Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([OH:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[C:15](Cl)[CH:14]=[CH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].O>CC(N(C)C)=O>[Cl:10][C:11]1[CH:16]=[C:15]([O:9][C:5]2[C:6]([CH3:8])=[N:7][C:2]([I:1])=[CH:3][CH:4]=2)[CH:14]=[CH:13][N:12]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: Cc1nc(I)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1nc(I)ccc1Oc1ccnc(Cl)c1
Temperature: 110 °C
Yield: 73.4 %

Procedure:
A mixture of 6-iodo-2-methylpyridin-3-ol (6.8 g, 28.9 mmol), 2,4-dichloropyridine (8.56 g, 57.9 mmol) and K2CO3 (4.00 g, 28.9 mmol) in DMA (50 mL) was heated at 110° C. for 16 h under argon. The mixture was cooled to RT, treated with H2O, extracted with EtOAc (2×) and the combined organics were washed with H2O, then brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 3-((2-chloropyridin-4-yl)oxy)-6-iodo-2-methylpyridine (7.35 g, 73%) as a white solid. MS (ESI) m/z: 346.9 (M+H+).
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:20][C:19]3[C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:17][C:16](Cl)=[N:15][C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)=[O:4].CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=2)O1>>[NH2:42][C:39]1[N:40]=[CH:41][C:36]([C:16]2[N:17]=[C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:19]3[S:20][C:12]([CH2:11][N:8]4[CH2:9][CH2:10][CH:5]([C:3]([NH:2][CH3:1])=[O:4])[CH2:6][CH2:7]4)=[CH:13][C:14]=3[N:15]=2)=[CH:37][N:38]=1
Reactant: CNC(=O)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: CNC(=O)C1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
1-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidine-4-carboxylic acid methylamide (Example 25) was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine in General Procedure A. Purification on silica yielded 115. NMR (CDCl3): 1.85-1.89 (m, 4H, 2×CH2), 2.08-2.18 (m, 3H, CH2+CH), 2.84 (d, 3H, CH3, J=4.8 Hz), 3.04 (m, 2H, CH2), 3.83 (s, 2H, CH2), 3.90-3.92 (m, 4H, 2×CH2), 4.04-4.06 (m, 4H, 2×CH2), 5.22 (s, 2H, NH2), 5.45 (sbr, H, NH), 7.26 (s, H, ArH), 9.30 (s, 2H, 2×ArH). MS: (ESI+): MH+=469.27
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[P:12]([O:21]C(C)C)([O:17][CH:18]([CH3:20])[CH3:19])[O:13][CH:14]([CH3:16])[CH3:15]>>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][P:12](=[O:21])([O:17][CH:18]([CH3:20])[CH3:19])[O:13][CH:14]([CH3:16])[CH3:15])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)OP(OC(C)C)OC(C)C
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Product: CC(C)OP(=O)(Cc1ccc([N+](=O)[O-])cc1)OC(C)C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
A mixture of 4-nitrobenzylbromide (15.0 g) and triisopropyl phosphite (15.9 g) was stirred for 3 hr while heating under reflux. The reaction mixture was subjected to silica gel column chromatography, and diisopropyl 4-nitrobenzylphosphonate (19.5 g) was obtained as an oil from a fraction eluted with ethyl acetate-chloroform (1:1, volume ratio). A mixture of this oil, 5% palladium-carbon (2.3 g) and ethanol (130 ml) was stirred at room temperature for 6 hr under a hydrogen atmosphere. The catalyst was filtered off and the filtrate (ethanol solution) was concentrated to give diisopropyl 4-aminobenzylphosphonate (17.2 g, yield 98%) as a yellow oil.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[CH2:25]Br>>[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[CH2:25][N:8]1[C:9]([S:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: Clc1cc(Cl)cc(CBr)c1
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(Cl)cc(Cl)c2)c1
Yield: 55.6 %

Procedure:
5-isopropyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 3,5-dichlorobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (250 mg, yield: 55.6%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10](O)[C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=3)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=2)[CH:17]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: COc1ccc2c(O)nc(-c3ccc(F)cc3)cc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nc(-c3ccc(F)cc3)cc2c1
Yield: 90.9 %

