Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15](O)=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C(Cl)(=O)C(Cl)=O.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)O)CCN(C)C1
Reactant: CN1CCNCC1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CC(=O)N2CCN(C)CC2)CCN(C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 13.4 %

Procedure:
2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid (0.57 g, 2.2 mmol) was taken in DCM, cooled to 0° C., oxalyl chloride (0.228 mL, 2.6 mmol) was added, followed by the addition of DMAP (catalytic amount) and stirred for 1 h at RT. Solvent was evaporated under nitrogen, N-methyl piperazine (0.269 mg, 24 mmol) and DMAP (80 mg) in DCM was added slowly drop wise at RT (under nitrogen) and stirred at RT for 30 min. Reaction mixture was quenched with water, neutralized with 10% NaHCO3 solution and extracted with ethyl acetate. Organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. Crude product was purified by reverse phase chromatography to afford 100 mg of 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(4-methylpiperazin-1-yl)ethanone as TFA salt.
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)[CH2:3][CH2:4][CH2:5][CH3:6].[C:14](OC(=O)C)(=[O:16])[CH3:15].N1C=CC=CC=1.CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:14]([O:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=1)[CH2:3][CH2:4][CH2:5][CH3:6])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCC(O)c1cccc(C)c1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCC(OC(C)=O)c1cccc(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
65.4 g of 3-(1-hydroxypentyl)toluene are dissolved in 500 ml of absolute methylene chloride at 0° C., and 104 ml of acetic anhydride, 89 ml of pyridine and 1 g of dimethylaminopyridine are added in succession. The reaction solution is stirred at 0° C. for 1 hour and at 25° C. for 2 hours and then poured onto 1 l of ice-water. After the organic phase has been separated off, it is extracted 3 times with 200 ml of methylene chloride each time. The organic phases are washed 3 times with 200 ml of 2N HCl each time, 3 times with 200 ml of saturated NaHCO3 each time and twice with 200 ml of water each time, dried over magnesium sulphate and concentrated in vacuo. The residue is distilled at 95° C./0.1 mm (bulb tube).
Reaction SMILES: [CH3:1][C:2]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:3]=1[O:4][CH2:5][C@H:6]([OH:41])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=1[C:16]1[NH:27][C:26]2[C:18](=[CH:19][C:20]3[CH2:21][N:22]([CH:29]4[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH2:31][CH2:30]4)[C:23](=[O:28])[C:24]=3[CH:25]=2)[N:17]=1.[CH3:47][C:48](O)=[O:49]>>[CH3:1][C:2]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:3]=1[O:4][CH2:5][CH:6]([O:41][C:48](=[O:49])[CH3:47])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=1[C:16]1[NH:27][C:26]2[C:18]([N:17]=1)=[CH:19][C:20]1[CH2:21][N:22]([CH:29]3[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH2:31][CH2:30]3)[C:23](=[O:28])[C:24]=1[CH:25]=2
Reactant: CC(=O)O
Reactant: Cc1ccc(OC[C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCN(CCS(C)(=O)=O)CC2)C4)c(C)c1
Product: CC(=O)OC(CNc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C1CCN(CCS(C)(=O)=O)CC1)C3)COc1ccc(C)cc1C

