Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19](Cl)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[N:12]=[CH:11][C:10]2=[O:23])=[C:4]([O:24][CH3:25])[CH:3]=1.ClCCl.[NH2:29][C:30]1[CH:34]=[CH:33][O:32][N:31]=1>N1C=CC=CC=1>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:29][C:30]4[CH:34]=[CH:33][O:32][N:31]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[N:12]=[CH:11][C:10]2=[O:23])=[C:4]([O:24][CH3:25])[CH:3]=1
Reactant: Nc1ccon1
Reactant: COc1cc(Br)c(F)cc1-n1c(=O)cnc2cc(S(=O)(=O)Cl)ccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(Br)c(F)cc1-n1c(=O)cnc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reaction time: 2 h
Yield: 82.1 %

Procedure:
A RBF was charged with 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-6-sulfonyl chloride (512.8 mg, 1.031 mmol), dichloromethane (1718 μl), and 3-aminoisoxazole (114 μl, 1.546 mmol) to give a thick suspension. Pyridine (3437 μl) was added relatively quickly, leading to thinner suspension. After 2 h, the mixture was concentrated in vacuo. The residue was partitioned between EtOAc and 2N aq. HCl. The layers were separated, and the aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (50-g SNAP Ultra column, 0-50% 3:1 EtOAc/EtOH in heptane with 10% DCM) to give 1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoxaline-6-sulfonamide (419.2 mg, 0.846 mmol, 82% yield) as a white foam. 1H NMR (400 MHz, DMSO-d6) δ=11.74 (br. s., 1H), 8.74 (d, J=1.9 Hz, 1H), 8.47 (s, 1H), 8.29 (d, J=2.2 Hz, 1H), 7.90 (dd, J=2.2, 8.9 Hz, 1H), 7.72 (d, J=6.1 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 6.98 (d, J=8.8 Hz, 1H), 6.48 (d, J=1.9 Hz, 1H), 3.74-3.71 (m, 3H), 3.32 (s, 3H). m/z (ESI) 495.0 (M+H)+.
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].CC(=CC)C.[F:16][C:17]1[CH:18]=[CH:19][C:20]([O:43][CH3:44])=[C:21]([C:23]2[N:27]=[C:26]([C:28]3[CH:29]=[C:30]([CH:41]=[O:42])[C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[CH3:40])=[CH:32][CH:33]=3)[O:25][N:24]=2)[CH:22]=1>O.O1CCOCC1>[F:16][C:17]1[CH:18]=[CH:19][C:20]([O:43][CH3:44])=[C:21]([C:23]2[N:27]=[C:26]([C:28]3[CH:29]=[C:30]([C:41]([OH:6])=[O:42])[C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[CH3:40])=[CH:32][CH:33]=3)[O:25][N:24]=2)[CH:22]=1
Reactant: O=P([O-])(O)O
Reactant: COc1ccc(F)cc1-c1noc(-c2ccc(-c3ccccc3C)c(C=O)c2)n1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(F)cc1-c1noc(-c2ccc(-c3ccccc3C)c(C(=O)O)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.6 %

