Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][S:7][CH2:8][C@@H:9]2[O:14][C@@H:13]([O:15][CH:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[CH2:17]Br)[CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1.[I-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][S:7][CH2:8][C@@H:9]2[O:14][C@@H:13]([O:15][CH:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[CH2:17][N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)[CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(CSC[C@H]2CCC[C@H](OC(CBr)c3ccc(Cl)cc3Cl)O2)cc1
Reactant: c1c[nH]cn1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(CSC[C@H]2CCC[C@H](OC(Cn3ccnc3)c3ccc(Cl)cc3Cl)O2)cc1

Procedure:
130 mg of the isomer of lesser polarity of trans-6-(4-chlorobenzylthiomethyl)-2-[2-bromo-1-(2,4-dichlorophenyl)ethoxy]tetrahydropyran, 67.5 mg of imidazole and 74 mg of sodium iodide were reacted in dimethylformamide at 130° C. for 9 hours and then treated and the product purified essentially as described in Example 34(b)(i), to give 60 mg of the title compound in the form of a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[C:17]([Cl:18])=[C:16]([OH:19])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[CH3:13])=O.Cl.[NH2:21][OH:22]>N1C=CC=CC=1>[Cl:1][C:2]1[C:17]([Cl:18])=[C:16]([OH:19])[CH:15]=[CH:14][C:3]=1[C:4](=[N:21][OH:22])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[CH3:13]
Reactant: NO
Reactant: Cc1cccc(C(=O)c2ccc(O)c(Cl)c2Cl)c1C
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cccc(C(=NO)c2ccc(O)c(Cl)c2Cl)c1C

Procedure:
A mixture of 31 g of 2,3-dichloro-4-hydroxy-2',3'-dimethylbenzophenone and 30.5 g of hydroxylamine hydrochloride in 250 ml of pyridine is refluxed for about one week. The pyridine is evaporated in vacuo and the residue is partitioned between ethyl acetate and 5% HCl. The ethylacetate extract is washed, dried over Na2SO4 and evaporated. Trituration with hexane gives 2,3-dichloro-4-hydroxy-2',3'-dimethylbenzophenone oxime.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:10]=2[CH2:11]Br)[CH:5]=[CH:6][CH:7]=1.[C-:20]#[N:21]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:10]=2[CH2:11][C:20]#[N:21])[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Sc2cccc(Br)c2)c(CBr)c1
Reactant: [C-]#N
Solvent: CCO
Product: N#CCc1cc([N+](=O)[O-])ccc1Sc1cccc(Br)c1

Procedure:
2.16 G. 2-(3'-bromophenylthio)-5-nitrobenzyl bromide is refluxed in 50 cc. ethanol and 2.4 g. of cyanide ion exchange resin for 1/2 hour. The mixture is filtered hot and the resin washed with ethyl acetate. The combined organic filtrates are evaporated to dryness to yield 1.85 g. of crude residue which is chromatographed on silica gel. Elution with benzene affords 800 mg. of the desired compound.
Reaction SMILES: [CH2:1]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH2:5][CH2:4][N:3]2[CH2:13][CH2:14][CH2:15][CH2:16][CH:2]12.[ClH:17].CN(C)CCCN=C=NCC.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:35]=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[NH2:34].C(N(C(C)C)CC)(C)C>ClCCl.Cl>[ClH:17].[ClH:17].[CH2:1]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([NH:34][C:33]2[CH:35]=[C:36]([O:40][CH3:41])[C:37]([O:38][CH3:39])=[C:31]([O:30][CH3:29])[CH:32]=2)=[O:12])[CH2:5][CH2:4][N:3]2[CH2:13][CH2:14][CH2:15][CH2:16][CH:2]12
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=C(O)CCCN1CCN2CCCCC2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(NC(=O)CCCN2CCN3CCCCC3C2)cc(OC)c1OC

Procedure:
1.2 g of the compound obtained in Step B, 1.05 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.92 g of 3,4,5-trimethoxyaniline in solution in 50 ml of dichloromethane and 1.75 ml of diisopropylethylamine are stirred, under argon, for 24 hours at room temperature. The reaction mixture is washed with 50 ml of water, decanted, dried over Na2SO4 and concentrated under a partial vacuum. The hydrochloride is then prepared in 20 ml of ethanol and 2 ml of an ethereal hydrogen chloride solution, enabling the expected product to be obtained.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@:20]([CH3:21])([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.Cl[C:23]([O:25][CH3:26])=[O:24]>N1C=CC=CC=1>[CH3:26][O:25][C:23]([O:11][C@H:10]1[CH2:9][CH2:8][C@H:7]2[C@H:6]3[C@H:5]([CH2:4][CH2:3][C@:2]12[CH3:1])[C@:20]1([CH3:21])[C:14](=[CH:15][C:16](=[O:17])[CH2:18][CH2:19]1)[CH2:13][CH2:12]3)=[O:24]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 76 %