Procedure:
A solution of 2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-[1-(2-methanesulfonyl-ethyl)-piperidin-4-yl]-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one (65 mg, 0.1 mmol) in HOAc (20 mL) was refluxed for 32 h and was evaporated. The residue was diluted with a mixed solvent of DCM/MeOH (1:5), basified with 28% aqueous NH4OH solution and concentrated. Chromatography of the residual crude with CH2Cl2/MeOH/28% aqueous NH4OH (110:10:1) followed by HPLC re-purification afforded the title compound in TFA salt form (8.69 mg, 11%). 1H NMR (DMSO-d6) δ 1.99-2.12 (4H), 2.05 (s, 3H, CH3), 2.16 (s, 3H, CH3), 2.22 (s, 3H, CH3), 3.15 (s, 3H, CH3), 3.25 (m, 2H), 3.52 (m, 2H), 3.60-3.78 (5H), 3.90 (s, 1H), 4.10-4.38 (4H), 4.49 (br s, 2H), 5.43 (br s, 2H, NH), 6.28 (d, J=8 Hz, 1H), 6.84 (d, J=6 Hz, 1H), 6.94 (d, J=6 Hz, 1H), 6.99 (s, 1H), 7.40 (m, 1H), 7.80 (br s, 1H), 9.80 (br s, 1H), 11.14 (br s, NH), 11.33 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 691.7 (MH+).
Reaction SMILES: [C:1]([OH:32])(=[O:31])[CH2:2][CH2:3][C@H:4]([NH:8][C:9]([C:11]1[CH:30]=[CH:29][C:14]([NH:15][CH2:16][CH:17]2[NH:28][C:27]3[C:25](=[O:26])[NH:24][C:22]([NH2:23])=[N:21][C:20]=3[NH:19][CH2:18]2)=[CH:13][CH:12]=1)=[O:10])[C:5]([OH:7])=[O:6].Cl>>[C:1]([OH:32])(=[O:31])[CH2:2][CH2:3][C@H:4]([NH:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([NH:15][CH2:16][C@H:17]2[NH:28][C:27]3[C:25](=[O:26])[NH:24][C:22]([NH2:23])=[N:21][C:20]=3[NH:19][CH2:18]2)=[CH:29][CH:30]=1)=[O:10])[C:5]([OH:7])=[O:6]
Reactant: Nc1nc2c(c(=O)[nH]1)NC(CNc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)CN2
Agent: Cl
Product: Nc1nc2c(c(=O)[nH]1)N[C@H](CNc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)CN2

Procedure:
One half of the mother liquor is precipitated with 1.1 g of ethanol, giving enriched amorphous (6R) tetrahydrofolic acid with a chemical content of 63.3% and a (6R) percentage of 75.9, while in the other half of the mother liquor the pH is rapidly brought to 3.5 using 6.3 g of hydrochloric acid, resulting in enriched, amorphous (6R)-tetrahydrofolic acid with a chemical content of 64.8% and a (6R) percentage of 75.9.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:20])[CH:11]=[C:12]([CH:17]([F:19])[F:18])[N:13]([CH2:15][CH3:16])[CH:14]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[F:19][CH:17]([F:18])[C:12]1[N:13]([CH2:15][CH3:16])[CH:14]=[C:9]([OH:8])[C:10](=[O:20])[CH:11]=1
Reactant: CCn1cc(OCc2ccccc2)c(=O)cc1C(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCn1cc(O)c(=O)cc1C(F)F
Yield: 64.2 %

Procedure:
A mixture of 5-benzyloxy-2-difluoromethyl-1-ethyl-1H-pyridin-4-one (2.00 g, 7.16 mmol) and 10% Pd/C (200 mg) in methanol (75 mL) was hydrogenated under 15.0 psi pressure in a hydrogen atmosphere in a Parr apparatus for 23 min. The reaction mixture was worked up as described above. The title compound (0.87 g, 64%) was obtained as an off-white solid. HPLC purity (peak area percent) of the compound is 97.7% at λ=280 nm using HPLC Method 1 as described above. 1H NMR (400 MHz, DMSO-D6) δ (ppm): 7.61 (s, 1H), 7.15 (t, J=52.7 Hz, 1H, CF2H), 6.46 (s, 1H), 4.03 (q, J=7.0 Hz, 2H, N—CH2), 1.31 (t, J=7.1 Hz, 3H, CH3); MS-ESI (m/z): 190.2 [M+1]+, 142.2 (100%); Anal. Calcd. for C8H9F2NO2: C, 50.80; H, 4.80; N, 7.40%. Found: C, 50.64; H, 4.85; N, 7.38%.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])=[O:7].[OH-].[K+].Br[CH2:22][CH:23]([CH3:25])[CH3:24]>CS(C)=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])=[O:7]
Reactant: CC(C)CBr
Reactant: Cc1c(NC(=O)c2ccco2)cccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1c(N(CC(C)C)C(=O)c2ccco2)cccc1[N+](=O)[O-]

Procedure:
The N-(2-furoyl)-2-methyl-3-nitroaniline (1 mmol) in DMSO was treated with potassium hydroxide (2.0 mmol) and 1-bromo-2-methylpropane (1.1 mmol) at 25° C. for 12 hr. Extraction and chromatography afforded N-(2-furoyl)-N-isobutyl-2-methyl-3-nitroaniline as a yellow syrup. TLC: Rf=0.40, 30% EtOAc-hexane.
Reaction SMILES: [Cl-].[Li+].[CH3:3][C:4]1([CH3:26])S[C@@H:7]2[C@H:9]([NH:12][C:13]([CH2:15][O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:14])[C:10](=[O:11])[N:6]2[C@H:5]1[C:23]([OH:25])=[O:24].[CH3:27]O>C(O)(C)(C)C.[Pt]>[CH3:27][O:25][C:23]([C:5]([N:6]1[C:10](=[O:11])[C@@H:9]2[C@H:7]1[O:14][C:13]([CH2:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[N:12]2)=[C:4]([CH3:26])[CH3:3])=[O:24]
Reactant: CO
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: [Pt]
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(C)(C)O
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H]2N=C(COc3ccccc3)O[C@H]21
Reaction time: 2.67 h
Yield: 80 %

