Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[OH:8].[CH3:9]N(C)C=O.C(=O)([O-])[O-].[K+].[K+].CI>>[Br:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[CH:3]=1
Reactant: Oc1ccncc1Br
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: Cn1ccc(=O)c(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.1 %

Procedure:
To a solution of 3-bromo-4-pyridinol (308.2 mg, 1.771 mmol) in N,N-dimethylformamide (10 mL, 100 mmol) was added potassium carbonate (371.0 mg, 2.684 mmol) and methyl iodide (133 uL, 2.14 mmol). The reaction was stirred at room temperature for 18 hours. The reaction mixture was filtered and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-20% methanol in dichloromethane) to yield 269.9 mg (81%) of 3-bromo-1-methylpyridin-4(1H)-one. LCMS (ESI): M+H=188.2; 1H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J=2.1 Hz, 1H), 7.68 (dd, J=7.4, 2.1 Hz, 1H), 6.21 (d, J=7.4 Hz, 1H), 3.65 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].[N:11]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[CH:8]=[C:6]2[C:5]([CH:9]=[N:11][NH:7]2)=[CH:4][C:3]=1[Cl:10]
Reactant: O=N[O-]
Reactant: Cc1cc(Cl)c(Br)cc1N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Clc1cc2cn[nH]c2cc1Br
Yield: 63.8 %

Procedure:
To 5-bromo-4-chloro-2-methylaniline (1 g, 4.54 mmol) in acetic acid (10 mL) was added a solution of sodium nitrite (0.329 g, 4.76 mmol) in water (1 mL). The mixture was heated at reflux for 2 hours and was subsequently cooled and concentrated. The residue was partitioned in water and extracted with EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated to give the title compound as a red-brown solid (0.67 g, 64%). ESI-MS m/z [M+H]+ 232.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]#[N:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(C1C=CC=CC=1S)#N.[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[C:36](=[O:38])[CH3:37].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[NH4+]>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[C:36](=[O:38])[CH2:37][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]#[N:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(F)cc1F
Reactant: N#Cc1ccccc1S(=O)(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: N#Cc1ccccc1S
Solvent: C1CCOC1
Product: N#Cc1ccccc1S(=O)(=O)c1ccc(CC(=O)c2ccc(F)cc2F)cc1
Temperature: 80 °C
Yield: 56 %

Procedure:
A mixture of 2-[(4-bromophenyl)sulfonyl]benzonitrile (prepared according to the methods of Example 1 Step 1 using 2-cyanobenzenethiol followed by Example 16 Step 1; 0.32 g, 0.993 mmol), 2′,4′-difluoroacetophenone (0.31 g, 1.99 mmol), potassium phosphate (0.48 g, 2.26 mmol), tris(dibenzylideneacetone)dipalladium(0) (9 mg, 0.0098 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (13 mg, 0.022 mmol) in tetrahydrofuran (1 mL) was degassed then heated at 80° C. under nitrogen for 14 hours. Saturated ammonium chloride solution was added and the products extracted into ethyl acetate. The organic layer was dried over MgSO4 and concentrated in vacuo while loading onto silica. Dry flash column chromatography eluting with 25-40% ethyl acetate/isohexane followed by recrystallisation from ethanol gave the title compound as a beige solid (0.22 g, 56%). δH (500 MHz, CDCl3): 8.33 (1H, d, J=8.0 Hz), 8.05 (2H, d, J=8.3 Hz), 7.95-7.89 (1H, m), 7.83-7.77 (2H, m), 7.70-7.68 (1H, m), 7.43 (2H, d, J=8.3 Hz), 7.00-6.96 (1H, m), 6.92-6.88 (1H, m), 4.33 (2H, d, J=2.7 Hz).
Reaction SMILES: [Si:1]([O:8][CH:9]([CH3:14])[CH2:10][C:11]([OH:13])=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:15]1([SH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:15]1([S:21][O:12][C:11](=[O:13])[CH2:10][CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH3:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Sc1ccccc1
Reactant: CC(CC(=O)O)O[Si](C)(C)C(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(CC(=O)OSc1ccccc1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
To a solution of 3.18 g (19.2 mmol) of (-)-3-t-butyldimethylsilyloxybutyric acid and 2.26 ml (22 mmol) of thiophenol dissolved in 100 ml of methylene chloride, 4.53 g (22 mmol) of N,N'-dicyclohexylcarbodiimide was added. After stirring the mixture at room temperature for 2 hours, the resultant was filtered and the filtrate was concentrated and distilled (110° to 116° C./0.3 mmHg) to give 5.00 g of (-)-3-t-butyldimethylsilyloxybutyric acid phenylthio ester (yield: 83%).
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:7]([N+:20]([O-])=O)[CH:6]=1)[CH3:2]>CCOC(C)=O.[Pd]>[NH2:20][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[NH:11][CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:4]([N:3]([CH2:1][CH3:2])[CH2:24][CH3:25])=[O:23]
Reactant: CCN(CC)C(=O)c1ccc(NCCc2ccccc2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)c1ccc(NCCc2ccccc2)c(N)c1
Yield: 100.6 %

