Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Li]CCCC.[C:15]1([C:21]2[S:25][C:24]([CH:26]=[O:27])=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:26]([C:24]2[S:25][C:21]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:22][CH:23]=2)[OH:27])=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cc1
Reactant: O=Cc1ccc(-c2ccccc2)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2ccc(-c3ccccc3)s2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
To a solution of 4-bromoanisole (0.6 g, 3.2 mmol) in THF was added n-BuLi (2.5M in hexane, 1.5 mL, 3.5 mmol) at −78° C., and continued to stir for 30 min. The product of step 1 (0.48 g, 2.6 mmol) was added. After it was stirred at −78° C. for 30 min, the reaction was allowed to warm to room temperature and stirred for an additional 1 h. The reaction was quenched with water, extracted with EtOAc, washed with brine and dried over Na2SO4. After the solvent was removed, the residue was purified by a column chromatography on silica gel to yield the title compound (0.6 g, 68%).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[C:5](=[CH:10][C:11]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=1)[C:6]([O:8]C)=[O:7].O.[OH-].[Li+]>CO.O>[NH:14]([C:12]1[CH:13]=[C:4]([C:3]([OH:28])=[O:2])[C:5](=[CH:10][C:11]=1[NH:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:6]([OH:8])=[O:7])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1cc(Nc2ccccc2)c(Nc2ccccc2)cc1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(Nc2ccccc2)c(Nc2ccccc2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A steady stream of argon is passed through a suspension of 26.35 g (70.0 mmol) of 4,5-bis(anilino)phthalic acid dimethylester in 230 ml of methanol, and a solution of 11.78 g (280 mmol, 2 eq) of lithium hydroxide monohydrate in 116 ml of water is added. The reaction mixture is heated toreflux for 2.5 h, cooled to RT and diluted with 400 ml water. Methanol is removed by evaporation, the resulting solution is cooled to 0°, and70 ml 4N hydrochloric acid are added. After 15 min. at 0°, the gray crystals are filtered off, washed with water and resuspended twice in 200 ml toluene with removal of the toluene by distillation to yield the title compound in the form of gray crystals, FAB-MS: 349 [M+ +H].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Cl[C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[N:12]1[CH:13]=[CH:14][CH:15]=[N:16][C:11]=1[O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: Clc1ncccn1
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1cccc(Oc2ncccn2)c1
Yield: 70.9 %

Procedure:
EX-605A) A slurry of 3-hydroxybenzaldehyde (1.22 g, 10 mmol), 2-chloropyrimidine (1.14 g, 10 mmol) and K2CO3 (1.65 g, 12 mmol) in DMSO (20 mL) was heated to 100° C. for 1 h. The cooled mixture was poured into water and extracted with Et2O. The organic layer was washed with 2.5 N NaOH, 1 N HCl, saturated NaHCO3 and brine, dried (MgSO4) and evaporated to yield 1.42 g (71%) of the desired 3-(2-pyrimidinyl-oxy)benzaldehyde product as a white solid which was used without further purification. 1H NMR (C6D6) δ7.12 (t, 1H), 7.54 (m, 1H), 7.66 (t, 1H), 7.78 (m, 1H), 7.83 (m, 1H), 8.64 (d, 2H), 10.05 (s, 1H).
Reaction SMILES: Br[CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1>>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([S:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH3:7]
Reactant: CCCCCCC(Br)C(=O)OCC
Reactant: COc1ccc(S)cc1
Product: CCCCCCC(Sc1ccc(OC)cc1)C(=O)OCC

