Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:12]([CH3:13])[C:11]2[C:10](=[O:14])[NH:9][C:8](=[O:15])[N:7]([CH3:16])[C:6]=2[N:5]=1.[C:17]([O:20][CH:21]([CH3:33])[CH2:22][CH2:23][CH2:24][CH2:25][C@H](Cl)CCCCC)(=[O:19])[CH3:18]>CS(C)=O>[C:17]([O:20][C@H:21]([CH3:33])[CH2:22][CH2:23][CH2:24][CH2:25][N:9]1[C:10](=[O:14])[C:11]2[N:12]([CH3:13])[C:4]([Br:3])=[N:5][C:6]=2[N:7]([CH3:16])[C:8]1=[O:15])(=[O:19])[CH3:18]
Reactant: CCCCC[C@@H](Cl)CCCCC(C)OC(C)=O
Reactant: Cn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(Br)n2C)n(C)c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.6 %

Procedure:
To a stirring suspension of sodium hydride (740 mg, 30.8 mmol) in anhydrous dimethylsulfoxide (120 ml) was added 8-bromo-3,7-dimethylxanthine (6.5 g, 25.0 mmol). After stirring at room temperature under argon for 1.5 hours, (R)-5-acetoxyhexyl-1-chlorohexane (4.91 g, 27.5 mmol) was added and the mixture was stirred at 80° C. for 18 hours. After cooling to room temperature, the reaction mixture was quenched by addition of saturated aqueous sodium chloride solution (300 ml) and extracted with ethyl acetate (3x 50 ml). The combined extracts were washed with water (2x 20 ml), with saturated aqueous sodium chloride solution (20 ml) and dried over magnesium sulfate. After evaporation of the solvent under reduced pressure, the crude product was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1 :1) to provide (R)-1-(5-acetoxyhexyl)-8-bromo-3, 7-dimethylxanthine (7.38 g, 74% yield) as a colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[N:13]=[C:12]([CH3:14])[C:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)=[O:6].CC(C)([O-])C.[K+].O>CN(C=O)C>[CH3:14][C:12]1[C:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)=[CH:10][CH:9]=[C:8]([N:7]2[CH2:2][CH2:3][CH2:4][C:5]2=[O:6])[N:13]=1
Reactant: COC(=O)c1ccc(-c2ccc(NC(=O)CCCCl)nc2C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(N3CCCC3=O)nc2C)cc1
Reaction time: 3 h
Yield: 85.3 %

Procedure:
A stirred solution of methyl 4[6-(4-chlorobutanoylamino)-2-methylpyridin-3-yl]benzoate (D8, 0.60 g, 1.7 mmole) in DMF (7 ml) at 25° C. under argon was treated portionwise over 15 minutes with potassium t-butoxide (0.23 g, 2.0 mmole). The mixture was stirred for 3 h, then poured into water (100 ml) and extracted with ethyl acetate. The extract was washed with water, dried (Na2SO4) and concentrated in vacuo to afford the title compound as an orange solid (0.45 g, 85%).
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:12][CH2:11][CH:10]1[CH2:9][N:8]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:7]2)=[O:5])C.[OH-].[Na+]>C(O)C>[CH2:16]([O:15][C:13]([N:8]1[CH2:9][CH:10]2[C:6]([C:4]([OH:5])=[O:3])([CH2:12][CH2:11]2)[CH2:7]1)=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)C12CCC1CN(C(=O)OCc1ccccc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CC2CCC2(C(=O)O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 920 mg (2.90 mmol) of 1-ethoxycarbonyl-3-benzyloxycarbonyl-3-azabicyclo[3.2.0]heptane in ethanol (10 ml) cooled in an ice bath was added 6 ml of 1N sodium hydroxide aqueous solution, followed by 2 hours of stirring at room temperature. After neutralization with 1N hydrochloric acid aqueous solution, ethanol was evaporated. The resulting residue was mixed with 1N hydrochloric acid aqueous solution and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. By evaporating the solvent, 847.2 mg (quantitative) of the title compound was obtained as a crude product.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:29]([O:31][CH2:32][CH3:33])=[CH2:30])CCC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:32]([O:31][C:29]([C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1)=[CH2:30])[CH3:33]
Reactant: CC(c1cc2cnn(C)c2cc1F)c1cnc2ccc(Cl)nn12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=C(OCC)c1ccc2ncc(C(C)c3cc4cnn(C)c4cc3F)n2n1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 64.5 %