Procedure:
Testosterone is treated with methyl chloroformate in pyridine to give 17β-methoxycarbonyloxyandrost4-en-3-one in 76% yield after recrystallization from methanol. A solution of the 17β-methoxycarbonyloxyandrost4-en-3-one in toluene is pyrolyzed at 460° C., and the crude product is recrystallized from acetone at room temperature to give androsta-4,16-dien-3-one in 90% yield. The androsta-4,16-dien-3-one is reduced at −55° with lithium tris(1,2-dimethylpropyl)hydridoborate in tetrahydrofuran to give a mixture of androsta-4,16-dien-3β-ol and androsta-4,16-dien-3α-ol; and chromatography on silica gel using dichloromethane/ethyl acetate gives pure androsta-4,16-dien-3β-ol and pure androsta-4,16-dien-3α-ol, each in 48% yield. These may be recrystallized (androsta-4,16-dien-3β-ol from cyclohexane at room temperature and androsta-4,16-dien-3α-ol from petroleum ether at −30° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([CH3:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[CH:27]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([CH3:15])=[CH:10][C:9]=1[NH:16][C:23](=[O:22])[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=2)[CH:27]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Product: Cc1cc(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)c(NC(=O)OC(C)(C)C)cc1Cl

Procedure:
The title compound was prepared from (2-amino-5-chloro-4-methyl-phenyl)-carbamic acid tert-butyl ester (Example J21) (257 mg, 1.0 mmol) and 3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K2) (297 mg, 1.0 mmol) according to the general procedure M. Obtained as an off-white foam (370 mg, 77%).
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[CH2:11]([N:17]=[C:18]=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C(Cl)Cl>[CH2:11]([NH:17][C:18](=[O:19])[NH:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: N[C@@H](CO)c1ccccc1
Reactant: CCCCCCN=C=O
Solvent: ClCCl
Product: CCCCCCNC(=O)N[C@@H](CO)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(2R)-2-amino-2-phenylethanol (960 mg) was dissolved in methylene chloride (20 ml) and cooled to 0° C. To the mixture was added hexyl isocyanate (1.0 ml) and the mixture was stirred for 30 minutes at 0° C. and then stirred for 1 hour at room temperature. The solution was washed with 1N hydrochloric acid and a saturated aqueous solution of sodium chloride, successively, dried and concentrated under reduced pressure. The obtained crystal was washed with diethyl ether to give the title compound (930 mg) having the following physical data.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([O:16][CH3:17])[CH:15]=2)[NH:12][C:11](=[O:18])[C:10]23OCC[O:19]2)=[C:5]([CH3:23])[O:4][N:3]=1.C(O)(=O)C.Cl>CCOC(C)=O>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([O:16][CH3:17])[CH:15]=2)[NH:12][C:11](=[O:18])[C:10]3=[O:19])=[C:5]([CH3:23])[O:4][N:3]=1
Reactant: COc1cc(-c2c(C)noc2C)cc2c1NC(=O)C21OCCO1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc(-c2c(C)noc2C)cc2c1NC(=O)C2=O
Reaction time: 1.5 h

Procedure:
A solution of compound 5′-(3,5-dimethylisoxazol-4-yl)-7′-methoxyspiro[[1,3]dioxolane-2,3′-indolin]-2′-one (57 mg, 0.18 mmol), acetic acid (1 mL), and hydrogen chloride solution (4 mL) was heated to 90° C. After 1.5 h, the mixture was cooled, EtOAc (20 mL) was added, washed with brine (15 mL×3), dried over Na2SO4, concentrated in vacuo to give the expected compound 5-(3,5-dimethylisoxazol-4-yl)-7-methoxyindoline-2,3-dione as a dark red solid (50 mg, crude, 102%). This material was used in the next step without further purification. MS (ESI) m/e [M+1]+ 273.
Reaction SMILES: [CH3:1][C:2]([CH3:37])([CH3:36])[CH2:3][CH2:4][N:5]1[C:10](=[O:11])[C:9]([C:12]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][C:15]=3[S:14](=[O:28])(=[O:27])[N:13]=2)=[C:8]([OH:29])[CH:7]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:6]12.[C:38](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH3:1][C:2]([CH3:37])([CH3:36])[CH2:3][CH2:4][N:5]1[C:10](=[O:11])[C:9]([C:12]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([N:22]([CH3:38])[S:23]([CH3:26])(=[O:24])=[O:25])=[CH:21][C:15]=3[S:14](=[O:28])(=[O:27])[N:13]=2)=[C:8]([OH:29])[CH:7]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:6]12
Reactant: CC(C)(C)CCN1C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)C2CCCCCCC21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(c1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)C3CCCCCCC3N(CCC(C)(C)C)C1=O)N2)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.9 %

