Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:13]([O-])=O)[NH:9][C:8](=[O:16])[NH:7][C:6]2=[O:17].CO.C(O)(=O)C>O1CCCC1.[Pd]>[NH2:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[NH:7][C:8](=[O:16])[NH:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2c(=O)[nH]c(=O)[nH]c2cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2c(=O)[nH]c(=O)[nH]c2cc1N
Yield: 96.5 %

Procedure:
120 mg (0.5 mmol) of 6-methoxy-7-nitro-1H-quinazoline-2,4-dione were taken up in a mixture of 5 ml of tetrahydrofuran, 5 ml of methanol and 5 ml of acetic acid and hydrogenated with palladium catalysis at room temperature for 3 hours. The reaction solution was heated to dissolve precipitated product and was filtered hot to remove the catalyst. The filtrate was concentrated and, after addition of toluene, again concentrated. 100 mg (100%) of the desired product were obtained.
Reaction SMILES: C[O:2][C:3](=[O:44])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11](C(OC(C)(C)C)=O)[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[N:21]([C:28]4[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=4[Cl:35])[N:22]=[CH:23][C:24]=3[CH:25]([CH3:27])[CH3:26])=[CH:14][C:13]=2[CH3:36])[CH:5]=1.Cl>O1CCOCC1>[Cl:35][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([Cl:34])[C:28]=1[N:21]1[C:20]([CH2:19][O:18][C:15]2[CH:16]=[CH:17][C:12]([NH:11][CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:44])=[O:2])=[C:13]([CH3:36])[CH:14]=2)=[C:24]([CH:25]([CH3:27])[CH3:26])[CH:23]=[N:22]1
Reactant: COC(=O)c1cccc(CN(C(=O)OC(C)(C)C)c2ccc(OCc3c(C(C)C)cnn3-c3c(Cl)cccc3Cl)cc2C)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1NCc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
To a 0° C. solution of 3-[(tert-Butoxycarbonyl-{4-[2-(2,6-dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-amino)-methyl]-benzoic acid methyl ester (797 mg, 1.24 mmol) in dioxane (10 mL) is added hydrochloric acid (3.12 mL, 12.40 mmol, 4M in dioxane) dropwise. The reaction is warmed to room temperature and is stirred overnight. The reaction mixture is concentrated under reduced pressure and the residue is partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layer is extracted with EtOAc and the combined organic layers are washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue is chromatographed (SiO2 120 g, 0% to 30% EtOAc/Hex) to yield the title compound (603 mg, 90%). ES/MS m/e (35Cl) 524.0 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:20])[CH:11]([O:18][CH3:19])[C:12]([O:14]CCC)=[O:13])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[K+:22].O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:20])[CH:11]([O:18][CH3:19])[C:12]([O-:14])=[O:13])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[K+:22]
Reactant: CCCOC(=O)C(OC)C(=O)Nc1cc(Cl)cc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC(C(=O)[O-])C(=O)Nc1cc(Cl)cc(Cl)c1
Yield: 15 %

Procedure:
n-Propyl 3-[(3,5-dichlorophenyl)amino]-2-methoxy-3-oxopropanoate (5.47 grams, 0.02 mole), prepared in Example LXXI (Compound 234) was saponified with potassium hydroxide (1.01 grams, 0.02 mole) in the presence of 75 milliliters of ethanol and 0.31 gram (0.02 mole) of water in a manner similar to that described in Example LXXI Part B. The potassium salt that separated from the reaction mixture was filtered off, washed with ethanol and dried to give 0.98 gram (0.003 mole) of potassium 3-[(3,5-dichlorophenyl)amino]-2-methoxy-3-oxopropanoate. NMR analysis of the product indicated the following:
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH3:11][N:12]([CH3:25])[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH:23]=O)=[CH:15][CH:14]=1.COC1C=C(OC)C=C2C=1C(=O)NC(C1C=CC=CN=1)=N2>>[CH3:11][N:12]([CH3:25])[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23]2[NH:10][C:1](=[O:9])[C:2]3[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:4]=2)=[CH:15][CH:14]=1
Reactant: CN(C)c1ccc(C=O)c2ccccc12
Reactant: NC(=O)c1ccccc1N
Agent: COc1cc(OC)c2c(=O)[nH]c(-c3ccccn3)nc2c1
Product: CN(C)c1ccc(-c2nc3ccccc3c(=O)[nH]2)c2ccccc12
Yield: 69 %

