Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:19][CH2:18][C:17]4[S:20][C:21](=[O:23])[NH:22][C:16]=4[CH2:15][CH2:14]3)=[O:12])[CH:10]=2)[CH:7]=1.[CH3:24]I.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:19][CH2:18][C:17]4[S:20][C:21](=[O:23])[N:22]([CH3:24])[C:16]=4[CH2:15][CH2:14]3)=[O:12])[CH:10]=2)[CH:7]=1
Reactant: O=C(c1cc2ncc(Br)cn2n1)N1CCc2[nH]c(=O)sc2CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c2c(sc1=O)CCN(C(=O)c1cc3ncc(Br)cn3n1)CC2

Procedure:
30.0 mg (0.076 mmol) 6-(6-bromo-pyrazolo[1,5-a]pyrimidine-2-carbonyl)-3,4,5,6,7,8-hexahydro-thiazolo[4,5-d]azepin-2-one, 6.3 μL (0.099 mmol) methyliodide, 3.7 mg (0.084 mmol) sodium hydride (50%) in 1.0 mL DMF were stirred at RT for 1 h. The reaction mixture was purified by HPLC chromatography and lyophilized. Yield: 5 mg (16% of theory). ESI-MS: m/z=408 (M+H)+; Rt(HPLC): 0.95 min. (Method N).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[N:18]=[CH:17]2)([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[OH:4].[H-].[Na+].Br[CH2:35][C:36]([O:38]CC)=[O:37].[OH-].[Na+]>CN(C=O)C.CO.[Cl-].[NH4+].C(OCC)(=O)C>[F:31][C:2]([F:1])([F:30])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:35][C:36]([OH:38])=[O:37])[CH:6]=1)([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[N:18]=[CH:17]2)[OH:4]
Reactant: OC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)(c1c[nH]c2ncccc12)C(F)(F)F
Reactant: CCOC(=O)CBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)Cn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2cccnc21
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To a solution of 110.0 mg (0.26 mmol) of 2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethanol in 2 mL of DMF was added 16 mg (0.4 mmol) of 60% sodium hydride in mineral oil followed by 32 μL (0.29 mmol) of ethyl bromoacetate. The reaction was monitored by TLC (ethyl acetate) indicating a new polar product. The reaction was diluted with methanol and made basic with 2N aqueous sodium hydroxide. The mixture stirred for 1 hour and was then monitored by LCMS indicating a mass corresponding to the carboxylic acid (M+=485.30). The reaction was diluted with 7 mL of saturated aqueous ammonium chloride and extracted with three 7 mL portions of ethyl acetate. The combined organic layers were washed with three 7 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 110 mg (88%) of (3-{2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-hydroxyethyl}pyrrolo[2,3-b]pyridin-1-yl)acetic acid which was used without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][C@@H:16]([CH2:21][C:22]#[C:23][C:24]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH:37]3[CH2:39][CH2:38]3)=[C:32]([Cl:40])[CH:31]=2)[N:27]=[CH:26][N:25]=1)[C:17]([O:19][CH3:20])=[O:18])=O)(C)(C)C>ClCCl>[NH2:15][C@@H:16]([CH2:21][C:22]#[C:23][C:24]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH:37]3[CH2:39][CH2:38]3)=[C:32]([Cl:40])[CH:31]=2)[N:27]=[CH:26][N:25]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)[C@H](CC#Cc1cc(-c2ccc(OC3CC3)c(Cl)c2)ncn1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](N)CC#Cc1cc(-c2ccc(OC3CC3)c(Cl)c2)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
Trifluoroacetic acid (6 ml) was added dropwise to a stirred solution of methyl (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-[6-(3-chloro-4-cyclopropoxyphenyl)pyrimidin-4-yl]pent-4-ynoate (2.26 g, 4.8 mmol) in dichloromethane (20 ml) and the mixture was stirred at room temperature overnight. After this time the reaction mixture was concentrated and the resulting residue redissolved in DCM (20 ml) before being washed with saturated sodium bicarbonate. The organic layer was separated, dried (MgSO4), filtered and concentrated to give the title compound (1.64 g, 92% yield) as a brown oil. Tr=1.63 min m/z (ES+) (M+H+) 372, 373.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2Br)[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][CH:27]=2)[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1C(=O)NN=C2COc3cc(Br)c(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Agent: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC1C(=O)NN=C2COc3ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Temperature: 25 °C
Yield: 87.4 %

