Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[N:13][C:14]([SH:17])=[N:15][CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH2:28][CH:27]([CH2:31][NH:32][C:33](=[O:36])[CH2:34]Cl)[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH2:28][CH:27]([CH2:31][NH:32][C:33](=[O:36])[CH2:34][S:17][C:14]2[N:13]=[CH:12][C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:16][N:15]=2)[CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCCC(CNC(=O)CCl)C1
Reactant: COc1ccc(-c2cnc(S)nc2)cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(-c2cnc(SCC(=O)NCC3CCCN(C(=O)OC(C)(C)C)C3)nc2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
5-(3,4-Dimethoxy-phenyl)-pyrimidine-2-thiol 1f (0.75 g, 3 mmol) was added to a solution of the 2-chloroacetamide 1d (1.3 g, ˜80% purity, ˜3.6 mmol, obtained from step 3) and diisopropylethylamine (0.78 mL, 4.5 mmol, 1.5 equiv) in dry CH2Cl2. The resulting suspension was stirred at rt for about 2 h, at which time the reaction mixture became a dark brown solution and all the solid disappeared. The mixture was then concentrated and chromatographed on silica gel (ethyl acetate). The fractions containing the major product were combined and concentrated to an oily residue. Trituration of the oil with ether afforded 3-({2-[5-(3,4-dimethoxy-phenyl)-pyrimidin-2-ylsulfanyl]-acetylamino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester 1g (0.83 g, 55%) as a dark brown solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][NH:9][CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:19][C:20]1[C:21]([CH2:25][N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])=[CH:22][S:23][CH:24]=1.CCN(C(C)C)C(C)C>CC#N>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:19][C:20]2[C:21]([CH2:25][N:26]3[C:34](=[O:35])[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:27]3=[O:36])=[CH:22][S:23][CH:24]=2)[CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1CNCc1ncccc1C
Reactant: O=C1c2ccccc2C(=O)N1Cc1cscc1CBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1CN(Cc1cscc1CN1C(=O)c2ccccc2C1=O)Cc1ncccc1C

Procedure:
Using General Procedure A: Reaction of bis-(3-methyl-pyridin-2-ylmethyl)-amine, 2-(4-Bromomethyl-thiophen-3-ylmethyl)-isoindole-1,3-dione, and DIPEA in CH3CN gave 2-(4-{[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-thiophen-3-ylmethyl)-isoindole-1,3-dione as a white foam. Deprotection with H2NNH2H2O using General Procedure E gave the free base as a pale yellow solid. Conversion to the HBr salt gave COMPOUND 396 as a beige solid. 1H NMR (D2O) δ 2.43 (s, 6H), 3.88 (s, 2H), 3.99 (s, 2H), 4.31 (s, 4H), 7.29 (d, 1H, J=3 Hz), 7.48 (d, 1H, J=3 Hz), 7.79 (dd, 2H, J=6.0, 7.8 Hz), 8.31 (d, 2H, J=7.8 Hz), 8.55 (d, 2H, J=6.0 Hz); 13C NMR (D2O) δ 17.39, 36.42, 53.37, 54.95, 126.10, 127.73, 128.48, 132.21, 134.97, 137.81, 139.23, 148.51, 150.64; ES-MS m/z 353 (M+H). Anal. Calcd. for C20H24N4S.3.2HBr.5H2O: C, 37.63; H, 4.77; N, 8.78; S, 5.02; Br, 40.05. Found: C, 37.52; H, 4.62; N, 8.68; S, 4.95; Br, 40.21.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([CH3:14])=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[N+:15]([CH3:18])([O-:17])=[O:16].C1CCN2C(=NCCC2)CC1>C(#N)C>[CH3:14][C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([CH2:18][N+:15]([O-:17])=[O:16])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C=C(C)c1ccccn1
Reactant: C[N+](=O)[O-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CC(C)(C[N+](=O)[O-])c1ccccn1