Procedure:
N-{3-[1-(3,3-Dimethyl-butyl)-4-hydroxy-2-oxo-1,2,4a,5,6,7,8,9,10,10a-decahydro-cycloocta[b]pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (prepared as described in Example 35b, 0.20 g, 0.36 mmol) was dissolved in N,N-dimethylformamide (12 mL). Potassium carbonate (0.10 g, 0.72 mmol) and iodomethane (0.025 mL, 0.40 mmol) were added sequentially. The reaction was stirred at 25° C. for 3 h. The reaction was quenched via the addition of 1.0 M aqueous hydrochloric acid solution (20 mL). The mixture was extracted with ethyl acetate (3×30 mL). The organic layers were combined and washed with saturated aqueous brine solution (20 mL) before they were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a golden oil. Purification by flash column chromatography (Teledyne Isco RediSep Flash Column 12 g; 0-20% ethyl acetate in dichloromethane) afforded the desired product, N-{3-[1-(3,3-dimethyl-butyl)-4-hydroxy-2-oxo-1,2,4a,5,6,7,8,9,10,10a-decahydro-cycloocta[b]pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-N-methyl-methanesulfonamide (0.018 g, 0.23 mmol, 9%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.00-1.02 (9H, m), 1.35-1.80 (14H, m), 2.87-2.88 (3H, m), 3.00-3.35 (2H, m), 3.36-3.38 (3H, m), 3.86-4.15 (2H, m), 7.20-7.28 (1H, m), 7.64-7.79 (2H, m). LC-MS (ESI) calcd for C26H38N4O6S2 566.73, found 567.4 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.C1C=C(Cl)C=C(C(OO)=[O:23])C=1.P([O-])([O-])([O-])=O>ClCCl>[CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N+:7]([O-:23])[CH:6]=[CH:5]2
Reactant: Cc1ccc2cnccc2c1[N+](=O)[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Product: Cc1ccc2c[n+]([O-])ccc2c1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
6-Methyl-5-nitroisoquinoline (100.0 g, 531 mmol) in Dichlormethane (1 L) was added to a 2 L 3-necked round bottomed flask and cooled to 5° C. Purified m-chloroperoxobenzoic acid (129 g, 749 mmol) was added to this stirred solution [m-CPBA was extracted with saturated Phosphate buffer pH 7.5 and DCM]. Initially with the addition of mCPBA the reaction exothermed, but then endothermed to 2° C. After 20 min, the contents in the flask solidified to a yellow/white solid and more DCM (300 mL) was added. The reaction was allowed to stir overnight at room temperature. DCM (2 L) was added and the mixture washed with 1 N NaOH (1 L), saturated sodium bicarbonate (1 L) and brine (1 L). The solution was dried over sodium sulfate and concentrated to give 6-methyl-5-nitroisoquinoline-N-oxide (81.7 g, 75%). MS (M+H)+ 205.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]([C:16]#[N:17])[C:13]([NH2:15])=[O:14]>O1CCOCC1>[NH2:17][C:16]1[NH:1][C:2]2[C:3]([C:12]=1[C:13]([NH2:15])=[O:14])=[CH:4][CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=2
Reactant: N#CC(C(N)=O)c1ccc(C(F)(F)F)cc1N
Solvent: C1COCCO1
Product: NC(=O)c1c(N)[nH]c2cc(C(F)(F)F)ccc12
Temperature: 100 °C
Reaction time: 36 h
Yield: 51 %