Procedure:
A solution of 3-(4-fluorophenyl)-6-methoxyisoquinolin-1-ol (350 mg, 1.300 mmol) in POCl3 (1.82 ml, 19.50 mmol) was refluxed (90° C.) for 4 h. The reaction mixture was concentrated. The residue was dissolved in DCM and the pH was adjusted to 7 with 4N NaOH. The organic phase was collected and dried over sodium sulfate, filtered, then concentrated under vacuum. The crude material was purified by silica gel chromatography using 50% DCM in Hexanes as eluent. The product fractions were collected and the solvent removed under vacuum to give 1-chloro-3-(4-fluorophenyl)-6-methoxyisoquinoline (340 mg, 91% yield). MS: MS m/z 288.1 (M++1).
Reaction SMILES: [Na].[C:2]1([NH:8][NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH:14]=[CH:15][C:16]#[N:17]>C(O)C>[NH2:17][C:16]1[CH2:15][CH:14]([C:13]2[CH:18]=[CH:19][C:20]([Cl:21])=[C:11]([Cl:10])[CH:12]=2)[N:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=1
Reactant: N#CC=Cc1ccc(Cl)c(Cl)c1
Reactant: NNc1ccccc1
Agent: [Na]
Solvent: CCO
Product: NC1=NN(c2ccccc2)C(c2ccc(Cl)c(Cl)c2)C1
Reaction time: 0.08 h

Procedure:
A 0.10 g. amount of sodium metal is dissolved in 25.0 ml. of absolute ethanol, then 2.16 g. of phenylhydrazine is added, followed in 5 minutes by 3.96 g. of 3,4-dichlorocinnamonitrile. The reaction mixture is refluxed for 5 hours, then is evaporated to dryness in vacuo. The procedure, as described in Example 15, is continued with a second recrystallization from the same solvent pair and treatment with a hydrous magnesium silicate to give 1.35 g. of the desired product as colorless needles, m.p. 150°-151.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(OCC)(=O)C>C(O)C>[C:26]1([CH2:25][CH2:24][CH2:23][N:11]2[CH2:12][CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: BrCCCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCN(CCCc2ccccc2)CC1
Temperature: 25 °C

Procedure:
To a solution of 4.50 g (22.47 mmol.) of 1-tert-butoxycarbonyl-2,3,5,6-tetrahydro-7H-1,4-diazepine in ethanol (50 ml) were added, at room temperature, 4.7 ml (33.72 mmol.) of triethylamine and 4.47 g (22.45 mmol.) of 1-bromo-3-phenylpropane. The mixture was heated under reflux for 8 hours under nitrogen atmosphere. To the reaction system were further added 4.7 ml (33.72 mmol.) of triethylamine and 4.47 g (22.45 mmol.) of 1-bromo-3-phenylpropane. The mixture was heated for 16 hours under reflux, which was cooled to room temperature. To the reaction system was added ethyl acetate, which was washed with water and a saturated aqueous saline solution, followed by drying over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a column chromatography. The solvent was distilled off under reduced pressure to give the object compound as a yellow liquid product. The yield was 5.41 g (76%).
Reaction SMILES: [C:1]1([C:7]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[C:18]=1[NH2:24]>CO.C(O)(=O)C>[C:1]1([C:7]2[N:23]=[C:19]3[CH:20]=[CH:21][CH:22]=[N:17][C:18]3=[N:24][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Reactant: Nc1cccnc1N
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc(-c2nc3cccnc3nc2-c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of benzil (45.7 g, 217 mmol) and pyridine-2,3-diamine (23.7 g, 217 mmol) in methanol (514 ml) and acetic acid (57 ml) was heated at 160° C. for 10 mins using microwave radiation. The reaction mixture was concentrated in vacuo. To the crude residue in methanol (510 ml) was added activated charcoal (25 g) and the suspension was stirred at 60° C. for 1 h. The suspension was filtered hot, cooled and then was stirred in an ice bath. The solid was filtered, washed with cold methanol (50 ml) and dried in vacuo at 40° C. overnight to afford the title compound as pale brown crystals.
Reaction SMILES: C1C2C=CC3C=CC=CC=3C(=O)C=2C=CC=1.Br[C:18]1[CH:35]=[CH:34][C:21]2[CH2:22][C:23](=[O:33])[CH2:24][C:25]3[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=3[C:27](=[O:28])[C:20]=2[CH:19]=1.ClC1C=CC2CC(=O)CC3C=CC=CC=3C(=O)C=2C=1.FC1C=CC2CC(=O)CC3C=CC=CC=3C(=O)C=2C=1>BrC1C=CC2C=CC3C=CC=CC=3C(=O)C=2C=1.ClC1C=CC2C=CC3C=CC=CC=3C(=O)C=2C=1.FC1C=CC2C=CC3C=CC=CC=3C(=O)C=2C=1.ClC1C=CC=CC=1Br>[O:33]=[C:23]1[CH2:22][C:21]2[CH:34]=[CH:35][CH:18]=[CH:19][C:20]=2[C:27](=[O:28])[C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[CH2:24]1
Reactant: O=C1Cc2ccccc2C(=O)c2cc(Br)ccc2C1
Agent: Clc1ccccc1Br
Agent: O=C1Cc2ccccc2C(=O)c2cc(Cl)ccc2C1
Agent: O=C1Cc2ccccc2C(=O)c2cc(F)ccc2C1
Product: O=C1Cc2ccccc2C(=O)c2ccccc2C1