Procedure:
2-(4-(Dimethylamino)naphthalen-1-yl)quinazolin-4(3H)-one was synthesized from anthranilamide and 4-dimethylamino-naphthalene-1-carbaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(4-(Dimethylamino)naphthalen-1-yl)quinazolin-4(3H)-one (240 mg, 69%) was isolated as a pale yellow solid. Selected data: MS (m/z): 316.08; MP 224-226° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][N:10]([CH2:19][C:20]2[C:21]([NH:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:22]3[CH:30]=[N:29][N:28]([CH2:31][CH3:32])[C:23]3=[N:24][C:25]=2[CH2:26][CH3:27])[C:11]([C:13]2([C:16]([NH2:18])=[O:17])[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:40][N:41]1[CH2:46][CH2:45][CH:44]([CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[C:50](B3OC(C)(C)C(C)(C)O3)[CH:49]=2)[CH2:43][CH2:42]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:8][C:7]1[C:2]([C:52]2[CH:51]=[CH:50][CH:49]=[C:48]([CH2:47][CH:44]3[CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH2:43]3)[CH:53]=2)=[CH:3][C:4]([CH2:9][N:10]([CH2:19][C:20]2[C:21]([NH:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:22]3[CH:30]=[N:29][N:28]([CH2:31][CH3:32])[C:23]3=[N:24][C:25]=2[CH2:26][CH3:27])[C:11]([C:13]2([C:16]([NH2:18])=[O:17])[CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:6]=1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(Cl)c(Br)c1)C(=O)C1(C(N)=O)CC1
Reactant: CN1CCC(Cc2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(Cl)c(-c2cccc(CC3CCN(C)CC3)c2)c1)C(=O)C1(C(N)=O)CC1
Temperature: 100 °C
Yield: 19.3 %