Procedure:
1,4-Dioxane (40 mL) was added to 2-(2-amino-4-trifluoromethylphenyl)-2-cyanoacetamide (Reference compound 21-1, 0.98 g, 4.0 mmol), and the mixture was stirred at 100° C. for 36 hours. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography to give the title reference compound (0.50 q) as a brown solid (yield 51%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[S:5][C:6]=1[C:7]([NH2:9])=[O:8].[CH:16]1([C:19](Cl)=O)[CH2:18][CH2:17]1>ClCCl>[CH:16]1([C:19]2[NH:1][C:2]3[N:3]=[C:4]([N:10]4[CH2:15][CH2:14][O:13][CH2:12][CH2:11]4)[S:5][C:6]=3[C:7](=[O:8])[N:9]=2)[CH2:18][CH2:17]1
Reactant: NC(=O)c1sc(N2CCOCC2)nc1N
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Product: O=c1nc(C2CC2)[nH]c2nc(N3CCOCC3)sc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-2-(4-morpholinyl)-1,3-thiazole-5-carboxamide (0.15 g, 0.657 mmol) in Dichloromethane (DCM) (2 ml) at 0° C. was added cyclopropanecarbonyl chloride (0.075 ml, 0.821 mmol) dropwise. The mixture was stirred at room temperature overnight, and then concentrated. To the resulting residue was added ethanol (1 mL) and 6N NaOH (0.8 mL). The mixture was stirred at room temperature for 3 h, and then acidified with 6N HCl (0.7 mL) to pH ˜5. The precipitate was collected, rinsed with water, and dried in vacuo to furnish crude 5-cyclopropyl-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one. (90 mg, 49%); LC/MS: MS (ES) m/e 279 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99-1.06 (m, 4H), 1.95 (ddd, J=10.6, 2.0, 1.8 Hz, 1H) 3.53-3.59 (m, 4H) 3.68-3.76 (m, 4H) 12.56 (br, s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH3:27])[C:12]([CH3:26])=[C:13]([CH2:15][NH:16][C:17]3[C:18]([F:25])=[C:19]([OH:24])[CH:20]=[CH:21][C:22]=3[F:23])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:35][C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37].O>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH3:27])[C:12]([CH3:26])=[C:13]([CH2:15][NH:16][C:17]3[C:18]([F:25])=[C:19]([CH:20]=[CH:21][C:22]=3[F:23])[O:24][CH2:35][C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)OC(=O)CBr
Reactant: Cc1cc(-c2ccc(F)c(F)c2)cc(CNc2c(F)ccc(O)c2F)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(-c2ccc(F)c(F)c2)cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2F)c1C
Reaction time: 0.17 h
Yield: 80.8 %

Procedure:
To a solution of 3-[[5-(3,4-difluorophenyl)-2,3-dimethyl-phenyl]methylamino]-2,4-difluoro-phenol (70 mg, 0.19 mmol, 1.0 eq) in acetone (2 mL) was added Cs2CO3 (90 mg, 0.28 mmol, 1.5 eq) at room temperature. The reaction mixture was stirred for 10 min then isopropyl bromoacetate (40 mg, 0.22 mmol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for a further 30 min then water was added and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether:EtOAc, 100:0 to 20:1) to give the title compound as a colorless oil (73 mg, 82%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)[CH3:2].[CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]([CH3:34])[CH3:33])[C:27]=1[N:35]=[C:36]=[O:37])([CH3:25])[CH3:24]>>[CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]([CH3:33])[CH3:34])[C:27]=1[NH:35][C:36](=[O:37])[N:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[CH:13][CH:12]=1)([CH3:24])[CH3:25]
Reactant: CCc1ccc(NCc2ccc(N3CCOCC3)cc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CCc1ccc(N(Cc2ccc(N3CCOCC3)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 1 using (4-ethylphenyl)(4-morpholinophenylmethyl)amine (0.63 g) and 2,6-diisopropylphenyl isocyanate (0.46 mL) as starting materials, N′-(2,6-diisopropylphenyl)-N-(4-ethylphenyl)-N-(4-morpholinophenylmethyl)urea (0.45 g) was obtained. melting point: 159–161° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[NH:25]1[CH2:28][CH2:27][C:26]1=[O:29]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:25]4[CH2:28][CH2:27][C:26]4=[O:29])=[CH:3][C:4]=3[F:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: O=C1CCN1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCC4=O)cc3F)CC2)c(C)c1
Yield: 32.1 %

Procedure:
Using (4-bromo-2-fluorophenyl) [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 114 and 2-azetidinone (30 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (47 mg) was obtained.
Reaction SMILES: [CH:1](=[O:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([Mg]Br)[CH2:9][CH2:10][CH3:11].[NH4+].[Cl-]>C1COCC1>[O:6]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:1]([OH:7])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCC[Mg]Br
Reactant: O=Cc1ccco1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCC(O)c1ccco1
Temperature: 25 °C