Procedure:
To a solution of 6-chloro-3-(1-(6-fluoro-1-methyl-1H-indazol-5-yl)ethyl)imidazo[1,2-b]pyridazine (900 mg, 1.910 mmol) in DMF (8 mL), was added Pd(Ph3P)4 (221 mg, 0.191 mmol). The mixture was stirred for 20 min, and tributyl(1-ethoxyvinyl)stannane (784 mg, 2.102 mmol) was added. The resulting mixture was heated to 100° C. until the LC-MS showed the reaction was complete. The reaction mixture was filtered through celite and the solid was washed with ether. The filtration was then washed with water, dried over Na2SO4, and concentrated to a residue, which was purified by silica gel column chromatography with gradient Hex:EA to give 6-(1-ethoxyvinyl)-3-(1-(6-fluoro-1-methyl-1H-indazol-5-yl)ethyl)imidazo[1,2-b]pyridazine (450 mg, 52%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[CH3:30][C:29]1[CH:28]=[CH:27][O:26][C:25]=1[C:23]([NH:22][C:18]1[CH:17]=[C:16]([C:15]#[C:14][C:12]2[CH:11]=[N:10][CH:9]=[C:8]([CH:13]=2)[C:7]([N:6]=[S@@:5]([CH2:4][CH2:3][CH2:2][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)(=[O:38])[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:31])[CH:21]=[CH:20][CH:19]=1)=[O:24]
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCBr)c3ccccc3)c2)c1
Reactant: C1COCCN1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=[S@](=O)(CCCN3CCOCC3)c3ccccc3)c2)c1

Procedure:
In a manner similar to that described for Example 508, N-[(3-bromopropyl)(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and morpholine were converted to the title compound.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1.C(N(CC)CC)C.[CH2:15]([O:22][C:23](ON1C(=O)CCC1=O)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCOCC1.O>[CH2:15]([O:22][C:23]([N:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)C1CNC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Yield: 88.2 %

Procedure:
To azetidine-3-carboxylic acid (49.5 mmol, 5 g) in dioxane (150 ml), water (150 ml) and triethylamine (54.4 mmol, 7.58 ml) was added N-(benzyloxycarbonyloxy)succinimide (51.9 mmol, 12.94 g) and stirred at room temperature for half an hour. The reaction mixture was quenched with water and 30 ml of 2N hydrochloric acid and extracted three times with dichloromethane. The organic layers were combined, filtered through a phase separation filter and concentrated in vacuo. The residue was dissolved in dichloromethane and extracted three times with aqueous saturated sodium hydrogencarbonate solution. The aqueous layers were combined, acidified with 2N hydrochloric acid and extracted three times with dichloromethane. The organic layers were combined, washed with brine, filtered through a phase separation filter and concentrated in vacuo to give 1-(benzyloxycarbonyl)azetidine-3-carboxylic acid (10.27 g).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:26][C:27]1[C:28]([F:52])=[CH:29][C:30]([Cl:51])=[C:31]([CH:50]=1)[O:32][C:33]1[CH:47]=[CH:46][C:36]2[N:37]=[C:38]([NH:40][C:41]([CH:43]3[CH2:45][CH2:44]3)=[O:42])[S:39][C:35]=2[C:34]=1[C:48]#[N:49]>O1CCCC1.C(OCC)(=O)C>[Cl:51][C:30]1[C:31]([O:32][C:33]2[CH:47]=[CH:46][C:36]3[N:37]=[C:38]([NH:40][C:41]([CH:43]4[CH2:45][CH2:44]4)=[O:42])[S:39][C:35]=3[C:34]=2[C:48]#[N:49])=[CH:50][C:27]([NH:26][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[C:4]([O:3][C:2]([F:1])([F:14])[F:13])[CH:5]=2)=[C:28]([F:52])[CH:29]=1
Reactant: N#Cc1c(Oc2cc(N)c(F)cc2Cl)ccc2nc(NC(=O)C3CC3)sc12
Reactant: O=C(O)c1cccc(OC(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1c(Oc2cc(NC(=O)c3cccc(OC(F)(F)F)c3)c(F)cc2Cl)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
To a solution of 3-(trifluoromethoxy)benzoic acid (68 mg, 0.330 mmol) in tetrahydrofuran (1 mL) were added oxalyl chloride (35 μL, 0.408 mmol) and N,N-dimethylformamide (5 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (1 mL). N-[6-(5-Amino-2-chloro-4-fluorophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (90 mg, 0.223 mmol) produced in Example 23(vi) was added to the solution, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate (15 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (7 mL) and saturated brine (7 ml), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=10/90→60/40), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (85 mg, 65%) as a white powder.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=CC=C[CH:8]=2)[N:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:20]1(O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>[OH-].[Na+]>[C:13]1([CH2:12][N:19]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:4]([NH2:3])=[C:9]3[CH2:8][CH2:2][CH2:11][CH:10]23)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1ccccc1
Reactant: NCc1ccccc1
Reactant: Clc1ccc2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Product: NC1=C2CCCC2N(Cc2ccccc2)c2ccccc21

