Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:42])[CH2:7][N:8]([CH:21]1[CH2:29][CH2:28][C:27]2[C:23](=[CH:24][N:25]([C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[C:37]([O:40][CH3:41])[N:38]=4)[N:33]=[CH:32][CH:31]=3)[N:26]=2)[CH2:22]1)[CH2:9][C:10]1[CH:11]=[CH:12][C:13]2[S:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=2[CH:20]=1)(C)(C)C>Cl.CCOCC>[CH3:41][O:40][C:37]1[N:38]=[C:39]2[C:34](=[CH:35][CH:36]=1)[N:33]=[CH:32][CH:31]=[C:30]2[N:25]1[CH:24]=[C:23]2[C:27]([CH2:28][CH2:29][CH:21]([N:8]([CH2:7][C:6]([OH:42])=[O:5])[CH2:9][C:10]3[CH:11]=[CH:12][C:13]4[S:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=4[CH:20]=3)[CH2:22]2)=[N:26]1
Reactant: COc1ccc2nccc(-n3cc4c(n3)CCC(N(CC(=O)OC(C)(C)C)Cc3ccc5c(c3)NC(=O)CS5)C4)c2n1
Agent: Cl
Solvent: CCOCC
Product: COc1ccc2nccc(-n3cc4c(n3)CCC(N(CC(=O)O)Cc3ccc5c(c3)NC(=O)CS5)C4)c2n1
Yield: 94.2 %

Procedure:
A solution of [[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)-amino]-acetic acid tert-butyl ester (5 mg, 0.009 mmol) in 4 M HCl in Et2O (1 mL) was stirred at RT for 3 h. The reaction mixture was concentrated to provide 4.5 mg (100%) of the title compound. MS (ESI): exact mass calculated for C27H26N6O4S, 530.17; m/z found, 531.08 [M+H]+.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:9][C:10](=[O:13])[CH2:11][NH2:12])[CH3:8].Br[CH2:15]/[CH:16]=[CH:17]/[CH2:18]Br.[ClH:20]>C1COCC1>[ClH:20].[CH2:7]([O:9][C:10]([C@:11]1([NH2:12])[CH2:18][C@@H:17]1[CH:16]=[CH2:15])=[O:13])[CH3:8]
Reactant: BrC/C=C/CBr
Reactant: CCOC(=O)CN
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: C=C[C@H]1C[C@@]1(N)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of potassium tert-butoxide (11.55 g, 102.9 mmol) in THF (450 mL) at −78° C. was added the commercially available N,N-dibenzyl imine of glycine ethyl ester (25.0 g, 93.53 mmol) in THF (112 mL). The reaction mixture was warmed to 0° C., stirred for 40 min, and was then cooled back to −78° C. To this solution was added trans-1,4-dibromo-2-butene (20.0 g, 93.50 mmol), the mixture stirred for 1 h at 0° C. and was cooled back to −78° C. Potassium tert-butoxide (11.55 g, 102.9 mmol) was added, the mixture immediately warmed to 0° C., and was stirred one more hour before concentrating in vacuo. The crude product was taken up in Et2O (530 mL), 1N aq. HCl solution (106 mL, 106 mmol) added and the resulting biphasic mixture stirred for 3.5 h at rt. The layers were separated and the aqueous layer was washed with Et2O (2×) and basified with a saturated aq. NaHCO3 solution. The desired amine was extracted with Et2O (3×) and the combined organic extract was washed with brine, dried (MgSO4), and concentrated in vacuo to obtain the free amine. This material was treated with a 4N HCl solution in dioxane (100 mL, 400 mmol) and concentrated to afford (1R,2S)/(1S,2R)-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester hydrochloride as a brown semisolid (5.3 g, 34% yield) identical to the material obtained from procedure A, except for the presence of a small unidentified aromatic impurity (8%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]([OH:23])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.Cl.[NH:58]1[CH2:61][CH:60]([C:62]#[N:63])[CH2:59]1>CN(C=O)C.CO>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]([N:58]1[CH2:61][CH:60]([C:62]#[N:63])[CH2:59]1)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC1CNC1
Reactant: Cc1nnc2ccc3c(cc(C(=O)O)n3Cc3ccccc3)n12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1nnc2ccc3c(cc(C(=O)N4CC(C#N)C4)n3Cc3ccccc3)n12
Reaction time: 0.03 h