Procedure:
Employing the procedure substantially as described in Example 1, Steps A through D, but substituting for the 5H-dibenzo[a,d]cyclohepten-5-one used in Step A thereof an equimolecular amount of 3-bromo-5H-dibenzo[a,d]cyclohepten-5-one, 3-chloro-5H-dibenzo[a,d]cyclohepten-5-one, or 3-fluoro-5H-dibenzo[a,d]cyclohepten-5-one, and o-chlorobromobenzene as solvent in Step B, there are produced, respectively, 2-bromo-6,12-dioxo-5,6,7,12-tetrahydrodibenzo[a,d]cyclooctene, m.p. 133°-138° C., 2-chloro-6,12-dioxo-5,6,7,12-tetrahydrodibenzo[a,d]cyclooctene, m.p. 148°-149° C., and 2-fluoro-6,12-dioxo-5,6,7,12-tetrahydrodibenzo[a,d]cyclooctene.
Reaction SMILES: [CH2:1]([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12][C:11]=2[CH:10]([C:22]([O:24][CH3:25])=[O:23])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29]O1.Cl.[OH-].[NH4+]>Cl.CO.O.CCOCC.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH:9]2[CH:30]([CH2:31][CH2:32][CH2:27][OH:26])[CH2:29][C:10]([C:22]([O:24][CH3:25])=[O:23])=[C:11]3[NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:19]23[CH2:20][CH2:21]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CCCCO1
Reactant: COC(=O)C1CN(Cc2ccccc2)CCc2c1[nH]c1ccccc21
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)C1=C2Nc3ccccc3C23CCN(Cc2ccccc2)C3C(CCCO)C1
Temperature: 110 °C
Reaction time: 12 h
Yield: 99.8 %

Procedure:
A mixture of methyl 3-benzyl-1,2,3,4,5,6-hexahydroazepino (4,5-b) indole-5-carboxylate (1.336 g, 4.0 mmol), 2-hydroxytetrahydropyran (0.980 g, 8.2 mmol), toluene (30 mL) and ether saturated with HCl gas (10 drops) was heated under a nitrogen atmosphere at 110° C. for 5 h. The reaction mixture was cooled, diluted with 15 mL of methanol and acidified with conc. hydrochloric acid. The reaction mixture was stirred for 12 h at 20° C., poured into 50 mL of water and made strongly basic with ammonium hydroxide. The toluene layer was separated and the aqueous portion extracted three times with 25 mL of dichloromethane. The combined organic solutions were washed three times with 25 mL of saturated brine, dried over sodium sulfate and concentrated at 50° C. under vacuum to provide 1.67 g (100%) of methyl 3-benzyl-1,2,3,3a,4,5-hexahydro-4-(3-hydroxypropyl)-7H-pyrrolo(2,3-d)carbazole-6-carboxylate, identical in spectroscopic properties and TLC Rf value to the product obtained in Example 1.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[C:23]1([S:29][CH2:30][CH2:31][CH2:32]Cl)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:32][CH2:31][CH2:30][S:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: ClCCCSc1ccccc1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCSc2ccccc2)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride and 3-phenylthiopropyl chloride were reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-2-methoxy-N-((1-(3-(phenylthio)propyl)piperidin-4-yl)methyl)-benzamide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](Cl)=[N:8][CH:9]=1)([O-:3])=[O:2].[NH:11]1[CH2:16][CH2:15][CH:14]([C:17]([NH2:19])=[O:18])[CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([NH2:19])=[O:18])[CH2:13][CH2:12]2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: NC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)C1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 100 °C
Yield: 92.9 %