Procedure:
Chloroquinoline derivative (Example 9(C)) (2.0 g, 9.8 mmol), benzylamine (1.2 g, 11.2 mmol) and phenol (4.0 g, 42.6 mmol) were heated at 180° C. for 3 hours. After cooling, 5M sodium hydroxide (50 cm3) was added and the organic components were extracted into dichloromethane, dried (Na2SO4), filtered and the solvent was evaporated. Any remaining volatiles were removed by distillation and the residue was dissolved in hot ethanol, decolorised (charcoal) and recrystallised to give an off-white powder.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:4]=[CH:5][C:6]2[C:15]([CH:16]=1)=[N:14][C:13]1[C:8](=[CH:9][CH:10]=[C:11]([N:17]([CH3:19])[CH3:18])[CH:12]=1)[CH:7]=2.[OH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][Br:32]>CN(C=O)C>[Br-:32].[OH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:14]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N:17]([CH3:19])[CH3:18])[CH:12]=2)[CH2:7][C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:20])[CH3:1])=[CH:16][C:15]1=2
Reactant: CN(C)c1ccc2cc3ccc(N(C)C)cc3nc2c1
Reactant: OCCCCCCCCCCBr
Solvent: CN(C)C=O
Product: CN(C)c1ccc2c(c1)N(CCCCCCCCCCO)c1cc(N(C)C)ccc1C2
Product: [Br-]

Procedure:
3,6-bis(dimethylamino)acridine (1.0 millimole) is dissolved in DMF (100 ml containing 1.1 equivalent of tertiary amine base. To this is added 10-hydroxy1-bromo decane (1.1 millimole), and the mixture is heated to reflux. When monitoring by TLC shows no remaining 3,6-bis(dimethylamino)acridine, the reaction is cooled and the 10-N(10-hydroxy-1-decyl)-3,6-bis(dimethylamino)acridine is isolated (0.75 millimoles).
Reaction SMILES: Cl.N[C@H]1C(=O)NC2C=CC=CC=2OC1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25]([NH:27][C@@H:28]1[C:34](=[O:35])[NH:33][C:32]3[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=3[O:30][CH2:29]1)=[O:26])=[CH:19]2.Cl.N[C@@H]1C(=O)NC2C=CC=CC=2OC1>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25]([NH:27][C@H:28]1[C:34](=[O:35])[NH:33][C:32]3[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=3[O:30][CH2:29]1)=[O:26])=[CH:19]2
Reactant: O=C(N[C@H]1COc2ccccc2NC1=O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Agent: N[C@@H]1COc2ccccc2NC1=O
Agent: N[C@H]1COc2ccccc2NC1=O
Product: O=C(N[C@@H]1COc2ccccc2NC1=O)c1cc2cc(Cl)ccc2[nH]1

Procedure:
The title compound was prepared from (R)-3-amino-2,3-dihydro-1,5-benzoxazepin-4(5H)-one hydrochloride salt by the procedures described for the preparation of (S)-3-(5-chloroindole-2-carbonylamino)-2,3-dihydro-1,5-benzoxazepin-4(5H)-one (Example 20) from (S)-3-amino-2,3-dihydro-1,5-benzoxazepin-4(5H)-one hydrochloride salt. HPLC/MS [M+H]+, 356.
Reaction SMILES: S(=O)(=O)(O)N.[C:6]1([N:12]2[CH:16]=[C:15]([CH:17]=[O:18])[CH:14]=[N:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl([O-])=[O:20].[Na+]>O.CC(C)=O>[C:6]1([N:12]2[CH:16]=[C:15]([C:17]([OH:20])=[O:18])[CH:14]=[N:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1cnn(-c2ccccc2)c1
Agent: NS(=O)(=O)O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1cnn(-c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.8 %

