Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C:17](N)=[O:18]>C1(C)C(C)=CC=CC=1>[CH2:1]([N:8]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:14]2[N:15]=[C:17]1[OH:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(N)=O
Reactant: Nc1cccnc1NCc1ccccc1
Solvent: Cc1ccccc1C
Product: Oc1nc2cccnc2n1Cc1ccccc1
Temperature: 25 °C

Procedure:
Grams 10 2-benzylamino-3-amino pyridine and 3 g urea in 50 ml xylene are heated under reflux for 3 hours. The reaction mixture is then cooled to room temperature, the undissolved product filtered and washed with toluene; the solid dried in vacuo at 80° C. gives 5.1 g 3-benzyl-2-hydroxy-3H-imidazo[4,5-b]pyridine which, recrystallized from absolute ethyl alcohol, melts at 177°-179° C.
Reaction SMILES: S(=O)(=O)(O)O.O.[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13](=O)[C:14]3[C:19]([C:20]=2[CH:21]=1)=[CH:18][CH:17]=[CH:16][N:15]=3>[Pd].CO>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[C@@H:19]([C:20]=2[CH:21]=1)[CH2:18][CH2:17][CH2:16][NH:15]3
Reactant: COc1ccc2c(c1)-c1cccnc1C2=O
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)[C@H]1CCCN[C@H]1C2
Temperature: 60 °C

Procedure:
A mixture of sulfuric acid (98%, 6 kg), water (6 L), and methanol (6 L) is added to an autoclave charged with 6-methoxy-indeno[2,1-b]pyridin-9-one (1.2 kg) and wet 10% palladium on carbon (50%, 0.48 kg). The autoclave is purged with nitrogen and filled then with hydrogen (100 psi). The mixture is heated to 60° C. and maintained at this temperature and hydrogen pressure until the starting material is completely consumed (2-12 h). The mixture is cooled to 50-55° C. and filtered over Celite. The Celite is washed with a warm 1:1 mixture of water and methanol several times (total 20 L). The combined filtrate is added to an autoclave charged with wet 10% palladium on carbon (50%, 0.96 kg). The autoclave is purged with nitrogen and filled then with hydrogen (100 psi). The mixture is heated to 60° C. and maintained at this temperature and hydrogen pressure until the intermediate is completely consumed (12-24 h). The mixture is cooled to ambient temperature and filtered over Celite. The Celite is washed with a mixture of methanol and water (5 L/5 L). The combined filtrate is cooled to 0-10° C. and the pH value is adjusted to 10-11 using 30% aqueous NaOH solution while maintaining the solution temperature below 40° C. Water (10 L) is added and the resulting mixture is extracted with dichloromethane (2×5 L). The combined extract is washed with 10% aqueous NaCl solution and concentrated. The residue is taken up twice in methyl ethyl ketone and concentrated again to give the crude title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[O:18]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCCO)C.O>[O:18]([C:25]1[CH:26]=[CH:27][C:28]([NH:29][C:2]2[C:11]3[C:6](=[CH:7][C:8]4[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=4[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])=[CH:30][CH:31]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: N#Cc1cnc2cc3ccccc3cc2c1Cl
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: CCOCCO
Product: N#Cc1cnc2cc3ccccc3cc2c1Nc1ccc(Oc2ccccc2)cc1
Yield: 73.4 %

Procedure:
A reaction mixture of 141.8 mg (0.59 mmol) of 4-chlorobenzo[g]quinoline-3-carbonitrile, 111.1 mg (0.60 mmol) of 4-phenoxyaniline and 57.8 mg (0.50 mmol) of pyridine hydrochloride in 8 ml of 2-ethoxyethanol is heated at 110–120° C. for 1 hour. After cooling, the mixture is diluted with water and made basic by addition of 125.0 mg (1.18 mmol) of sodium carbonate. The precipitate is collected by filtration and washed with water. Drying in vacuo yields the crude product. The crude product is purified by chromatography, eluting with a methylene chloride/methanol gradient from 100:0 to 86:14, to provide 167.8 mg (73.4%) of the pure product as a yellow solid, mp 250–251° C.
Reaction SMILES: C[O:2][P:3]([O:6][CH3:7])[O:4][CH3:5].Cl[C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10]>>[CH:12]([O:11][C:9]([P:3](=[O:2])([O:6][CH3:7])[O:4][CH3:5])=[O:10])([CH3:14])[CH3:13]
Reactant: COP(OC)OC
Reactant: CC(C)OC(=O)Cl
Product: COP(=O)(OC)C(=O)OC(C)C