Procedure:
A solution of 6 g of the compound obtained in Step 1, 3.36 ml of nitromethane and 4.26 ml of DBU dissolved in 120 ml of acetonitrile was heated to reflux for 36 hours. After the reaction was completed, the reaction solution was distilled under reduced pressure. The residue thus obtained was purified by a silica gel column chromatography using a mixture of ethyl acetate and n-hexane of 1:9 to obtain 1.8 g of the title compound as a syrup.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=O)[CH2:10][O:11][CH2:12][CH3:13])=[C:6]([NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH:5]=[C:4]([CH3:20])[N:3]=1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:10][O:11][CH2:12][CH3:13])[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]=2[CH:5]=[C:4]([CH3:20])[N:3]=1
Reactant: CCOCC(=O)Nc1c(NCC(C)C)cc(C)nc1Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOCc1nc2c(Cl)nc(C)cc2n1CC(C)C
Temperature: 135 °C
Reaction time: 48 h

Procedure:
N-[2-Chloro-4-(2-methylpropylamino)-6-methylpyridin-3-yl]-2-ethoxyacetamide (3.64 g), anhydrous toluene (100 ml), and phosphorus oxychloride (10.2 ml) were combined in a sealed glass tube and heated to 135° C. for 16 hours. The resulting reaction mixture was cooled, and the phosphorus oxychloride and toluene were removed under reduced pressure. The resulting black oil was dissolved in ethyl acetate, and the resulting solution was washed with saturated aqueous sodium bicarbonate. The basic aqueous layer was then washed with ethyl acetate. The organic layers were combined and concentrated to a black oil under reduced pressure. The oil was put through a column of silica gel using 60/40 ethyl acetate/hexane. The resulting eluted solution was dried under reduced pressure to a brown oil, which solidified after sitting for 48 hours. NMR analysis of the resulting product (2.59 g) indicated only minor impurities, and the product was carried on to the next step.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[CH3:12][NH2:13]>>[CH3:12][NH:13][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: CN
Product: CNCc1ccc(C(=O)O)cc1

Procedure:
4-Bromomethyl-benzoic acid (5 g, 22.8 mmol) is treated with a methylamine solution (40%, 75 mL, 867 mmol) for 4 days at ambient temperature. The resulting mixture is evaporated and the residue purified by flash chromatography.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].I[CH2:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:18]=3)([CH2:13][CH2:14]1)[O:11][CH2:10]2>N1C=CC=CC=1.CCOC(C)=O.[Zn]>[O:23]([C:19]1[CH:18]=[C:17]([C:12]23[CH2:15][CH2:16][C:9]([CH2:8][CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])([CH2:14][CH2:13]2)[CH2:10][O:11]3)[CH:22]=[CH:21][CH:20]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: ICC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Reactant: C=CC(=O)OC
Agent: [Zn]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)CCCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Temperature: 50 °C
Yield: 70.2 %

