Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[N+:13]([C:7]1[CH:6]=[C:5]2[C:10]([CH2:11][C:2]([CH3:12])([CH3:1])[CH2:3][NH:4]2)=[CH:9][CH:8]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: CC1(C)CNc2ccccc2C1
Agent: O=S(=O)(O)O
Product: CC1(C)CNc2cc([N+](=O)[O-])ccc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
1,2,3,4-Tetrahydro-3,3-dimethylquinoline (51 mg, 0.32 mmol) was dissolved in sulfuric acid (0.5 mL) and the temperature lowered to 0° C. To this solution 90% fuming nitric acid (14 mL, 0.32 mol) was added slowly and the mixture stirred at 0° C. for 1 h, then warmed to rt. The reaction mixture was then poured onto 1 g of ice and extracted with dichloromethane (2×5 mL). The organic phase was washed with saturated aqueous NaHCO3 (3 mL) and concentrated in vacuo to a reddish residue that was subjected to chromatography (silica gel, hexanes/ethyl acetate, 85:15) which afforded 39 mg (58%) of 7-nitro-1,2,3,4-tetrahydro-3,3-dimethylquinoline. Data for 7-nitro-1,2,3,4-tetrahydro-3,3-dimethylquinoline: 1H NMR (400 MHz, CDCl3) 7.40 (dd, J=8.3, 2.1, 1H), 7.29 (d, J=1.8, 1H), 7.01 (d, J=8.3H, 1H), 4.25 (s, 1H), 2.98 (s, 2H), 2.54 (s, 2H), 1.01 (s, 6H).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].COC1C=CC(C[S:23][CH:24]2[CH2:28][CH2:27][NH:26][C:25]2=[O:29])=CC=1>C1(OC)C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[SH:23][CH:24]1[CH2:28][CH2:27][NH:26][C:25]1=[O:29]
Reactant: COc1ccc(CSC2CCNC2=O)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCC1S
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
20 ml of trifluoroacetic acid and 0.41 ml of trifluoromethanesulfonic acid were added, whilst ice-cooling, to a solution of 949 mg of 3-(4-methoxybenzylthio)pyrrolidin-2-one in 4 ml of anisole, and then the mixture was stirred at room temperature for 30 minutes. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure to leave a residue, which was purified by column chromatography through silica gel, eluted with a 10:1 by volume mixture of ethyl acetate and methanol, to give 728 mg of the title compound as an oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[N:2]1.[Br:13]Br>C(O)(=O)C>[Br:13][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][N:2]=[C:3]2[C:10]([OH:12])=[O:11]
Reactant: BrBr
Reactant: O=C(O)c1n[nH]c2ccccc12
Solvent: CC(=O)O
Product: O=C(O)c1n[nH]c2ccc(Br)cc12
Temperature: 120 °C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
A suspension of indazole-3-carboxylic acid (CX) (1.0 g, 6.16 mmol) in glacial acetic acid (60 mL) was heated at 120° C. to get a clear solution. The solution was cooled to 90° C. A solution of bromine (0.633 mL, 12.33 mmol) in glacial acetic acid (2 mL) was added slowly to the solution while heating at 90° C. The solution was further heated 16 h at 90° C. The solution was cooled to room temperature, poured into ice water and further stirred at room temperature for 15 min The solids formed were filtered, washed with cold water and dried under vacuum at room temperature to get 5-bromo-1H-indazole-3-carboxylic acid (CXV) as a white solid (1.30 g, 5.39 mmol, 87.5% yield). 1H NMR (DMSO-d6) δ ppm 13.95 (s, 1H), 13.18 (br s, 1H), 8.21 (d, J=1.2 Hz, 1H), 7.65 (d, J=7.0 Hz, 1H), 7.56 (dd, J=7.0, 1.2 Hz, 1H); ESIMS found for C8H4BrN2O2 m/z 242.0 (M+H).
Reaction SMILES: [ClH:1].[CH3:2][CH:3]1[CH2:7][CH2:6][CH:5]([CH3:8])[N:4]1[CH2:9][CH:10]([N:12]1[C:25]2[CH:24]=[C:23]([C:26](=[S:28])[NH2:27])[CH:22]=[CH:21][C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11].[CH2:29](N)[CH2:30][CH3:31].S>C(O)C>[ClH:1].[CH3:8][CH:5]1[CH2:6][CH2:7][CH:3]([CH3:2])[N:4]1[CH2:9][CH:10]([N:12]1[C:25]2[CH:24]=[C:23]([C:26](=[S:28])[NH:27][CH2:29][CH2:30][CH3:31])[CH:22]=[CH:21][C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11]
Reactant: CCCN
Reactant: CC(CN1C(C)CCC1C)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Agent: Cl
Agent: S
Solvent: CCO
Product: CCCNC(=S)c1ccc2c(c1)N(C(C)CN1C(C)CCC1C)c1ccccc1S2
Temperature: 120 °C