Procedure:
From 10.0 ml (85 mmole) of trimethylphosphite and 7.8 g (64 mmole) of i-propyl chloroformate. (100° C., 2 hours). Yield 8.0 g (64%). Bp2 90°-2° C. nD25 1,4202.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([O:15][C:16]1[N:21]=[CH:20][C:19]([C:22]2[C:27](=[O:28])[N:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[C:37]([C:42]#[N:43])=[CH:38][CH:39]=[CH:40][CH:41]=4)=[CH:32][CH:31]=3)[C:25]([CH2:44][CH2:45][CH3:46])=[N:24][C:23]=2[CH2:47][CH3:48])=[CH:18][CH:17]=1)[CH3:14]>C(OCC)(=O)C>[CH2:13]([O:15][C:16]1[N:21]=[CH:20][C:19]([C:22]2[C:27](=[O:28])[N:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:42]4[NH:3][C:4](=[O:7])[O:5][N:43]=4)=[CH:32][CH:31]=3)[C:25]([CH2:44][CH2:45][CH3:46])=[N:24][C:23]=2[CH2:47][CH3:48])=[CH:18][CH:17]=1)[CH3:14]
Reactant: CCCc1nc(CC)c(-c2ccc(OCC)nc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(-c2ccc(OCC)nc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
A mixture of hydroxylammonium chloride (0.67 g), sodium hydrogen carbonate (0.95 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[5-(6-ethoxypyridin-3-yl)-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.54 g) was added, and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.28 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.32 g, 60%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Cl)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:26][C:27]1[S:28][C:29]([CH3:32])=[N:30][N:31]=1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][S:26][C:27]3[S:28][C:29]([CH3:32])=[N:30][N:31]=3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCCCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: Cc1nnc(S)s1
Product: Cc1nnc(SCCCC(=O)NC/C=C\COc2cc(CN3CCCCC3)ccn2)s1
Yield: 78 %

Procedure:
Following a procedure similar to that described in Example 34, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 2-mercapto-5-methyl -1,3,4-thiadiazole as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 65°-68° C., in a 78% yield.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.[H-].[Na+].CS(O[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27][CH2:26]1)(=O)=O.COC1C=C2C(C=CC(=O)N2CCN2CCC(NC(=O)OC(C)(C)C)CC2)=CC=1>ClCCl.CO>[C:35]([O:34][C:32]([NH:31][CH:28]1[CH2:27][CH2:26][N:25]([CH2:24][CH2:23][N:7]2[C:6]3[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=[CH:11][C:5]=3[O:4][CH2:3][C:2]2=[O:1])[CH2:30][CH2:29]1)=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: COC(=O)c1ccc2c(c1)NC(=O)CO2
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc2c(c1)N(CCN1CCC(NC(=O)OC(C)(C)C)CC1)C(=O)CO2
Yield: 85 %

Procedure:
Methyl 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (Intermediate 86) (330 mg, 1.59 mmol) was deprotonated with sodium hydride and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (5.6 mmol) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/methanol (20:1) gave the product in 85% yield as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14](SC)=[C:15]([S:18]([CH3:21])(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:24][CH:25]([NH2:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([NH:30][CH:25]([CH3:24])[C:26]([CH3:29])([CH3:28])[CH3:27])=[C:15]([S:18]([CH3:21])(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC(N)C(C)(C)C
Reactant: COc1cc(NC(SC)=C(C#N)S(C)(=O)=O)cc(C(F)(F)F)c1
Product: COc1cc(NC(NC(C)C(C)(C)C)=C(C#N)S(C)(=O)=O)cc(C(F)(F)F)c1
Yield: 40 %

Procedure:
3-(3-Methoxy-5-trifluoromethyl-phenylamino)-2-methylsulfonyl-3-methylsulfanyl-propenenitrile (0.22 g, 0.6 mmol) was stirred in 1,2,2-trimethylpropylamine (1 ml) for 17 h at 75° C. under nitrogen. Work-up as described in EXAMPLE 17, 2) without chromatography gave 100 mg (40%) of the title compound. Mp 110-113° C. 1H NMR (200 MHz, CDCl3): δ=0.87 (s, 9H), 1.01 (d, 3H), 3.08 (m, 1H), 3.10 (s, 3H), 3.87 (s, 3H), 6.81 (br s, 1H), 6.95 (br s, 1H), 6.97 (br s, 1H); Analysis: calc. for C18H24N3O3S: C, 51.54%; H, 5.77%; N, 10.02%; Found: C, 51.77%; H, 6.05%; N, 9.80%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:25]([O:28][CH2:29][C:30]1[C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=[CH:32][C:31]=1[N:45]1[CH2:50][CH2:49][C:48]2[C:51]3[CH2:57][CH2:56][CH2:55][CH2:54][C:52]=3[S:53][C:47]=2[C:46]1=[O:58])(=[O:27])[CH3:26]>>[C:25]([O:28][CH2:29][C:30]1[C:31]([N:45]2[C:46](=[O:58])[C:47]3[S:53][C:52]4[CH2:54][CH2:55][CH2:56][CH2:57][C:51]=4[C:48]=3[CH2:49][CH2:50]2)=[CH:32][CH:33]=[CH:34][C:35]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:27])[CH3:26]
Reactant: Cn1cc(Br)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCc2c(sc3c2CCCC3)C1=O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)c(=O)n(C)c2)cccc1N1CCc2c(sc3c2CCCC3)C1=O
Yield: 65 %