Procedure:
A degassed mixture of 4-(7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (Preparation #1, Step D, 1.70 g, 5.74 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (3.55 g, 11.48 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloride dichloromethane complex (0.494 g, 0.675 mmol) and K2CO3 (1.58 g, 11.48 mmol) in dioxane (10 mL) and water (2 mL) was heated to reflux for 6 h. The reaction mixture was cooled to ambient temperature and filtered through a pad of Celite®. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 40% EtOAc in petroleum ether) to give 4-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2.0 g, 87%) as a pale white solid. LC/MS (Table 1, Method 3) Rt=1.398 min.; MS m/z: 399 [M+H]+.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(O[C:13](=[O:48])[CH2:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]([O:26][CH3:27])=[O:25])[CH:22]=2)[C:17]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[C:16]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[NH:40]C(OC(C)(C)C)=O)(C)(C)C.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.O>[CH:28]1([C:17]2[C:18]3[CH:19]=[CH:20][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:23]=3[N:15]3[C:16]=2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[NH:40][C:13](=[O:48])[CH2:14]3)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3NC(=O)OC(C)(C)C)n(CC(=O)OC(C)(C)C)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)Nc1ccccc1-3
Temperature: 100 °C
Yield: 75000 %

Procedure:
TFA (5 mL) was added to a solution of methyl 1-(2-tert-butoxy-2-oxoethyl)-2-(2-(tert-butoxycarbonylamino)phenyl)-3-cyclohexyl-1H-indole-6-carboxylate (5.6 g, 10 mmol) in toluene (90 mL) and heated at 100° C. for 1 h. The reaction mixture was allowed to cool and then was carefully poured into a solution of NaHCO3 (10 g) in H2O (200 mL) while stirring. The resulting white precipitate was collected by filtration, flushed with water and EtOAc and dried under N2 to yield methyl 13-cyclohexyl-5H-indolo[1,2-d][1,4]benzodiazepine-6(7H)-one-10-carboxylate (2.9 g, 7.5 mol, 75%) as white solid. LCMS: m/e 389 (M+H)+, ret time 2.22 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:7][C:8]1[N:12]2[N:13]=[C:14](Cl)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1>>[N:1]1([C:14]2[CH:15]=[CH:16][C:11]3[N:12]([C:8]([NH2:7])=[N:9][N:10]=3)[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: Nc1nnc2ccc(Cl)nn12
Product: Nc1nnc2ccc(N3CCCCC3)nn12

Procedure:
A mixture of piperidine and 3-amino-6-chloro-1,2,4-triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 2 to give 6-piperidin-1-yl-[1,2,4]triazolo[4,3-b]pyridazin-3-amine.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.C1([C@H]([NH:20][C@@H:21]2[CH2:30][CH2:29][C:24]3([O:28][CH2:27][CH2:26][O:25]3)[CH2:23][C@@H:22]2[C:31]([O:33][CH2:34][CH3:35])=[O:32])C)C=CC=CC=1>C(O)C.[Pd]>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[NH2:20][C@@H:21]1[CH2:30][CH2:29][C:24]2([O:28][CH2:27][CH2:26][O:25]2)[CH2:23][C@@H:22]1[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)[C@H]1CC2(CC[C@H]1N[C@H](C)c1ccccc1)OCCO2
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)[C@H]1CC2(CC[C@H]1N)OCCO2
Reaction time: 16 h
Yield: 99.1 %