Procedure:
Following general procedure 2C: A mixture of N,N-diethyl-3-nitro-4[(2-phenylethyl)amino]benzamide (0.170 g, 0.498 mmol) and 10% Pd/C in EtOAc (10 mL) was hydrogenated at 40 psi. Usual work-up provided the title compound (0.156 g) which was used without further purification. MS (ESI) (M+H)+=312.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:15][CH:14]([C:16]2[C:17]([C:22]3[CH2:23][CH2:24][N:25]([C:28](=[O:30])[CH3:29])[CH2:26][CH:27]=3)=[N:18][CH:19]=[CH:20][N:21]=2)[CH2:13]1)=[O:11]>CO.[Pd]>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:15][CH:14]([C:16]2[C:17]([CH:22]3[CH2:23][CH2:24][N:25]([C:28](=[O:30])[CH3:29])[CH2:26][CH2:27]3)=[N:18][CH:19]=[CH:20][N:21]=2)[CH2:13]1)=[O:11]
Reactant: CC(=O)N1CC=C(c2nccnc2C2CN(C(=O)c3nc4ccccc4[nH]3)C2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(=O)N1CCC(c2nccnc2C2CN(C(=O)c3nc4ccccc4[nH]3)C2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.5 %

Procedure:
A mixture of 1-(4-{3-[1-(1H-benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-3,6-dihydro-2H-pyridin-1-yl)-ethanone (170 mg, 0.42 mmol) and wet Pd—C (50%, 50 mg) in MeOH (30 mL) was stirred under H2 (30 psi) at RT for 2 h then the reaction mixture was filtered through CELITE® and washed with MeOH. The filtrate was concentrated in vacuo and the residue was purified by ISCO silica gel column (10% to 50% EtOAc in petroleum ether) to give 1-(4-{3-[1-(1H-benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-1-yl)-ethanone (101 mg, 0.25 mmol, 60% yield).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[CH:6]1([CH3:16])[CH2:11][CH2:10][CH:9]([CH:12]([CH3:14])[CH3:13])[CH:8](O)[CH2:7]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][CH:8]1[CH:9]([CH:12]([CH3:14])[CH3:13])[CH2:10][CH2:11][CH:6]([CH3:16])[CH2:7]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: CC1CCC(C(C)C)C(O)C1
Reactant: C=CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=CC(=O)OC1CC(C)CCC1C(C)C
Temperature: 150 °C