Procedure:
1-Phenyl-1H-pyrazole (250 mg, 1.7 mmol) was added to a cold (0-4° C.) solution of DMF (1.5 g, 1.6 mL, 9.7 mmol) and POCl3 (1.86 g, 1.1 mL, 19.2 mmol) and stirring continued for 10 minutes. The resulting mixture was heated at 106° C. for 2.5 hrs. The reaction mixture was cooled and quenched with ice cold water, basified with 20% aqueous NaOH solution, the solid was collected to afford 330 mg (crude) of 1-phenyl-1H-pyrazole-4-carbaldehyde. 1H NMR (300 MHz, CDCl3): δ 10.0 (s, 1H), 8.45 (s, 1H), 8.2 (s, 1H), 7.75 (d, 2H), 7.55 (t, 2H), 7.45 (t, 1H). Sulphamic acid (253 mg, 2.6 mmol) in water (0.5 mL) was added at 0° C. to a mixture of phenyl-1H-pyrazole-4-carbaldehyde (0.5 g, 2.34 mmol) in acetone (3 mL). After 2 minutes sodium chlorite (315 mg, 3.5 mmol) was added and the resulting mixture was stirred at 0° C. for 30 minutes. Water was added and the solid obtained was isolated by filtration to afford 140 mg (85% yield) of 1-phenyl-1H-pyrazole-4-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[N:14]=[CH:15][N:16]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)([OH:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[CH3:37][O:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][C:44]=1[O:45][CH3:46].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:37][O:38][C:39]1[CH:40]=[C:41]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([C:13]3[N:14]=[CH:15][N:16]([C:18]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:17]=3)([OH:12])[CH:9]([CH3:11])[CH3:10])=[CH:6][CH:7]=2)[CH:42]=[CH:43][C:44]=1[O:45][CH3:46]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: CC(C)C(O)(c1ccc(Br)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)cc1OC
Yield: 85.6 %

Procedure:
By the reaction in the same manner as in Example 29-(i) using 1-(4-bromophenyl)-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (1.50 g), 3,4-dimethoxyphenylboronic acid (762 mg), 2M aqueous sodium carbonate solution (2.79 ml) and tetrakis(triphenylphosphine)palladium(0) (96.7 mg), the colorless amorphous title compound (1.42 g) was obtained.
Reaction SMILES: [C:1]([C:9]1[CH:19]=[C:18]([O:20]CC2C=CC=CC=2)[C:17]([O:28][CH3:29])=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.Cl>[Ti](Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>[C:1]([C:9]1[CH:19]=[C:18]([OH:20])[C:17]([O:28][CH3:29])=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(OC)c(OCc2ccccc2)cc1C(=O)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1cc(OC)c(O)cc1C(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a mixture of ethyl 2-benzoyl-4-benzyloxy-5-methoxy-benzoate (reference example 11-1) (848 mg) and dichloromethane (30 mL) was added titanium tetrachloride (0.31 mL) under room temperature. After stirring for 30 minutes, 2 mol/L hydrochloric acid and ethyl acetate were added to the mixture. The separated organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 10%-100% ethyl acetate/hexane, gradient elution) to give the title compound (550 mg).
Reaction SMILES: ClC1C=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=O)[CH2:11][CH2:10][N:9]2[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])=[CH:4]C=1.FC1C=CC([Mg]Br)=CC=1.O.[NH2:35]N.[NH:37]1[CH2:42]CC(=O)CC1>>[CH:5]([CH:8]1[N:9]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[CH2:10][C:11]2[CH:42]=[N:37][NH:35][C:12]=2[CH2:13]1)([CH3:4])[CH3:6]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)C(c2ccc(Cl)cc2)C1
Reactant: O=C1CCNCC1
Reactant: NN
Agent: Fc1ccc([Mg]Br)cc1
Solvent: O
Product: CC(C)C1Cc2[nH]ncc2CN1C(=O)OCc1ccccc1

