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[C:11]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)(=O)[CH3:12]>C(O)C>[ClH:1].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]/[N:10]=[C:11](\[C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)/[CH3:12])=[CH:5][CH:4]=1
Reactant: NNc1ccc(Br)cc1
Reactant: CC(=O)c1cccnc1
Agent: Cl
Solvent: CCO
Product: C/C(=N/Nc1ccc(Br)cc1)c1cccnc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of 4-bromophenylhydrazine hydrochloride (11.5 g, 50 mmol) in anhydrous ethanol (200 mL) is added 3-acetylpyridine (6.1 g, 50 mmol). The mixture is heated to 90° C. and stirred for 3 h, cooled to room temperature and filtered through a sintered glass funnel. The solid is washed with ethanol and placed under high vacuum overnight to give N-(4-bromo-phenyl)-N′-[1-pyridin-3-yl-eth-(Z)-ylidene]-hydrazine hydrochloride as a yellow solid.