Procedure:
A mixture of Zn (622 mg, 9.52 mmol), anhydrous pyridine (5 mL) and methyl acrylate (0.95 mL, 9.52 mmol) was warmed to 50° C., after which NiCl2.6H2O (283 mg, 1.19 mmol) was added. The resulting mixture was heated to 65° C. for 1 h and stirred until the color of the solution became reddish-brown, then was cooled to 0° C., after which a solution of 4-(iodomethyl)-1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octane (500 mg, 1.190 mmol) in pyridine (2 mL) was added. The reaction mixture was allowed to warm to rt overnight, then was diluted with EtOAc (10 mL) and the resulting mixture was filtered off through a pad of CELITE®. The filtrate was washed with 1 N aq. HCl and brine, dried (MgSO4), and concentrated in vacuo. The residual crude oil was purified by flash chromatography (SiO2; gradient from 0 to 50% EtOAc:hexanes) to afford the title compound as a colorless oil (318 mg, 73% yield). LCMS, [M+H]+=381, 1H NMR (400M Hz, CDCl3) δ 7.39-7.24 (m, 3H), 7.19-7.06 (m, 3H), 7.04-6.98 (m, 2H), 6.86 (ddd, J=8.1, 2.4, 0.9 Hz, 1H), 3.82 (s, 2H), 3.70 (s, 3H), 2.31 (t, J=7.3 Hz, 2H), 2.10-1.98 (m, 4H), 1.76-1.57 (m, 6H), 1.22-1.12 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:4][CH:5]([OH:9])[CH2:6][CH:7]=[CH2:8])[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:13][CH:14]([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17]>O1CCCC1>[CH2:16]([O:15][CH:14]([O:18][CH2:19][CH3:20])[CH2:13][O:9][CH:5]([CH2:6][CH:7]=[CH2:8])[CH2:4][CH:1]1[CH2:3][CH2:2]1)[CH3:17]
Reactant: CCOC(CBr)OCC
Reactant: C=CCC(O)CC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(CC1CC1)OCC(OCC)OCC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 1-cyclopropylpent-4-en-2-ol (C65) (16 g, 0.127 mmol) in tetrahydrofuran (200 mL) was added to a 0° C. suspension of sodium hydride (60% in mineral oil, 15.2 g, 0.38 mol) in tetrahydrofuran (400 mL). After stirring at room temperature for 10 minutes, 2-bromo-1,1-diethoxyethane (97%, 75 g, 0.38 mol) was added drop-wise at room temperature. The reaction mixture was heated to 70° C. for 24 hours. It was then cooled to 0° C., slowly quenched with water (200 mL) and extracted with dichloromethane (3×500 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo; purification via silica gel chromatography (Gradient: 0% to 10% ethyl acetate in petroleum ether) afforded the product as a yellow oil. Yield: 20 g, 83 mmol, 65%. 1H NMR (400 MHz, CDCl3) δ 5.79-5.89 (m, 1H), 5.04 (dt, J=14.0, 1.6 Hz, 2H), 4.60 (t, J=5.2 Hz, 1H), 3.64-3.73 (m, 2H), 3.51-3.62 (m, 4H), 3.45 (quintet, J=6.0 Hz, 1H), 2.31 (t, J=6.4 Hz, 1H), 1.50 (quintet, J=6.8 Hz, 1H), 1.20-1.30 (m, 2H), 1.21 (dt, J=6.8, 1.2 Hz, 6H), 0.72-0.80 (m, 1H), 0.38-0.49 (m, 2H), −0.02-0.10 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([CH3:15])=[C:10]([CH2:12][CH2:13][OH:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)[OH:17].O>CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[C:1]1([C:7]2[O:8][C:9]([CH3:15])=[C:10]([CH2:12][C:13]([OH:17])=[O:14])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(C)=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1CC(=O)O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 1.0 g of 2-phenyl-4-hydroxyethyl5-methyloxazole in 20 ml of acetone was added a solution consisting of 1 g of chromium trioxide, 0.9 ml of concentrated sulfuric acid and 4 ml of water and the reaction stirred at room temperature for 40 minutes. The reaction mixture was poured into water (60 ml) and the product extracted with 150 ml of ethyl acetate. The organic layer was washed with water (2×50 ml) and dried over sodium sulfate. Removal of the solvent gave the crude product as an oil. The residue was dissolved in 80 ml of ethyl acetate and the product extracted with 100 ml of 0.25N aqueous sodium hydroxide. The aqueous layer was separated, acidified with 1N hydrochloric acid and the product extracted with 150 ml of ethyl acetate. The organic phase was separated, dried over sodium sulfate and concentrated to give a yellow solid, 500 mg.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:14]([O-])=O)[CH2:6]1)=[O:4].[H][H]>[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH2:14])[CH2:6]1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)C1Cc2cccc([N+](=O)[O-])c2C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C1Cc2cccc(N)c2C1
Yield: 9.8 %