Procedure:
Lithium chloride (6.7 mg) was dissolved in a mixture of 2 ml of methanol and 0.5 ml of tert-butyl alcohol. Thereto was added 72 mg of methyl ester of penicillin V to prepare an electrolyte. Electrolysis was performed at a temperature of less than -70° C. and 10 to 15 V for 160 minutes (5 F) by dipping platinum electrodes (1 cm2) in the electrolyte and passing constant current of 10 mA through the electrolyte. Thereafter, the reaction mixture was stirred at less than -10° C. for about 30 minutes and extracted with ethyl acetate. The extract was treated in the same manner as in Example 1, affording 53 mg of contemplated compound in 80% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[N:6]=[CH:5][N:4]=1.[CH3:15][S:16]([C:19]1[CH:20]=[C:21]([C:31](O)=[O:32])[C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)(=[O:18])=[O:17]>>[CH3:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:21]([C:31]([N:12]2[CH2:13][CH2:14][N:9]([C:7]3[N:8]=[C:3]([O:2][CH3:1])[N:4]=[CH:5][N:6]=3)[CH2:10][CH2:11]2)=[O:32])[CH:20]=1)(=[O:17])=[O:18]
Reactant: COc1ncnc(N2CCNCC2)n1
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)O)c1
Product: COc1ncnc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3-c3ccccc3)CC2)n1

Procedure:
The tide compound was prepared according to the procedure E described for Example 9 from 2-Methoxy-4-piperazin-1-yl-[1,3,5]triazine [59215-45-1] and 4-Methanesulfonyl-biphenyl-2-carboxylic acid (Example V). MS (ISP): 454.5 MH+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][OH:8])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:12][C:13]1[N:14]=[N:15][C:16](Br)=[CH:17][CH:18]=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:9])[CH2:7][O:8][C:16]1[N:15]=[N:14][C:13]([Br:12])=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Brc1ccc(Br)nn1
Reactant: CC(C)(C)OC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(Br)nn1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
277.8 mg (2.1 mmol) of hydroxyacetic acid tert-butyl ester and 100.9 mg of sodium hydride (55% in mineral oil) in 15 ml of DMF were stirred at room temperature for 30 min. Then 500 mg (2.1 mmol) of 3,6-dibromopyridazine were added, and the reaction mixture was stirred at 60° C. for 2 h. After evaporation to dryness, the residue was stirred with ethyl acetate, the solution filtered, evaporated, and the crude product (450 mg) directly employed in the subsequent step.
Reaction SMILES: [NH2:1][C@H:2]([C@H:4]1[CH2:8][N:7]([C@H](C2C=CC=CC=2)C)[C:6](=[O:17])[CH2:5]1)C.F[C:19](F)(F)C(O)=O>>[NH2:1][CH2:2][C@@H:4]1[C@@H:8]([CH3:19])[NH:7][C:6](=[O:17])[CH2:5]1
Reactant: O=C(O)C(F)(F)F
Reactant: C[C@H](N)[C@@H]1CC(=O)N([C@@H](C)c2ccccc2)C1
Product: C[C@H]1NC(=O)C[C@@H]1CN
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
20 mg (R)-4-((S)-1-aminoethyl)-1-((S)-1-phenylethyl)pyrrolidine-2-one (I.22) was dissolved in trifluoroacetic acid and stirred for 90 min in the microwave at 150° C. The mixture was concentrated and used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[CH2:9]([Li])[CH:10]=[CH2:11].O>C1COCC1>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:8])[CH2:11][CH:10]=[CH2:9])=[CH:3][CH:2]=1
Reactant: [Li]CC=C
Reactant: O=Cc1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: C=CCC(O)c1ccncc1
Temperature: 0 °C
Yield: 63 %