Procedure:
10% Pd/C (Degussa, 50% wet, 1.0 g, 9.40 mmol) was carefully wetted down under argon with ethanol, and then (7S,8R)-ethyl 8-((R)-1-phenylethylamino)-1,4-dioxaspiro[4.5]decane-7-carboxylate p-toluenesulfonic acid salt (10.3 g, 20.37 mmol) in ethanol (75 mL) was added. The mixture was then hydrogenated on a Parr Shaker apparatus for about 16 hours at 50 psi. Under argon, the reaction was carefully filtered through a fiberglass filter paper. The filtrate was concentrated to give (7S,8R)-ethyl 8-amino-1,4-dioxaspiro[4.5]decane-7-carboxylate p-toluenesulfonic acid salt (8.10 g, 20.18 mmol, 99% yield) as a tacky white glass. MS (ESI+)=230.12 (M+H)+.
Reaction SMILES: [OH-].C[Sn+](C)C.[C:6]([C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14](=[O:23])[N:15]2[CH2:18][C:19]([O:21]C)=[O:20])=[CH:10][CH:9]=1)#[N:7]>ClCCCl.ClCCl>[C:6]([C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14](=[O:23])[N:15]2[CH2:18][C:19]([OH:21])=[O:20])=[CH:10][CH:9]=1)#[N:7]
Reactant: COC(=O)Cn1c(=O)ccc2ccc(C#N)cc21
Agent: C[Sn+](C)C
Agent: [OH-]
Solvent: ClCCl
Solvent: ClCCCl
Product: N#Cc1ccc2ccc(=O)n(CC(=O)O)c2c1
Yield: 88.9 %

Procedure:
Trimethyl tin hydroxide (0.388 g, 2.14 mmol) was added to a solution of methyl 2-(7-cyano-2-oxoquinolin-1(2H)-yl)acetate (0.104 g, 0.429 mmol) in 1,2-dichloroethane (5 mL) and the resulting suspension was stirred at reflux for 4 h. The reaction mixture was diluted with dichloromethane and washed with 1N aqueous HCl. Filtration of the organic phase provided 87 mg (89%) of 2-(7-cyano-2-oxoquinolin-1(2H)-yl)acetic acid. Retention time (min)=0.987, method [1], MS(ESI) 229.1 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=2)=[CH:16][CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:10][OH:11])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=2)=[CH:16][CH:15]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)C(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CO)Cc1ccc(-c2ccc(F)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 83.1 %