Procedure:
Freshly distilled furfural (233.5 g, 2.43 mol) was dissolved in 200 mL freshly distilled THF and added dropwise to a solution of butylmagnesium bromide (2.0 M in THF, 1460 mL, 2.92 mol) at 0° C. under dry nitrogen. After the addition was complete, the mixture was allowed to warm to room temperature overnight. The reaction was recooled to 0° C. and carefully poured into 2 L of cold sat. NH4Cl. The layers were separated, and the aqueous phase was extracted with ether. The combined organic layers were washed with saturated NaCl, dried over MgSO4, evaporated, and vacuum distilled to give 325.6 g (87%): bp 72°-73° C. (0.6 mmHg); 1H NMR (300 MHz, CDCl3) d 7.38 (1H, dd J=1 Hz), 6.33 (1H, m), 6.22 (1H, dd, J=3 Hz), 4.67 (1H, t, J=6 Hz), 2.9 (3H, m), 1.35 (4H, m), 0.90 (3H, t, J=7 Hz); mass spectrum (FAB): 170 (M+NH4).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]=1[N+:19]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N

Procedure:
Prepared from (2-nitro-4-thiophen-2-yl-phenyl)-carbamic acid tert.-butyl ester (Example C3) by catalytic hydrogenation with Pd/C according to the general procedure G (method a). Obtained as a beige powder (151 mg).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][N:7]=1.[IH:12].[OH-].[Na+]>O>[I:12][C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nc2c(Cl)nccn2n1
Reactant: I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc2c(I)nccn2n1
Temperature: 50 °C
Reaction time: 16 h
Yield: 92.7 %

Procedure:
8-Chloro-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine (5.500 g; 32.43 mmol) is suspended in water (40.0 ml) before HI (67%, 21.855 ml; 194 mmol) is added. The mixture is stirred at 50° C. for 16 h and monitored by HPLC. The mixture is cooled to Rt, diluted with water. After adding NaOH till pH 14 is reached, the resulting suspension is cooled to 0° C. and all solids are filtered off giving 8-Iodo-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine (7.850 g; 30.074 mmol) as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.Cl.[NH:15]1[CH2:20][CH2:19][C:18]2([CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:21]2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:15]3[CH2:20][CH2:19][C:18]4([CH:29]=[CH:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[O:21]4)[CH2:17][CH2:16]3)=[CH:7][CH:6]=2)[S:12][N:11]=1
Reactant: C1=CC2(CCNCC2)Oc2ccccc21
Reactant: Cc1nsc(-c2ccc(Cl)nn2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nsc(-c2ccc(N3CCC4(C=Cc5ccccc5O4)CC3)nn2)n1

Procedure:
The object product (111 mg, 41%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-thiadiazol-5-yl)pyridazine (150 mg), spiro[chromene-2,4′-piperidine] hydrochloride (190 mg) and potassium carbonate (274 mg).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[N:6][CH:7]=[C:8]([CH:12]=2)[C:9]([OH:11])=O)[CH2:3][CH2:2]1.[N:19]1([NH2:25])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[N:6][CH:7]=[C:8]([CH:12]=2)[C:9]([NH:25][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:11])[CH2:2][CH2:3]1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CC2)c1
Reactant: NN1CCOCC1
Product: O=C(NN1CCOCC1)c1cnc(OCC(F)(F)F)c(C2CC2)c1

Procedure:
The title compound was synthesized in analogy to the procedure described in Example 34 c), using 5-cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (example 34b) and morpholin-4-ylamine as starting materials (CAN 4319-49-7); MS (ESI) 346.4 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][O:14][C:15]3[CH:24]=[C:23]4[C:18]([CH2:19][CH2:20][N:21]([C:25](=[S:27])[NH2:26])[CH2:22]4)=[CH:17][CH:16]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Cl.[CH2:29](O)C.CI>CO>[CH3:29][S:27][C:25]([N:21]1[CH2:20][CH2:19][C:18]2[C:23](=[CH:24][C:15]([O:14][CH2:13][CH:10]3[CH2:9][CH2:8][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH2:12][CH2:11]3)=[CH:16][CH:17]=2)[CH2:22]1)=[NH:26]
Reactant: NC(=S)N1CCc2ccc(OCC3CCN(c4ccncc4)CC3)cc2C1
Reactant: CCO
Agent: Cl
Solvent: CI
Solvent: CO
Product: CSC(=N)N1CCc2ccc(OCC3CCN(c4ccncc4)CC3)cc2C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
7-[1-(Pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carbothioamide (200 mg) was treated with hydrogen chloride—ethanol solution. To a suspension of the obtained residue in methanol (6 ml) was added methyl iodide (0.1 ml), and the mixture was stirred at 60° C. for 2 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was dissolved in water and ethanol and neutralized with ion-exchange resin (IRA-410). This was filtrated and the filtrate was concentrated and dried under reduced pressure to give the title compound (200 mg).