Procedure:
A mixture of methyl-4-nitroindane-2-carboxylate (2.4 g, 0.11 mol) and 10% palladium on carbon (1.1 g, 0.01 mol) in ethyl acetate (15 mL) was shaken under 55 PSI hydrogen for 1 hour. It was then filtered and the filtrate was concentrated to give 2.07 g white solid (100%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[C:13]([CH3:25])[S:12][C:11]=2[CH:26]=1.[CH2:27]([NH2:30])[CH2:28][CH3:29]>>[CH3:25][C:13]1[S:12][C:11]2[CH:26]=[C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:30][CH2:27][CH2:28][CH3:29])[CH:8]=[CH:9][C:10]=2[C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1
Reactant: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(C(F)(F)F)cc1
Reactant: CCCN
Product: CCCNCCCCOc1ccc2c(-c3ccc(C(F)(F)F)cc3)c(C)sc2c1

Procedure:
According to the method in example 31, 6-(4-Bromo-butoxy)-2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophene and N-propyl amine were converted to yield {4-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-propyl-amine as yellowish oil, MS: 422 (MH+).
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([CH:10]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1>O>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([CH:10]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CC2C(C1=O)C2c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCN1CC2C(C1)C2c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.3 %

Procedure:
To a solution of 3-hexyl-6-phenyl-3-azabicyclo[3.1.0]hexan-2-one (Preparation 27, 40 mg, 0.15 mmol) in anhydrous tetrahydrofaran (2 ml) at room temperature under nitrogen, was added dropwise a solution of lithium aluminium hydride 1.0 M in tetrahydrofuran (0.3 ml, 0.3 mmol), then the mixture was heated to 60□ C. for 4 hours, cooled and stirred at room temperature for 64 hours. Water (30 ml) was carefully added, then the mixture was extracted with ethyl acetate (2×25 ml). The combined extracts were washed with water (30 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica (1.5 g) column chromatography eluting with 80:20:1 ethyl acetate:hexane:ammonia solution (0.880). Product-containing fractions were combined and concentrated in vacuo to give the title compound as a pale yellow oil (14 mg, 38%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]([CH2:20][CH3:21])([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[C:6]1=[O:22].CCN(CC)CC.[C:30]([N:34]=[C:35]=[O:36])([CH3:33])([CH3:32])[CH3:31]>CN(C=O)C>[C:30]([NH:34][C:35]([NH:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]([CH2:20][CH3:21])([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[C:6]1=[O:22])=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)N=C=O
Reactant: CCC1(c2cccc(OC)c2)CCCCN(CCN)C1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC1(c2cccc(OC)c2)CCCCN(CCNC(=O)NC(C)(C)C)C1=O
Reaction time: 18 h

Procedure:
To a solution of 1-(2-amino-ethyl)-3-ethyl-3-(3-methoxy-phenyl)-azepan-2-one hydrochloride (as described in Example 51, Step C) (0.27 g, 0.826 mmol) in DMF (5.0 mL) was added NEt3 (0.35 mL, 2.48 mmol) and t-butylisocyanate (0.29 mL, 2.48 mmol) and the solution was stirred for 18 hr. The DMF was removed in vacuo, and the residue partitioned between EtOAc and H2O. The organic layer was washed with brine and dried (MgSO4), and the solvents removed in vacuo to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][C:6]1[CH:19]=[C:9]2[NH:10][C:11](=[O:18])[C:12]3[C:17]([N:8]2[N:7]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3.[F:23][C:24]1[CH:29]=[C:28]([Sn](CCCC)(CCCC)CCCC)[CH:27]=[CH:26][N:25]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.CCOC(C)=O.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]>[F:23][C:24]1[CH:29]=[C:28]([C:2]2[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=2)[CH2:5][C:6]2[CH:19]=[C:9]3[NH:10][C:11](=[O:18])[C:12]4[C:17]([N:8]3[N:7]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:27]=[CH:26][N:25]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(F)c1
Reactant: O=c1[nH]c2cc(Cc3cccc(Br)c3)nn2c2ccccc12
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc(Cc3cccc(-c4ccnc(F)c4)c3)nn2c2ccccc12

