Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].[CH2:18](Br)[CH2:19][CH2:20][CH3:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]([F:17])([F:15])[F:16]
Reactant: FC(F)(F)c1cc(C2CCNCC2)ccc1Cl
Reactant: CCCCBr
Product: CCCCN1CCC(c2ccc(Cl)c(C(F)(F)F)c2)CC1

Procedure:
Beginning with 4-(4-Chloro-3-trifluoromethyl-phenyl)-piperidine and 1-butylbromide, the title compound was recovered by the procedure described in Example 2. MS m/z (rel. intensity, 70 eV) 319 (M+, 6), 278 (31), 277 (19), 276 (bp), 70 (30).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:21])[N:4]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:13]([NH:15][CH3:16])=[O:14])[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O.[F:35][C:36]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:37]=1[CH2:38]Br>O>[F:35][C:36]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:37]=1[CH2:38][O:8][C:7]1[CH:6]=[C:5]([CH3:9])[N:4]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:13]([NH:15][CH3:16])=[O:14])[C:3](=[O:21])[C:2]=1[Br:1]
Reactant: CNC(=O)c1ccc(C)c(-n2c(C)cc(O)c(Br)c2=O)c1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CNC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 30 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
3-(3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-N,4-dimethylbenzamide (9) (1 kg, 2.85 moles), potassium carbonate (0.43 kg, 3.11 moles), 1-methyl-2-pyrrolidinone (4.0 L) and 2,4-difluorobenzyl bromide (0.71 kg, 3.42 moles) were mixed together and heated at 30° C. for 2 hours. The reaction mixture was diluted with water (12.5 L) over a period of 30 to 60 minutes and then stirred for 30 to 60 minutes. The product was filtered and washed with water. (−)-3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)-N,4-dimethylbenzamide (1) (1.36 kg, 95% purity, greater than 99% ee) was obtained.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[C:21]([Cl:22])=[C:20]([Cl:23])[C:10]2[S:11][C:12]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:13][C:9]=2[CH:8]=1)C.[OH-].[Na+]>C(O)C>[Cl:22][C:21]1[C:7]([O:6][CH2:5][C:4]([OH:24])=[O:3])=[CH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)[S:11][C:10]=2[C:20]=1[Cl:23]
Reactant: CCOC(=O)COc1cc2cc(C3CCCCC3)sc2c(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1cc2cc(C3CCCCC3)sc2c(Cl)c1Cl
Reaction time: 2 h
Yield: 82.2 %

Procedure:
A mixture of 11.8 g of ethyl[ (6,7-dichloro-2-cyclohexylbenzo[b]thien-5-yl)oxy]acetate, 250 ml of 20% sodium hydroxide and 250 ml of 95% ethanol is refluxed for 2 hrs. and allowed to cool. The solvent is removed. The residue is stirred in 350 ml of 6 N hydrochloric acid for 2 hrs. The mixture is filtered and the solid is air-dried, taken up in ether and redried over anhydrous magnesium sulfate and filtered. Recrystallization of the residue from acetone-hexane gives 9.0 g of [(6,7-dichloro-2-cyclohexylbenzo[b]thien-5-yl)oxy]acetic acid, mp 167°-167.5°.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13](=O)[CH3:14])=[CH:9][CH:8]=2)=[C:4]([F:18])[CH:3]=1.[NH2:19][OH:20]>C(O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13](=[N:19][OH:20])[CH3:14])=[CH:9][CH:8]=2)=[C:4]([F:18])[CH:3]=1
Reactant: NO
Reactant: CC(=O)c1ccc(Oc2ccc(Cl)cc2F)cc1
Solvent: CCO
Product: CC(=NO)c1ccc(Oc2ccc(Cl)cc2F)cc1