Procedure:
4.75 g (50 mmol) of pyridine-4-carboxaldehyde was dissolved in 50 ml THF and cooled to 0° C. Allyl lithium was then added with stirring until the mixture turned the dark color characteristic of the allyl lithium solution. After stirring for an additional 5 minutes, water was slowly added at 0° C. until two phases formed and all precipitate was dissolved. The THF layer was separated, dried over MgSO4, and evaporated in vacuo to an oil. Flash chromatography yielded 4.69 g (63%) of product as an oil. 1H NMR (CDCL3): 8.5 and 7.3 (4H, pyridyl), 5.8 and 5.15 (3H, vinyl), 4.75 (1H, CHOH), 3.6 (1H, OH), and 2.5 (2H, CH2) ppm.
Reaction SMILES: O[CH:2]=[C:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=O.Cl.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][NH2:23])=[CH:18][CH:17]=1.Cl>C(O)C>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:4]3[C:5]4[C:10]([CH2:11][C:3]=3[CH:2]=[N:23]2)=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:18][CH:17]=1
Reactant: COc1ccc(NN)cc1
Reactant: O=C1C(=CO)Cc2ccccc21
Agent: Cl
Solvent: CCO
Product: COc1ccc(-n2ncc3c2-c2ccccc2C3)cc1

Procedure:
2-Hydroxymethylene inden-l-one (Example 1(ii) (a) (4.0 g; 25 mmol), p-methoxyphenyl hydrazine hydrochloride (Aldrich) (4.41 g; 25.25 mmol), 10 M hydrochloric acid (1 cm3) and ethanol (30 cm3), were heated under reflux, for 21 hours. After cooling, the mixture was concentrated in vacuo and the residue dissolved in dichloromethane, then washed with 2M NaOH, dried, filtered and concentrated in vacuo. Purification by column chromatography [Eluant: (dichloromethane: ethanol: ammonia (200:8:1)] Kugelrohr distillation (170° C.; 0.02 mmHg) and recrystallisation (ethanol) afforded needle shaped crystals, m.p. 102-103° C.
Reaction SMILES: [C:1]1(=O)[CH2:7][CH2:6]C[CH2:4][CH2:3][CH2:2]1.[CH:9](OC)([O:12][CH3:13])[O:10][CH3:11].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:11][O:10][C:9]1([O:12][CH3:13])[CH2:4][CH2:3][CH2:2][CH2:1][CH2:7][CH2:6]1
Reactant: COC(OC)OC
Reactant: O=C1CCCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC1(OC)CCCCCC1
Temperature: 27.5 °C
Reaction time: 1.5 h

Procedure:
To a flask with reflux condenser (5 g) cycloheptanone, and 10 ml methanol was taken. (10 ml) (2.0 eq.) trimethyl orthoformate and several crystals of p-toluenesulfonic acid were added in to the reaction mixture and the mixture was stirred at 25-30° C. to about 1.5 hrs. Color of the reaction mixture became pale yellow. Reaction was monitored by TLC. Then remove the methanol on rotavapour. Water was added in to the reaction mixture and extract with ethyl acetate. Organic layer was washed with 5% sodium bicarbonate solution then water and brine solution. Concentrate it on rotavapor yellow colored oily product obtained.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:18])[CH:11]=[C:12]([CH:15]([F:17])[F:16])[NH:13][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[F:17][CH:15]([F:16])[C:12]1[NH:13][CH:14]=[C:9]([OH:8])[C:10](=[O:18])[CH:11]=1
Reactant: O=c1cc(C(F)F)[nH]cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=c1cc(C(F)F)[nH]cc1O
Reaction time: 0.25 h
Yield: 88.7 %