Procedure:
A mixture of N1-[(3-bromo-4-chlorophenyl)methyl]-N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,1-cyclopropanedicarboxamide (60 mg, 0.097 mmol), 1-methyl-4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}piperidine (39 mg, 0.097 mmol), Na2CO3 (30.9 mg, 0.291 mmol) and PdCl2(dppf) (7.10 mg, 9.71 μmol) was diluted in a mixture of 1,4-dioxane (3 mL) and water (1 mL) in a 2-5 mL Biotage microwave reaction tube. The mixture was degassed by bubbling argon through it for 5 min and was then heated in a Biotage microwave at normal absorption for 10 min at 100° C. The crude mixture was filtered through a PL-Thiol MP SPE+ and was then washed with ethyl acetate and water. The organic layer was concentrated under vacuum to obtain the crude residue. It was purified by reverse phase hplc with a Gilson HPLC (acidic conditions: 0.1% TFA in the solvents), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined and washed with saturated NaHCO3 and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and then concentrated under vacuum to give N1-({6-chloro-3′-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)-N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,1-cyclopropanedicarboxamide as a solid (13.6 mg, 19.3%). LC-MS m/z 726 M+, 0.77 min (ret time).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH2:17][CH2:16]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[N:36]1[CH:41]=[CH:40][CH:39]=[C:38]([N:42]=[C:43]=[O:44])[CH:37]=1.O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:22][C:23]([OH:25])=[O:24])[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:43](=[O:44])[NH:42][C:38]2[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=2)[CH2:17][CH2:16]3)(=[O:10])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)CN(c1ccc2c(c1)CCN2)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Reactant: O=C=Nc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(O)CN(c1ccc2c(c1)CCN2C(=O)Nc1cccnc1)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
220 mg tert.butyl [(3,5-dichloro-phenylsulphonyl)-(2,3-dihydro-1H-indol-5-yl)-amino]-acetate are dissolved in 10 ml dichloromethane. 166 mg potassium carbonate and 121 mg 3-pyridylisocyanate are added and the mixture is stirred overnight at ambient temperature. The reaction mixture is divided between water and dichloromethane. The aqueous phase is extracted twice with dichloromethane and the combined organic phases are dried on sodium sulphate. The solvent is eliminated in vacuo and the residue is taken up in 8 ml dichloromethane. 4 ml trifluoroacetic acid are added and the mixture is stirred for 2 hours at ambient temperature. The solvents are eliminated in vacuo and the residue is extracted from diisopropylether and petroleum ether. The solid is suction filtered and dried in vacuo.
Reaction SMILES: C([Li])CCC.Br[C:7]1[N:12]=[C:11]([CH3:13])[C:10]([O:14][CH3:15])=[C:9]([CH3:16])[CH:8]=1.[Br:17][C:18]1[CH:23]=[C:22](/[C:24](/[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[C:39]#[N:40])=[N:25]\S(C(C)(C)C)=O)[CH:21]=[CH:20][N:19]=1.Cl.C(OCC)C>C1COCC1.CO>[Br:17][C:18]1[CH:23]=[C:22]([C:24]2([C:7]3[CH:8]=[C:9]([CH3:16])[C:10]([O:14][CH3:15])=[C:11]([CH3:13])[N:12]=3)[C:32]3[C:33](=[C:34]([F:38])[CH:35]=[CH:36][CH:37]=3)[C:39]([NH2:40])=[N:25]2)[CH:21]=[CH:20][N:19]=1
Reactant: COc1c(C)cc(Br)nc1C
Reactant: CC(C)(C)S(=O)/N=C(\c1ccnc(Br)c1)c1cccc(F)c1C#N
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: COc1c(C)cc(C2(c3ccnc(Br)c3)N=C(N)c3c(F)cccc32)nc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 103 %

Procedure:
n-Butyllithium (0.229 mL, 0.57 mmol) was added to 6-bromo-3-methoxy-2,4-dimethylpyridine (124 mg, 0.57 mmol) in THF (7 mL) at −78° C. under nitrogen atmosphere. The reaction was stirred for 30 min before (E)-N-((2-bromopyridin-4-yl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (180 mg, 0.44 mmol) in THF (2 mL) was added. The reaction was kept at −78° C. for 1 hour and then allowed to reach room temp. Methanol (5 mL) was added followed by hydrochloric acid in diethylether (1.323 mL, 1.32 mmol) and the reaction mixture was stirred 1 hour at room temperature. NaHCO3(sat) was added and the mixture was extracted with EtOAc (×2). The combined organic phases were dried and concentrated to give the title compound (200 mg, 97%), which was used without further purification. MS (ES+) m/z 441, 443 [M+1]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[NH:15][N:14]=[C:13]([CH3:16])[C:8]=2[C:9](Cl)=[N:10][CH:11]=1)=[O:5])C.[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18]>>[CH2:17]([N:19]([CH2:20][CH3:21])[C:9]1[C:8]2[C:13]([CH3:16])=[N:14][NH:15][C:7]=2[C:6]([C:4]([OH:3])=[O:5])=[CH:11][N:10]=1)[CH3:18]
Reactant: CCOC(=O)c1cnc(Cl)c2c(C)n[nH]c12
Reactant: CCNCC
Product: CCN(CC)c1ncc(C(=O)O)c2[nH]nc(C)c12

Procedure:
2.4 g. of 4-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine-7-carboxylic acid ethyl ester is refluxed with 20 ml. of diethylamine for 24 hours. The excess diethylamine is removed by distillation and the residue treated with 20 ml. of water. 4-Diethylamino-3-methyl-1H-pyrazolo[4,3-c]pyridine-7-carboxylic acid ethyl ester precipitates and is recrystallized from ethyl acetate. Yield 2.1 g. (76%), m.p. 85°-88°. Hydrolysis of this product with aqueous sodium hydroxide yields 4-diethylamino-3-methyl-1H-pyrazolo[4,3-c]pyridine-7-carboxylic acid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([C:13]#[C:14][C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][C:16]=2[C:24](OCC)=[O:25])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.S(=O)(=O)(O)O>O1CCCC1.O>[C:7]1([C:13]#[C:14][C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][C:16]=2[CH2:24][OH:25])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1nc2ccccn2c1C#Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1nc2ccccn2c1C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 30.9 %