Procedure:
A mixture of 3.4 g (12.8 mmol) of 1-[4-(4-chloro-2-fluoro-phenoxy)-phenyl]-ethanone and 3.0 mL hydroxylamine solution (50% in water) in 100 mL ethanol was refluxed for five hours. Then the mixture was evaporated to dryness, the residue was combined with approx. 15 mL water and extracted three times with 10 mL ethyl acetate. The extracts were washed with saturated sodium chloride solution, dried and evaporated down. The product thus obtained was reacted further without any further purification.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[N-:12]=[N+]=[N-].[Na+]>OS(O)(=O)=O.C(Cl)Cl>[NH:12]1[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:2][CH2:1][CH2:11][C:9]1=[O:10]
Reactant: O=C1CCCc2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CCCc2ccccc2N1

Procedure:
A sample of alpha tetralone (Aldrich, 36.5 g, 0.25 mol) was converted to the title material by the method of EXAMPLE 50 using 19.5 g (0.3 mol) of sodium azide in a mixture of 300 mL of conc H2SO4 and 100 mL of CH2Cl2. This procedure yielded after recrystallization from EtOH 12.1 g (30%) of the title product.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:18]([O:22][C:23]([N:25]([CH2:27][C:28](O)=[O:29])[CH3:26])=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]([CH2:27][C:28]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8])=[O:29])[CH3:26])=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1ccc(Cn2cnc(N)c2C(N)=O)cc1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Product: Cc1ccc(Cn2cnc(NC(=O)CN(C)C(=O)OC(C)(C)C)c2C(N)=O)cc1
Yield: 60 %

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 17, using 1.61 g (6.99 mmol) of 4-amino-1-(4-methylbenzyl)-5-imidazolecarboxamide prepared in the same manner as in Example 87 and 2-(N-t-butyloxycarbonyl-N-methylamino)acetic acid instead of 3-pyridylacetic acid hydrochloride to obtain 1.70 g of 4-(2-(N-t-butyloxycarbonyl-N-methylamino)acetylamino)-1-(4-methylbenzyl)-5-imidazolecarboxamide (yield 60%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[CH2:24][C:25](O)=O)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C(OCC)(=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[CH2:24][C:25]1[NH:9][C:5]2[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=2[N:10]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Reactant: Nc1cc(F)c(F)cc1N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCCC1Cc1nc2cc(F)c(F)cc2[nH]1
Reaction time: 4 h
Yield: 15.7 %

Procedure:
4,5-Difluoro-benzene-1,2-diamine (1.00 g, 6.9 mmol) and 2-carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (Beckett et al, J. Med. Chem., 563, 1969) (1.69 g, 6.9 mmol) were heated at 120° C. with stirring, under argon for 4 h. A further portion of 2-carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (0.85 g) was added and heating was continued for a further 2 h. The cooled reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate (2×) and brine, dried (MgSO4) and the solvent removed in vacuo. The residue was chromatographed (silica gel, 0-30% ethyl acetate-pentane) to give a yellow solid which was triturated with diethyl ether to afford the title compound as a pale brown solid (0.38 g, 15%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([F:18])[CH:7]=1.[C:19](Cl)(=[O:22])[CH2:20][CH3:21].Cl>C(=S)=S>[F:18][C:8]1[CH:7]=[C:6]([Br:5])[CH:11]=[CH:10][C:9]=1[C:12]1[CH:17]=[CH:16][C:15]([C:19](=[O:22])[CH2:20][CH3:21])=[CH:14][CH:13]=1
Reactant: CCC(=O)Cl
Reactant: Fc1cc(Br)ccc1-c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCC(=O)c1ccc(-c2ccc(Br)cc2F)cc1
Temperature: 0 °C
Yield: 33.9 %