Procedure:
5-Benzyloxy-2-difluoromethyl-1H-pyridin-4-one (300 mg, 1.19 mmol) was dissolved in methanol (20 mL) to give clear a yellow solution. Pd/C (55 mg) was added at RT. After purging with hydrogen gas, the mixture was hydrogenated at 50 psi H2 pressure for 15 min. The reaction mixture was filtered through a short pre-treated CELITE™ bed. The filtrate was collected, and the solvent was removed in vacuo to give the title compound as an off-white solid (170 mg, 88%) with an HPLC purity (peak percent area) of 98.8%. HPLC Method 1 is used (see Example 1). 1H NMR (300 MHz, DMSO-D6) (ppm): 10.3 (br s, 1H), 7.97 (s, 1H), 6.98 (s, 1H), 6.72 (t, J=55.4 Hz, 1H); MS (m/z) 162.2 [M+1]+, 142.1 (100%).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([CH3:6])([OH:5])[CH3:4].[O-:13][C:14]#[N:15].[K+]>O>[OH:5][C:3]([CH3:6])([CH3:4])[C@@H:2]([NH:1][C:14]([NH2:15])=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(O)[C@@H](N)c1ccccc1
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(O)[C@@H](NC(N)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-1-amino-2-methyl-1-phenylpropan-2-ol (2.0 g, 10 mmol) in H2O (10 mL) was added potassium cyanate (0.85 g, 12 mmol) and the contents were stirred at ambient temperature for 2 h. The solid thus obtained was filtered and washed successively with H2O (2×5 mL) and dried in air to afford (S)-1-(2-hydroxy-2-methyl-1-phenylpropyl)urea. 1H NMR (400 MHz, DMSO-d6) δ 7.25-7.15 (m, 5H), 6.52 (d, J=9.2 Hz, 1H), 5.50 (s, 2H), 4.50 (s, 1H), 4.41 (d, J=9.2 Hz, 1H), 1.10 (s, 3H), 0.93 (s, 3H). Anal. Calcd. C11H16N2O2 208.3. Found 209.2 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.CC1(C)[O:30][CH:29]([CH2:31][NH2:32])[CH2:28][O:27]1>>[CH3:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([N:13]1[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:24])[CH2:15][CH2:14]1)[CH:3]=[C:2]2[NH:32][CH2:31][CH:29]([OH:30])[CH2:28][OH:27]
Reactant: CC1(C)OCC(CN)O1
Reactant: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)cc(NCC(O)CO)c2c1

Procedure:
The title compound was prepared in analogy to Example 32-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in analogy to the one in Example 18-1) and 1-(2,2-dimethyl-1,3-dioxolan-4-yl)methanamine. MS obsd. (ESI+) [(M+H)+] 412, 1H NMR (400 MHz, CD3OD) δ ppm 7.78 (d, J=7.33 Hz, 1 H), 7.74 (dd, J=7.58, 1.26 Hz, 1 H), 7.62 (s, 1 H), 7.55-7.39 (m, 3 H), 7.33 (dd, J=8.34, 1.52 Hz, 1 H), 6.13 (s, 1 H), 5.24 (dd, J=16.04, 2.91 Hz, 2 H), 4.82 (d, J=7.58 Hz, 1 H), 4.76 (d, J=14.15 Hz, 2 H), 4.06-3.83 (m, 1 H), 3.75-3.63 (m, 2 H), 3.63-3.52 (m, 1 H), 3.45 (d, J=3.79 Hz, 2 H), 3.37 (td, J=6.88, 4.42 Hz, 1 H), 2.43 (s, 3 H).
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]([NH:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH2:27])[CH:23]=3)[N:18]=2)[CH2:8]1>>[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]([NH:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH:27][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH:23]=3)[N:18]=2)[CH2:8]1
Reactant: Nc1ccc2nc(NC3COc4ccccc43)ccc2c1
Reactant: CC(C)N=C=O
Product: CC(C)NC(=O)Nc1ccc2nc(NC3COc4ccccc43)ccc2c1

Procedure:
The title compound was prepared in accordance with the general method described in example 3 from isopropyl isocyanate and N2-(2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine; MS: m/e=363.3 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11](O)=[O:12])[N:8]([CH2:14][C:15]2[CH:19]=[C:18]([C:20]3[S:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[O:17][N:16]=2)[N:7]=1)=[O:5])[CH3:2].CO>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][OH:12])[N:8]([CH2:14][C:15]2[CH:19]=[C:18]([C:20]3[S:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[O:17][N:16]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C(=O)O)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1cc(CO)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Temperature: 40 °C

Procedure:
To a solution of 4 g 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-pyrazole-3,5-dicarboxylic acid 3-ethyl ester in 50 ml THF 26 ml BH3*THF (1M in THF) were added slowly at RT. Then the mixture was warmed to 40° C. for 6 h. After cooling to 0° C. 20 ml MeOH were added cautiously and the mixture was concentrated to dryness. The residue was again codistilled with 20 ml of MeOH and then purified by chromatography on silica gel eluting with n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.9 g.
Reaction SMILES: [F:1][C:2](=[C:11]([F:13])[F:12])[CH2:3][CH2:4][S:5][C:6]1[O:7][CH:8]=[CH:9][N:10]=1.ClC1C=CC=C(C(OO)=[O:22])C=1>ClCCl>[F:1][C:2](=[C:11]([F:12])[F:13])[CH2:3][CH2:4][S:5]([C:6]1[O:7][CH:8]=[CH:9][N:10]=1)=[O:22]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)=C(F)CCSc1ncco1
Solvent: ClCCl
Product: O=S(CCC(F)=C(F)F)c1ncco1
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.9 %

