Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1B(O)O.[N+:13]([C:16]1[CH:17]=[C:18](I)[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14].C([O-])([O-])=O.[K+].[K+]>CO.O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:13]([O-:15])=[O:14])[CH:21]=1
Reactant: COc1ccc(C)cc1B(O)O
Reactant: O=[N+]([O-])c1cccc(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C)cc1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction mixture of 2-methoxy-5-methylphenyl boronic acid (1.65 g, 10 mmol), 3-nitro-iodobenzen (2.49 g, 10 mmol), K2CO3 (2.76 g, 20 mmol), palladium(II)acetate (112 mg, 0.5 mmol) in methanol (75 ml) and water (15 ml) was stirred at rt overnight. The reaction mixture was diluted with ethyl acetate (300 ml) washed with diluted Na2S2O7 aq., water, brine, and dried over Na2SO4. After removal of solvent, 2.5 g (100%) of I-69 was obtained.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:34]([O:38][C:39](=[O:68])[NH:40][CH:41]([C:45](=[O:67])[NH:46][C:47]1[S:48][C:49]([O:59][C:60]2[CH:65]=[CH:64][C:63]([F:66])=[CH:62][CH:61]=2)=[C:50]([C:52]2[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=2)[N:51]=1)[CH2:42][CH2:43]O)([CH3:37])([CH3:36])[CH3:35]>C1COCC1>[C:34]([O:38][C:39](=[O:68])[NH:40][CH:41]1[CH2:42][CH2:43][N:46]([C:47]2[S:48][C:49]([O:59][C:60]3[CH:61]=[CH:62][C:63]([F:66])=[CH:64][CH:65]=3)=[C:50]([C:52]3[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=3)[N:51]=2)[C:45]1=[O:67])([CH3:35])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)NC(CCO)C(=O)Nc1nc(-c2ccc(F)cc2)c(Oc2ccc(F)cc2)s1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(c2nc(-c3ccc(F)cc3)c(Oc3ccc(F)cc3)s2)C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
DIAD (0.22 mL, 1.1 mmol) was added to a solution of PPh3 (300 mg, 1.15 mmol) in THF (5 mL) at room temperature. The mixture was stirred at room temperature for 5 min. To this was added a solution of {1-[5-(4-Fluoro-phenoxy)-4-(4-fluoro-phenyl)-thiazol-2-ylcarbamoyl]-3-hydroxy-propyl}-carbamic acid tert-butyl ester (438 mg, 0.867 mmol) in THF (15 mL). The mixture was stirred at room temperature for 30 min and partitioned between EtOAc and aqueous K2CO3. The organic extract was dried over MgSO4, concentrated and chromatographed to give the title compound. 1H NMR (400 MHz, CDCl3) δ 1.47 (s, 9H), 2.10-2.20 (m, 1H), 2.79-2.87 (m, 1H), 3.87-3.95 (m, 1H), 4.35-4.41 (m, 1H), 4.45-4.52 (m, 1H), 5.08-5.13 (m, 1H), 6.95-7.08 (m, 6H), 7.90-7.95 (m, 2H). m/z 488.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21]>C(Cl)Cl.O>[C:20]([NH:1][C:2]1[C:3]([I:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1cccc(N)c1I
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1cccc(NC(C)=O)c1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
To a solution of methyl 3-amino-2-iodobenzoate (70.0 g, 253 mmol) in methylene chloride (1000 mL) was added triethylamine (52.8 mL, 379 mmol) and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added acetyl chloride (35.9 mL, 505 mmol) at 0° C. and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/10) to give the title compound (76.6 g, yield 95%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][NH2:31])[CH2:25][CH2:24]1>>[O:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][NH:31][C:14]([C:11]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][CH2:10]2)=[O:15])[CH2:25][CH2:24]1
Reactant: NCCN1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCCN2CCOCC2)(c2ccccc2)CC1

Procedure:
Prepare by the method of Example 20.9 using 1-tert-butoxycarbonyl-4-phenyl-piperidine-4-carboxylic acid (7 mmol) and 2-morpholino-ethylamine (7 mmol) to give the title compound: Rf =0.49 (silica gel, 6% methanol/dichloromethane).
Reaction SMILES: [H-].[Na+].[S:3]([C:7]1[NH:8][CH:9]=[CH:10][N:11]=1)([CH3:6])(=[O:5])=[O:4].Cl[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].O>CN(C)C=O.C(Cl)Cl>[S:3]([C:7]1[N:8]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=[CH:10][N:11]=1)([CH3:6])(=[O:5])=[O:4]
Reactant: CS(=O)(=O)c1ncc[nH]1
Reactant: CCOC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)Cn1ccnc1S(C)(=O)=O
Temperature: 20 °C
Yield: 88 %