Procedure:
A solution of sodium chlorite (59 mg; 0.65 mmol; 5.5 eq.) and sodium dihydrogenphosphate (51 mg; 0.43 mmol; 3.6 eq.) in water (1 mL) was added to a mixture of 2-methyl-2-butene (0.13 mL) and 4-[3-(5-fluoro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-2′-methylbiphenyl-2-carbaldehyde (46.2 mg; 0.12 mmol; 1 eq.) in dioxane (1 mL) and the reaction was stirred at room temperature for 16 hours. The suspension was partitioned between water and ethyl acetate. The aqueous phase was acidified to pH 3-4 with acetic acid and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (43 mg; 89%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:39].[CH3:40][N:41]1[CH2:46][CH2:45][CH:44]([NH2:47])[CH2:43][CH2:42]1.C(N(CC)C(C)C)(C)C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:47][CH:44]3[CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH2:43]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:39]
Reactant: CN1CCC(N)CC1
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(NC2CCN(C)CC2)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 83.1 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide (10 mg, 0.018 mmol) in THF (5 mL) were added 1-methyl-4-piperidinamine (10 mg, 0.088 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.574 mmol). The resultant solution was stirred at room temperature over might. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (9 mg, 83%). LC-MS m/z 602 (M+H)+; 1H-NMR (MeOD) δ 1.47 (m, 2H), 1.84 (m, 4H), 2.24 (s, 3H), 2.33 (s, 3H), 2.79 (m, 2H), 3.20 (m, 1H), 4.13 (s, 2H), 7.15 (m, 4H), 7.53 (m, 2H), 7.72 (m, 2H), 7.82 (s, 1H), 7.98 (d, 1H).
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([Br:15])=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].[CH3:16][N:17]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]2[CH:29]=[CH:28]C(N)=[CH:26][CH:25]=2)[CH2:19][CH2:18]1>C(O)(C)C>[Br:15][C:7]1[S:6][C:5]2[C:3](=[O:4])[N:12]([C:14]3[CH:28]=[CH:29][C:24]([N:20]4[CH2:21][CH2:22][CH2:23][N:17]([CH3:16])[CH2:18][CH2:19]4)=[CH:25][CH:26]=3)[CH:11]=[N:10][C:9]=2[CH:8]=1
Reactant: CN1CCCN(c2ccc(N)cc2)CC1
Reactant: COC(=O)c1sc(Br)cc1N=CN(C)C
Solvent: CC(C)O
Product: CN1CCCN(c2ccc(-n3cnc4cc(Br)sc4c3=O)cc2)CC1

Procedure:
5-Bromo-3-(dimethylaminomethyleneamino)thiophene-2-carboxylic acid methyl ester was reacted with 4-(4-methyl[1,4]diazepan-1-yl)phenylamine by method A1 with addition of isopropanol in addition. The product with the molecular weight of 419.34 (C18H19BrN4OS) was obtained in this way; MS (EST): 419, 421 (N+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH2:13]([S:15][C:16]1[C:17]([C:22]([NH2:24])=[O:23])=[N:18][CH:19]=[CH:20][CH:21]=1)[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].C1N2CCN(CC2)C1>O.CS(C)=O>[CH2:13]([S:15][C:16]1[C:17]([C:22]([NH:24][C:2]2[CH:7]=[CH:6][C:5]([S:8][C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=2)=[O:23])=[N:18][CH:19]=[CH:20][CH:21]=1)[CH3:14]
Reactant: CCSc1cccnc1C(N)=O
Reactant: FC(F)(F)Sc1ccc(Cl)nc1
Agent: C1CN2CCN1CC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CCSc1cccnc1C(=O)Nc1ccc(SC(F)(F)F)cn1
Temperature: 70 °C
Reaction time: 1 h
Yield: 37.6 %

Procedure:
A mixture of 0.64 g of 2-chloro-5-trifluoromethylsulfanylpyridine, 0.54 g of 3-ethylsulfanylpicolinic acid amide, 1.96 g of cesium carbonate, 0.33 g of DABCO and 5 mL of DMSO was stirred at 70° C. for 1 hour. Water was added to the reaction mixture cooled to room temperature, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.40 g of 3-ethylsulfanyl-N-(5-trifluoromethylsulfanylpyridin-2-yl)picolinamide (hereinafter, referred to as Compound of Present Invention 48).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([N+:11]([O-])=O)[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[H][H]>C(O)C.O=[Pt]=O>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[NH2:11])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(C)Oc1cccc(N)c1