Procedure:
A mixture of 5-nitro-2-chloro-pyridine (2 g, 12.6 mmol), piperidine-4-carboxylic acid amide (1.78 g, 13.9 mmol), and potassium carbonate (3.48 g, 25.2 mmol) in anhydrous 1,4 dioxane (65 mL) was heated in an oil bath at 100° C. for 5 hr. The reaction was diluted with water (500 mL) and extracted with ethyl acetate (500 mL). The resulting yellow precipitate that form in both layers was filtered off and washed with minimal ethyl acetate, dichloromethane, and hexanes, and dried. The aqueous layer was extracted with dichloromethane (three times with 200 mL each). This dichloromethane layer was washed with brine, combined with the original ethyl acetate extract dried over sodium sulfate, and concentrated to a yellow solid. The yellow solid and the original yellow filtered precipitate were combined to give 5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid amide (2.93 g, 112%) as a yellow solid. LCMS calcd for C11H14N4O3 (m/e) 250, obsd 251 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C[C:10]1[CH:15]=[CH:14][C:13](N)=[C:12]([N+]([O-])=O)[C:11]=1[OH:20].S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>N.O>[CH:7]1[C:2](=[N:1][C:14]2[CH:13]=[CH:12][C:11]([OH:20])=[CH:10][CH:15]=2)[CH:3]=[CH:4][C:5](=[O:8])[CH:6]=1
Reactant: Nc1ccc(O)cc1
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1O
Agent: N
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: O=C1C=CC(=Nc2ccc(O)cc2)C=C1
Temperature: 0 °C

Procedure:
0.01 mole (1.09 g) of para-amino-phenol and 0.01 mole (1.68 g) of 2-methyl-5-amino-6-nitro phenol are dissolved in 15 cc of ammonia (22° Be) to which have been added 15 cc of water. To this resulting solution maintained at a temperature of about 0° C., there is added, with agitation, 0.02 mole (4.6 g) of ammonium persulfate in 20 cc of water. The agitation is maintained for 30 minutes, after which the indophenol which has precipitated in the form of its ammonium salt is filtered. The thus recovered crude product is treated with water to which has been added acetic acid to obtain the indophenol in its free form. After filtering the indophenol, washing it with water and drying it under a vacuum, there is obtained a product which melts with decomposition above 260° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([NH2:31])[C:27]([CH3:33])([CH3:32])[CH2:26]2)=[CH:21][C:20]=1[O:34][CH3:35]>>[NH2:31][CH:28]1[CH2:29][CH2:30][N:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:2]3[N:7]=[C:6]([C:8]4[C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[NH:10][CH:9]=4)[C:5]([Cl:17])=[CH:4][N:3]=3)=[C:20]([O:34][CH3:35])[CH:21]=2)[CH2:26][C:27]1([CH3:33])[CH3:32]
Reactant: COc1cc(N2CCC(N)C(C)(C)C2)ccc1N
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Product: COc1cc(N2CCC(N)C(C)(C)C2)ccc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (Intermediate 2) and 1-(4-amino-3-methoxyphenyl)-3,3-dimethylpiperidin-4-amine (180 mg, 0.72 mmol) (Intermediate 43).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:5]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17].[CH3:26][C:27]1[NH:31][N:30]=[N:29][N:28]=1>>[F:15][C:12]1[CH:11]=[CH:10][C:9]([CH:6]2[N:5]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)(=[O:17])=[O:18])[CH:4]([CH2:3][CH2:2][N:29]3[N:30]=[N:31][C:27]([CH3:26])=[N:28]3)[CH2:8][CH2:7]2)=[CH:14][CH:13]=1
Reactant: Cc1nnn[nH]1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCl)CCC2c2ccc(F)cc2)cc1
Product: Cc1ccc(S(=O)(=O)N2C(CCn3nnc(C)n3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=430.4 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(2-chloro-ethyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 5-methyl-1H-tetrazole.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Cl[C:11]([CH3:15])([CH3:14])[C:12]#[CH:13]>C(OCC#C)C#C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:9][C:11]([CH3:15])([CH3:14])[CH:12]=[CH:13][C:7]=2[CH:8]=1)#[N:2]
Reactant: C#CC(C)(C)Cl
Reactant: N#Cc1ccc(O)cc1
Agent: C#CCOCC#C
Product: CC1(C)C=Cc2cc(C#N)ccc2O1

Procedure:
According to EPO 0 076 075 describing the possibilities for preparing Kromakalim 4-cyano-phenol of the formula (I) ##STR4## is reacted with 3-chloro-3-methyl-butyne resulting in propargyl-ether of the formula (IX) ##STR5## which is then subjected to ring closure to produce 6-cyano-2,2-dimethyl-2H-1-benzopyran of the formula (III) ##STR6## The compound of the formula (III) is then converted through 6-cyano-trans-3-bromo-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-ol to 6-cyano-3,4-dihydro-3,4-epoxy-2,2-dimethyl-2H-1-benzopyran of the formula (V). ##STR7## From the compound of the formula (V) the end-product of the formula (VI) can be obtained by three independent routes.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])=[CH:4][CH:3]=1.[C:15]1([CH:21]([NH2:32])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH2:9][C:10](=[O:12])[NH:32][CH:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=2)=[O:7])=[CH:13][CH:14]=1
Reactant: NC(c1ccccc1)c1cccc(C(F)(F)F)c1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Product: O=C(CNC(=O)c1ccc(F)cc1)NC(c1ccccc1)c1cccc(C(F)(F)F)c1