Procedure:
Sodium hydride (50% suspension in mineral oil) (5.04 g.) is added, under a nitrogen atmosphere, to a solution of 2-mesyl-imidazole (15.3 g.) in dimethylformamide (130 cc.). Ethyl chloroacetate (12.9 g.) is then added. Reaction is allowed to take place for 20 hours, with stirring, at a temperature of about 20° C. The reaction mixture is then poured into water (4 liters) and extraction is effected using methylene chloride (1 liter). The methylene chloride extracts are washed with water, dried over sodium sulphate, treated with decolorising charcoal and then concentrated to dryness under reduced pressure (0.5 mm.Hg) to yield ethyl (2-mesyl-imidazol-1-yl)-acetate (21.4 g.) in the form of an oil.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[O:4][N:3]=1.[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26]O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26][O:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:13]([F:14])([F:16])[F:15])=[CH:11][CH:12]=2)[O:4][N:3]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Oc1cc(-c2ccc(C(F)(F)F)cc2)on1
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(C(F)(F)F)cc2)on1
Yield: 80 %

Procedure:
3-Hydroxy-5-(4-trifluoromethylphenyl)isoxazole (0.2 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.15 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.26 g, 81%) as a colorless powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]#[N:5].N[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[SH:13]>CCO>[S:13]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:5]=[C:4]1[CH2:3][CH2:2][NH2:1]
Reactant: Nc1ccccc1S
Reactant: N#CCCN
Solvent: CCO
Product: NCCc1nc2ccccc2s1
Temperature: 25 °C

Procedure:
A solution of 50 mg of 3-aminopropionitrile and 596 mg of 2-aminothiophenol in EtOH (15 mL) was heated at reflux for six h. After cooling the solution to room temperature, the reaction was concentrated and the residue was purified by silica gel chromatography to afford the title compound as a red oil. MS (M+H)+=179.1.
Reaction SMILES: [C:1](Cl)([Cl:3])=[S:2].[C:5]1([N:11]2[C:15]([SH:16])=[N:14][N:13]=[N:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CCN(CC)CC>C1COCC1>[Cl:3][C:1]([S:16][C:15]1[N:11]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:12]=[N:13][N:14]=1)=[S:2]
Reactant: S=C(Cl)Cl
Reactant: Sc1nnnn1-c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: S=C(Cl)Sc1nnnn1-c1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 31.6 %

Procedure:
To a solution of thiophosgene (1.29 g, 0.0112 mol) in THF (40 ml) at 5° C. was added a solution of 1-phenyl-1H-tetrazole-5-thiol (2.0 g, 0.0112 mol) and Et3N (1.94 ml, 0.0134 mol) in THF (30 ml). The mixture was stirred at 5° C. for 30 min and then at r.t. for 1 hr. 20 min. The precipitate was filtered and washed with THF. The filtrate was evaporated in vacuo. To the obtained residue was added ether and the insoluble material was filtered off. The filtrate was evaporated in vacuo to give a solid which was recrystallized from CHCl3 --hexane. 0.91 g of the compound was obtained. 27.6% yield. IR (Nujol): 1725, 1585 cm-1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18].[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[F:27])[NH2:23]>COC(O)C.C(OCC)(=O)C>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:17]#[N:18])[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1[N+](=O)[O-]
Reactant: Nc1ccc(F)c(Cl)c1
Agent: COC(C)O
Solvent: CCOC(C)=O
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1[N+](=O)[O-]
Yield: 48.2 %

Procedure:
A mixture of 4.4 g (16.7 mmol) of 4-chloro-7-methoxy-6-nitro-quinoline-3-carbonitrile and 2.67 g (18.3 mmol) of 3-chloro-4-fluoro aniline in 110 ml of methoxyethanol was refluxed under nitrogen for 4 hours. The reaction mixture was diluted with ethyl acetate and wash with sodium bicarbonate solution and sodium chloride solution. The organic layer was dried over sodium sulfate and then the solvent was removed under vacuum. The residue was chromatographed on silica gel eluting with mixture of ethyl acetate and methanol to give 3 g yellow solid: mass spectrum (electrospray, m/e): 372.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([C:15]3[CH:20]=[CH:19][N:18]=[C:17](Cl)[CH:16]=3)[N:9]=2)=[CH:4][CH:3]=1.[C:22]([NH:26][S:27]([C:30]1[S:31][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:34]=1)(=[O:29])=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([NH:26][S:27]([C:30]1[S:31][C:32]([C:17]2[CH:16]=[C:15]([C:10]3[N:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH:13]=[C:12]([CH3:14])[N:11]=3)[CH:20]=[CH:19][N:18]=2)=[CH:33][CH:34]=1)(=[O:28])=[O:29])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-c2ccnc(Cl)c2)n1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-c2ccnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1