Procedure:
26 g of acrylic acid, 24 g of menthol and 15 g of p-toluenesulfonic acid in 500 mL of toluene were heated under reflux at an oil temperature of 150° C. for 19 h. Subsequently, the reaction mixture was quenched by the addition of salt saturated sodium bicarbonate solution. The mixture was then extracted with ether, the organic layers were combined and washed with salt saturated sodium bicarbonate solution and then with an aqueous solution of sodium hydride, salt saturated ammonium chloride solution, and then dried over salt saturated brine and sodium sulfate anhydrous. Finally, the resultant oily product was evaporated under reduced pressure to obtain menthyl acrylate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([CH3:31])=[C:22]([NH:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=4)[N:17]=3)[N:14]=2)=[C:5]([C:32]([F:35])([F:34])[F:33])[CH:4]=1)#[N:2].Cl.[NH2:37][OH:38].CCN(CC)CC>C(O)C>[OH:38][N:37]=[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([CH3:31])=[C:22]([NH:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=4)[N:17]=3)[N:14]=2)=[C:5]([C:32]([F:33])([F:35])[F:34])[CH:4]=1)[NH2:2]
Reactant: Cc1ccc(-c2cn3nc(-c4ccc(C#N)cc4C(F)(F)F)ccc3n2)cc1NC(=O)C(C)(C)C
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc(-c2cn3nc(-c4ccc(C(N)=NO)cc4C(F)(F)F)ccc3n2)cc1NC(=O)C(C)(C)C
Temperature: 80 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
A 500-mL flask is charged with N-(5-(6-(4-cyano-2-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-2-yl)-2-methylphenyl)pivalamide (7.496 g, 0.0157 mol), hydroxylamine hydrochloride (6.55 g, 0.0942 mol), Et3N (15.32 mL, 0.1099 mol), ethanol (82.5 mL) and the resulting mixture is stirred for 2 hours at 80° C. The mixture is concentrated onto celite and purified by silica gel chromatography (eluted by 0 to 100% of 10:1 EtOAc:MeOH in CH2Cl2). The isolated solid material (over 20 g) contains triethylamine and hydroxylamine salts, and the salts stay even after attempted recrystallization with isopropanol. This solid product is then added to a stirred mixture of saturated aqueous NaHCO3 and EtOAc. Solid suspension is collected by filtration. The liquid portion is back extracted with EtOAc and the organic layers are combined, dried with Na2SO4, concentrated to afford additional solid product. The combined solid product is dried on a lyophilizer overnight, recrystallized from hot Isopropanol to afford the desired title product (6.56 g). LCMS (m/z)=511.6 [M+H]+, tR=2.49 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][Si](C(C)(C)C)(C)C)=[CH:15][C:14]=2[CH3:27])[CH3:12])=[CH:6][C:5]=1[CH3:28].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C1COCC1>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=2[CH3:27])[CH3:12])=[CH:6][C:5]=1[CH3:28]
Reactant: COC(=O)c1ccc(CN(C)c2ccc(O[Si](C)(C)C(C)(C)C)cc2C)cc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN(C)c2ccc(O)cc2C)cc1C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
To a solution of 4-({[4-(tert-butyl-dimethyl-silanyloxy)-2-methyl-phenyl]-methyl-amino}-methyl)-2-methyl-benzoic acid methyl ester (1.0 g, 2.1 mmol) in THF (20.0 mL) is added 1.0 M TBAF/THF (3.2 mL, 3.2 mmol) at room temperature. The reaction mixture is stirred for 1.0 h. The mixture is partitioned between EtOAc (30 mL) and water (30 mL). The organic phase is washed with brine (30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography to afford the title compound as oil (0.45 g, 62%). LC-ES/MS m/e 300.3 (M+1), 298.3 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[CH:14]=3)=[CH:11][N:10]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[S:38](Cl)(=[O:40])=[O:39].[Na]>N1C=CC=CC=1>[F:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[S:38]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[CH:14]=3)=[CH:11][N:10]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[N:9]=2)[CH:3]=1)(=[O:40])=[O:39]
Reactant: CNc1cc(-c2cn(Cc3ccc(OC)cc3)nc2-c2cccc(N)c2)ccn1
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Agent: [Na]
Solvent: c1ccncc1
Product: CNc1cc(-c2cn(Cc3ccc(OC)cc3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
250 mg (0.65 mmol) of 4-[3-(3-aminophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]-N-methylpyridin-2-amine (prepared as described in Example 29) were dissolved in 10 ml of dry pyridine and 87 μl of 2,5-difluorobenzensulfonylchloride were added The reaction was stirred at room temperature overnight, then poured into aqueous sodium hydrogenocarbonate and extracted with dichloromethane. The organic layer was dried over sodium sulphate and evaporated in vacuo. The residue was then triturated with diethylether, giving 300 mg of the title compound (82%).
Reaction SMILES: I[C:2]1([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]=[CH:4][S:3]1.C([Sn](CCCC)(CCCC)[C:17]1[S:21][C:20]([C:22]2[S:23][C:24]([Sn](CCCC)(CCCC)CCCC)=[CH:25][C:26]=2[P:27]([O:34][CH2:35][CH2:36][CH2:37][CH3:38])([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:28])=[CH:19][C:18]=1P(OCCCC)(OCCCC)=O)CCC.[Cu]C#N.[F-].[K+]>C1(C)C=CC=CC=1>[CH2:35]([O:34][P:27]([C:5]1[CH:6]=[C:2]([C:7]2[S:8][C:9]([C:24]3[S:23][CH:22]=[CH:26][CH:25]=3)=[CH:10][CH:11]=2)[S:3][C:4]=1[C:24]1[S:23][C:22]([C:20]2[S:21][C:17]([C:20]3[S:21][CH:17]=[CH:18][CH:19]=3)=[CH:18][CH:19]=2)=[C:26]([P:27]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])([O:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:28])[CH:25]=1)([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:28])[CH2:36][CH2:37][CH3:38]
Reactant: CCCCOP(=O)(OCCCC)c1cc([Sn](CCCC)(CCCC)CCCC)sc1-c1cc(P(=O)(OCCCC)OCCCC)c([Sn](CCCC)(CCCC)CCCC)s1
Reactant: IC1(c2cccs2)CC=CS1
Agent: N#C[Cu]
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCCOP(=O)(OCCCC)c1cc(-c2ccc(-c3cccs3)s2)sc1-c1cc(P(=O)(OCCCC)OCCCC)c(-c2ccc(-c3cccs3)s2)s1
Yield: 39 %