Procedure:
Prepared in analogy to example 1.1 from (4-fluoro-benzoylamino)-acetic acid (CA [366-79-0]) and rac-C-phenyl-C-(3-trifluoromethyl-phenyl)-methylamine (CA [70428-92-1]). MS (m/e): 429.4 (MH−, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([NH:19][C:20]([NH:22][CH2:23][CH2:24][OH:25])=[O:21])[CH:17]=[CH:18][C:13]=2[N:12]([CH3:26])[C:11](=[O:27])[CH2:10][N:9]=1.[C:28](Cl)(=[O:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:28]([O:25][CH2:24][CH2:23][NH:22][C:20]([NH:19][C:16]1[CH:17]=[CH:18][C:13]2[N:12]([CH3:26])[C:11](=[O:27])[CH2:10][N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:14]=2[CH:15]=1)=[O:21])(=[O:30])[CH3:29]
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2cc(NC(=O)NCCO)ccc21
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OCCNC(=O)Nc1ccc2c(c1)C(c1ccccc1F)=NCC(=O)N2C

Procedure:
11.1 g (0.03 M) of 1-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-3-(2-hydroxyethyl)urea are stirred at room temperature for 18 hours in 150 ml of acetonitrile with 3.9 ml of acetyl chloride and 9 g of powdered potassium carbonate. The mixture is concentrated on a rotary evaporator and the residue is purified on a 500 g silica gel column using methylene chloride/ethanol as the eluting agent. After crystallisation from ethyl acetate, there is obtained 2-[3-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-ureido]ethyl acetate which melts at 196°-198° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH3:11])(=[O:10])=[O:9])[C:3]=1[NH2:12].[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([Cl:21])=[CH:16][N:15]=1>>[Cl:13][C:14]1[N:19]=[C:18]([NH:12][C:3]2[C:4]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:17]([Cl:21])=[CH:16][N:15]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CS(=O)(=O)c1cccc(F)c1N
Product: CS(=O)(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-(2-fluoro-6-methanesulfonyl-phenyl)-amine was prepared from 2-Fluoro-6-methanesulfonyl-phenylamine and 2,4,5-trichloropyrimidine in an analogous manner to Example 1251d to afford an orange solid (1.38 g, 62%). MP 212-215, HPLC purity 95%, LCMS 338 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.33 (s, 1H), 8.23 (s, 1H), 7.88 (d, J=2.7 Hz, 1H), 7.90-7.87 (m, 2H), 3.01 (s, 3H).
Reaction SMILES: [N:1]([CH2:4][C:5]1([CH3:20])[CH2:9][C:8]2[CH:10]=[C:11]([Cl:19])[CH:12]=[C:13]([C:14]3[CH:18]=[CH:17][S:16][CH:15]=3)[C:7]=2[O:6]1)=[N+]=[N-]>[Pt]>[Cl:19][C:11]1[CH:12]=[C:13]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)[C:7]2[O:6][C:5]([CH2:4][NH2:1])([CH3:20])[CH2:9][C:8]=2[CH:10]=1
Reactant: CC1(CN=[N+]=[N-])Cc2cc(Cl)cc(-c3ccsc3)c2O1
Agent: [Pt]
Product: CC1(CN)Cc2cc(Cl)cc(-c3ccsc3)c2O1

Procedure:
Treatment of (±)-(5-chloro-2-methyl-7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.00 g, 10.0 mmol), thiophene-3-boronic acid (1.92 g, 15.0 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.82 g, 1.0 mmol), and potassium carbonate (2.76 g, 20.0 mmol) generally according to the procedure described for Intermediate 35 provided (±)-(5-chloro-2-methyl-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (2.00 g, 30.7 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-5-chloro-2-methyl-7-thien-3-yl-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (0.250 g, 5 wt. %) generally according to the procedure described for Example 1 afforded 0.7 g (22%0 of (±)-(5-chloro-2-methyl-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylamine as a white solid, hydrochloride salt. mp 295-298° C. (dec); Anal. calcd. for C14H14ClNOSHCl: C, 53.17; H, 4.78; N, 4.43. Found: C, 52.80; H, 4.74; N, 4.24.