Procedure:
5-{4-[4-(4-Chloro-phenyl)-6-methyl-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic acid tert-butylamide was prepared from 4-(4-chloro-phenyl)-2-(2-chloro-pyridin-4-yl)-6-methyl-pyrimidine (example E.45) (0.22 g, 0.7 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.31 g, 0.9 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.12 g) which was subsequently deprotected.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14]O)=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]=[N:10]1.C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:20][CH2:14][C:13]1[N:9]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])[N:10]=[N:11][C:12]=1[CH:16]([CH3:18])[CH3:17]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1CBr
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
To a solution of (1-(2,6-dichlorophenyl)-4-isopropyl-1H-1,2,3-triazol-5-yl)methanol (3.0 g, 0.01048 mol) and CBr4 in CH2Cl2 (15 ml) is added a solution of triphenylphosphine (3.50 g, 0.01334 mol) in CH2Cl2 (10 ml) at 0° C. Stir the solution for 4 h at room temperature and concentrate in vacuo to give crude product. Purify by column chromatography over silica gel eluting with 7:3 hexane/ethyl acetate to give 3.0 g (82%) of the title compound. ES/MS m/e (79Br/81Br) 348/350 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15](Cl)=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([SH:29])=[CH:25][CH:24]=1.C([O-])(=O)C.[Na+]>C(O)C>[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29][C:15]2[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)(=[O:11])=[O:10])=[CH:13][C:14]=2[N+:19]([O-:21])=[O:20])=[CH:25][CH:24]=1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Nc2ccc(Br)cc2)ccc1Cl
Reactant: Nc1ccc(S)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc(Sc2ccc(S(=O)(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A mixture of the product of Example 78A (500 mg, 1.277 mmol), 4-aminothiophenol (240 mg, 1.915 mmol) and anhydrous sodium acetate (524 mg, 6.384 mmol) in anhydrous ethanol (9 mL) was heated at reflux under a nitrogen atmosphere for 1 hour. The reaction was cooled to room temperature and the ethanol removed by rotary evaporation under vacuum. The residue was taken up in ethyl acetate (100 mL) and washed with water (2×50 mL) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum, co-evaporating the oil with methylene chloride/hexanes to obtain the title compound as an orange foam (613 mg, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:11]([O:15][C:16](=[O:22])[N:17]([CH2:19][CH2:20]O)[CH3:18])([CH3:14])([CH3:13])[CH3:12].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:11]([O:15][C:16](=[O:22])[N:17]([CH2:19][CH2:20][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2)[CH3:18])([CH3:14])([CH3:13])[CH3:12]
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: Oc1cccc2[nH]ccc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(CCOc1cccc2[nH]ccc12)C(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 70.7 %

Procedure:
To a cooled (0° C.) solution of 4-hydroxyindole (2.92 g) and (2-hydroxy-ethyl)-methyl-carbamic acid tert-butyl ester (3.50 g) in 100 mL of THF was added PPh3 (5.8 g) followed by the dropwise addition of diisopropylazodicarboxylate (4.44 g) over 10 minutes. After 16 h the reaction was worked up in the normal manner and the crude oil was purified by chromatography to afford 4.1 g of [2-(1H-indol-4-yloxy)-ethyl]-methyl-carbamic acid tert-butyl ester. MS: 313 (M+Na)+.
Reaction SMILES: [O:1]=[C:2]1[NH:14][C:12]2[C:13]3[C:5](=[CH:6][N:7]([CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O>>[O:1]=[C:2]1[NH:14][C:12]2[C:13]3[C:5](=[CH:6][N:7]([CH2:15][C:16]([OH:18])=[O:17])[C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)Cn1cc2c3c(cccc31)NC(=O)CC2
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1cc2c3c(cccc31)NC(=O)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (5-oxo-3,4,5,6-tetrahydro-1H-azepino[4,3,2-cd]indol-1-yl)acetate from Step D (100 mg, 0.33 mmol) in (1 mL) was added TFA (0.25 mL, 3.3 mmol) and the resulting mixture was stirred at ambient temperature for 1 h. The mixture was concentrated in vacuo to give the title compound. MS: m/z=245 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][NH:10][CH:11]2[CH2:13][CH2:12]2)[CH:5]=[CH:4][N:3]=1.[CH3:14][O-:15].[Na+]>O1CCOCC1>[CH:11]1([NH:10][CH2:9][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([O:15][CH3:14])[C:7]=2[CH3:8])[CH2:13][CH2:12]1
Reactant: C[O-]
Reactant: Cc1c(CNC2CC2)ccnc1Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1nccc(CNC2CC2)c1C
Yield: 90.1 %

