Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C@@H:4]([NH2:29])[CH2:5][NH:6][C:7](=[O:28])[CH2:8][CH2:9][NH:10][C:11](=[O:27])[CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C(N(CC)CC)C.[C:38]1([S:44](Cl)(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>ClCCl>[CH3:1][O:2][C:3](=[O:30])[C@@H:4]([NH:29][S:44]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:46])=[O:45])[CH2:5][NH:6][C:7](=[O:28])[CH2:8][CH2:9][NH:10][C:11](=[O:27])[CH2:12][CH2:13][CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:18][CH2:19]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)[C@@H](N)CNC(=O)CCNC(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CNC(=O)CCNC(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1)NS(=O)(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
The compound (120 mg) obtained in the above (5) is dissolved in dichloromethane (3 ml), and thereto are added triethylamine (98 μl) and benzenesulfonyl chloride (54 μl) at room temperature, and the mixture is stirred for 30 minutes. Triethylamine (98 μl) and benzenesulfonyl chloride (81 μl) are further added, and the mixture is stirred for 90 minutes. The mixture is evaporated under reduced pressure to remove the solvent, and to the residue is added ethyl acetate. The mixture is washed successively with 1N hydrochloric acid (twice), a saturated brine (once), a saturated aqueous sodium hydrogen carbonate solution (twice) and a saturated brine (twice), and dried over anhydrous magnesium sulfate. The desiccant is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (silica gel; 20 g, solvent; chloroform-methanol=30:1 to 10:1). The fractions containing the title compound are concentrated under reduced pressure to give the title compound (151 mg).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[CH2:24][CH2:25][C:26](=[O:28])[CH3:27])C1C=CC=CC=1.C(=O)(O)[O-].[Na+].[H][H]>[Pd].C(O)C>[CH3:23][C:15]([C:13]1[CH:12]=[CH:11][C:10]([CH2:24][CH2:25][C:26](=[O:28])[CH3:27])=[C:9]([OH:8])[CH:14]=1)([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCC(C)(C)c1ccc(CCC(C)=O)c(OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCCCCC(C)(C)c1ccc(CCC(C)=O)c(O)c1
Yield: 93 %

Procedure:
A mixture of 0.5 g. (1.31 mmols.) of 4-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-2-butanone, 360 mg. of solid sodium bicarbonate, 100 mg. of 10% palladium-on-carbon and 10 ml. of ethanol is stirred under one atmosphere of hydrogen pressure for one hour. The reaction mixture is filtered through diatomaceous earth with ethyl acetate and the filtrate evaporated to an oil. The oil is purified via column chromatography on 100 g. of silica gel eluted with 50% ether-cyclohexane to yield 247 mg. (93%) of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[C@H:12]1[CH2:14][O:13]1.[CH3:15][C:16]1[C:24]2[CH2:23][O:22][C:21](=[O:25])[C:20]=2[CH:19]=[CH:18][C:17]=1[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[OH:13][C@@H:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[CH3:1])[CH2:14][N:31]1[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][C:17]2[CH:18]=[CH:19][C:20]3[C:21](=[O:25])[O:22][CH2:23][C:24]=3[C:16]=2[CH3:15])[CH2:29][CH2:30]1
Reactant: Cc1c(CCN2CCNCC2)ccc2c1COC2=O
Reactant: Cc1c([C@H]2CO2)ccc2c1COC2=O
Product: Cc1c(CCN2CCN(C[C@@H](O)c3ccc4c(c3C)COC4=O)CC2)ccc2c1COC2=O