Procedure:
A solution of 3-isopropoxynitrobenzene (8.5 g, 50 mmol) and PtO2 (0.3 g) in 200 ml of ethanol was shaken under 40 psi hydrogen at room temperature for 1.5 hours. The mixture was filtered through Celite, and the filtrate was concentrated in vacuo to provide 7.08 g of light oil (3-isopropoxyaniline). The oil was added to isatoic anhydride (7.35 g, 45 mmol) along with 15 ml of ethyl acetate. The mixture was heated in a 90° oil bath under nitrogen for two hours. The product crystallized from the reaction mixture upon the addition of hexanes. Filtration of the reaction mixture provided 10.19 g (83%) of 2-amino-N-(3-isopropoxyphenyl)benzamide as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:10]=2)[N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[NH2:26]>CCOC(C)=O>[CH3:33][O:32][C:28]1[CH:27]=[C:25]([NH:26][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:10]=3)[N:3]=2)[CH:24]=[C:23]([O:22][CH3:21])[C:29]=1[O:30][CH3:31]
Reactant: Clc1cncc(Oc2cccc(-c3ccccc3)c2)n1
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: CCOC(C)=O
Product: COc1cc(Nc2cncc(Oc3cccc(-c4ccccc4)c3)n2)cc(OC)c1OC
Yield: 78 %

Procedure:
Using Method EE (reaction time: 4 hours) with 2-chloro-6-[(3-phenyl)-phenyl-oxy]-pyrazine (100 mg, 0.35 mmol) and 3,4,5-trimethoxyaniline (84 mg, 0.46 mmol), and purification by column chromatography (AcOEt), the title compound was obtained (117 mg). Yield: 78%.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:5][CH:4]([C:6](O)=[O:7])[CH2:3]1.C(Cl)(=O)C([Cl:13])=O>ClCCl>[CH3:1][C:2]1([CH3:9])[CH2:5][CH:4]([C:6]([Cl:13])=[O:7])[CH2:3]1
Reactant: CC1(C)CC(C(=O)O)C1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC1(C)CC(C(=O)Cl)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3,3-Dimethyl-cyclobutanecarboxylic acid (Parkway Scientific, New York, N.Y., USA) (500 mg, 3.90 mmol) was dissolved in dichloromethane (3 mL) and oxalyl chloride (1.02 mL, 11.7 mmol) was added. The solution was stirred at room temperature for 4 h before concentrating in vacuo to provide 3,3-dimethylcyclobutanecarbonyl chloride which was carried on without purification. 1H NMR (400 MHz, CDCl3) δ 3.49 (quin, J=8.9 Hz, 1H) 2.27-2.15 (m, 2H) 2.14-2.06 (m, 2H) 1.18 (s, 3H) 1.12 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][N:56]1[CH:60]=[C:59]([S:61](Cl)(=[O:63])=[O:62])[N:58]=[C:57]1[CH3:65]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:61]([C:59]2[N:58]=[C:57]([CH3:65])[N:56]([CH3:55])[CH:60]=2)(=[O:63])=[O:62])[CH2:49][CH2:48]1
Reactant: Cc1nc(S(=O)(=O)Cl)cn1C
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(S(=O)(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)cn1C
Yield: 24 %