Procedure:
At room temperature, 0.0643 g (0.220 mmols) of 2-iodobithiophene and 0.0046 g (0.00398 mmols) of commercially available tetrakistriphenylphosphine palladium were dissolved in toluene, to which 0.113 g (0.100 mmol) of 5,5′-bis(tributylstannyl)-4,3′-bis(dibutoxyphosphoryl)-[2,2′]-bithiophene and 0.0018 g (0.020 mmols) of commercially available copper(I) cyanide were added at room temperature. Thereafter, the reaction mixture was heated and stirred under reflux for 3 hours. After the reaction, the reaction mixture was cooled down to room temperature, to which a potassium fluoride aqueous solution was added, followed by stirring for 1 hour. Subsequently, the solid was removed by celite filtration and the filtrate was extracted with ethyl acetate. The organic phase was washed with a saturate saline solution and dried over anhydrous sodium sulfate. The solvent was removed by distilling off under reduced pressure, and the resulting crude product was purified with a PTLC plate (developed with ethyl acetate:hexane=1:10) to obtain the specified substance in the form of a red solid at a yield of 0.0345 g (yield: 39%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1)[CH:6]=[C:5]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18]
Reactant: COc1ccccc1-c1c[nH]c2ccc(F)cc12
Reactant: O=C(Cl)c1cccnc1
Product: COc1ccccc1-c1cn(C(=O)c2cccnc2)c2ccc(F)cc12
Yield: 66 %