Procedure:
A solution of 10-((2RS)-1-[(2RS,5RS)-2,5-dimethyl-1-pyrrolidinyl]-2-propyl}-2-phenothiazinecarbothioamide hydrochloride (0.9 g) and propylamine (2.9 cc) in absolute ethanol (20 cc) is saturated with hydrogen sulphide and heated for 12 hours to a temperature in the region of 120° C. After cooling, the solution obtained is purged with nitrogen and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is dissolved in ethyl acetate (100 cc) and I the solution is washed with distilled water (2×20 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual yellow oil (1.09 g) is purified by chromatography on a column (height: 30 cm; diameter: 1 cm) of silica gel (0.04-0.063 mm) with a slight excess pressure of nitrogen (40 kPa), eluting with methylene chloride (200 cc) and then with a mixture (95:5 by volume) (250 cc) of methylene chloride and methanol and collecting 50-cc fractions. The combined fractions 3 to 7 are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual yellow oil (0.75 g) is dissolved in ethyl acetate (20 cc) and treated with stirring, with a 3N solution (0.6 cc) of hydrochloric acid in ethyl ether. The gum formed is separated by decanting the solvent, taken up in solution in 2-propanol (2 cc) and treated with ethyl ether (10 cc). The solid formed is drained, washed with ethyl ether (2×5 cc) and dried under reduced pressure (5 mm Hg; 0.68 kPa) at 40° C. 10-{(2RS)-1-[(2 RS,5RS)-2,5-Dimethyl-1-pyrrolidinyl]-2-propyl}-N-propyl-2-phenothiazinecarbothioamide hydrochloride (0.63 g) is thereby obtained in the form of a yellow solid, m.p. 138°-140° C. (melts forming a paste).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16](Cl)[C:15]3[C:10](=[C:11]([O:23][CH3:24])[C:12]([O:21][CH3:22])=[C:13]([O:19][CH3:20])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[CH2:25]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([N:35]3[CH2:36][CH2:37][N:32]([CH2:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:33][CH2:34]3)[C:15]3[C:10](=[C:11]([O:23][CH3:24])[C:12]([O:21][CH3:22])=[C:13]([O:19][CH3:20])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COc1cc2c(Cl)nc(-c3ccc(Cl)cc3)nc2c(OC)c1OC
Product: COc1cc2c(N3CCN(Cc4ccccc4)CC3)nc(-c3ccc(Cl)cc3)nc2c(OC)c1OC
Temperature: 150 °C