Procedure:
To a solution of 6-benzyl-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid (0.010 g, 0.034 mmol, Example 58, Step 4) in DMF (0.5 mL) was added N,N-diisopropylethylamine (0.035 mL, 0.20 mmol) followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.023 g, 0.060 mmol). After stirring for 2 minutes, azetidine-3-carbonitrile hydrochloride (0.012 g, 0.10 mmol, PharmaBlock) was added. When the reaction was determined complete by LCMS, the mixture was diluted with MeOH and purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (6 mg, 50%).
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].[N+:11]([O-])([OH:13])=[O:12]>CC(O)=O>[N+:11]([C:7]1[CH:8]=[C:1]([O:9][CH3:10])[C:2]([O:3][CH3:4])=[CH:5][CH:6]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: COc1ccccc1OC
Solvent: CC(=O)O
Product: COc1ccc([N+](=O)[O-])cc1OC

Procedure:
In SCHEME 5 veratrol (12) is selectively nitrated with 70% HNO3 in AcOH to give 4-nitroveratrol (21). Subsequent reaction of (21) with Buli and TMEDA in THF followed by trimethylborate and hydrochloric acid gives boronic acid (22). Boronic acid (22) is reacted under inert conditions with a brominated aromatic or heteroaromatic ester of generell type (15) under Suzuki-type basic conditions (Pd(PPh3)4 and aqueous sodium bicarbonate in dimethoxyethane) to a biaryl of type (23). Biaryl (23) is further hydrolized with aqueous lithium hydroxide in THF and MeOH or MeCN to give the corresponding carboxylic acid (24) which is converted to a building block of type (25) by reaction with oxalyl chloride in anhydrous dichloromethane.
Reaction SMILES: C([N:4]1[C:9](=[O:10])[NH:8][C:7](=[O:11])[CH:6]=[N:5]1)(=O)C.N1C=CC=CC=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>O1CCOCC1>[C:19]1([C:18]([N:8]2[C:7](=[O:11])[CH:6]=[N:5][NH:4][C:9]2=[O:10])=[O:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)n1ncc(=O)[nH]c1=O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: O=C(c1ccccc1)n1c(=O)cn[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
To a solution of 2-acetyl-1,2,4-triazine-3,5(2H,4H)-dione (1.05 g, 6.77 mmol) in 1,4-dioxane (11 ml) and pyridine (1.64 ml, 20.31 mmol) was treated dropwise at 5° C. with benzoyl chloride (0.90 ml, 7.78 mmol), then the mixture was stirred at room temperature overnight. The day after, 0.1 eq of benzoyl chloride was added and the mixture was stirred at rt for further 4 hours. The reaction mixture was then filtered to remove the piridinium salt and the filtered was evaporated under vacuum. The residue was dissolved in ethanol (23 ml) and then hydrochloride acid 37% (0.74 ml, 24.19 mmol) was added and the reaction was refluxed for 15 minutes. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica eluting with a gradient of methanol in DCM (from 0 to 4%) to afford the title compound as a white solid (0.35 g, 23.47%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH:13]([S:19][CH3:20])[CH:14]([C:16]([OH:18])=O)[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([NH2:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.C1C=C2N=NN(O)C2=CC=1.O.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH:13]([S:19][CH3:20])[CH:14]([C:16](=[O:18])[NH:29][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CSC(C(C)C(=O)O)C1CCCN1C(=O)OC(C)(C)C
Reactant: NCCc1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CSC(C(C)C(=O)NCCc1ccccc1)C1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 41.2 %

Procedure:
To a stirred solution of the crude 2-(2-carboxy-1-methylsulfanyl-propyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (223 mg) obtained above in CH2Cl2 (3 ml) was added phenethylamine(0.18 ml, 1.41 mmol), WSCI monohydrochloride(203 mg, 1.06 mmol), HOBt monohydrate(162 mg, 1.06 mmol) and diisopropylethylamine(0.37 ml, 2.12 mmol) at room temperature. After being stirred at room temperature for 4.5 hr, the mixture was quenched with 1N HCl (20 ml), extracted with AcOEt, dried (MgSO4) and concentrated in vacuo to give a crude oil, which was purified by flash column chromatography (hexane:AcOEt=3:1) to give 2-(1-methylsulfanyl-2-phenethylcarbamoyl-propyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as an oil(123 mg, 43%).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]1[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[C:14](=[O:20])[N:13]([CH3:21])[C:12]2[CH:22]=[C:23]([CH2:26][NH2:27])[CH:24]=[CH:25][C:11]1=2)[CH3:9].[N+:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38])([O-:30])=[O:29].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:8]([N:10]1[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[C:14](=[O:20])[N:13]([CH3:21])[C:12]2[CH:22]=[C:23]([CH2:26][NH:27][S:37]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[N+:28]([O-:30])=[O:29])(=[O:38])=[O:39])[CH:24]=[CH:25][C:11]1=2)[CH3:9]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CNS(=O)(=O)c3ccccc3[N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (0.6 ml) was added to a dichloromethane solution (6 ml) of 1-ethyl-3,3,5-trimethyl-7-aminomethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (1.0 g). The mixture was cooled with ice. 2-Nitrobenzenesulphonyl chloride (0.80 g) was added, and the mixture was stirred at room temperature overnight. A saturated sodium bicarbonate solution was added to the reaction mixture, followed by extraction using dichloromethane.
Reaction SMILES: O1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:15])=[O:7].[C:16]1(C(O)=O)[C:25]2[C:20](=CC=CC=2)[CH:19]=[CH:18][CH:17]=1>>[C:2]1([C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:15])=[O:7])[C:25]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCCN1C(=O)c1ccco1
Reactant: O=C(O)c1cccc2ccccc12
Product: O=C1CCCCCN1C(=O)c1cccc2ccccc12