Procedure:
5-((1S)-1-hydroxy-2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-4-methyl-2-benzofuran-1(3H)-one was prepared in a similar fashion to that described for the synthesis of EXAMPLE 12 starting from 4-methyl-5-[(2S)-oxiran-2-yl]-2-benzofuran-1(3H)-one and 4-methyl-5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[CH3:10][O:11][C:12]([CH:14]1[N:19]([C:20](=[O:34])[CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][C:17]2[N:35](CC(=O)C3C=CC=CC=3)[CH2:36][NH:37][C:16]=2[CH2:15]1)=[O:13].C(#N)C>CCOCC>[CH3:10][O:11][C:12]([CH:14]1[N:19]([C:20](=[O:34])[CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18][C:17]2[N:35]=[CH:36][N:37]([CH2:5][C:4]3[CH:7]=[CH:8][CH:9]=[C:2]([CH3:1])[CH:3]=3)[C:16]=2[CH2:15]1)=[O:13]
Reactant: Cc1cccc(CBr)c1
Reactant: COC(=O)C1CC2=C(CN1C(=O)C(c1ccccc1)c1ccccc1)N(CC(=O)c1ccccc1)CN2
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)C1Cc2c(ncn2Cc2cccc(C)c2)CN1C(=O)C(c1ccccc1)c1ccccc1

Procedure:
A solution of 2.7 mL 3-methylbenzyl bromide, 5.0 g methyl-5-diphenylacetyl-3-(2-oxo-2-phenylethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylate and 50 mL acetonitrile is heated at reflux 4 hr. The cooled solution is added dropwise to 750 mL vigorously stirred ether and the resulting precipitate is collected by filtration. This precipitate is dissolved in 75 mL methanol and treated with 16 g zinc dust and 75 mL acetic acid. The resulting suspension is sonicated 6 hr then the solution is filtered from excess zinc. The filtrate is dissolved in 400 mL dichloromethane and treated dropwise with 650 mL 10% Na2CO3 with vigorous stirring. The organic phase is separated, dried, concentrated and the major product is isolated by chromatography on silica gel (chloroform-methanol, 99.5:0.5) as a crisp foam. NMR (CDCl3) 4.97 (s, 2H, NCH2Ar).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].CCN(CC)CC.[CH3:23][N:24]([CH3:30])[C@@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1>C(Cl)Cl>[CH3:23][N:24]([CH3:30])[C@@H:25]1[CH2:29][CH2:28][N:27]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[C:12]([F:15])([F:14])[F:13])[CH2:26]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: O=[N+]([O-])c1ccc(CBr)c(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)[C@@H]1CCN(Cc2ccc([N+](=O)[O-])cc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
To a solution of crude 1-(bromomethyl)-4-nitro-2-(trifluoromethyl)benzene (17.5 mmol, 75% pure) in 40 mL of DCM was added Et3N (2.69 mL, 19.3 mmol) and (R)-(+)-3-(dimethylamino)pyrrolidine (2.0 g, 17.5 mmol). After stirring overnight at ambient temperature under an atmosphere of N2, the reaction solution was concentrated, added aq. NaHCO3 (100 mL), and the resulting mixture extracted with DCM (4×50 mL). The combined organic layer was dried over Na2SO4, filtered, concentrated, and the resulting residue was purified by silica gel chromatography (eluted with 0-10% MeOH/DCM) to provide 3.35 g of product as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Br[CH2:18][C:19]([NH2:21])=[O:20]>>[C:15]([C:7]1[C:8]([C:11]([F:12])([F:14])[F:13])=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([CH2:18][C:19]([NH2:21])=[O:20])[C:2]([CH3:1])=[CH:10]2)#[N:16]
Reactant: NC(=O)CBr
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(N)=O