Procedure:
A mixture of Example 61B (0.1 g, 0.282 mmol), 2-fluoro-4-(tributylstannyl)pyridine (0.11 g, 0.285 mmol) triethylamine (0.11 g, 1.1 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.039 g, 0.01 mmol) and tri-o-tolylphosphine (0.007 g, 0.023 mmol) in DMF (2 mL) was heated at 100° C. for 6 hr. The mixture was diluted with EtOAc and washed with sat NaHCO3, H2O and brine, then evaporated. The residue was purified by chromatography on silica gel with 20% to 80% ethylacetate in hexane to provide the desired product. 1H NMR (500 MHz, DMSO-d6) δ ppm 4.10 (s, 2 H) 5.75 (s, 1 H) 7.44-7.53 (m, 4 H) 7.68-7.74 (m, 2 H) 7.83-7.88 (m, 2 H) 8.04 (d, J=8.24 Hz, 1 H) 8.11 (d, J=6.71 Hz, 1 H) 8.30 (d, J=5.49 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:16])=O>CN(C)C1C=CC=CC=1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:16])=[N:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2cc(Br)ccc2c(=O)[nH]1
Solvent: CN(C)c1ccccc1
Product: Cc1nc(Cl)c2ccc(Br)cc2n1
Temperature: 60 °C
Yield: 60.2 %

Procedure:
A suspension of 0.45 g (1.87 mmol) of 7-bromo-2-methyl-3H-quinazolin-4-one in 0.48 ml N,N-dimethylaniline was treated with 1.41 ml (15.4 mmol) phosphorous oxychloride and heated at 60° C. for 2 h. The reaction mixture was evaporated in vacuo and the residue taken up in 20 ml water, neutralized with 10 ml saturated aqueous sodium bicarbonate and twice extracted with 25 ml dichloromethane. The organic layer is washed with 25 ml water, 25 ml brine, dried over magnesium sulfate and evaporated in vacuo. The residue is purified by chromatography on silica gel with heptane/ethylacetate (2:1) to give 0.29 g (59%) of 7-bromo-4-chloro-2-methyl-quinazoline as an orange solid. Mp. >82° C. EI mass spectrum, m/e: 258 (M calculated for C9H6BrClN2: 258).
Reaction SMILES: [CH3:1][S:2]([OH:4])=[O:3].[Na].Br[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1.CNCCNC>CS(C)=O>[F:14][C:9]1[CH:8]=[C:7]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:12]=[CH:11][C:10]=1[OH:13]
Reactant: Oc1ccc(Br)cc1F
Reactant: CS(=O)O
Agent: CNCCNC
Agent: [Na]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(O)c(F)c1
Yield: 70 %

Procedure:
A stirred mixture of sodium methane sulfinic acid (51.0 g, 4.009 equivalents), 4-bromo-2-fluorophenol (23.8 g, 1.000 equivalent), copper(I) trifluoromethanesulfonate benzene complex (6.28 g, 0.1001 equivalents), N,N′-dimethylethylenediamine (DMEDA, 2.2 g, 0.2003 equivalents), and dimethylsulfoxide (DMSO, 104 g) was heated under nitrogen at 130°-135° C. for 18 hours. Substantially all of the DMSO solvent was then removed from the reaction mixture by rotary evaporation at 1 torr with a 120° C. oil bath. To the brown oily distillation residue were added ethyl acetate (90 g) and water (100 g). After the resulting mixture had been heated and agitated to facilitate dissolution of the reaction mixture in the two liquid phases, it was filtered through a coarse sintered glass filter funnel containing a Whatman filter paper disc and 30 g of Celite. Addition of concentrated aqueous HCl (20 g) to the filtrate lowered the pH of the aqueous phase to less than 3. The phases were separated, and the aqueous phase was extracted two more times with ethyl acetate (90 g each). The combined organic phases were extracted with three 100-gram-portions of 1 M aqueous NaOH to extract the sodium salt of the phenoxide product into the aqueous phase. The aqueous phases were combined, acidified with cooling and concentrated aqueous HCl (40 g) to a pH less than 3, and then extracted with four 90-gram-portions of ethyl acetate to return the product as the free phenol to the organic phase. The organic phases were combined, dried over magnesium sulfate (15 grams), filtered, and concentrated by rotary evaporation at reduced pressure to provide product (4) (16.6 g, 70% yield) as a clear orange to brown oil, which solidified on standing.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH2:20][CH2:21][NH:22][C:23]([C:25]1[CH:29]=[C:28]([CH:30]([C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=2[F:39])O)[O:27][N:26]=1)=[O:24]>ClCCl>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH2:20][CH2:21][NH:22][C:23]([C:25]1[CH:29]=[C:28]([CH:30]([C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=2[F:39])[F:7])[O:27][N:26]=1)=[O:24]
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cc(C(O)c2cc(F)ccc2F)on1
Solvent: ClCCl
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cc(C(F)c2cc(F)ccc2F)on1
Temperature: 25 °C
Reaction time: 3 h
Yield: 6.7 %