Procedure:
40 g of aluminum chloride and 280 ml of carbon disulfide were taken into a flask, cooled with an ice-salt bath to 0° C. or lower and stirred. A solution of 70 g of 4-bromo-2-fluorobiphenyl as dissolved in 180 ml of carbon disulfide was dropwise added thereto. A solution of 26 g of propionic acid chloride as dissolved in 100 ml of carbon disulfide was dropwise added thereto at 0° C. or lower. After addition, the whole was stirred for 2 hours at 0° C. or lower and then at room temperature overnight. After reaction, the reaction solution was poured into 30 ml of concentrated hydrochloric acid and 300 g of ice and extracted with chloroform. The organic layer was washed three times with water, two times with an aqueous 2% sodium hydroxide solution and then three times with water, and chloroform and carbon disulfide were removed by distillation. The residue was recrystallized from a mixed solvent comprising acetone and methanol to obtain 29 g of 2-fluoro-4-bromo-4'-propionylbiphenyl.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([NH:24][CH3:25])[CH:21]([CH3:23])[CH3:22]>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:24]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH3:25])[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCC(C)C
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Product: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Cl

Procedure:
The title compound was prepared from (4,5-dichloro-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A20) (5.0 g, 16.3 mmol) and N-isobutyl-methylamine (7.09 g, 81.4 mmol) in DMSO (50 mL) at RT according to the general procedure C. Obtained as a brown oil (5.79 g, 99%).
Reaction SMILES: C([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]1[O:23][C:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[N:25][N:26]=1)C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[F:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][C:24]2[O:23][C:22]([C:10]3[N:11]=[C:12]4[N:17]([C:18](=[O:19])[C:9]=3[OH:8])[CH2:16][CH2:15][O:14][C:13]4([CH3:21])[CH3:20])=[N:26][N:25]=2)=[CH:29][CH:30]=1
Reactant: CC1(C)OCCn2c1nc(-c1nnc(Cc3ccc(F)cc3)o1)c(OCc1ccccc1)c2=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OCCn2c1nc(-c1nnc(Cc3ccc(F)cc3)o1)c(O)c2=O
Yield: 62.7 %

Procedure:
A solution of 3-(benzyloxy)-2-(5-(4-fluorobenzyl)-1,3,4-oxadiazol-2-yl)-9,9-dimethyl-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one (0.071 g, 0.15 mmol) in TFA (5 mL) was stirred 22 h at room temperature. The reaction mixture was then concentrated and purified by preparative HPLC on a C18 column using water/MeOH containing 0.1% TFA as eluent to afford the title compound (0.035 g, 60% yield) as white solid. 1HNMR (500 MHz, CDCl3) δ: 9.71 (1H, s), 7.35 (2H, dd, J=8.6, 5.5 Hz), 7.06 (2H, t, J=8.6 Hz), 4.30 (2H, s), 4.07-4.03 (4H, m), 1.63 (6H, s). HRMS (M+H) calcd for C18H18N4O4F: 373.1312. found: 373.1326. Anal calcd for C18H17N4O4F: C, 58.06; H, 4.60; N, 15.04. found: C, 57.88; H, 4.72; N, 14.87.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1)=[CH2:9].[H-].[Na+].[C:18]1([C:24]2[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[C:18]1([C:24]2[CH:25]=[CH:26][C:27]([CH2:28][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:8]([CH2:10][N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)=[CH2:9])=[CH:30][CH:31]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C=C(Cn1ccnc1)c1ccccc1O
Reactant: ClCc1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(Cn1ccnc1)c1ccccc1OCc1ccc(-c2ccccc2)cc1