Procedure:
(2R)-tert-Butoxycarbonylamino-3-(3′-chloro-4′-fluoro-biphenyl-4-yl)-propionic acid (2.0 g, 5.07 mmol) was dissolved in 15 mL anhydrous THF and BH3:THF (11 mL, 11.0 mmol, 1M solution in THF) was added dropwise at 0° C. and stirred for 10 h at room temperature. Excess BH3:THF was quenched by adding methanol (˜1 mL) at 0° C. Solvent was removed under vacuum and residue was dissolved in EtOAc (20 mL) and washed with water, brine and dried over Na2SO4. Solvent was removed under vacuum and silica gel column chromatography (CH2Cl2:MeOH) gave (R)-[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-hydroxymethyl-ethyl]-carbamic acid tert-butyl ester as white solid (1.6 g).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4][S:5][CH2:6][CH2:7]Cl.[CH3:9][C:10]1[CH:22]=[CH:21][C:13]([CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:12][CH:11]=1.[OH-].[K+]>CS(C)=O>[CH2:2]([N:18]1[CH2:19][CH2:20][N:15]([CH2:14][C:13]2[CH:21]=[CH:22][C:10]([CH3:9])=[CH:11][CH:12]=2)[CH2:16][CH2:17]1)[CH2:3][S:4][S:5][CH2:6][CH2:7][N:18]1[CH2:19][CH2:20][N:15]([CH2:14][C:13]2[CH:12]=[CH:11][C:10]([CH3:9])=[CH:22][CH:21]=2)[CH2:16][CH2:17]1
Reactant: ClCCSSCCCl
Reactant: Cc1ccc(CN2CCNCC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1ccc(CN2CCN(CCSSCCN3CCN(Cc4ccc(C)cc4)CC3)CC2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of bis(2-chloroethyl)disulfide (2.9 g) in dimethylsulfoxide (5 ml) is added dropwise to a warmed mixture of (4-methylbenzyl)piperazine (5.7 g), potassium hydroxide (5.0 g), and dimethylsulfoxide (55 ml). The resulting mixture is stirred an additional 4 hours after which it is poured over ice/water and the product extracted with methylene chloride, dried and concentrated. The resulting oil (6.5 g) is purified on a silica gel column (methylene chloride:methanol, 95:5), and the salt precipitated with ethereal hydrochloric acid to provide, after recrystallization from ethanol/water, 1,1'-(dithiodi-2,1-ethanediyl)bis[4-(4-methylbenzyl)piperazine] tetrahydrochloride as a white crystalline solid, m.p. 280°-282° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1OS(C1C=CC(C)=CC=1)(=O)=O)(=[O:3])[CH3:2].[CH:22]#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CCCCCCC.CCOC(C)=O>[C:22]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[NH:4][C:1](=[O:3])[CH3:2])#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: C#CCCCCC
Reactant: CC(=O)Nc1ccccc1OS(=O)(=O)c1ccc(C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCCCC#Cc1ccccc1NC(C)=O

Procedure:
This product was prepared from toluene-4-sulfonic acid 2-acetylamino-phenyl ester and 1-heptyne following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 8:2; yield (92 mg, 80%); 1H NMR δ (CDCl3): 8.47 (d, J=8.51 Hz, 1H), 7.93 (br s, 1H), 7.36 (dm, 1H), 7.31-7.23 (m, 1H), 7.02 (t, J=7.22 Hz, 1H), 2.53 (t, J=7.08 Hz, 2H), 2.21 (s, 3H), 1.63 (p, J=7.11 Hz, 2H), 1.48-1.3 (m, 4H), 0.92 (t, J=7.2 Hz, 3H); LCMS m/z: 229.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:17])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH3:16].[C:18]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][C:21]=1[O:30][CH2:31][CH3:32])#[N:19]>C1COCC1.C1COCC1.CN(C=O)C>[CH3:3][O:4][C:5](=[O:17])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([S:26]([C:23]2[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[C:21]([O:30][CH2:31][CH3:32])[CH:22]=2)(=[O:28])=[O:27])[C:8]=1[CH3:16]
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Reactant: CCOc1cc(S(=O)(=O)Cl)ccc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOc1cc(S(=O)(=O)n2c(C)c(CC(=O)OC)c3cccnc32)ccc1C#N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred, ice-cooled (0° C.) suspension of sodium hydride (26.3 mg of a 60% dispersion in mineral oil, 0.686 mmol) in dry THF (10 ml) under an inert atmosphere of Argon is added dropwise (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((0.1 g, 0.49 mmol) in THF/DMF (4 ml of a 3:1 mixture). The reaction mixture is stirred at 0° C. for 1 hour and then treated with 4-cyano-3-ethoxy-benzenesulfonyl chloride (168 mg, 0.686 mmol) in dry THF (1 ml). Stirring continued at 0° C. for 10 minutes and at room temperature for 10 minutes and then the reaction mixture is poured onto water (50 ml). The mixture is extracted with ethyl acetate (2×50 ml) and the organic portions are combined, washed brine (50 ml), dried (MgSO4) and concentrated in vacuo. The resulting crude is purified by chromatography on silica eluting with iso-hexane/ethyl acetate (0%-20% ethyl acetate) to yield the titled product. (MH+ 414).
Reaction SMILES: [O:1]=[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=2)=[N:4][NH:3]1.NC1N=NC=C(C2C=CC(C(OCC)=O)=CC=2)N=1.NC1N=NC(C2C=CC(C(OCC)=O)=CC=2)=CN=1>>[O:1]=[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:17][CH:18]=2)=[N:4][NH:3]1
Reactant: CCOC(=O)c1ccc(-c2cnc(=O)[nH]n2)cc1
Agent: CCOC(=O)c1ccc(-c2cnc(N)nn2)cc1
Agent: CCOC(=O)c1ccc(-c2cnnc(N)n2)cc1
Product: O=C(O)c1ccc(-c2cnc(=O)[nH]n2)cc1