Procedure:
By following the procedure of Example 1 substantially faithfully while using 10.0 g of 5-fluoro-3-(2-methoxyphenyl)indole in the place of 3-phenylindole and using nicotinoyl chloride in the place of benzoyl chloride, 9.5 g of 5-fluoro-3-(2-methoxyphenyl)-1-nicotinoylindole (66.0%) was obtained.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:18])[O:9][CH2:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[C:1]1(/[C:7](=[C:11](\[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)/[CH2:10][OH:9])/[CH2:8][OH:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1OCC(c2ccccc2)=C1c1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OC/C(=C(\CO)c1ccccc1)c1ccccc1
Reaction time: 3 h

Procedure:
After dissolving compound 18 (1.00 g, 4.23 mmol) in THF (20 ml), the temperature was reduced to or and DIBAL-H (12.96 ml) was dropped. After the agitation for 3 hours was carried out, the reaction was terminated and the extraction was conducted with EA. The organic layer was washed five times with brine and the column chromatography was carried out to obtain compound 19.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O>C(Cl)Cl>[CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[C:10]=1[Br:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1cc(NCc2ccccc2)ccn1Cc1cccc(F)c1
Solvent: ClCCl
Product: O=c1c(Br)c(NCc2ccccc2)ccn1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(benzylamino)-1-(3-fluorobenzyl)pyridin-2(1H)-one (0.50 g, 1.62 mmol) in anhydrous CH2Cl2 (10 mL) was added N-bromosuccinimide (NBS, 0.30 g, 1.7 mmol). The reaction was stirred at room temperature under a nitrogen atmosphere for 3 h. The reaction mixture was purified by flash chromatography (silica gel) using EtOAc in hexanes (1:1 v/v). The appropriate fractions were combined and concentrated.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[CH2:16]([O:23][C:24]1[CH:25]=[C:26]([Mg]Br)[CH:27]=[CH:28][CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:24]1[CH:29]=[C:28]([C:7]2([OH:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:3][CH:2]2[CH3:1])[CH:27]=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: Br[Mg]c1cccc(OCc2ccccc2)c1
Product: CC1CN(C(=O)OC(C)(C)C)CCC1(O)c1cccc(OCc2ccccc2)c1
Yield: 44 %

Procedure:
This compound was prepared from tert-Butyl 3-methyl-4-oxopiperidine-1-carboxylate and 3-benzyloxyphenylmagnesium bromide as described in Step 1 of Example 6 in 44% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH:23]([C:26]1[CH:30]=[C:29]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[N:28]([C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)[N:27]=1)([CH3:25])[CH3:24]>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([NH:19][C:32]([NH:31][C:29]2[N:28]([C:41]3[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=3)[N:27]=[C:26]([CH:23]([CH3:25])[CH3:24])[CH:30]=2)=[O:33])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CC(C)c1cc(NC(=O)Oc2ccccc2)n(-c2cccnc2)n1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)C)nn4-c4cccnc4)c3)c2cc1OC
Yield: 28.9 %