Procedure:
A mixture of (2-chloro-3-methylpyridin-4-ylmethyl)cyclopropylamine (10.0 g, 50.8 mmol) and sodium methoxide (13.73 g, 254 mmol) in dioxan (40 mL) was heated to reflux for 48 h. The reaction mixture was filtered through Celite, and the remaining solid was washed with Et2O (2×). The solvents were removed under reduced pressure. Purification by FC yielded the title compound (8.8 g, 90%) as a pale, yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][OH:13].Cl.[N-]=[C:16]=[O:17].[K+]>O>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]([CH2:10][CH2:11][CH2:12][OH:13])[C:16](=[O:17])[NH:1][C:2]=2[CH:7]=1
Reactant: [N-]=C=O
Reactant: Nc1cc(Cl)ccc1NCCCO
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=c1[nH]c2cc(Cl)ccc2n1CCCO
Reaction time: 20 h
Yield: 32 %

Procedure:
To a stirred solution of 40 parts of 3-[(2-amino-4-chlorophenyl)amino]-1-propanol in 140 parts of water and 24 parts of a hydrochloric acid solution 10N is added dropwise a solution of 18 parts of potassium isocyanate in 40 parts of water (exothermic reaction: temperature rises to 35° C). Upon completion, stirring is continued first for 30 minutes at room temperature and further for 20 hours at reflux temperature. The reaction mixture is allowed to stirr over week-end without heating. The precipitated product is filtered of and treated with a diluted hydrochloric acid solution in 4-methyl-2-pentanone. The whole is stirred and the layers are separated. The 4-methyl-2-pentanone-phase is washed with water, dried, filtered and evaporated, yielding 18 parts (32%) of 5-chloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one; mp. 148.8° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:15]([F:16])=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][N:7]=2)[CH2:3][CH2:2]1.C1COCC1.[OH-].[Li+].Cl>CO>[CH:1]1([CH2:4][O:5][C:6]2[C:15]([F:16])=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][N:7]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1cnc(OCC2CC2)c(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cnc(OCC2CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 73.7 %

Procedure:
A mixture of methyl 6-(cyclopropylmethoxy)-5-fluoronicotinate (1.75 g), THF (15 mL), methanol (1.7 mL) and 2 M aqueous lithium hydroxide solution (7.8 mL) was stirred at room temperature for 20 min. The reaction mixture was neutralized with 1 M hydrochloric acid at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure, and the obtained solid was washed with diethyl ether to give the title compound (1.21 g).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[CH2:13](O)[CH3:14].[OH-].[Na+]>O>[CH2:13]([O:9][C:8](=[O:10])[CH:7]=[CH:6][C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:12][CH:11]=1)[CH3:14]
Reactant: Nc1ccc(C=CC(=O)O)cc1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)C=Cc1ccc(N)cc1
Yield: 78 %