Procedure:
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride as starting materials in 24% yield. LCMS for C29H33ClN9O3S (M+H)+: m/z=622.2.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[NH:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:3]([CH:2]=[O:1])[C:4]=2[CH:5]=[CH:6]1
Reactant: OCc1cccc2[nH]ccc12
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=Cc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Tetrapropylammonium perruthenate (0.3 g, 0.85 mmol) was added in portions to a mixture of alcohol product from Step A (2.5 g, 17 mmol), N-methylmorpholine N-oxide (3.0 g, 25 mmol) and 4 A molecular sieves (3.0 g) in anhydrous methylene chloride (30 mL) at room temperature. The mixture was stirred at room temperature under nitrogen for 1 h and then filtered. The filtrate was concentrated in vacuo, and the residue was purified by chromatography (SiO2, CH2Cl2) to provide indole-4-aldehyde as a white powder (2.0 g, 80%): 1H NMR (300 MHz, CDCl3) δ 10.2 (s, 1H), 8.52 (br s, 1H), 7.64-7.69 (m, 2H), 7.31-7.44 (m, 3H); CI MS m/z=146 [C9H7NO+H]+.
Reaction SMILES: [Br-].[Br:2][CH2:3][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[CH2:29]1[CH2:42][O:41][C:31]([CH3:40])([CH2:32][CH:33]=[CH:34][C:35]([CH3:39])=[CH:36][CH:37]=O)[O:30]1.O>O1CCCC1>[CH2:29]1[CH2:42][O:41][C:31]([CH3:40])([CH2:32][CH:33]=[CH:34][C:35]([CH3:39])=[CH:36][CH:37]=[CH:3][Br:2])[O:30]1
Reactant: BrC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C=CCC1(C)OCCO1)=CC=O
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C=CCC1(C)OCCO1)=CC=CBr
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
Anhydrous tetrahydrofuran (22 cc) and bromomethyltriphenylphosphonium bromide (1.7 g, 3.9 mmol) are introduced into a 50-cc round-bottomed flask. This is cooled to -70° C. and potassium tert-butylate (0.44 g) is then added over 10 minutes. The mixture is stirred for 1 hour 30 minutes and 7,7-ethylenedioxy-3-methyl-2,4-octadienal (0.5 g) is then added in solution in tetrahydrofuran (3 cc) over 10 minutes. The temperature is allowed to rise to 10° C. and stirring is then performed for 2 hours 20 minutes. Water (12 cc) is quickly added and stirring is then performed for 15 minutes. After extraction, the organic phases are dried over magnesium sulphate. After evaporation of the solvents, the product obtained is placed in a mortar and is taken up with petroleum ether; the triphenylphosphine oxide which precipitates is ground until white and is then separated by filtration. After evaporation of the petroleum ether, 8,8-ethylenedioxy-1-bromo-4-methyl-1,3,5-nonatriene (0.49 g) is obtained, its characteristics being as follows:
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)=[N:8][CH:9]=1.Br[C:16]1C(C)=CC(N)=NC=1>>[CH3:16][C:5]1[C:4]([CH:2]2[CH2:3][O:1]2)=[CH:9][N:8]=[C:7]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)[CH:6]=1
Reactant: Cc1cc(N)ncc1Br
Reactant: c1cc(-n2cnnn2)ncc1C1CO1
Product: Cc1cc(-n2cnnn2)ncc1C1CO1

Procedure:
4-Methyl-5-(oxiran-2-yl)-2-(1H-tetrazol-1-yl) pyridine was prepared in a similar fashion to that described for the synthesis of 5-(oxiran-2-yl)-2-(1H-tetrazol-1-yl)pyridine (INTERMEDIATE 32) starting from commercially available 5-bromo-4-methylpyridin-2-amine to provide the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]2.[OH:24]O>C(O)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]2)=[O:24]
Reactant: O=C1CCc2cc(OCCCCSc3ccccn3)ccc2N1
Reactant: OO
Solvent: CC(=O)O
Product: O=C1CCc2cc(OCCCCS(=O)c3ccccn3)ccc2N1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
32.8 gm (0.1 mol) of 6-[4-(2-pyridyl-mercapto)-butoxy]-3,4-dihydro-carbostyril were dissolved in 330 ml of glacial acetic acid, and 10.2 gm (0.105 mol) of 35% hydrogen peroxide were added. The solution was stirred for 15 hours at about 20° C. The glacial acetic acid was distilled off at 60° C. in vacuo, the residue was washed with ether, and the thus obtained crude product was recrystallized twice from xylene in the presence of activated charcoal. Colorless crystals with a melting point of 144.5°-146° C. were obtained. Yield: 27.5 gm (79.8% of theory).
Reaction SMILES: CC(C)(OC([NH:7][C@H:8]([C:28]([NH:30][C@@H:31]([C:33]([NH:35][CH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:34])[CH3:32])=[O:29])[CH2:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([O:17][C:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])=[CH:12][C:11]=1[CH3:27])=O)C.[ClH:46].O1CCOCC1>C(O)(=O)C>[ClH:46].[CH3:16][C:15]1[CH:14]=[C:13]([O:17][C:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[CH:12]=[C:11]([CH3:27])[C:10]=1[CH2:9][C@@H:8]([C:28]([NH:30][C@@H:31]([C:33]([NH:35][CH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:34])[CH3:32])=[O:29])[NH2:7]
Reactant: Cc1cc(OC(=O)Oc2ccccc2)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)NCCCc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cc1cc(OC(=O)Oc2ccccc2)cc(C)c1C[C@H](N)C(=O)N[C@H](C)C(=O)NCCCc1ccccc1