Procedure:
Following Example 136e, 170b and (2-{6-oxo-8-thia-5-azatricyclo[7.4.0.02,7]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 111a were reacted to give 170c in 65% yield. LCMS: (M+H)+ 668
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[CH:4]1[NH2:10].C(N(CC)CC)C.[Cl:18][C:19]1[CH:20]=[C:21]([CH:39]=[CH:40][C:41]=1[CH3:42])[CH2:22][N:23]1[C:27]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)=[CH:26][C:25]([C:36](Cl)=[O:37])=[N:24]1>C(Cl)Cl>[CH3:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[CH:4]1[NH:10][C:36]([C:25]1[CH:26]=[C:27]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)[N:23]([CH2:22][C:21]2[CH:39]=[CH:40][C:41]([CH3:42])=[C:19]([Cl:18])[CH:20]=2)[N:24]=1)=[O:37]
Reactant: CC1CCCC(C)C1N
Reactant: Cc1ccc(Cn2nc(C(=O)Cl)cc2-c2ccc(Cl)c(Cl)c2)cc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(Cn2nc(C(=O)NC3C(C)CCCC3C)cc2-c2ccc(Cl)c(Cl)c2)cc1Cl
Yield: 32.8 %

Procedure:
This compound is prepared by the procedure described in step B of EXAMPLE 36 from 0.605 g of 2,6-dimethylcyclohexylamine hydrochloride, 1 ml of triethylamine in 15 ml of DCM and 1.5 g of the compound obtained in step A of EXAMPLE 36 in 15 ml of DCM. 0.6 g of the expected product is obtained; m.p.=59.9° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([NH:12][C:13]([NH2:15])=[S:14])[CH:9]=[CH:10][CH:11]=1.Br.[C:17]([NH:20][C:21]1(NC2C=C(C=CC=2)C(O)=O)[NH:25][C:24]([CH3:31])(C2SC=NC=2)[CH2:23][S:22]1)(=[O:19])[CH3:18].[CH3:42][CH2:43]O>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([NH:12][C:13]2[S:14][CH:42]=[C:43]([C:23]3[S:22][C:21]([NH:20][C:17](=[O:19])[CH3:18])=[N:25][C:24]=3[CH3:31])[N:15]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCO
Reactant: CC(=O)NC1(Nc2cccc(C(=O)O)c2)NC(C)(c2cncs2)CS1
Reactant: NC(=S)Nc1cccc(C2OCCO2)c1
Agent: Br
Product: CC(=O)Nc1nc(C)c(-c2csc(Nc3cccc(C4OCCO4)c3)n2)s1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
According to the general procedure 1, N-[3-(1,3-dioxolan-2-yl)phenyl]thiourea (prepared from 3-aminobenzyldehyde ethylene acetal (Alfa), following procedure D) is added to a solution of N-[5-(bromoacetyl)-4-methyl-1,3-thiazol-2-yl]acetamide (Intermediate 1) in EtOH. The mixture is stirred 5 hours at RT. The solvents are evaporated and the desired product is purified by crystallization. N-(2-{[3-(1,3-dioxolan-2-yl)phenyl]amino}-4′-methyl-4,5′-bi-1,3-thiazol-2′-yl)acetamide is isolated as a beige solid (320 mg; 88%). HPLC, Rt: 3.26 min (purity: 90.29%).
Reaction SMILES: [OH:1][C:2]1[C:10]2[NH:9][C:8]([CH3:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:14][C:15]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([CH3:24])[C:16]=1[CH2:17]Br.C(Cl)Cl>C(#N)C.O>[CH3:14][C:15]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([CH3:24])[C:16]=1[CH2:17][O:1][C:2]1[C:10]2[NH:9][C:8]([CH3:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(F)cc(C)c1CBr
Reactant: Cc1nc2cccc(O)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: Cc1nc2cccc(OCc3c(C)cc(F)cc3C)c2[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 6.1 %