Procedure:
In a flask placed under an argon flow, 0.078 g (1.984 mmol) of LAH were dissolved in 1.4 ml of tetrahydrofurane and then with vigorous magnetic stirring, a solution of 0.3 g (0.992 mmol) of ethyl 3-(phenylethynyl)imidazo[1,2-a]pyridine-2-carboxylate in 3.3 ml of tetrahydrofurane was added drop wise. The mixture was stirred at r.t. for 15 min and then 0.2 ml of water were added with caution, followed by a solution of 0.2 ml of sulfuric acid in 1.5 ml of water. After separation, the organic phase was washed with 50 ml of water. The aqueous phase was extracted with 3×50 ml of ethyl acetate and then the combined organic phases were washed with 100 ml of a saturated NaCl aqueous solution and then dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on a silica gel cartridge (eluent: heptane/ethyl acetate gradient, from 40% to 30% of heptane, v/v). 0.076 g (yield=30%) of (3-(phenylethynyl)imidazo[1,2-a]pyridin-2-yl)methanol were obtained as a pale yellow solid. LC-MS: m/z=249 (MH+); UV purity at 254 nm=97%. 1H NMR (300 MHz, DMSO) δ 8.59 (dt, J=6.7, 1.1 Hz, 1H), 7.77-7.56 (m, 3H), 7.56-7.32 (m, 4H), 7.11 (td, J=6.8, 1.1 Hz, 1H), 5.33 (t, J=5.9 Hz, 1H), 4.67 (d, J=5.9 Hz, 2H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)=[O:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:20][C:17]2[CH:18]=[CH:19][C:14]([C:12](=[O:13])[CH3:11])=[CH:15][CH:16]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 90 °C
Yield: 99.8 %

Procedure:
To a mixture of 1-fluoro-4-nitrobenzene (5.0 g, 35.43 mmol) and 4-hydroxyacetophenone (4.82 g, 35.40 mmol) in DMF (40 mL) was added potassium carbonate (9.79 g, 70.86 mmol). The reaction mixture was heated at 90° C. overnight. After the completion of the reaction as confirmed by TLC, the reaction mixture was diluted with EtOAc (200 mL) and washed with water (3×30 mL). The organic layer was separated, dried over Na2SO4 and concentrated in vacuo to afford the title compound (9.09 g, 99%) as a solid which was used as such in the next step.
Reaction SMILES: [O:1]=[C:2]([NH:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([OH:28])=[O:27])[C:3](=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=[O:5].C1COCC1.C(=O)([O-])[O-].[Ca+2:42]>O>[Ca+2:42].[O:5]=[C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([O-:11])=[O:10])[C:3](=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]([NH:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([O-:28])=[O:27])=[O:1]
Reactant: O=C(Nc1ccccc1C(=O)O)C(=Cc1ccccc1)C(=O)Nc1ccccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1C(=O)[O-])C(=Cc1ccccc1)C(=O)Nc1ccccc1C(=O)[O-]

Procedure:
The Compound 11 (430 mg 1 mmol) was treated with THF (20 ml) and water (10 ml), and further with calcium carbonate (100 mg, 1 mmol), and the mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered by suction, and the solvent was removed from the filtrate. The residue was washed with acetone to give the desired calcium salt in pale yellow solid (420 mg, yield, 89.6%). m.p., 300° C. or higher.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14](O)=[O:15])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[C:7](=[O:12])[C:6]=2[CH:13]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][OH:15])[C:5]2[O:9][C:8]([CH3:10])([CH3:11])[C:7](=[O:12])[C:6]=2[CH:13]=1
Reactant: CC1(C)Oc2c(C(=O)O)cc(Cl)cc2C1=O
Solvent: C1CCOC1
Product: CC1(C)Oc2c(CO)cc(Cl)cc2C1=O
Yield: 11 %