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 2-bromoacetamide: 1H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J=8.5 Hz, 1H), 7.71 (bs, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.35 (bs, 1H), 6.55 (s, 1H), 4.89 (s, 2H), 2.39 (s, 3H); MS (ES) m/z 282 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[CH2:4][CH:5]1[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][NH:6]1.CCN(C(C)C)C(C)C.[C:29](Cl)(=[O:32])[O:30][CH3:31]>C(Cl)Cl>[F:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[CH2:4][CH:5]1[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][N:6]1[C:29]([O:30][CH3:31])=[O:32]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(Cc2cc(F)ccc2F)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2cc(F)ccc2F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a solution of methyl 2-(2,5-difluorobenzyl)piperidine-4-carboxylate (6.65 g, 24.69 mmol) in DCM (100 mL) and DIPEA (5.16 mL, 29.63 mmol) was added methyl carbonochloridate (2.53 mL, 32.10 mmol) dropwise at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with 0.15 M HCl (250 mL). The organic phase was separated, washed with satd NaHCO3, dried using a phase separator and evaporated to yield dimethyl 2-(2,5-difluorobenzyl)piperidine-1,4-dicarboxylate (8.1 g, 100%). MS m/z 328 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16]C(=O)OC(C)(C)C)=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.[C:24](OCC)(=[O:30])[C:25](OCC)=[O:26]>>[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][C:6]2[C:7]3[NH:8][C:25](=[O:26])[C:24](=[O:30])[NH:1][C:2]=3[N:3]=[CH:4][CH:5]=2)=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(N)c2N)cc1
Reactant: CCOC(=O)C(=O)OCC
Product: Nc1ccc(Oc2ccnc3[nH]c(=O)c(=O)[nH]c23)cc1
Yield: 25 %

Procedure:
A solution of tert-butyl 4-(2,3-diamino pyridin-4-yloxy)phenylcarbamate (0.320 g, 1.0 mmol) in diethyl oxalate (2 ml) is reacted twice for 10 minutes in a microwave reactor (180 C, 150 W). The solution is cooled and the solid filtered and washed with cold ethanol. Obtained 8-(4-aminophenoxy)pyrido[2,3-b]pyrazine-2,3(1H,4H)-dione (70 mg, 25% yield) as a grey solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]([OH:30])=O)[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:17](=[O:33])[N:18]([CH3:32])[C:19]2=[O:31])=[N:14]1.N.[C:39](P(=O)(OCC)OCC)#[N:40]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]([NH:40][CH3:39])=[O:30])[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:34][CH:35]([CH3:36])[CH3:37])[C:17](=[O:33])[N:18]([CH3:32])[C:19]2=[O:31])=[N:14]1
Reactant: CCOP(=O)(C#N)OCC
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3ccnc4ccc(Cl)cc34)nc21
Agent: N
Product: CNC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2ccnc3ccc(Cl)cc23)n(C)c1

Procedure:
This compound was synthesized by the reaction of 5-{2-[(6-chloroquinolin-4-yl)methyl]-7-isobutyl-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and ammonia using diethyl cyanophosphonate as a coupling reagent. Mass: 534.17 (M+H).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].C[O-].[Na+:7].CN(C)/[CH:10]=[CH:11]/[C:12](=O)[CH:13]([O:16][CH3:17])[O:14][CH3:15]>CO>[CH3:15][O:14][CH:13]([O:16][CH3:17])[C:12]1[CH:11]=[CH:10][N:4]=[C:2]([S-:3])[N:1]=1.[Na+:7]
Reactant: NC(N)=S
Reactant: COC(OC)C(=O)/C=C/N(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1ccnc([S-])n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of thiourea (64.7 g, 850 mmol, 1.13 equiv.), sodium methanolate (95%, 40.5 g, 751 mmol, 1.0 equiv.) in methanol (500 mL, 1.5 M) was stirred at room temperature for 30 minutes. A solution of (E)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (1) (130 g, 751 mmol) in methanol (200 mL) was added and the reaction stirred at room temperature for 2 h. The crude sodium 4-(dimethoxymethyl)pyrimidine-2-thiolate (2) was used directly in the next step without further purification. LC-MS m/z 209 (M+1). Reference: WO 2006/0097341A1 (incorporated by reference), pg 67.
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][SH:3].O.[I-:6].F[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=1[CH3:14].[OH-].[Na+]>O1CCCC1>[I-:6].[SH:3][CH2:2][CH2:1][S:4][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=1[CH3:14]
Reactant: SCCS
Reactant: C[n+]1ccccc1F
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[n+]1ccccc1SCCS
Temperature: 23 °C