Procedure:
A mixture of 2.0 g of 2-(4-chlorophenyl)-4-chloro-6,7,8-trimethoxyquinazoline and 5.0 g of N-benzylpiperazine was heated at 150° C. for 1 h. After cooling, 20 ml of ice water were added and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The oily crude product thus obtained was recrystallized from isopropanol. Yield: 1 g. M.p.: 150° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Cl:9]N1C(=O)CCC1=O.O>ClCCl>[Cl:9][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[CH:3][C:2]=1[F:1]
Reactant: Nc1cccc(F)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: ClCCl
Product: Nc1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 96 ml of 3-fluoroaniline in 1000 ml of dichloromethane, 147 g of N-chlorosuccinimide was added at 0° C. and stirred for 12 hours at room temperature. Water was added to the reaction solution which then was extracted with chloroform. The extract was washed with saturated brine, dried on anhydrous sodium sulfate and distilled. The residue was separated and purified on silica gel column chromatography (hexane/ethyl acetate=5/1) to provide 21 g of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([F:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[N:17]=[C:16]2Cl)=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH3:28][CH2:29][O-:30].[Na+]>C(O)C>[CH2:29]([O:30][C:16]1[N:15]([C:11]2[C:12]([F:14])=[CH:13][C:2]([Cl:1])=[C:3]([CH:10]=2)[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5])[C:20](=[O:21])[C:19]([F:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[N:17]=1)[CH3:28]
Reactant: CC[O-]
Reactant: CC(C)OC(=O)c1cc(-n2c(Cl)nc(C(F)(F)F)c(F)c2=O)c(F)cc1Cl
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(C(F)(F)F)c(F)c(=O)n1-c1cc(C(=O)OC(C)C)c(Cl)cc1F

Procedure:
using isopropyl 2-chloro-5-[2-chloro-5-fluoro-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-4-fluorobenzoate and sodium ethylate in ethanol there is obtained isopropyl 5-[2-ethoxy-5-fluoro-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-2-chloro-4-fluorobenzoate, 1H-NMR (CDCl3, 400 MHz): 7.83 ppm (d,1H), 7.40 ppm (d,1H), 5.27 ppm (m,1H), 4.48 ppm (m,2H), 1.39 ppm (d,3H), 1.38 ppm (d,3H), 1.29 ppm (t,3H);
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:10]=[CH2:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)Cl>[C:1]([NH:8][C@H:9]([CH:10]1[CH2:11][O:27]1)[CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C1CO1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
2.6 g of Boc-1(S)-cyclohexylmethylprop-2-en-1-ylamine are dissolved in 50 ml of CH2Cl2, and 1.9 g of m-chloroperbenzoic acid in 50 ml of CH2Cl2 are added dropwise at 0° C. The reaction solution is stirred at R.T. for 36 h and is then extracted first with 100 ml of 5% strength aqueous Na2SO3 solution and then with 100 ml of saturated aqueous Na2CO3 solution. Drying over Na2SO4 and concentration in vacuo are followed by chromatography on silica gel (mobile phase MTB/cyclohexane 1:1) resulting in the title compound as a colorless oil, diastereomer ratio 3:1 to 5:1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:15]([O:19][C:20]([N:22]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].CC([O-])(C)C.[K+].CCOC(C)=O>COCCOC>[C:15]([O:19][C:20]([N:22]1[CH2:28][CH2:27][CH2:26][N:25]([C:2]2[CH:3]=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)c1cc(Br)c2ncccc2c1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)c1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)c2ncccc2c1
Temperature: 60 °C
Yield: 66.5 %

Procedure:
A mixture of 8-Bromo-6-isopropyl-quinoline (1.38 g, 5.51 mmol, 1.04 equiv) and 1-(tert-butoxycarbonyl)homopiperazine (1.06 g, 1.0 equiv) in 5.5 mL of DME was degassed with compressed nitrogen gas for 5 minutes. To the mixture was added t-BuOK (0.83 g, 1.4 equiv). After degassing for another 2 minutes, allylchloro[1,3-(2,6-di-isopropylphenyl)imidazol-2-ylidene]palladium (II) (Nolan's catalyst, 61 mg, 0.02 equiv) was added and the resulting mixture was heated to 60° C. overnight, then cooled down to room temperature. EtOAc (˜70 mL) was added and the mixture was filtered through celite. The filtrate was washed with saturated aqueous NaHCO3 (70 mL) and brine (70 mL), dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography using 5% to 20% EtOAc in hexane to afford the title compound (1.3 g, 64%). MS (ES) m/z 370.2 (M+H+).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[N:10]=[C:9]2[CH3:22])=[CH:6][CH:7]=1.[CH3:23][O-:24].[Na+].O>CO>[Cl:21][C:17]1[CH:16]=[C:15]([C:14]#[C:13][C:11]2[N:10]=[C:9]([CH3:22])[N:8]([C:5]3[N:4]=[N:3][C:2]([O:24][CH3:23])=[CH:7][CH:6]=3)[CH:12]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1ccc(Cl)nn1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(-n2cc(C#Cc3cccc(Cl)c3)nc2C)nn1
Temperature: 25 °C