Procedure:
Synthesized as for N-(2-furoyl)caprolactam (Example X) using 1-naphthoic acid in place of 2-furoic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[C:23]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:22][N:21]=[C:20]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:19]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.CO>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:17][C:18]1[C:23]([NH:24][C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])=[CH:22][N:21]=[C:20]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)/C(=C/c1cc(-c2ccccc2)ncc1NC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C(Cc1cc(-c2ccccc2)ncc1NC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 94.4 %

Procedure:
A suspension of 3D (1.1 g, 2.18 mmol) and platinium 5% wt. on activated carbon (800 mg) in THF (80 mL) and MeOH (80 mL) was stirred at RT under H2 at 70 psi for 2 days. After this time, no starting material was detected by LC-MS. The reaction mixture was filtered and the filtrate was concentrated to give the title compound as a off-white foam (1.04 g, 94%). LC/MS (method A): retention time=3.19 min (M+H)+=506.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.Cl[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:1]2[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(Cc2ccc(OC)cc2)c1
Reaction time: 16 h
Yield: 89.4 %

Procedure:
To ethyl 1H-pyrazole-4-carboxylate (5.01 g, 35.7 mmol) in DMF (60 mL) was added 1-(chloromethyl)-4-methoxybenzene (6.16 g, 39.3 mmol) and K2CO3 (7.41 g, 53.6 mmol). The reaction mixture was stirred for 16 hours and concentrated under reduced pressure to remove DMF. The residue was diluted with EtOAc (100 mL), washed with H2O (30 mL) and brine (20 mL), dried (Na2SO4) and concentrated. Silica gel chromatography (EtOAc/hexanes 1:5) provided the desired product (8.31 g).
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=O)[CH3:5].COC(OC)[N:11]([CH3:13])C.O1CCCC1.O.[NH2:22]N>O.C(OCC)(=O)C>[CH3:5][C:4]1[NH:22][N:11]=[CH:13][C:3]=1[C:2](=[O:7])[CH3:1]
Reactant: NN
Reactant: CC(=O)CC(C)=O
Reactant: COC(OC)N(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cn[nH]c1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A mixture of pentane-2,4-dione (10.01 g) and 1,1-dimethoxy-N,N-dimethylmethanamine (12.51 g) was stirred at 80° C. for 1 hr. Tetrahydrofuran (20 mL) was added to the reaction mixture, hydrazine hydrate (7.51 g) was added by small portions under ice-cooling, and the mixture was stirred at room temperature for 30 min. The reaction mixture was allowed to warm to room temperature, ethyl acetate (100 mL) and water (100 mL) were added, and the separated aqueous layer was extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine (20 mL) and dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give 1-(5-methyl-1H-pyrazol-4-yl)ethanone (12.40 g) as a colorless oil. This was dissolved in N,N-dimethylformamide (10 mL), bromomethylbenzene (18.80 g) and potassium carbonate (15.20 g) were added and the mixture was stirred at 60° C. for 18 hr. The reaction mixture was allowed to warm to room temperature, ethyl acetate (100 mL) and water (100 mL) were added, and the separated aqueous layer was extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine (20 mL) and dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (9.80 g) as a pale-yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:50])[C:30]([CH3:49])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][CH3:48])=[C:42]([CH:46]=2)[C:43](O)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:26][O:27][C:28]1[C:29](=[O:50])[C:30]([CH3:49])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][CH3:48])=[C:42]([CH:46]=2)[C:43]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]
Reactant: COc1ccc(N)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC)c(C(=O)Nc3ccc(OC)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.4 %