Procedure:
To a mixture of 1,2-ethanedithiol (0.63 mL, 7.5 mmol), water (21 mL) and tetrahydrofuran (4 mL) were added simultaneously 2-fluoro-1-methylpyridinium iodide, described by G. B. Barlin and J. A. Benbow, J.C.S. Perkin II, 790 (1974), (0.90 g, 3.72 mmol) and 1N sodium hydroxide solution (5-6 mL) to keep the pH of the mixture between 6 and 7. When the addition of 2-fluoro-1-methylpyridinium iodide was completed, the reaction mixture was stirred at 23° C. while the pH was kept at 7.1 by the addition of the 1N sodium hydroxide solution. When the pH of the mixture was stabilized at 7.1, the solvents were evaporated under high vacuum until dryness. The solid was triturated in ether (3×10 mL) and in acetonitrile (2×8 mL). The ether solution was dried (MgSO4) and concentrated to give 0.10 g of N-methyl-2(1H)-pyridothione. The acetonitrile solution was dried (MgSO4) and concentrated to give 0.74 g of 2-(2-mercaptoethylthio)-1-methylpyridinium iodide and/or fluoride mixed with some inorganic salts; ir (KBr) νmax : 1617 (pyridinium) cm-1, 1Hmr (DMSO-d6) δ: 2.75-3.1 (m, 2H, CH2SH), 3.4-3.9 (m, CH2S and SH), 4.17 (s, 3H, CH3 on pyridinium), 7.6-9.2 (m, 4H, H's of pyridinium). The acetonitrile insoluble material (0.38 g) was 1,2-di(1-methylpyridinium-2-thio)ethane diiodide or/and difluoride or monoiodidemonofluoride mixed with some inorganic salts; 1Hmr (DMSO-d6) δ: 3.90 (4H, s, SCH2CH2S), 4.21 (6H, s, CH3 's on pyridinium), 7.7-9.1 (8H, m, H's of pyridiniums). The thiol was used without any further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[N:21]1([CH2:20][CH2:19][O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:27]=[CH:28][N:29]=[C:2]([N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[CH:3]=3)=[CH:9][CH:10]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(Cl)c1
Reactant: C1CCNC1
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(N2CCCC2)c1

Procedure:
Compound is formed by reacting 2-chloro-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-isonicotinamide and pyrrolidine under conditions described in general procedure A. 1H NMR (300 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.21 (m, 2H), 7.83 (m, 1H), 7.59 (m, 2H), 7.42 (d, 1H), 7.10 (m, 2H) 7.02 (m, 2H), 4.31 (t, 2H), 3.61 (m, 4H), 3.49 (m, 4H), 2.87 (t, 2H), 2.58 (m, 4H), 1.99 (m, 4H). MS: 447.2 (M+1).
Reaction SMILES: [CH3:1][C:2]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][C:4]([CH3:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:5].[C:26](=O)([O-:28])[O-:27].[K+].[K+].C(=O)=O.O>C1C=CC=CC=1>[CH3:1][C:2]([C:19]1[CH:24]=[C:23]([C:26]([OH:28])=[O:27])[C:22]([OH:25])=[CH:21][CH:20]=1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:3][C:4]([CH3:5])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:12]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(CC(C)(c1ccccc1)c1ccc(O)cc1)c1ccccc1
Agent: O=C=O
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(CC(C)(c1ccccc1)c1ccc(O)c(C(=O)O)c1)c1ccccc1
Temperature: 180 °C
Reaction time: 5 h
Yield: 84.9 %