Procedure:
3-Chloro-6-[4-(3-chloro-phenylethynyl)-2-methyl-imidazol-1-yl]-pyridazine (100 mg, 0.30 mmol) was dissolved in 2 mL methanol and 1.5 mL sodium methanolate solution were added. The reaction mixture was refluxed for 3 h. After cooling to room temperature the reaction mixture was treated with 30 mL water and extracted three times with ethyl acetate (50 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated and the desired product was obtained as a white solid (53 mg, 53%), MS: m/e=325.3 (M+H+).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:12]=2[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1.CN(C1C=CC=CN=1)C.Cl>C(Cl)Cl.C(Cl)CCl>[C:1]1([S:7]([NH:10][C:11]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:12]=2[C:13]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=2)=[O:15])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=C(O)c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)c1ccc(NC(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.8 %

Procedure:
To a suspension of 2-phenylsulfonylamino-5-chlorobenzoic acid (250 mg; prepared in Reference Example 3.) and methyl p-aminobenzoate (133 mg) in methylene chloride (5 ml), EDC (168 mg) and dimethylaminopyridine (20 mg) were added. The mixture was stirred for 3 days at room temperature. The reaction mixture was poured into diluted HCl and extracted with ethyl acetate. The organic layer was washed, dried over and concentrated under reduced pressure. The residue was purified on silica gel column chromatography (AcOEt-benzene) to give the title compound (142 mg) having the following physical data.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:38]=[CH:37][C:6]([O:7][C:8]2[N:12]([CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[N:11]=[C:10]([C:19]3[CH:20]=[C:21]([C:25]4([NH:29]C(=O)OC(C)(C)C)[CH2:28][O:27][CH2:26]4)[CH:22]=[CH:23][CH:24]=3)[CH:9]=2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:29][C:25]1([C:21]2[CH:20]=[C:19]([C:10]3[CH:9]=[C:8]([O:7][C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:39])[F:40])=[CH:38][CH:37]=4)[N:12]([CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[N:11]=3)[CH:24]=[CH:23][CH:22]=2)[CH2:28][O:27][CH2:26]1
Reactant: CN(C)C(=O)Cn1nc(-c2cccc(C3(NC(=O)OC(C)(C)C)COC3)c2)cc1Oc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)Cn1nc(-c2cccc(C3(N)COC3)c2)cc1Oc1ccc(C(F)(F)F)cc1
Reaction time: 1 h

Procedure:
A stirred solution of tert-butyl [3-(3-{5-(4-trifluoromethylphenoxy)-1-[2-(dimethylamino)-2-oxoethyl]-1H-pyrazol-3-yl}phenyl)oxetan-3-yl]carbamate (70 mg, 0.13 mmol) in 2 mL of CH2Cl2 was cooled in an ice bath. To the solution was added 1 mL of TFA and the mixture was stirred for 1 h. The cooling bath was removed and the mixture was stirred at ambient temperature for 1 h. 10% Aqueous Na2CO3 solution was added and the mixture was extracted with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to give 2-{3-[3-(3-aminooxetan-3-yl)phenyl]-5-(4-trifluoromethylphenoxy)-1H-pyrazol-1-yl}-N,N-dimethylacetamide as an oil. Calcd (M+1)+: 461.4. Found: 461.5
Reaction SMILES: [O:1]=[C:2]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]2)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[H][H]>C(O)C.[C].[Pd]>[OH:1][CH:2]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]2)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: [H][H]
Reactant: O=C1CCc2cc(C(=O)CCN3CCC(c4ccccc4)CC3)ccc2N1
Agent: [Pd]
Solvent: CCO
Product: O=C1CCc2cc(C(O)CCN3CCC(c4ccccc4)CC3)ccc2N1