Procedure:
To a solution of 5-chloro-2,2-dimethyl-3-oxo-2,3-dihydrobenzofuran-7-carboxylic acid (655) (2.67 g, 11.1 mmol) in tetrahydrofuran (56 mL) was added BH3.tetrahydrofuran (11.1 mL, 11.1 mmol) drop wise and stirred overnight. The reaction was quenched with water and methanol and then extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and then dried over sodium sulfate, filtered and concentrated in vacuo. The crude compound was purified by flash column chromatography on silica gel with hexanes and EtOAc (50%) to afford 5-chloro-7-(hydroxymethyl)-2,2-dimethylbenzofuran-3(2H)-one (656) (278 mg). The saturated sodium bicarbonate layer was acidified to recover the starting acid (655) (1.68 g).
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[NH2:12][C:13]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:14]=1[C:15](O)=[O:16].[NH4+].[Cl-]>CCCCCC.CCOCC>[NH2:12][C:13]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:14]=1[C:15]([C:8]1[N:7]([CH3:6])[CH:11]=[CH:10][N:9]=1)=[O:16]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: Cn1ccnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: Cn1ccnc1C(=O)c1cc(Cl)ccc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.6 %

Procedure:
To a solution of nBuLi (0.0730 mol) in hexane was added N-methyl imidazole (0.0608 mol) drop wise at −40° C. over 30 min under a nitrogen atmosphere. The resulting yellow solution was stirred for a further 3 hr at rt, and then refluxed for 1 h. 2-amino-5-chlorobenzoic acid (1.74 g, 0.01014 mole) in dry ether (60 ml) was then added to the reaction mixture. The reaction mixture was stirred overnight at rt. To the reaction mixture was added saturated NH4Cl solution and the resulting mixture extracted with ethyl acetate (2×150 ml). The combined organic layers were dried over Na2SO4. After removal of solvent, the residue was purified by the flash chromatography using ethyl acetate/hexane (1:4) as eluent. Crystallization of the product from Et2O/hexane mixture gave 300 mg (13.7%) of product as yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[S:13][CH:14]=[CH:15][C:16]=1[CH3:17])[NH:10][CH3:11].[Br:18]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:18])=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[S:13][CH:14]=[CH:15][C:16]=1[CH3:17])[NH:10][CH3:11]
Reactant: CNC(Cc1ccccc1N)c1sccc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CNC(Cc1cc(Br)ccc1N)c1sccc1C
Reaction time: 8 h

Procedure:
A stirred solution of 5.02 g of 2-amino-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine and 79 ml of dimethylformamide was treated with a solution of 4.71 g N-bromosuccinimide in 55 ml of dimethylformamide. The solution was stirred for 8 h with the exclusion of moisture and then concentrated to an oil on a rotary evaporator (70° C.) under high vacuum. The oil was diluted with distilled water (100 ml) and basified with a 10% sodium hydroxide solution (25 ml). The basic solution was extracted with dichloromethane (3×100 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to an oil. Thin layer chromatography (silica gel, methanol eluent) indicated a 2-component mixture.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:58])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[C:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]4[NH:36][C:37]([CH:40]5[CH2:44][C:43]([F:46])([F:45])[CH2:42][N:41]5[C:47](=[O:57])[CH:48]([NH:52][C:53]([O:55][CH3:56])=[O:54])[CH:49]([CH3:51])[CH3:50])=[N:38][CH:39]=4)=[CH:31][CH:30]=3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].CO[C:61](=O)[NH:62]C(C(N1CCCC1C1NC(C2C=CC(Br)=CC=2)=CN=1)=O)C(C)C.COC(=O)NC(C(N1CC(F)(F)CC1C1NC(C2C=CC(C#C)=CC=2)=CN=1)=O)C(C)C.COC(=O)NC(C(N1CCCC1C1NC(C2C=CC(C#C)=CC=2)=CN=1)=O)C(C)C>>[CH3:1][O:2][C:3](=[O:58])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH:14]([C:61]#[N:62])[CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[C:28][C:29]3[CH:30]=[CH:31][C:32]([C:35]4[NH:36][C:37]([CH:40]5[CH2:44][C:43]([F:45])([F:46])[CH2:42][N:41]5[C:47](=[O:57])[CH:48]([NH:52][C:53]([O:55][CH3:56])=[O:54])[CH:49]([CH3:51])[CH3:50])=[N:38][CH:39]=4)=[CH:33][CH:34]=3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(C#Cc3ccc(-c4cnc(C5CC(F)(F)CN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Agent: C#Cc1ccc(-c2cnc(C3CC(F)(F)CN3C(=O)C(NC(=O)OC)C(C)C)[nH]2)cc1
Agent: C#Cc1ccc(-c2cnc(C3CCCN3C(=O)C(NC(=O)OC)C(C)C)[nH]2)cc1
Product: COC(=O)NC(C(=O)N1CC(C#N)CC1c1ncc(-c2ccc(C#Cc3ccc(-c4cnc(C5CC(F)(F)CN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C