Procedure:
Using the procedure described in Example 306A, to a solution of 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (92 mg, 0.3 mmol), prepared as described in Example 115B, in THF (2 ml) was added DMAP (20 mg, 0.16 mmol) and phenyl 3-isopropyl-1-(pyridin-3-yl)-1H-pyrazol-5-ylcarbamate (106 mg, 0.33 mmol), described in Example 350A. The crude was purified by silica gel chromatography (DCM/MeOH 2-10%) to afford 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-isopropyl-1-(pyridin-3-yl)-1H-pyrazol-5-yl)urea (47 mg, 28%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.23 (d, J=7 Hz, 6H), 2.90 (m, 1H), 3.99 (s, 6H), 6.36 (s, 1H), 7.24 (d, J=7.5 Hz, 1H), 7.35 (d, J=4.8 Hz, 1H), 7.40-7.47 (m, 3H), 7.56 (dd, J=4.8, 1H), 7.77 (s, 1H), 7.97 (d, J=8.1 Hz, 1H), 8.58 (d, J=4.8 Hz, 2H), 8.69 (s, 1H), 8.78 (d, J=2.4 Hz, 1H), 9.19 (s, 1H); LC-MS (ESI) m/z 542 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([OH:15])[CH2:10][CH2:11][O:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[C:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[CH2:10][CH2:11][O:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)OCCC2O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc2c(c1)OCCC2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
The crude 7-tert-butyl-chroman-4-ol from step B was dissolved in 50 ml dichloromethane. Pyridinium chlorochromate (4.31 g, 20 mmol) was added and the reaction mixture was stirred at ambient temperature for 3 hours, diluted with hexanes and filtered through a pad of celite. Solvent was removed from the filtrate under reduced pressure and the residue filtered through a pad of silica gel, eluting with 20% ethyl acetate:hexanes. Removal of solvent gave 2.37 g of crude product, which was chromatographed on silica gel with an eluent of 10% ethyl acetate: hexanes to give 1.50 g of the title compound (73% for 3 steps). 1H NMR (300 MHz, CDCl3) δ 7.83 (d, 1H, J=8.1 Hz), 7.07 (dd, 1H, J=8.3 and 1.9 Hz), 6.97 (d, 1H, J=1.7 Hz), 4.62 (m, 2H), 2.78 (m, 2H), 1.31 (s, 9H). MS (DCI) m/e 205 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:16]([CH3:33])[C:17](=[O:32])[CH2:18][N:19]2[C:24]3[CH:25]=[C:26]([Cl:30])[C:27]([Cl:29])=[CH:28][C:23]=3[O:22][CH2:21][C:20]2=[O:31])[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH3:34][S:35]([NH:38][C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1)(=[O:37])=[O:36]>>[Cl:30][C:26]1[C:27]([Cl:29])=[CH:28][C:23]2[O:22][CH2:21][C:20](=[O:31])[N:19]([CH2:18][C:17]([N:16]([CH3:33])[CH:8]([C:5]3[CH:6]=[CH:7][C:2]([C:42]4[CH:41]=[CH:40][C:39]([NH:38][S:35]([CH3:34])(=[O:36])=[O:37])=[CH:44][CH:43]=4)=[CH:3][CH:4]=3)[CH2:9][N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[O:32])[C:24]=2[CH:25]=1
Reactant: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(Br)cc1
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Product: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(-c2ccc(NS(C)(=O)=O)cc2)cc1

Procedure:
The title compound was prepared according to example 33, using the intermediate from step c) and {4-[(methylsulfonyl)amino]-phenyl}boronic acid, MS (ES) m/e 647 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]2[CH:6]3[CH2:17][CH:8]([C:9]4[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=4[C:4]=2[CH:3]=1)[CH2:7]3.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C@:26]([OH:30])([C:28]#[CH:29])[CH3:27])[CH:22]=1>>[OH:30][C@:26]([C:23]1[CH:22]=[C:21]([CH3:20])[O:25][N:24]=1)([CH3:27])[C:28]#[C:29][C:2]1[CH:19]=[CH:18][C:5]2[CH:6]3[CH2:17][CH:8]([C:9]4[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=4[C:4]=2[CH:3]=1)[CH2:7]3
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Reactant: NC(=O)c1nc2c(s1)C1CC(C1)c1ccc(Br)cc1-2
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)sc2C2CC3C2)no1
Yield: 58 %

Procedure:
Similar to as described in General Procedure G, 9-bromo-5,6-dihydro-4H-4,6-methanobenzo[6,7]cyclohepta[1,2-d]thiazole-2-carboxamide was reacted with (2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol to give the titled compound as a colorless solid (14.3 mg, 58%).