Procedure:
2-(4-Methoxy-phenylsulfanyl)-octanoic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from ethyl 2-bromooctanoate (11.8 g, 47.3 mmol) and 4-methoxythiophenol (6 g, 43 mmol). Yield: 7.24 g (57%); clear oil; MS: 311.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[O:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]2([OH:15])[CH2:13][CH2:14][O:9][CH2:10][CH2:11]2)=[CH:3][CH:4]=1
Reactant: O=C1CCOCC1
Reactant: Brc1ccc(Br)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: OC1(c2ccc(Br)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1,4-Dibromobenzene (1 17.96 g, Aldrich) in tetrahydrofuran (THF) (700 ml) was cooled to -7020 C. under nitrogen and butylithium (175 ml) was added dropwise. After stirring the mixture for 15 minutes, tetrahydro-4H-pyran4-one (25 g, Aldrich) in the THF (300 ml) was added. The reaction was left for 2 hours before being allowed to warm to room temperature. The reaction mixture was shaken with 5% citric acid (800 ml), then extracted with diethyl ether (3×600 ml). The combined organic layers were washed with water (500 ml), and dried over MgSO4. Removal of the solvent from the filtrate gave the crude tide product as an off-white solid.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])[N:20]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.[C:39](=O)([O-])[O-].[K+].[K+].IC.[H-].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([N:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([O:34][CH2:35][CH:36]([CH3:37])[CH3:38])[N:20]=3)[CH3:39])[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CC(c1cc(NCc2ccc(-c3cc(OC)ccc3F)c(OCC(C)C)n2)ncn1)C1CC1
Agent: [Cl-]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)CC(c1cc(N(C)Cc2ccc(-c3cc(OC)ccc3F)c(OCC(C)C)n2)ncn1)C1CC1
Temperature: 40 °C
Reaction time: 17 h
Yield: 56.2 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(6-(((5-(2-fluoro-5-methoxyphenyl)-6-isobutoxypyridin-2-yl)methyl)amino)pyrimidin-4-yl)propanoate (52 mg) in DMF (3.0 mL) were added potassium carbonate (21 mg) and iodomethane (20 μL), and the mixture was stirred at 40° C. for 17 hr. 60% Sodium hydride (10 mg) was added, and the mixture was stirred at room temperature for 1 hr. Saturated aqueous ammonium chloride solution was added, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (30 mg) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:21])=[CH:4][C:3]=1[CH:22]=O.[OH-].[K+].[C:26]1([CH2:31][C:32]#[N:33])[CH2:30][CH2:29][CH2:28][CH:27]=1>CS(C)=O>[NH2:33][C:32]1[C:31]([C:26]2[CH2:30][CH2:29][CH2:28][CH:27]=2)=[CH:22][C:3]2[C:2](=[CH:7][CH:6]=[C:5]([C:8]3[C:9]([CH3:21])=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:4]=2)[N:1]=1
Reactant: Cc1cccc(C(=O)N2CCCC2)c1-c1ccc(N)c(C=O)c1
Reactant: N#CCC1=CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1cccc(C(=O)N2CCCC2)c1-c1ccc2nc(N)c(C3=CCCC3)cc2c1

Procedure:
A solution of 4-amino-2′-methyl-6′-(pyrrolidine-1-carbonyl)biphenyl-3-carbaldehyde (0.040 g, 0.13 mmol, prepared as in Example 57, Steps 2-5), KOH (10.9 mg, 0.195 mmol) (11 M solution, 18 uL), 1-cyclopenteneacetonitrile (0.022 mL, 0.20 mmol) and DMSO (0.8 mL) was heated in a Biotage microwave at 140° C. for 5 min. LCMS indicated good conversion to desired product. The crude material was purified by prep HPLC (21-60% CH3CN/water modified with 0.1% TFA), and again by prep HPLC (10-90% CH3CN/water modified with 0.1% NH4OH) to give (2-(2-amino-3-cyclopentenylquinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanone as a yellow solid. MS (ESI, pos. ion) m/z: 398 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([OH:9])=O)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.Cl.[CH3:23][NH:24][O:25][CH3:26].N1C=CC=CC=1>CN(C)C=O.ClCCl>[CH3:23][N:24]([O:25][CH3:26])[C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:12]([N+:13]([O-:15])=[O:14])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
Cool a mixture of 3,4-dinitrobenzoic acid (195 g, 0.92 moles), 1.3 L of dry dichloromethane, and 2 mL dimethylformamide to −12° C. under a nitrogen atmosphere. Add oxalyl chloride (134 ml, 1.54 moles) dropwise via addition funnel over 35 minutes and stir the reaction mixture at room temperature under a nitrogen atmosphere overnight. Remove excess oxalyl chloride from the reaction mixture by repetitive cycles of concentrating a dichloromethane solution of the reaction mixture under reduced pressure. Cool a mixture of the residue in 1 L dichloromethane to −5° C. under a nitrogen atmosphere and add N,O-dimethylhydroxylamine hydrochloride (98.7 g, 1.01 moles) followed by the careful addition of 209 mL (2.62 moles) of dry pyridine in portions. Stir the mixture at room temperature for 4 hours and then concentrate under reduced pressure. Suspend the residue in 500 mL dichloromethane and concentrate under reduced pressure twice. Suspend the residue in 500 mL dichloromethane and filter. Store the filtrate at −13° C. for 3 days, filter the solid and rinse with cold dichloromethane. Dilute the filtrate with water (40 mL) and stored at −13° C. again to provide a second crop. Dry the combined crops under reduced pressure to provide 182 g (77%) of the desired compound.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]([CH3:8])[CH2:6][C@@H:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])[N:18]=2)[CH2:4][C@H:3]1[NH:33]C(=O)OC(C)(C)C.[C:41](OC(=O)C)(=[O:43])[CH3:42]>>[C:41]([NH:1][C@@H:2]1[C@@H:7]([CH3:8])[CH2:6][C@@H:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])[N:18]=2)[CH2:4][C@H:3]1[NH2:33])(=[O:43])[CH3:42]
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1N
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N[C@H]1[C@H](N)C[C@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H]1C
Yield: 13 %