Procedure:
2.2 Grams of 6-[1-oxo-3-(4-phenyl-1-piperidyl)propyl]-3,4-dihydrocarbostyril and 0.5 g of 5%-palladium carbon were dispersed in 80 ml of ethanol and stirred under 2 atmospheric pressure of hydrogen gas at a room temperature for 5 hours. The reaction mixture was filtered to remove the palladium black and the mother liquor was concentrated under a reduced pressure. The residue thus obtained was recrystallized from ethanol to obtain 1.5 g of 6-[1-hydroxy-3-(4-phenyl-1-piperidyl)propyl]-3,4-dihydrocarbostyril in colorless plate-like crystals. Melting point: 155.5°-156° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:7](=[O:18])[C:6](=[O:19])[NH:5]2.[CH3:20][C:21](=O)[CH2:22][CH2:23][C:24](=O)[CH3:25]>C(O)(=O)C>[Cl:12][C:11]1[CH:10]=[C:9]2[C:4]([NH:5][C:6](=[O:19])[C:7](=[O:18])[N:8]2[CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:3][C:2]=1[N:1]1[C:24]([CH3:25])=[CH:23][CH:22]=[C:21]1[CH3:20]
Reactant: CC(=O)CCC(C)=O
Reactant: COC(=O)Cn1c(=O)c(=O)[nH]c2cc(N)c(Cl)cc21
Solvent: CC(=O)O
Product: COC(=O)Cn1c(=O)c(=O)[nH]c2cc(-n3c(C)ccc3C)c(Cl)cc21
Temperature: 0 °C
Yield: 75.3 %

Procedure:
6.0 g (20.2 mmol) of 6-amino-7-chloro-1-(methoxycarbonylmethyl)-2,3(1H,4H)-quinoxalinedione and 2.4 ml (20.2 mmol) of 2,5-hexanedione were refluxed in 75 ml of glacial acetic acid for 0.5 h. The mixture was then poured into ice-water and the precipitate was filtered off with suction to yield 5.5 g (74%) of the product.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:4]=[C:3]1[S:15][CH3:16].[Br:17]Br>C(O)(=O)C>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([Br:17])=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:4]=[C:3]1[S:15][CH3:16]
Reactant: BrBr
Reactant: CSc1nc(-c2ccncc2)cc(=O)n1C
Solvent: CC(=O)O
Product: CSc1nc(-c2ccncc2)c(Br)c(=O)n1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-Methyl-6-(4-pyridyl)-2-methylthio-4(3H)-pyrimidinone (1.00 g 4.29 mmol) was dispersed in acetic acid (24 ml) and to the clear solution Bromine (0.5 ml, 1.5 g 9.38 mmol) was added. The reaction mixture stirred at room temperature for 24 h. The mixture was concentrated and the residue was co-evaporated with toluene until all bromine is removed. The crude compound is ready to use in next step. MS(m/z): 312 and 314. C10H11BrN3OS requir. 311 and 313. 1H-NMR(DMSO-d6):d 8.75 (m, 2H, pyridyl) 8.19 (m, 2H, pyridyl), 3.67 (s, 3H, N—CH3), 2.80 (s, 3H, S—CH3).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][C:19]2[C:24]([CH3:25])=[CH:23][C:22]([C:26]#[N:27])=[CH:21][C:20]=2[CH3:28])=[N:4][C:5]([NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[N:6][C:7]=1Cl.[NH3:29].O1CCOCC1>O>[NH2:29][C:7]1[C:2]([Br:1])=[C:3]([O:18][C:19]2[C:24]([CH3:25])=[CH:23][C:22]([C:26]#[N:27])=[CH:21][C:20]=2[CH3:28])[N:4]=[C:5]([NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[N:6]=1
Reactant: N
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc(Cl)c1Br
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc(N)c1Br
Reaction time: 48 h
Yield: 40.4 %