Procedure:
4-hydroxy -2-methylbenzimidazole (0.57 g, 3.8 mmol) was dissolved in acetonitrile (4 ml). To the solution were added sodium hydroxide (0.17 g, 43 mmol) (dissolved in 1 ml water) and 2,6-dimethyl-4-fluorobenzylbromide (0.82 g, 3.8 mmol) dissolved in acetonitrile (6 ml) and the reaction mixture was refluxed for 80 min. and was stirred for 20 h. at ambient temperature. To the reaction mixture was added methylene chloride (25 ml) and water (25 ml). The organic layer was separated, washed three times with 2 M NaOH, dried over sodium sulfate and was evaporated under reduced pressure. The residue was crystallized from ethyl acetate and was then purified twice by column chromatography on silica gel a) methylene chloride: methanol (10:1) b) ethyl acetate: methanol:acetic acid: water (96:6:6:4). There was obtained 0.066 g (6%) of the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:14][C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[C:3]1=[O:15])[CH2:10][CH2:9][CH2:8][CH2:7]3.[Al+3].[Cl-].[Cl-].[Cl-].[Br:20]Br.O>C(Cl)Cl>[Br:20][C:12]1[CH:13]=[C:4]2[C:3](=[O:15])[CH:2]([CH3:1])[CH2:14][C:5]2=[C:6]2[C:11]=1[CH2:10][CH2:9][CH2:8][CH2:7]2
Reactant: CC1Cc2c(ccc3c2CCCC3)C1=O
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC1Cc2c(cc(Br)c3c2CCCC3)C1=O
Reaction time: 1 h

Procedure:
In a three-necked round-bottom 500 ml flask equipped with a reflux condenser, dropping funnel with pressure-equalizing, and mechanical stirrer a solution of 55.0 g (0.275 mol) of 2-methyl-1,2,6,7,8,9-hexahydro-3H-cyclopenta[a]naphthalen-3-one in 50 ml of CH2Cl2 was added dropwise with vigorous stirring for 1 h at −10° C. to a suspension of 92 g (0.69 mol) of AlCl3 in 100 ml of CH2Cl2. This mixture was stirred additionally for 1 h at this temperature; then 14.2 ml (44.0 g, 0.275 mol) of bromine was added dropwise with vigorous stirring for 1 h. The resulting mixture was stirred for 2 h at −10° C. and then overnight at ambient temperature, and, then, it was poured on 1000 cm3 of cold water. The organic layer was separated, the aqueous layer was extracted with 3×200 ml of methyl-tert-butyl ether. The combined extract was washed with saturated aqueous Na2SO3 to eliminate bromine and with aqueous Na2CO3. It was then dried over K2CO3, and evaporated to dryness. Fractional distillation gave a yellowish liquid, b.p. 195-198° C./4 mm Hg. Yield 58.3 g (76%).
Reaction SMILES: BrC1C=C2C(=[CH:9][CH:10]=1)NC=C2.CN1CCC(=O)CC1.[OH-].[K+].Br[C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[C:31]1[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH:36]=1.CC=[CH:40][NH:41][SH:42](=[O:44])=[O:43]>CO>[CH3:40][NH:41][S:42]([CH2:9][CH2:10][C:22]1[CH:30]=[CH:29][C:28]2[NH:27][CH:26]=[C:25]([CH:31]3[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]3)[C:24]=2[CH:23]=1)(=[O:44])=[O:43]
Reactant: CN1CC=C(c2c[nH]c3ccc(Br)cc23)CC1
Reactant: CC=CN[SH](=O)=O
Reactant: Brc1ccc2[nH]ccc2c1
Agent: CN1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CNS(=O)(=O)CCc1ccc2[nH]cc(C3CCN(C)CC3)c2c1

Procedure:
In another process as described in US '841, if the reaction of 5-bromoindole with 1-methylpiperidin-4-one by means of KOH in methanol is carried out at reflux temperature the resulting product is 5-bromo-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole which is further condensed with N-methylvinylsulfonamide as described above to obtain naratriptan.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:10]2=[O:19])=[CH:5][CH:4]=1)[CH3:2].O=C(Cl)[O:22][C:23](Cl)(Cl)Cl.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][N:16]([C:23]([N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:22])[CH2:15][CH2:14]3)[C:10]2=[O:19])=[CH:7][CH:8]=1)[CH3:2]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: C1CCNCC1
Reactant: CCc1ccc(N2CCC3(CCNCC3)C2=O)cc1
Product: CCc1ccc(N2CCC3(CCN(C(=O)N4CCCCC4)CC3)C2=O)cc1