Procedure:
33.0 g (0.1 mole) of p-(1,3-dimethyl-1,3-diphenylbutyl)phenol and 100 g of anhydrous potassium carbonate were placed in an autoclave and thereto, carbon dioxide gas was introduced at a pressure of 40 Kg/cm2. Then, the mixture was shaken at 180° C. for 5 hours. After cooling to room temperature, the pressure in the autoclave was returned to atmospheric pressure and then, 200 ml of water and 400 ml of benzene were added to the reaction product in the autoclave, followed by heating them in order to dissolve the reaction product in these solvents. The organic phase separated out was taken out of the autoclave and shaken with a dilute hydrochloric acid solution to convert the potassium salt into the corresponding free acid. Then, it was washed with water, dried and then, concentrated in order to remove the benzene. Thus, white needle crystal was separated out. The crystal was filtered off to obtain 31.8 g of 5-(1,3-dimethyl-1,3-diphenylbutyl)salicylic acid (yield: 85%, mp: 153°-155° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][C:7]([CH3:20])=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:25]3[CH:24]=[C:23]([O:22][CH3:21])[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=3)[CH2:36][CH2:35]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][C:7]([CH3:20])=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(C)c(C)cc2nc1OC
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3nc4cc(C)c(C)cc4nc3OC)CC2)c1
Yield: 75 %

Procedure:
Ethyl N-(2-methoxy-6,7-dimethylquinoxalin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 183 to obtain the titled compound (yield, 75%). 1H NMR (300 MHz, CDCl3) δ 2.33 (s, 3H), 2.39 (s, 3H), 3.21-3.29 (m, 4H), 3.75 (m, 4H), 3.79 (s, 3H), 4.11-4.13 (m, 3H), 6.06 (s, 1H), 6.12 (s, 2H), 7.52 (s, 1H), 7.59 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[N:5]=[CH:4][N:3]=1.[CH3:16][CH:17]([OH:20])[C:18]#[CH:19].[H-].[Na+].O>CN(C)C=O>[F:15][C:9]1[C:10]([F:14])=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:20][CH:17]([CH3:16])[C:18]#[CH:19])[N:3]=[CH:4][N:5]=1
Reactant: Fc1cccc(-c2cc(Cl)ncn2)c1F
Reactant: C#CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CC(C)Oc1cc(-c2cccc(F)c2F)ncn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.7 %