Procedure:
2-(2-Hydroxyphenyl)-3-(imidazol-1-yl)-1-propene (400 mg, 2.0 mmole) was dissolved in dimethylformamide (5 ml) and sodium hydride (60% dispersion in oil)(110 mg, 2.75 mmole) was added to the solution with stirring and ice-cooling. After stirring for additional 30 minutes, 4-phenylbenzylchloride (490 mg, 2.42 mmole) was added and the mixture was stirred overnight at room temperature. Then, the mixture was poured into water (50 ml) and extracted with diethyl ether (75 ml×2). The extract was washed with water (50 ml×2) and dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was subjected to chromatography on a silica gel column and eluted with methylene chloride/methanol to obtain the title compound (0.41 g, 55.9%), m.p. 90°-92° C. (recrystallized from ethyl acetate/n-hexane).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:20][CH:21]1[CH2:26][CH:25]2[CH2:27][CH:23]([C:24]2([CH3:29])[CH3:28])[CH:22]1[CH2:30]O.[CH2:32]([N:34](S(F)(F)F)[CH2:35]C)C.C(=O)([O-])O.[Na+]>ClCCl>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:20][CH:21]1[CH2:26][CH:25]2[CH2:27][CH:23]([C:24]2([CH3:29])[CH3:28])[CH:22]1[CH2:30][N:34]([CH3:35])[CH3:32]
Reactant: CC1(C)C2CC(Nc3cnn(CC(=O)NCc4ccncc4)c(=O)c3Br)C(CO)C1C2
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)CC1C(Nc2cnn(CC(=O)NCc3ccncc3)c(=O)c2Br)CC2CC1C2(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 16 %

Procedure:
rac-2-[5-Bromo-4-{[2-(hydroxymethyl)-6,6-dimethylbicyclo[3.1.1]hept-3-yl]amino}-6-oxopyridazin-1(6H)-yl]-N-(pyridin-4-ylmethyl)acetamide (43 mg, 0.0877 mmol) in dichloromethane (3 mL) was mixed with (diethylamino)sulfur trifluoride (17 μL, 0.128 mmol) at ˜78° C. and stirred at −78° C. for 10 minutes and then stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was mixed with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by thin layer silica gel chromatography (chloroform/methanol=10/1) to give the desired product (16% yield).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].B(F)(F)F.[CH3:32]COCC>CO>[F:1][C:2]1[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:32])=[O:5]
Reactant: CCOCC
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)c(F)c1
Agent: FB(F)F
Solvent: CO
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC)c(F)c1
Temperature: 0 °C

Procedure:
A solution of 50.5 g of 2-fluoro-4-(hexadecylamino)benzoic acid and 34.4 ml of boron trifluoride etherate in 200 ml of methanol is stirred under reflux for 44 hours, allowed to cool, and poured into 1.20 liters of ice cold 5% aqueous sodium carbonate solution. The white solid is collected by filtration and recrystallized from benzene-ethanol to yield methyl 2-fluoro-4-(hexadecylamino)benzoate.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([F:19])([F:18])[C:9]1[C:14]([C:15]([OH:17])=O)=[CH:13][N:12]=[CH:11][CH:10]=1.CN(C)C=O.Br.[CH2:26]([N:33]1[C:37](=[NH:38])[S:36][CH:35]=[N:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[CH2:26]([N:33]1[C:37](=[N:38][C:15]([C:14]2[CH:13]=[N:12][CH:11]=[CH:10][C:9]=2[C:8]([F:7])([F:19])[F:18])=[O:17])[S:36][CH:35]=[N:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(O)c1cnccc1C(F)(F)F
Reactant: N=c1scnn1Cc1ccccc1
Agent: Br
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(N=c1scnn1Cc1ccccc1)c1cnccc1C(F)(F)F
Temperature: 20 °C
Reaction time: 1 h
Yield: 15.7 %