Procedure:
Method 4 was followed using tert-butyl ((1R,2R,3S,5R)-2-amino-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methylcyclohexyl)carbamate and acetic anhydride to give N-(4-((1R,3R,4R,5S)-4-acetamido-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide in 13% yield. LC/MS (m/z)=498.3 (MH+), Rt=0.58 min.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][NH:11][CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1>C(#N)C>[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][N:11]2[CH2:10][CH2:9][NH:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12]2)=[CH:16][CH:15]=1
Reactant: c1ccc(C2CNCCN2)cc1
Reactant: ClCc1ccc(Br)cc1
Solvent: CC#N
Product: Brc1ccc(CN2CCNC(c3ccccc3)C2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2 g of 2-phenylpiperazine were dissolved in acetonitrile and cooled to 0° C. A solution of 0.5 quiv. 4-bromobenzylchloride in acetonitrile was added dropwise over 1 h. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (silica, eluent dichloromethane, 0-5% methanol) to afford 1 g of 1-(4-bromo-benzyl)-3-phenyl-piperazine. ES MS (+) m/z 301.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.[CH2:16]([NH2:19])[CH:17]=[CH2:18]>O1CCCC1.O>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([NH:19][CH2:16][CH:17]=[CH2:18])=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CC(Oc2ccc(Br)cc2)C1
Reactant: C=CCN
Solvent: C1CCOC1
Solvent: O
Product: C=CCNC(=O)N1CC(Oc2ccc(Br)cc2)C1
Reaction time: 18 h
Yield: 59.5 %

Procedure:
A stirred solution of 5.8 g (0.02 mole) of 3-(4-bromophenoxy)-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was treated with 4.5 g (0.06 mole) of 2-propenylamine and stirring continued for 18 hr. The reaction mixture was diluted with 200 ml of water and the oil which separated slowly solidified. After collecting the solid by filtration, it was triturated 4 times with boiling isopropyl ether. The combined triturates upon cooling yielded 3.7 g (59.5%) of white crystals, m.p. 100°-101° C.
Reaction SMILES: [OH:1][C@H:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].C(N(CC)CC)C.[C:21](OC(=O)C)(=[O:23])[CH3:22].S(=O)(=O)(O)O>ClCCl.CN(C)C1C=CN=CC=1>[C:21]([O:1][C@H:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)[C@H](O)CCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@H](CCc1ccccc1)C(=O)O
Reaction time: 3 h
Yield: 99.1 %

Procedure:
A(ii)(a) A solution of 18 g of 2(R)-hydroxy-4-phenylbutanoic acid in 200 ml of dichloromethane containing 20.5 g of triethylamine and 250 mg of 4-(dimethylamino)pyridine was stirred at room temperature and treated dropwise with 12 g of acetic anhydride. The resulting mixture was stirred for a further 3 hours and then acidified by the addition of 125 ml of 2N sulphuric acid. The organic phase was separated and washed with two 100 ml portions of 2N sulphuric acid, then with 100 ml of water and finally with 100 ml of saturated sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated in vacuo to give 22 g of 2(R)-acetoxy-4-phenylbutanoic acid as a colouless viscous oil; [α]43620 =+13.7° (c=1 in ethanol).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:10][CH2:11][CH2:12][CH3:13])[C:5]([CH3:9])=[C:6]([CH3:8])[CH:7]=1.[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>N1C=CC=CC=1.O1CCCC1.C(OCC)(=O)C>[CH2:10]([N:4]1[C:5]([CH3:9])=[C:6]([CH3:8])[CH:7]=[C:2]([NH:1][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:16]([F:15])=[CH:17][CH:18]=2)[C:3]1=[O:14])[CH2:11][CH2:12][CH3:13]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCCCn1c(C)c(C)cc(N)c1=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCn1c(C)c(C)cc(NC(=O)c2ccc(F)cc2)c1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 54.2 %