Procedure:
4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-chloro-2-pyrimidinyl]amino]-benzonitrile (0.00250 mol) and NH3/1,4-dioxane 0.5M (0.015 mol) were heated in a pressure vessel at 150° C. for 4 days. The sample was allowed to sit at ambient conditions for 2 days. Water was added slowly to the mixture until a precipitate formed. The mixture was stirred for 2 hours and filtered. The solid was recrystallized from CH3CN to obtain 0.58 g (fraction 1). The filtrate was evaporated (fraction 2). Both fractions were combined and purified by column chromatography, eluting with CH2Cl2. The resulting residue of the desired fraction was recrystallized from CH3CN to yield 0.44 g of 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile (40.5%). The sample was dried at 80° C. for 16 hours at 0.2 mm Hg (interm. 30). 4-[[4-amino-5-chloro-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile (interm. 31) was prepared according to an analogous procedure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][C@H:21]3[CH2:23][O:22]3)[N:9]=2)=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CCO.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][C@H:21]([OH:22])[CH2:23][N:35]3[CH2:34][CH2:33][N:32]([C:26]4[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=4[CH3:24])[CH2:37][CH2:36]3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(Cl)cc1N1CCNCC1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(Br)cc3)nn2C[C@H]2CO2)C1
Solvent: CCO
Solvent: ClCCl
Product: CC(=O)N1CCc2c(c(-c3ccc(Br)cc3)nn2C[C@H](O)CN2CCN(c3cc(Cl)ccc3C)CC2)C1
Temperature: 70 °C
Reaction time: 18 h
Yield: 35.1 %

Procedure:
(S)-1-[3-(4-Bromo-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (37 mg, 0.98 mmol) and 4-(2-methyl-5-chlorophenyl)piperazine (36 mg, 0.17 mmol) were combined in EtOH (0.4 mL) and heated to 70° C. After 18 h the mixture was allowed to cool, diluted with CH2Cl2 and purified by preparative TLC (silica, 8% MeOH/CH2Cl2) to give 35 mg (61%) the title compound. HPLC (reverse phase conditions): tR=4.41 min. MS (electrospray): m/z calculated for C28H3435Cl79BrN5O2 [M++H], 586.16, found 586.2. 1H NMR (CDCl3, 400 MHz, a mixture of amide rotamers): 7.56 (d (partially obscured), J=8.5, Hz, 2H), 7.53 (s, 4H), 7.48 (d, J=8.5 Hz, 2H), 7.08 (br d, J=8.5 Hz, 1H), 6.95 (m, 2H), 4.85 and 4.73 (A and B of AB quartet, Jab=15.6 Hz, 1H), 4.62 (s, 1H), 4.20 (m, 2H), 4.04 (m, 2H), 3.90-3.71 (m, 2H), 2.92-2.53 (m, 11H), 2.21 (s, 1.5H), 2.16 (s, 1.5H).
Reaction SMILES: [I:1][C:2]1[CH:11]=[N:10][C:5]2[NH:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[I:1][C:2]1[CH:11]=[N:10][C:5]2[NH:6][CH2:7][CH2:8][N:9]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:19])[C:4]=2[CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Ic1cnc2c(c1)NCCN2
Product: O=C(c1ccccc1)N1CCNc2ncc(I)cc21
Yield: 61 %

Procedure:
7-Iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (50 mg) was reacted with benzoyl chloride as in General Procedure 2 to give the title compound as a pale yellow solid (61% yield). M.p. 164-166° C., LCMS: m/z=366.00 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.45-3.50 (m, 2H), 3.90 (t, J=4.8 Hz, 2H), 7.37-7.47 (m, 6H), 7.95 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[OH:15][CH2:16][CH2:17][S:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([S:18]([CH2:17][CH2:16][OH:15])(=[O:20])=[O:19])=[CH:29][CH:28]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)CCO)cc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(S(=O)(=O)CCO)cc1

Procedure:
5 g of 4-fluorobenzonitrile was used in Procedure Q with 2-mercaptoethanol to afford 4-(2-hydroxyethylthio)benzonitrile. 900 mg of 4-(2-hydroxyethylthio)benzonitrile was reacted via Procedure T to give 4-(2-hydroxyethylthio)benzoic acid. 1.0 g of 4-(2-hydroxyethylthio)benzoic acid was reacted via Procedure R to give 4-(2-hydroxyethylsulfonyl)benzoic acid. 80 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-hydroxyethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxyethylsulfonyl)benzamide. MS (Q1) 417.0 (M)+.