Procedure:
Title compound was prepared according to the method employed to prepare [1-(2-{5-[4-(4-{2-[4,4-Difluoro-1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenylethynyl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (Example AB1) substituting (1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-cyano-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester for (1-{2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (400 mg, 0.89 mmol), and (1-{2-[5-(4-ethynyl-phenyl)-1H-imidazol-2-yl]-4,4-difluoro-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester for (1-{2-[5-(4-ethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester. 1H NMR (MeOH-d4, 400 MHz) δ: 7.71-7.61 (m, 4H) 7.46-7.34 (m, 4H), 5.30 (m, 1H), 5.14 (m, 1H), 4.55-4.45 (m, 2H), 4.20-3.94 (m, 5H), 3.61 (s, 6H), 3.47-3.40 (m, 2H), 2.84-2.76 (m, 3H), 2.52 (m, 1H), 1.96-1.91 (m, 2H), 0.96-0.83 (m, 12H); MS (ESI) m/z 824 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[NH:27][S:28]([CH:31]=[CH2:32])(=[O:30])=[O:29])=[CH:16][N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].Cl.[NH:34]1[CH2:39][CH2:38][CH2:37][C@@H:36]([OH:40])[CH2:35]1>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[NH:27][S:28]([CH2:31][CH2:32][N:34]3[CH2:39][CH2:38][CH2:37][C@@H:36]([OH:40])[CH2:35]3)(=[O:30])=[O:29])=[CH:16][N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: C=CS(=O)(=O)N[C@@H]1CCc2c(-c3cnc(-c4ccc(OC(C)C)c(C#N)c4)s3)cccc21
Reactant: O[C@@H]1CCCNC1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2ncc(-c3cccc4c3CC[C@H]4NS(=O)(=O)CCN3CCC[C@@H](O)C3)s2)cc1C#N
Temperature: 80 °C
Yield: 88.2 %

Procedure:
Prepared using General Procedure 13. To a solution of (R)-N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)ethenesulfonamide (10 mg, 0.02 mmol) in DMF (0.5 mL) was added (R)-piperidin-3-ol hydrochloride (20.6 mg, 0.15 mmol) and the reaction was heated to 80° C. for 18 h. The product was purified by preparative HPLC to give 10 mg (80%) of N-((R)-4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)-2-((R)-3-hydroxypiperidin-1-yl)ethanesulfonamide 143. LCMS-ESI (m/z) calculated for C29H34N4O4S2: 566.2; found 567.2 [M+H]+, tR=2.62 min.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH:23]5[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.[CH2:36]=O>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH:23]5[CH2:28][CH2:27][CH2:26][N:25]([CH3:36])[CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1
Reactant: C=O
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C1CCCNC1
Product: CN1CCCC(N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(1-methylpiperidin-3-yl)-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-piperidin-3-yl-1,3-thiazolidine-2,4-dione (Example 124) and formaldehyde following General Procedure R.