Procedure:
In 6 ml of N,N-dimethylformamide were dissolved 150 mg of 4-chloro-6-(2,3-difluorophenyl)pyrimidine and 56 mg of 3-butyn-2-ol, to which 32 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 12 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 120 mg of 4-(2,3-difluorophenyl)-6-(1-methyl-2-propynyloxy)pyrimidine (the present compound (134)).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14](N)[N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].N1C=CC=CC=1.N([O-])=O.[Na+].[FH:29]>>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:29])[N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: F
Reactant: CCOC(=O)[C@H]1CC[C@H](c2cccc(N)n2)CC1
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCOC(=O)[C@H]1CC[C@H](c2cccc(F)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Batch 2: To a solution of trans-4-(6-amino-pyridin-2-yl)-cyclohexanecarboxylic acid ethyl ester (0.25 g, 1.0 mmol) in 70% hydrogen fluoride in pyridine (2.4 ml, 92 mmol) was added solid sodium nitrite (0.076 g, 1.1 mmol) at 0-5° C. The cooling bath was removed after 20 minutes and the reaction mixture was stirred for 30 minutes at room temperature. The reaction mixture was partitioned between an ice-water mixture (100 ml) and tert-butyl methyl ether (100 ml). The organic layer was collected. The aqueous layer was extracted with two 100-ml portions of tert-butyl methyl ether. The combined organic layers were washed with one 30-ml portion of 2M aqueous sodium hydroxide solution, one 30-ml portion of brine, dried over anhydrous sodium sulfate and concentrated to dryness to give the crude title compound (0.145 g). The batches were combined and purified by flash-chromatography with n-heptane/ethyl acetate as eluent to give the title compound (0.16 g, 51%) as colorless oil. MS m/e: 252 ([M+H]+)
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9](Cl)(=[O:11])=[O:10].[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([CH3:30])[CH:29]=1)[NH2:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CN1CCOCC1>ClCCl>[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([NH:26][S:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:14])([F:13])[F:1])(=[O:11])=[O:10])[CH:27]=[C:28]([CH3:30])[CH:29]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cc(N)cc(OCc2ccccc2)c1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1cc(NS(=O)(=O)c2ccccc2C(F)(F)F)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
2-Trifluoromethylbenzenesulfonyl chloride (490 mg, 2.0 mmol) was added to a solution of 3-benzyloxy-5-methylaniline (426 mg, 2.0 mmol), as prepared in the preceding step, and N-methylmorpholine (0.5 mL) in dichloromethane (10 mL). The mixture was stirred at ambient temperature overnight. After adding additional dichloromethane (100 mL), the dichloromethane solution was washed with saturated aqueous NaHCO3 (2×50 mL), 10% HCl (2×50 mL), and brine (2×50 mL), and dried over Na2SO4. After evaporating the solvent in vacuo, the residue was purified by flash column chromatography (4:1 dichloromethane/hexane) to give the title compound as white solid (700 mg, 83%). 1H-NMR (300 MHz, CDCl3) δ 7.93 (d, J=7.8 Hz, 1 H), 7.85 (d, J=7.3 Hz, 1 H), 7.63 (t, J=7.7 Hz, 1 H), 7.53 (t,J=7.7 Hz, 1 H), 7.38 (m, 5 H), 6.60 (s, 1 H), 6.55 (s, 2 H), 6.40 (s, 1 H), 4.98 (s, 2 H), 2.20 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][O:13][CH:14]1[CH2:19][CH2:18][N:17]([CH:20]([C:23]2[CH:24]=[N:25][C:26]([CH3:29])=[N:27][CH:28]=2)[CH2:21][NH2:22])[CH2:16][CH2:15]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:22][CH2:21][CH:20]([N:17]1[CH2:16][CH2:15][CH:14]([O:13][CH3:12])[CH2:19][CH2:18]1)[C:23]1[CH:24]=[N:25][C:26]([CH3:29])=[N:27][CH:28]=1)=[O:6]
Reactant: COC1CCN(C(CN)c2cnc(C)nc2)CC1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: COC1CCN(C(CNC(=O)c2cccc(Cl)c2Cl)c2cnc(C)nc2)CC1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(4-methoxypiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:13](=[O:19])[NH:14]2>[Cu]I.CN(C=O)C.CCN(CC)CC>[C:1]1([C:7]#[C:8][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2/[C:12](=[CH:20]/[C:21]2[NH:22][CH:23]=[CH:24][C:25]=2[O:26][CH3:27])/[C:13](=[O:19])[NH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#Cc3ccccc3)c21

Procedure:
Using general Method D above, phenyl acetylene (32 mg, 0.31 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.16 mmol) (Starting Material 1) using DPPFPdCl2 (6.5 mg) (Aldrich) and CuI (1.5 mg) (Aldrich) as catalyst in DMF (2 mL) and Et3N (3 mL) as solvent at 85° C. for 18 h, to yield (Z)-1,3-dihydro-4-(phenylethynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 20 mg, 37%)
Reaction SMILES: O1[C:11]2([CH3:12])[CH:2]1[C:3](=[O:14])[C:4]1[C:9]([C:10]2=[O:13])=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:15]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C(O)C>[CH3:12][C:11]1[C:10](=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:14])[C:2]=1[N:18]1[CH2:17][CH2:16][N:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19]1
Reactant: CCOC(=O)N1CCNCC1
Reactant: CC12OC1C(=O)c1ccccc1C2=O
Solvent: CCO
Product: CCOC(=O)N1CCN(C2=C(C)C(=O)c3ccccc3C2=O)CC1
Temperature: 50 °C
Reaction time: 12 h
Yield: 30.5 %

Procedure:
A mixture of 1.88 g of 2,3-epoxy-3-methyl-1,4-naphthoquinone, 3.16 g of piperazinecarboxylic acid, ethyl ester and 100 ml of absolute ethanol was stirred for 12 hours at 50°C. The solvent was then removed and the remainder filtered through a one inch plug of silica gel and eluted with chloroform. The eluate was evpaorated, giving 1 g of the desired product as a viscous red oil.