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-Ethyl-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and piperidine. MS (ESI): 370.3 (MH+).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[N:16]=[C:17]([CH2:45][CH2:46][CH3:47])[N:18]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=3)=[CH:33][CH:32]=2)[C:19](=[O:29])[C:20]=1[O:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]=1)[CH3:14]>C(OCC)(=O)C>[CH2:13]([C:15]1[N:16]=[C:17]([CH2:45][CH2:46][CH3:47])[N:18]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[C:43]3[NH:3][C:4](=[O:7])[O:5][N:44]=3)=[CH:33][CH:32]=2)[C:19](=[O:29])[C:20]=1[O:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]=1)[CH3:14]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1nc(CC)c(Oc2cc(C)ccn2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(CC)c(Oc2cc(C)ccn2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
A mixture of hydroxylammonium chloride (0.17 g), sodium hydrogen carbonate (0.24 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-{[4-ethyl-5-[(4-methylpyridin-2-yl)oxy]-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.13 g) was added, and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL). N,N′-carbonyldiimidazole (0.07 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.07 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.1 g, 64%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:22][N:23]2[CH:27]=[CH:26][N:25]=[C:24]2[CH3:28])[N:19]=[N:20][CH:21]=1>>[ClH:15].[CH3:28][C:24]1[N:23]([CH2:22][C:18]2[N:19]=[N:20][CH:21]=[C:16]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:14])([F:13])[F:1])[CH:5]=3)[CH:17]=2)[CH:27]=[CH:26][N:25]=1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Product: Cc1nccn1Cc1cc(-c2cccc(OC(F)(F)F)c2)cnn1
Product: Cl

Procedure:
The title compound, MS: m/e=335.3 (M+H+), was prepared from 3-(trifluoromethoxy)phenylboronic acid and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][N:7]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:10]=3[C:11]=2[N:12]=1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[OH-].[NH4+]>CN(C)C=O>[ClH:1].[Cl:17][C:15]1[CH:14]=[CH:13][C:10]2[C:11]3[N:12]=[C:2]([N:29]4[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]4)[N:3]=[CH:4][C:5]=3[CH2:6][N:7]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9]=2[CH:16]=1
Reactant: Fc1ccccc1C1=NCc2cnc(Cl)nc2-c2ccc(Cl)cc21
Reactant: CN1CCNCC1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CN1CCN(c2ncc3c(n2)-c2ccc(Cl)cc2C(c2ccccc2F)=NC3)CC1
Product: Cl
Temperature: 0 °C

Procedure:
To a solution of 3.0 g (0.00838 mol) of 2,9-dichloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine in 8 ml of N,N-dimethylformamide was added 2 g (0.02 mol) of N-methylpiperazine. After 20 hr ice water (40 ml) was added to the reaction which was then filtered. The solid was partitioned between 50 ml of dichloromethane and 50 ml of 1N hydrochloric acid, and the pH was adjusted to 1-2 with ammonium hydroxide. The resulting precipitate was filtered and recrystallized twice from methanol to give white prisms, mp 187°-194° C. The acid layer was made basic with ammonium hydroxide, and extracted with 100 ml of dichloromethane which was dried and evaporated. The oil was acidified with 1N hydrochloric acid, adjusted to pH 1-2 with ammonium hydroxide, cooled and filtered. The precipitate was recrystallized from methanol to give a further crop of the product.
Reaction SMILES: CN(C)N=[C:4]([CH2:6][CH:7]([OH:29])[CH:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[C:23]([Cl:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[CH:20][N:19]=2)=[CH:13][CH:12]=1)[CH3:9])[CH3:5].I([O-])(=O)(=O)=[O:32].[Na+]>CO.P([O-])([O-])([O-])=O.O>[OH:29][CH:7]([CH:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[C:23]([Cl:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[CH:20][N:19]=2)=[CH:13][CH:12]=1)[CH3:9])[CH2:6][C:4](=[O:32])[CH3:5]
Reactant: CC(CC(O)C(C)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)=NN(C)C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)CC(O)C(C)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
The above hexanone hydrazone (1 mmol) is dissolved in 10 ml of methanol with 2 ml of 2M pH 7 phosphate buffer, and a solution of sodium periodate (2.2 mmol) in 2 ml of water is added, with stirring. The mixture is stirred for 3 hours, after which the solvent is removed and the residue is extracted with chloroform. The extract is washed with water and dried and the solvent is removed to give 4-hydroxy-5-[4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy]-2-hexanone (C'; Q1 is N, Y is chloro, Z is trifluoromethyl, R1 is methyl and R2 is methyl).