Procedure:
Diethylaminosulfur trifluoride (0.033 mL; 0.197 mmol) was added to a solution of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-((2,5-difluorophenyl)(hydroxy)methyl)isoxazole-3-carboxamide (0.074 g; 0.171 mmol) in dichloromethane (5 mL) at −78° C., the resulting mixture was stirred at room temperature for 3 hours, cooled to 0° C. and quenched with water. The layers were separated, the aqueous layer was extracted with dichloromethane. The organic layers rejoined were dried over magnesium sulphate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) and by preparative HPLC method 2 to yield 0.005 g (7%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-((2,5-difluorophenyl)fluoromethyl)isoxazole-3-carboxamide as a white solid.
Reaction SMILES: N#N.Cl[C:4]1[N:5]=[N+:6]([O-:19])[C:7]2[C:16]3[CH2:15][N:14]([CH3:17])[CH2:13][CH2:12][C:11]=3[CH:10]=[CH:9][C:8]=2[N:18]=1.[Sn](CC)(CC)(CC)[CH2:21][CH3:22]>COCCOC.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>[CH2:21]([C:4]1[N:5]=[N+:6]([O-:19])[C:7]2[C:16]3[CH2:15][N:14]([CH3:17])[CH2:13][CH2:12][C:11]=3[CH:10]=[CH:9][C:8]=2[N:18]=1)[CH3:22]
Reactant: CN1CCc2ccc3nc(Cl)n[n+]([O-])c3c2C1
Reactant: CC[Sn](CC)(CC)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: COCCOC
Product: CCc1nc2ccc3c(c2[n+]([O-])n1)CN(C)CC3
Temperature: 85 °C
Reaction time: 18 h
Yield: 59.1 %

Procedure:
Pd(PPh3)4 (108 mg, 0.09 mmol) was added to a N2-purged, stirred solution of chloride 263 (225 mg, 0.9 mmol) and Et4Sn (0.36 mL, 1.8 mmol) in DME (15 mL) and the mixture was stirred at 85° C. for 18 h under N2. The solution was cooled to 20° C. and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (2-10%) of MeOH/DCM, to give 1-oxide 264 (130 mg, 60%) as a brown solid: mp 99-102° C.; 1H NMR δ 7.75 (d, J=8.6 Hz, 1H, H-5), 7.62 (d, J=8.6 Hz, 1H, H-6), 4.38 (s, 2H, H-10), 3.05-3.11 (m, 2H, H-7), 2.98 (q, J=7.6 Hz, 2H, CH2), 2.73 (t, J=5.9 Hz, 2H, H-8), 2.57 (s, 3H, NCH3), 1.42 (t, J=7.6 Hz, 3H, CH3); 13C NMR δ 167.1, 148.4, 137.1, 136.9, 136.3, 129.7, 126.1, 57.4, 50.5, 45.9, 30.7, 30.2, 12.2; MS (APCI) m/z (MH+, 100%). HRMS (FAB+) calcd for C13H17N4O (MH+) m/z 245.1402, found 245.1403.