Procedure:
The product of Example 13 is dissolved in glacial acetic acid and reacted with 6.8N HCl-dioxane according to the method of Example 3 to produce the titled hydrochloride compound.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.Br[CH:13]([CH:33]([CH3:35])[CH3:34])[C:14]([O:16]C(C#N)C1C=CC=C(OC2C=CC=CC=2)C=1)=[O:15]>>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][C@H:13]([C:14]([OH:16])=[O:15])[CH:33]([CH3:35])[CH3:34])=[CH:5][CH:4]=1
Reactant: CC(C)C(Br)C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: CC(C)[C@H](Nc1ccc(C(F)(F)F)cc1)C(=O)O

Procedure:
Following the procedure of Example 6, 4-trifluoromethylaniline is reacted with α-cyano-m-phenoxybenzyl α-bromoisovalerate to yield the α-cyano-m-phenoxybenzyl ester of N-(4-trifluoromethylphenyl)valine, MS m/e 468.2 (M+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>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>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([C:14]2[S:13][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][C:5]=1[C:8](=[O:10])[CH3:9]
Reactant: COc1cc(I)ccc1C(C)=O
Reactant: OB(O)c1cccs1
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+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2cccs2)ccc1C(C)=O
Temperature: 25 °C
Yield: 97.1 %

Procedure:
Ex-57a: 4′-iodo-2′-methoxyacetophenone (1.08 g, 3.9 mmol) in ethylene glycol dimethyl ether (50 ml) was degassed for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.456 g, 0.39 mmol), thiophene-2-boronic acid (0.75 g, 5.9 mmol), and sodium carbonate solution (2 m, 4 ml, 8 mmol) were added. The mixture was stirred at reflux under nitrogen for 24 hours. Upon cooling to room temperature, it was poured into water and extracted with dichloromethane. The organic phase was dried over sodium sulfate and evaporated. Silica gel chromatography (hexane/ethyl acetate, 3:1) gave 0.88 g (98%) of the desired 2′-methoxy-4′-(thien-2-yl)acetophenone.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH2:9]([OH:11])[CH3:10]>>[C:1]1([C:10]2[C:9]([OH:11])=[N:7][C:2]3[C:1]([N:8]=2)=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: Nc1ccccc1N
Product: Oc1nc2ccccc2nc1-c1ccccc1
Yield: 95 %

Procedure:
Phenylglioxalic acid (26.6 mmol) was mixed with o-phenylenediamine (40 mmol) and stirred in 40 ml of ethanol for 30 min. The reaction mixture was filtered to give, after evaporation of solvent, the crude product. Recrystallization from ethanol gave pure yellow crystalls in 95% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10](=[O:12])[CH3:11].[CH3:13][Mg]Br.CCOCC>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]([OH:12])([CH3:13])[CH3:11]
Reactant: C[Mg]Br
Reactant: COc1cccc(N)c1C(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cccc(N)c1C(C)(C)O
Temperature: 0 °C