Procedure:
3-Amino-1-butyl-5,6-dimethyl-2-pyridone (5-004-02) (117 mg) was dissolved in pyridine, (1 mL), and the reaction mixture was stirred under ice-cooling and nitrogen atmosphere, and to the reaction mixture was added dropwise a solution of 4-fluorobenzoyl chloride (0.08 mL) in tetrahydrofuran (1 mL) over 10 min, followed by stirring at the same condition. After 3 h, the reaction mixture was diluted with ethyl acetate and poured into ice-water, extracted once with ethyl acetate, washed with aqueous hydrochloric acid solution, water, an aqueous solution of sodium bicarbonate, and water, dried over magnesium sulfate, and evaporated under reduced pressure. The obtained crystal residue (202 mg) was recrystallized from methylene chloride/n-hexane to give 1-butyl-3-(4-fluorobenzoyl)amino-5,6-dimethyl-2-pyridone (5-004) (103 mg, 54.2%, m.p. 129 to 130° C.) as a colorless needle.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:17]1[C:22]([C:23]([O:25]C)=O)=[C:21]([O:27][CH3:28])[N:20]=[CH:19][CH:18]=1.[NH3:29]>CO>[CH3:28][O:27][C:21]1[N:20]=[CH:19][CH:18]=[C:17]2[C:22]=1[C:23](=[O:25])[NH:29][C:15]([CH2:14][CH2:13][CH2:12][N:3]1[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]1=[O:11])=[CH:16]2
Reactant: COC(=O)c1c(C#CCCCN2C(=O)c3ccccc3C2=O)ccnc1OC
Reactant: N
Solvent: CO
Product: COc1nccc2cc(CCCN3C(=O)c4ccccc4C3=O)[nH]c(=O)c12
Temperature: 115 °C

Procedure:
Methyl 4-(5-(1,3-dioxoisoindolin-2-yl)pent-1-ynyl)-2-methoxynicotinate (100 mg, 0.26 mmol) is dissolved in 7% NH3 in MeOH (3 mL) and heated at 115° C. in a sealed tube for 24 hours. The reaction mixture is cooled and the solvents are removed by evaporation. The cyclized product is separated using silica gel column chromatography using hexan:ethyl acetate as solvent. MS m/z 364.1 (M+1).
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:15][CH2:16][C:17]1[C:18]([F:34])=[C:19]([O:24][C:25]2[CH:26]=[C:27]([CH:30]=[C:31]([Cl:33])[CH:32]=2)[C:28]#[N:29])[C:20]([Cl:23])=[CH:21][CH:22]=1.[NH:35]1[CH:39]=[N:38][C:37]([C:40](O)=[O:41])=[N:36]1>CN(C=O)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][NH:15][C:40]([C:37]2[N:38]=[CH:39][NH:35][N:36]=2)=[O:41])=[C:18]([F:34])[C:19]=1[O:24][C:25]1[CH:26]=[C:27]([C:28]#[N:29])[CH:30]=[C:31]([Cl:33])[CH:32]=1
Reactant: O=C(O)c1nc[nH]n1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3nc[nH]n3)c2F)c1
Yield: 39.1 %

Procedure:
The title compound was prepared in a similar manner to that described herein using EDC (0.068 g, 0.354 mmol), HOBT (0.048 g, 0.354 mmol), 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.100 g, 0.321 mmol) and 1H-1,2,4-triazole-3-carboxylic acid (0.036 g, 0.321 mmol) in DMF (2 mL) to give title compound (0.051 g, 39%) as a white solid. 1H NMR (400 MHz, DMSO-d6) (95° C.) δ ppm 14.24 (br. s., 1H), 8.60 (br. s., 1H), 7.72 (s, 1H), 7.33-7.49 (m, 5H), 4.55 (d, 2H). ES MS: m/z 406 (M+1).
Reaction SMILES: [O:1]=[C:2]1[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:5](=[O:12])[CH2:4][S:3]1.[F:13][C:14]1[CH:31]=[CH:30][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([CH:28]=O)=[CH:25][CH:26]=3)[CH:21]=[N:20]2)=[C:16]([C:32]([F:35])([F:34])[F:33])[CH:15]=1>>[F:13][C:14]1[CH:31]=[CH:30][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24](/[CH:28]=[C:4]4/[C:5](=[O:12])[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:2](=[O:1])[S:3]/4)=[CH:25][CH:26]=3)[CH:21]=[N:20]2)=[C:16]([C:32]([F:33])([F:35])[F:34])[CH:15]=1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(F)cc2C(F)(F)F)c1
Reactant: CS(=O)(=O)NN1C(=O)CSC1=O
Product: CS(=O)(=O)NN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(F)cc3C(F)(F)F)c2)C1=O