Procedure:
32.6 parts of 4-amino-cinnamic acid are heated under reflux for three hours in a mixture comprising 100 parts of absolute ethyl alcohol and 20 parts of 66°Be sulphuric acid. The product is poured on to 200 parts of water and 200 parts of ice, made alkaline to pH 8 by the addition of 38 parts of a 35° Be solution of sodium hydroxide, and the solid is filtered off, washed with water and recrystallised from 150 parts of ethyl alcohol and 150 parts of water. Ethyl-p-amino-cinnamate is thus obtained. Yield 78% M.p. 68°-69° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[N:5]([CH2:11][CH2:12][CH3:13])[C:4](=[O:14])[CH:3]=1.[N:15]([O-])=[O:16].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[N:5]([CH2:11][CH2:12][CH3:13])[C:4](=[O:14])[C:3]=1[N:15]=[O:16]
Reactant: CCCn1c(=O)cc(N)n(CC)c1=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCn1c(=O)c(N=O)c(N)n(CC)c1=O
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of 6-amino-1-ethyl-3-propyl-1,3-dihydropyrimidine-2,4-dione (1.4 g, 7.1 mmol) in a mixture of 50% acetic acid/water (35 ml) was added sodium nitrite (2 g, 28.4 mmol) in portions over a period of 10 minutes. The mixture was stirred at 70° C. for 1 hour, then the reaction mixture concentrated to a low volume under reduced pressure. The solid was filtered off, and washed with water, to provide 6-amino-1-ethyl-5-nitroso-3-propyl-1,3-dihydropyrimidine-2,4-dione, a compound of formula (1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:29]=[CH:28][C:27]2[N:26]([CH2:30][O:31][CH3:32])[C:25]3[C:33](=[O:45])[N:34]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[N:35]=[C:36]([CH2:37]O)[C:24]=3[C:23]=2[CH:22]=1.[Br:46]C(Br)(Br)Br.C1CCCCC1>ClCCl>[Br:46][CH2:37][C:36]1[C:24]2[C:23]3[CH:22]=[C:21]([F:20])[CH:29]=[CH:28][C:27]=3[N:26]([CH2:30][O:31][CH3:32])[C:25]=2[C:33](=[O:45])[N:34]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:35]=1
Reactant: COCn1c2ccc(F)cc2c2c(CO)nn(-c3ccccc3)c(=O)c21
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCCCC1
Product: COCn1c2ccc(F)cc2c2c(CBr)nn(-c3ccccc3)c(=O)c21
Reaction time: 2 h
Yield: 77.8 %

Procedure:
4.5 g (17.1 mmol) of triphenylphosphine are added to a solution of 3.2 g (9 mmol) of 8-fluoro-1-(hydroxymethyl)-5-(methoxymethyl)-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indol-4-one and of 6.3 g (19 mmol) of tetrabromomethane in 200 ml of dichloromethane. The mixture is stirred for 2 h, 50 ml of cyclohexane are added and the precipitate is collected by filtration and dried under reduced pressure. 2.9 g (7 mmol) of solid are isolated, which solid is used as is in the following stage.
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:41][CH3:42])[CH2:5][CH2:6][O:7][C:8]1[CH:40]=[CH:39][C:11]([C:12]([C:14]2[C:15]3[CH:33]=[CH:32][C:31]([O:34]S(C)(=O)=O)=[CH:30][C:16]=3[S:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22]([O:25]S(C)(=O)=O)=[CH:21][CH:20]=2)=[O:13])=[CH:10][CH:9]=1)[CH3:3].O1CCCC1.[OH-].[Na+]>CO>[CH2:41]([N:4]([CH2:2][CH3:3])[CH2:5][CH2:6][O:7][C:8]1[CH:40]=[CH:39][C:11]([C:12]([C:14]2[C:15]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][C:16]=3[S:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[O:13])=[CH:10][CH:9]=1)[CH3:42]
Reactant: CCN(CC)CCOc1ccc(C(=O)c2c(-c3ccc(OS(C)(=O)=O)cc3)sc3cc(OS(C)(=O)=O)ccc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(CC)CCOc1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1

Procedure:
A 4 g. portion of the product of Example 6 above was added to 100 ml. of tetrahydrofuran, 40 ml. of methanol and 10 ml. of 5 N sodium hydroxide, and the mixture was stirred at ambient temperature for 24 hours. The volatile portions were then evaporated under vacuum, and the product was worked up as described above in Example 19. The yellow solid obtained was dried, and was purified by chromatography as described above in Example 20. The process gave 2.0 g. of a yellow foam, which was identified as the expected product by its nmr spectrum (taken in dmso-d6 at 100 mHz): δ0.93 (6H, t, J=7 Hz, CH2CH3); 2.50 (4H, q, J=7 Hz, CH2CH3); 2.72 (2H, t, J=6 Hz, NCH2); 4.01 (2H, t, J=6 Hz, OCH2CH2N); 6.67 (2H, d, J=9 Hz aromatic o to OH); 6.85 (1H, q, JH4-H5 =9 Hz, JH5-H7 =2 Hz, H5 of benzothiophene ring); 6.88 (2H, d, J=9 Hz, aromatic o to OCH2); 7.18 (2H, d, J=9 Hz, aromatic m to OH); 7.27 (1H, d, J=9 Hz, H4 of benzothiophene ring); 7.34 (1H, d, J=2 Hz, H7 of benzothiophene ring); 7.66 (2H, d, J=9 Hz, aromatic o to CO); 9.72 (2H, broad s, OH). High resolution mass spectrum: calculated for C27H27NO4S: 461.16607, found 461.16551; Ultraviolet spectrum λmax (ε) taken in ethanol 290 cm (34,000); infrared absorption in KBr at 1608 cm-1 attributable to the eneone system.