Procedure:
Using the procedure of example 86a except substituting ethyl 4-(3-oxo-2,3-dihydro-[1,2,4]triazin-6-yl)-benzoate (reference example 87b) for a mixture of ethyl 4-(3-amino-[1,2,4]triazin-5-yl)benzoate and ethyl 4-(3-amino-[1,2,4]triazin-6-yl)benzoate afforded the title compound: 1H NMR (DMSO-d6) d 3.90 [(0.2H, d, J=4.9 Hz), (hydrate)], 7.72 (0.80H, s), 8.05 (3.2H, s), 8.11 [(0.4H, d, J=7.7 Hz), (hydrate)], 8.32 [(0.4H, d, J=7.7 Hz), (hydrate)], 8.77 [(0.2H, s), (hydrate)].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:12]#[N:13])[C:10]=1[OH:11])[C:5]([OH:7])=[O:6].Cl>C(O)CCC>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:12]#[N:13])[C:10]=1[OH:11])[C:5]([O:7][CH2:3][CH2:2][CH2:10][CH3:9])=[O:6]
Reactant: N#Cc1cc(C(=O)O)cc(O)c1O
Agent: Cl
Solvent: CCCCO
Product: CCCCOC(=O)c1cc(O)c(O)c(C#N)c1
Temperature: 100 °C

Procedure:
A solution containing 0.5 g of 3,4-dihydroxy-5-cyanobenzoic acid in 10 ml of 1-butanol was saturated with gaseous hydrogen chloride at 0° C. The solution was then heated for 3 h at 100° C. The solvent was evaporated in vacuo and dichloromethane was added to the residue. The formed crystals were filtered. Yield 0.19 g (30%), m.p. 135°-140° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1.[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1B(O)O>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH:31]1[C:32]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][C:30]=1[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(N3CCCC3)c2)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Nc1ccc(S(=O)(=O)c2cc(-c3ccc4ccccc4c3)nc(N3CCCC3)c2)cc1
Yield: 35.4 %