Procedure:
N-[(5Z)-5-({1-[4-Fluoro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methanesulfonamide was prepared from N-(2,4-dioxothiazolidin-3-yl)methanesulfonamide (from Example 360) and [4-fluoro-2-(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (from Example 5) following General Procedure E.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([CH3:23])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][N:19]=[CH:18][CH:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1(C)[O:51][CH2:50][CH:49]([CH2:52]O)[CH2:48][O:47]1.S(=O)(=O)(O)O.[OH-].[Na+]>O1CCCC1.O>[CH3:25][O:24][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:52][CH:49]([CH2:50][OH:51])[CH2:48][OH:47])[N:9]=[CH:8][CH:7]=[C:6]2[O:12][C:13]1[C:14]([CH3:23])=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][N:19]=[CH:18][CH:17]=2
Reactant: CC1(C)OCC(CO)CO1
Reactant: COc1cc2c(Oc3cc4cnccc4nc3C)ccnc2cc1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(Oc3cc4cnccc4nc3C)ccnc2cc1OCC(CO)CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.4 %

Procedure:
3-(7-Hydroxy-6-methoxy-quinolin-4-yloxy)-2-methyl-[1,6]naphthyridine (85 mg) was dissolved in tetrahydrofuran (2 ml) to prepare a solution. Triphenylphosphine (134 mg), (2,2-dimethyl-[1,3]dioxan-5-yl)-methanol (45 mg), and diethylazodicarboxylic acid (0.1 ml) were added to the solution, and the mixture was stirred at room temperature for 4 hr. Further, 1 N sulfuric acid (4 ml) was added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was brought to 0° C., was stirred, and was made alkaline by the addition of a 10% aqueous sodium hydroxide solution. Water was added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (66 mg, yield 63%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=O)C.[Br:13]Br>C(O)(=O)C>[Br:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[NH:4][CH2:5][CH2:6]2
Reactant: CC(=O)N1CCc2ccccc21
Reactant: BrBr
Solvent: CC(=O)O
Product: Brc1ccc2c(c1)CCN2
Yield: 85 %

Procedure:
Gall et al. [J. Org. Chem., Vol. 20 (1955), p. 1538] describes the direct bromination of 1-acetyl-indoline in glacial acetic acid with bromine followed by saponification to obtain 5-bromo-indoline in 85% yield but attempts to repeat the process with chlorine results in only about a 45% yield of 5-chloro-1-acetyl-indoline. The latter result is not surprising in view of references such as Thesing et al. [Chem. Ber., Vol. 95 (1962), p. 2205], German Pat. No. 1,123,668, British Pat. No. 919,864 and the Chemistry of Heterocyclic Compounds, Vol. 25, Indoles, part II, Wiley Interscience, New York, London, Sidney, Toronto, 1972 p. 129 which teach that the reaction of N-acetylated-indoline-2-sulfonates in glacical acetic acid with chlorine, hypochlorous acid or alkali metal hypochlorites results in a variety of chlorinated products including 5- and 7-chloro compounds. Japanese Patent Application Ser. No. P 69-27967 (1969) teaches that these difficulties may be avoided by reacting 1-acetyl-indoline with N-chlorosuccinimide in carbon tetrachloride.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[CH2:7](Br)[CH:8]=[CH2:9].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:9]([N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]1)[CH:8]=[CH2:7]
Reactant: Cc1c[nH]cn1
Reactant: C=CCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCn1cnc(C)c1
Yield: 38 %

Procedure:
4-Methylimidazole (2.0 g, 24.36 mmol), allyl bromide (2.2 mL, 24.36 mmol), N,N-diisopropylethylamine (5.0 mL, 29.24 mmol) in DMF (50 mL) were stirred at 80° C. overnight. Then the reaction mixture was cooled, quenched with saturated NaHCO3 (30 mL), and extracted with CH2Cl2 (4×40 mL). The combined organic layers were dried (MgSO4), filtered, concentrated, and dried in vacuo to afford a brown oil. Purification by flash column chromatography on silica using 2% CH3OH/CH2Cl2 afforded the product as a yellow oil (1.13 g, 40%). 1H NMR (CDCl3) (as a mixture of regio-isomers) δ 2.17 and 2.22 (s, total 3H), 4.44-4.48 (m, total 2H), 5.19-5.24 (m, total 2H), 5.89-6.00 (m, total 1H), 6.61 and 6.79 (s, total 1H), 7.35 and 7.39 (s, total 1H).