Procedure:
1.0 g of 2-(3,4,4-trifluoro-3-butenylthio)oxazole and 1.5 g of m-chloroperbenzoic acid (purity about 70%) were added to 50 ml of dichloromethane and stirred at room temperature for 20 hours. The reaction mixture was washed with 50 ml of 1N aqueous solution of sodium hydroxide and dried with magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by column chromatography (eluent: ethyl acetate:dichloromethane=1:4) to obtain 1.0 g of 2-(3,4,4-trifluoro-3-butenylsulfinyl)oxazole as colorless oil (yield 92.9%, n20D=1.4820).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[C:7]([S:15]([CH3:17])=[O:16])=[N:8][C:9]([CH3:14])=[CH:10][C:11]=1[S:12][CH3:13])=[O:4].[N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[NH:20][C:19]=1[S:27]([CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:28].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[NH:20][C:19]=1[S:27]([CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][N:34]([CH2:2][C:3]([NH:5][C:6]2[C:7]([S:15]([CH3:17])=[O:16])=[N:8][C:9]([CH3:14])=[CH:10][C:11]=2[S:12][CH3:13])=[O:4])[CH2:33][CH2:32]1)=[O:28]
Reactant: CSc1cc(C)nc(S(C)=O)c1NC(=O)CBr
Reactant: O=S(CCN1CCNCC1)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cc(C)nc(S(C)=O)c1NC(=O)CN1CCN(CCS(=O)c2nc3ccccc3[nH]2)CC1
Reaction time: 12 h
Yield: 49.6 %

Procedure:
To a solution of this sulfoxide (21.4 mg, 0.063 mmol) in DMF (1 ml) were added 1-[2-(benzimidazol-2-ylsulfinyl)ethyl]piperazine (17.6 mg, 0.063 mmol) obtained in Example 146 and potassium carbonate (17.5 mg, 0.127 mmol), and stirred for 12 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution successively, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by a silica gel preparative thin layer chromatography (developing solvent; chloroform:sat. ammonia methanol=5:1) to provide 16.7 mg (yield 49%) of the desired compound as pale yellow oil. IR (KBr) cm−1: 3190, 2993, 1674, 1571, 1484. 1H-NMR (CD3OD) δ: 2.15-2.65 (14H, m), 2.63-2.84 (5H, m), 2.89 (2H, s), 3.34 (1H, dt, J=12.0, 6.0 Hz), 3.43 (1H, dt, J=12.0, 6.0 Hz), 7.22 (1H, s), 7.23-7.28 (2H, m), 7.55-7.59 (2H, m).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[NH:13][C:12](=O)[C:11]2=[C:15](C)[N:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[N:10]2[N:9]=1.[CH3:29]OCCOC>>[CH3:29][C:8]1([NH2:7])[NH:13][CH2:12][C:11]2=[CH:15][N:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[N:10]2[NH:9]1
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)n2nc(N)[nH]c(=O)c12
Reactant: COCCOC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC1(N)NCc2cnc(-c3cccc(C(F)(F)F)c3)n2N1
Temperature: 0 °C

Procedure:
Lithium aluminum hydride was added in portions to a stirring solution of 2-amino-5-methyl-7-[3-(trifluoromethyl)phenyl]imidazo[5,1-f][1,2,4]triazin-4(3H)-one (Intermediate 43) (2.0 g, 6.47 mmol) in DME (50 mL) at rt. The resultant mixture was then heated to reflux for 2 h. The reaction mixture was then cooled to 0° C. and carefully quenched with H2O. After extraction into EtOAc., the combined organic extracts were dried (MgSO4), filtered, and concentrated. Purification of the residue by chromatography afforded 2-methyl-7-[3-(trifluoromethyl)phenyl]-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-amine (0.60 g) as a pale yellow solid. 1H NMR (DMSO-d6): δ8.67-8.60 (m, 1H), 8.54 (s, 1H), 7.61-7.54 (m, 2H), 6.55 (s, 1H), 5.50 (s, 2H), 4.35 (s, 2H), 2.06 (s, 3H). MS m/z 294 (M−1).