Procedure:
1-(2-Amino-6-methoxyphenyl)ethanone (500 mg, 3.03 mmol) was dissolved in THF (7.5 mL) and cooled to 0° C. A 3M solution of Methyl magnesium bromide in Et2O (2.12 ml, 6.36 mmol) was added drop wise keeping the temperature below 10° C. The reaction was quenched with an aqueous saturated solution of NH4Cl (7.5 mL) keeping the temperature below 15° C. The mixture was diluted with water and ethyl acetate, two phases separated and the organic layer was washed twice with brine, dried over Na2SO4 and evaporated to dryness affording the title compound (500 mg) as light orange solid.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([C:21]#[N:22])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+]>CO.C(#N)C>[NH2:29][CH:1]([C:4]1[N:5]=[C:6]([C:21]#[N:22])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2]
Reactant: CC(=O)c1nc(C#N)c2ccccc2c1-c1cccc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CC(N)c1nc(C#N)c2ccccc2c1-c1cccc(F)c1
Temperature: 65 °C

Procedure:
A mixture of 3-acetyl-4-(3-fluorophenyl)isoquinoline-1-carbonitrile (4 mg, 0.01 mmol) and ammonium acetate (10.6 mg, 0.138 mmol) in methanol (0.078 mL) and acetonitrile (0.078 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling to room temperature, sodium cyanoborohydride (1.7 mg, 0.028 mmol) was added. The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature and quenched with sat. sodium bicarbonate, extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The residue was used directly in the next step. LCMS calculated for C18H15FN3 (M+H)+: m/z=292.1; Found: 292.1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:12]=[N:13][C:14]([N:17]2[CH2:29][CH2:28][C:27]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][C:19]=3[CH2:18]2)=[N:15][CH:16]=1)=[O:10].[H-].[Na+].[C:32](Cl)(=[O:34])[CH3:33]>CN(C=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:12]=[N:13][C:14]([N:17]2[CH2:29][CH2:28][C:27]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([C:32](=[O:34])[CH3:33])[C:19]=3[CH2:18]2)=[N:15][CH:16]=1)=[O:10]
Reactant: CC(=O)Cl
Reactant: O=C(NOC1CCCCO1)c1cnc(N2CCc3c([nH]c4ccccc34)C2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)n1c2c(c3ccccc31)CCN(c1ncc(C(=O)NOC3CCCCO3)cn1)C2
Reaction time: 0.33 h
Yield: 60.2 %

Procedure:
To a stirred solution of N-(tetrahydro-2H-pyran-2-yloxy)-2-[1,3,4,9-tetrahydro-2H-b-carbolin-2-yl]pyrimidine-5-carboxamide (120 mg, mmol) in DMF (5 mL) was added sodium hydride (22 mg) at 0° C. and the mixture was stirred for 20 min. Acetyl chloride (30 mg, mmol) was added and the reaction was allowed to attain room temperature and stirred 3 hours. After completion, the reaction mixture was partitioned between EtOAc and water. The organic layer was separated and washed with water, saturated sodium bicarbonate and concentrated. Pure N-(tetrahydro-2H-pyran-2-yloxy)-2-[9-acetyl-1,3,4,9-tetrahydro-2H-b-carbolin-2-yl]pyrimidine-5-carboxamide (80 mg, 60% yield) was obtained by column chromatography m/e=436 (M+1).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[C:5]1([CH:12]=[CH:11][CH:10]=[C:8]([OH:9])[CH:7]=1)[OH:6].F>>[OH:6][C:5]1[CH:7]=[C:8]([OH:9])[CH:10]=[CH:11][C:12]=1[C:2]([NH2:3])=[S:1]
Reactant: N#C[S-]
Reactant: Oc1cccc(O)c1
Agent: F
Agent: [K+]
Product: NC(=S)c1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
At a temperature and in the manner as described in Example 1, 39 g of potassium thiocyanate (0.4 mol) and 38.5 g of resorcinol (0.35 mol) are stirred with 0.3 l of 98% hydrofluoric acid, and subsequently, the mixture is stirred for 5 hours at room temperature. 0.25 l of hydrofluoric acid are then distilled off, and the residue is mixed with a small amount of ice, which causes 47 g of 2,4-dihydroxy-thiobenzamide to crystallize. This corresponds to a yield of 80% of the theoretical yield, relative to the resorcinol used. The melting point is 164° - 166° C.