Procedure:
A mixture of 191 mg (0.5 mmole) 4-(2-bromo-6-pyrrolidine-1-yl-pyridine-4-sulfonyl)-phenylamine, 95 mg (0.55 mmole) 2-naphthylboronic acid, 18 mg bis(triphenylphosphine)-palladium(II)-chloride is refluxed for 2 hours in 20 ml toluene and 5 ml 2N aqueous potassium carbonate. The solvents are removed in vacuo. Flash chromatography (silicagel, ethyl acetate/hexane 1/1) of the residue yields 76 mg (36%) pure 4-(2-naphthalen-2-yl-6-pyrrolidine-1-yl-pyridine-4-sulfonyl)-phenylamine as a pale yellow solid mp.: 244-246° C.
Reaction SMILES: C(O)CO.C(=O)=O.[C:8]([O:11][CH2:12][CH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([CH:20]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:22]=[O:23])[CH2:16][CH2:15]1)(=[O:10])[CH3:9].[BH4-].[Na+]>C(O)C>[C:8]([O:11][CH2:12][CH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([CH:20]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:22][OH:23])[CH2:16][CH2:15]1)(=[O:10])[CH3:9]
Reactant: CC(=O)OCC[C@H]1CC[C@H](C(CC=O)NC(=O)OC(C)(C)C)CC1
Agent: O=C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: OCCO
Solvent: CCO
Product: CC(=O)OCC[C@H]1CC[C@H](C(CCO)NC(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a cooled (ethylene glycol+dry ice) solution of 2-(trans-4-(1-(tert-butoxycarbonylamino)-3-oxopropyl)cyclohexyl)ethyl acetate (1.88 g, 5.5 mmol) in ethanol (90 mL) was added NaBH4 (0.212 g, 5.5 mmol). The mixture was stirred at −10˜15° C. for 10 min and 0° C. for 10 min, and then quenched by addition of saturated aqueous NH4Cl solution (30 mL) and brine (30 mL). After removal of the volatile by evaporation, the aqueous residue was extracted with EtOAc, dried over Na2SO4. Purification by flash column chromatography (eluent: 30% EtOAc in hexanes to 40%) gave the alcohol product (1.0 g, 53%). LC/MC: 366.1 (MNa)+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[N:7]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[N:6]=[CH:5][CH:4]=1.[C:19]([C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[C:19]([C:23]1[CH:24]=[CH:25][C:26]([NH:27][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([N:7]3[C:3]([C:2]([F:1])([F:18])[F:17])=[CH:4][CH:5]=[N:6]3)=[CH:16][CH:15]=2)=[CH:28][CH:29]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O=C(O)c1ccc(-n2nccc2C(F)(F)F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(-n3nccc3C(F)(F)F)cc2)cc1
Temperature: 65 °C

Procedure:
The product from Example 37A (37.3 mg, 0.146 mmol), 4tert-butylaniline (28 μL, 0.18 mmol), PS-DCC (1.27 mmol/g, 0.342 g, 0.435 mmol), HOBT (20.2 mg, 0.149mmol), and triethylamine (0.062 mL, 0.45 mmol) in DMF (1.5 mL) were combined and heated at 65° C. for 16 hours. The mixture was allowed to cool to room temperature, filtered, and the filtrate was diluted with diethyl ether (20 mL). The diethyl ether was washed with water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (15% ethyl acetate in hexanes) to provide the title compound as a solid. 1H NMR (300 MHz, CDCl3) δ 7.99 (d, 2H), 7.83 (br s, 1H), 7.76 (m, 1H), 7.63 (d, 2H), 7.52 (d, 2H), 7.41 (d, 2H), 6.87 (m, 1H), 1.33 (s, 9H); MS (m/z) 388.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[O:12].[OH-:13].[K+]>C(O)C>[CH3:1][C:2]([CH3:11])([CH2:3][OH:13])[CH:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[OH:12]
Reactant: [OH-]
Reactant: O=Cc1ccc2ccccc2c1
Agent: [K+]
Solvent: CCO
Product: CC(C)(CO)C(O)c1ccc2ccccc2c1
Reaction time: 0.17 h
Yield: 181.3 %

Procedure:
2-Naphthoaldehyde (26.0 g, 0.167 mol) and isobutylaldehyde (24.0 g, 0.33 mol) were dissolved in ethanol (50 ml) with heating. 85% Potassium hydroxide (11.0 g, 0.167 mol) dissolved in ethanol (150 ml) was added dropwise to the above solution with stirring. Exothermic reaction started immediately, and the temperature reached to 51° C. and then decreased. After the dropping was completed for about 10 min, the solution was stirred at 55 to 60° C. for 4 hr. The reaction solution was concentrated under reduced pressure, and water (150 ml) was added thereto and the mixture was extracted with chloroform (100 ml) twice. The extract was washed with saturated brine, dehydrated with anhydrous sodium sulfate and concentrated to give the title compound as a brown oil (34.86 g, yield 91.0%).