Procedure:
p-Methoxyaniline (0.043 g, 0.347 mmol), triethylamine (0.035 g, 0.347 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.059 g, 0.347 mmol) were added to a methylene chloride solution (5 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-methoxybenzoic acid (0.060 g, 0.173 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (ethyl acetate) to obtain the titled compound (0.044 g, 0.0975 mmol, 56%).
Reaction SMILES: C([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:33])[C:14]=2[NH:18][C:19](=[O:32])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)[C:9]1=[O:34])[CH3:7])(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>O>[Cl:33][C:13]1[C:14]([NH:18][C:19](=[O:32])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:30])([F:31])[F:29])[CH:22]=2)=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:34])[N:8]([C@H:6]([CH3:7])[CH2:5][OH:4])[CH:17]=[CH:16]2
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(NC(=O)Cc3ccc(F)c(C(F)(F)F)c3)c(Cl)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C[C@H](CO)n1ccc2c(NC(=O)Cc3ccc(F)c(C(F)(F)F)c3)c(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
A round bottom flask was charged with (R)-2-(6-chloro-5-(2-(4-fluoro-3-(trifluoromethyl)phenyl)acetamido)-1-oxoisoquinolin-2(1H)-yl)propyl acetate (250 mg, 0.00050 mol), potassium carbonate (100 mg, 0.00075 mol) and methanol (8 mL, 0.2 mol) and 2 drops of water. The reaction was stirred at room temperature for 30 minutes. The reaction mixture was filtered, washed with methanol. The solvent was removed and the residue purified by preparative HPLC (reverse phase) to obtain the product as an off white solid (about 150 mg). MS m/z=457.4 (M+1). 1H NMR (400 MHz; DMSO) δ 10.17 (s, 1H), 8.16 (d, J=8.85 Hz, 1H), 7.82 (d, J=7.76 Hz, 1H), 7.72-7.74 (m, 1H), 7.59 (d, J=8.84 Hz, 1H), 7.54-7.49 (m, 2H), 6.42 (d, J=7.50 Hz, 1H), 5.03-4.93 (m, 2H), 3.90 (s, 2H), 3.66-3.56 (m, 2H), 1.28 (d, J=7.63 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[S:9][C:10]([C:14]([OH:16])=O)=[C:11]([CH3:13])[N:12]=2)[C:4](=[O:17])[CH:3]=1.[O:18]1[CH:22]=[CH:21][N:20]=[C:19]1[CH2:23][NH2:24]>>[OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[S:9][C:10]([C:14]([NH:24][CH2:23][C:19]3[O:18][CH:22]=[CH:21][N:20]=3)=[O:16])=[C:11]([CH3:13])[N:12]=2)[C:4](=[O:17])[CH:3]=1
Reactant: NCc1ncco1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)O
Product: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ncco1
Yield: 25 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid to react with oxazol-2-ylmethanamine, the title compound was obtained as a colorless solid in 25% yield: 1H NMR (300 MHz, DMSO-d6) δ 11.51 (s, 1H), 8.84 (t, J=5.7 Hz, 1H), 8.59 (d, J=8.0 Hz, 1H), 8.02 (s, 1H), 7.12 (s, 1H), 6.26 (dd, J=8.0, 2.5 Hz, 1H), 5.82 (d, J=2.5 Hz, 1H), 4.48 (d, J=5.7 Hz, 2H), 2.53 (s, 3H); MS (ES+) m/z 333.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5]([O:8]C)=[C:4]2[O:10][C:11]([CH3:13])=[CH:12][C:3]=12.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[C:3]2[CH:12]=[C:11]([CH3:13])[O:10][C:4]=2[C:5](=[O:8])[NH:6][CH:7]=1
Reactant: COc1ncc(Br)c2cc(C)oc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc2c(Br)c[nH]c(=O)c2o1
Temperature: 0 °C
Yield: 88.4 %

Procedure:
To a mixture of 4-bromo-7-methoxy-2-methylfuro[2,3-c]pyridine (3.0 g, 12.4 mmol) in DCM (30 mL) was stirred at 0° C. under an atmosphere of nitrogen was added BBr3 (15.5 g, 62.0 mmol) dropwise. The mixture was stirred at 0° C. for 3 h. The mixture was concentrated in vacuo to afford the title compound (2.50 g, 88%). The material was immediately used in the next step without any further purification. LCMS (M+H)+=229.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH:23]([OH:25])[CH3:24])=[CH:15][C:14]=3[F:26])=[O:9])=[CH:4][CH:3]=1.CO.C#C>C(Cl)Cl.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][CH2:22][CH:23]([OH:25])[CH3:24])=[CH:15][C:14]=3[F:26])=[O:9])=[CH:27][CH:28]=1
Reactant: CC(O)C#Cc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Agent: [Pd]
Agent: C#C
Solvent: ClCCl
Solvent: CO
Product: CC(O)CCc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reaction time: 1 h
Yield: 71 %