Procedure:
5-(4-Chlorophenylsulfonyl)-6-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-Benzyl 2-(4-fluorophenyl)-4-oxopiperidine-1-carboxylate, prepared as described for compound 67 in Example using 4-fluorophenylmagnesium bromide, was formylated and treated with hydrazine hydrate as described for compound 50 in Example 1 to give benzyl 6-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate. This compound was then deprotected and treated with 4-chlorophenylsulfonyl chloride followed by NaOH as described for compound 52 in Example 1.
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[CH2:15][C:16]([CH2:18][NH:19][N:20]=[C:21](C)C(OCC)=O)=[O:17].Cl.[CH3:29]N(C=O)C>>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[C:15]1[C:2](=[O:4])[N:20]([CH3:21])[N:19]=[C:18]([CH3:29])[C:16]=1[OH:17]
Reactant: CCOC(=O)C(C)=NNCC(=O)Cc1c(F)cccc1Cl
Reactant: CC(C)(C)[O-]
Reactant: CN(C)C=O
Agent: Cl
Agent: [K+]
Product: Cc1nn(C)c(=O)c(-c2c(F)cccc2Cl)c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2.1 g (2 eq) of potassium t-butoxide in 10 ml of DMF was initially charged, and 2.8 g (9.4 mmol) of ethyl 2-{[2-(2-chloro-6-fluorophenyl)acetyl]methylhydrazono}propionate in 10 ml of DMF was slowly added dropwise at <0° C. The mixture was allowed to warm to RT and then stirred for a further 0.5 hour. The reaction solution was then poured into 100 ml of cooled 1N hydrochloric acid and extracted twice with in each case 250 ml of ethyl acetate. The combined organic phases were washed with 50 ml of saturated sodium chloride solution and then dried with sodium sulfate, concentrated under reduced pressure and purified by column chromatography (silica gel, ethyl acetate/n-heptane gradient). This gave 1.2 g of pure product.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH:7][C:8]2[C:9]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([CH3:24])([CH3:23])[CH3:22])=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:4][C:3]=1[C:25]([F:28])([F:27])[F:26].[O:29](C(OC(C)(C)C)=O)[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=O.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C1COCC1>[Br:1][C:2]1[S:6][C:5]([N:7]([C:8]2[C:9]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([CH3:24])([CH3:22])[CH3:23])=[N:10][CH:11]=[CH:12][CH:13]=2)[C:30](=[O:29])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[N:4][C:3]=1[C:25]([F:27])([F:26])[F:28]
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1Nc1nc(C(F)(F)F)c(Br)s1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(c1nc(C(F)(F)F)c(Br)s1)c1cccnc1Oc1ccccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of N-(5-bromo-4-(trifluoromethyl)thiazol-2-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine (Example 323a, 135 mg, 0.29 mmol), BOC2O (75 mg, 0.34 mmol), DMAP (5 mg) and DIPEA (59 μL, 0.34 mmol) in THF (5 mL) was stirred at rt for 5 h. The solvent was removed and the residue was purified by flash chromatography (silica, 0-50% EtOAc/hexane gradient) provided Example A125a (149 mg) as a white foam. (M+H)+=574.2.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:28](=[O:29])[CH2:27][C:24]3[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: Cc1ccc(CC(=O)O)cc1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Product: Cc1ccc(CC(=O)Nn2nc(-c3ccc(Cl)cc3)c3ccccc3c2=O)cc1

Procedure:
The product of Example 86A and 2-(4-methylphenyl)acetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.40-8.42 (m, 1H), 7.90-8.03 (m, 2H), 7.71-7.73 (m, 1H), 7.53-7.68 (m, 4H), 7.25-7.27 (m, 2H), 7.15-7.17 (m, 2H), 3.64 (s, 2H), 2.29 (s, 3H); MS (APCI+) M/Z 404 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]2[C:13]=1[CH2:14][CH2:15][C:16]2([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:22][OH:23].C(N(CC)C(C)C)(C)C.Cl>C(Cl)Cl>[F:11][C:12]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]2[C:13]=1[CH2:14][CH2:15][C:16]2([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH:22]=[O:23]
Reactant: CC(C)(C)OC(=O)NC1(CO)CCc2c(F)cc(F)cc21
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C=O)CCc2c(F)cc(F)cc21
Temperature: -60 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of oxalyl chloride (0.91 mL, 10.4 mmol) in CH2Cl2 (40 mL) at −78° C. was added DMSO (1.48 mL, 20.9 mmol), dropwise, over 5 min. The reaction mixture was stirred for 30 min, during which time it warmed to −60° C., then a solution of tert-butyl [4,6-difluoro-1-(hydroxymethyl)-2,3-dihydro-1H-inden-1-yl]carbamate from Step E (2.08 g, 6.95 mmol) in CH2Cl2 (22 mL) was added, dropwise, over 30 min. During the addition, the reaction temperature rose to −45° C. and it was stirred at this temperature for an additional 15 min. To the resulting mixture was added N,N-diisopropylethylamine (7.28 mL, 41.7 mmol), dropwise, over 2 min. The mixture was allowed to warm to 0° C., stirred for 15 min then poured into ice (60 mL) and 1 N aqueous HCl (30 mL). The resulting mixture was extracted with CH2Cl2 (2×100 mL). The combined organic extracts were washed with H2O (30 mL), then brine (50 mL), then dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=224 (M−OC4H9).