Procedure:
A mixture of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxy-1-butynyl)-3-quinolinecarboxamide from Example No. 96 (173.7 mg) and Pd/C (10%, 34.7 mg) was dissolved in 3:1 CH2Cl2 :MeOH. The reaction mixture was placed under the Parr hydrogenator and monitored with the OAMS for complete reduction of the acetylene. The reaction was completed in 1 hr and filtered over celite to remove the palladium. The filtrate was condensed to obtain a yellow solid. The crude product was recrystallized with EtOAc/hexanes to yield 123.8 mg (71%) of the desired product as an off-white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)([CH3:20])[CH3:19])=[N+:13]([O-:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:16]2[C:27]3[CH:26]=[C:25]([C:28]#[N:29])[CH:24]=[CH:23][C:22]=3[O:21][C:18]([CH3:20])([CH3:19])[CH2:17]2)=[N+:13]([O-:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C=Cc1ccc(OCc2ccccc2)c[n+]1[O-])Oc1ccc(C#N)cc1
Solvent: Cc1ccccc1
Product: CC1(C)CC(c2ccc(OCc3ccccc3)c[n+]2[O-])c2cc(C#N)ccc2O1
Yield: 20.1 %

Procedure:
2.24 g of 5-benzyloxy-2-[3-(4-cyanophenoxy)-3-methyl-1-butenyl]pyridine N-oxide in 45 ml of toluene were heated to 80° C. for 12 hours. The solvent was removed by evaporation and the residue was chromatographed on silica gel using diethyl ether/methanol (97.5:2.5) for the elution to give 0.45 g of 5-benzyloxy-2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide in the form of a white solid of melting point 224° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C@H:13]([CH:17]([CH3:19])[CH3:18])[C:14]([OH:16])=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(NC(=NC(C)C)O[C:26]([CH3:29])([CH3:28])[CH3:27])(C)C>C(Cl)Cl>[C:26]([O:15][C:14](=[O:16])[C@H:13]([NH:12][S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH:17]([CH3:19])[CH3:18])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)N=C(NC(C)C)OC(C)(C)C
Reactant: COc1ccc(S(=O)(=O)N[C@@H](C(=O)O)C(C)C)cc1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N[C@@H](C(=O)OC(C)(C)C)C(C)C)cc1
Temperature: 0 °C

Procedure:
To an ice-cooled solution of 2(R)-(4-methoxybenzenesulfonylamino)-3-methylbutyric acid (30 g, 104.4 mmol), [prepared as described in Example 2, step 1 above], in methylene chloride was added N,N′-diisopropyl-O-tert-butylisourea [can be prepared by the procedure described in Lon J. Mathias, Synthesis, 561-576, (1979)] (75 mL, 3.5 M solution) via additional funnel over 45 min. The reaction mixture was maintained at 0° C. for 2 h, and then allowed to warm to room temperature overnight. Purification by flash chromatography on a silica gel column using (10-20%) ethyl acetate/hexanes as the eluant gave of 2(R)-(4-methoxybenzenesulfonylamino)-3-methylbutyric acid tert-butyl ester (18 g) as a white crystalline solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].[I-:13].[K+].II.[CH3:17][N:18]1[CH2:23][CH2:22][CH2:21][N:20]=[C:19]1[SH:24]>CO.O>[IH:13].[CH3:17][N:18]1[CH2:23][CH2:22][CH2:21][N:20]=[C:19]1[S:24][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]=1[C:10]([OH:12])=[O:11]
Reactant: [I-]
Reactant: CN1CCCN=C1S
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: II
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN1CCCN=C1Sc1c(C(=O)O)[nH]c2ccccc12
Product: I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 28.98 g of indole-2-carboxylic acid in 300 ml of methanol is added to a well-stirred solution of 90 g of potassium iodide and 45.6 g of iodine in 270 ml of water at room temperature. This mixture is further treated with a solution of 23.4 g of 1-methyl-1,4,5,6-tetrahydro-2-pyrimidinethiol in 420 ml of warm methanol. The reaction mixture is stirred for 2 hours at room temperature and worked up in the manner described unter Example 1 to yield 3-(1-methyl-1,4,5,6-tetrahydro-2-pyrimidinylthio)-indole-2-carboxylic acid hydriodide which melts at 230°-231° after recrystallization from a mixture of methanol, ethyl acetate and ether.