Procedure:
Oxalyl chloride (0.6 ml) was added to a suspension of 4-trifluoromethylnicotinic acid (1 g) and a catalytic amount of N,N-dimethylformamide in dichloromethane, and stirred at 20° C. for 1 hour. 4-Benzyl-5-imino-1,3,4-thiadiazoline hydrobromide (1.44 g) was added under ice cooling, and was stirred at 20° C. for 1 hour. The mixture was then washed (water), dried (magnesium sulfate), evaporated and the residue recrystallized (ethanol) to give 4-benzyl-5-(4-trifluoromethyl-3-pyridylcarbonyl)imino-1,3,4-thiadiazoline (0.3 g, Compound E-39).
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][C:6]([NH2:8])=[S:7])[CH3:4].[Cl:9][CH2:10][C:11]([CH2:13]Cl)=[O:12].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[OH:12][C:11]1([CH2:10][Cl:9])[CH2:13][S:7][C:6]([CH2:5][N:3]([CH3:4])[CH3:2])=[N:8]1
Reactant: O=C(CCl)CCl
Reactant: CN(C)CC(N)=S
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(C)CC1=NC(O)(CCl)CS1
Temperature: 60 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
A mixture of dimethylaminothioacetamide hydrochloride 54.0 g, 350 mmol), 1,3-dichloroacetone (52.0 g, 409 mmol) and sodium bicarbonate (64.0 g, 762 mmol) in 300 ml of toluene was stirred at 60° C. for 2 hours. The hot reaction solution was then cooled and salts which had precipitated during the reaction were removed by filtration. An equal volume of petroleum ether was then added to the filtrate and solids precipitated. These solids were recovered by filtration to afford 55.5 g of titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[CH3:17].[NH2:18][C:19]1[C:23]([C:24]#[N:25])=[CH:22][NH:21][N:20]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:20]3[N:21]=[CH:22][C:23]([C:24]#[N:25])=[C:19]3[N:18]=2)=[CH:4][C:3]=1[CH3:17]
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1Cl
Reactant: N#Cc1c[nH]nc1N
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C#N)c3n2)ccc1Cl
Yield: 38 %

Procedure:
Reaction of 1-(4-chloro-3-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (264 mg, 1.0 mmol), prepared from commercially available 4-chloro-3-methyl-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as an off-white solid (128 mg, 38%). MS (ISP) 337.1 [(M+H)+]; mp 216° C.
Reaction SMILES: S([CH2:11][N+:12]#[C-])(C1C=CC(C)=CC=1)(=O)=O.CC([O-])(C)C.[K+].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[N:30]3[CH2:31][S:32][CH2:33][C:29]3=[C:28]([CH:34]=O)[CH:27]=2)[CH:21]=1.CO>COCCOC>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[N:30]3[CH2:31][S:32][CH2:33][C:29]3=[C:28]([CH2:34][C:11]#[N:12])[CH:27]=2)[CH:21]=1
Reactant: O=Cc1cc(-c2cccnc2)n2c1CSC2
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Product: N#CCc1cc(-c2cccnc2)n2c1CSC2
Temperature: -30 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
A solution of tosylmethyl isocyanide (7.5 g) in 1,2-dimethoxyethane (50 cc) is added over 20 minutes at a temperature of about -30° C. to a solution of potassium tert-butylate (8.7 g) in 1,2-dimethoxyethane (140 cc) cooled to a temperature of about -30° C. The solution obtained is cooled to a temperature of about -60° C., and then a solution of 5-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxaldehyde (8 g) in 1,2-dimethoxyethane (70 cc) is added to it over 30 minutes at a temperature of about -60° C. The solution obtained is brought to a temperature of about 0° C. over 1 hour and then kept at this temperature for 1 hour and 20 minutes. Methanol (105 cc) is then added over 15 minutes, at a temperature of between 3 and 7° C. The solution obtained is heated at a temperature of about 72° C. for 1 hour and 15 minutes and is then stirred at a temperature of about 20° C. for 16 hours. Three-quarters of the solvent are evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 40° C. The residue is taken up with a mixture of distilled water (350 cc) and ethyl acetate (250 cc). The organic phase is separated off and the aqueous phase is extracted 3 times with ethyl acetate (750 cc in total). The organic extracts are combined, washed 3 times with distilled water (450 cc in total), dried over anhydrous magnesium sulphate, treated with decolourising charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 50° C. A crude product (7.6 g) is thus obtained. This product is chromatographed on a 2.7 cm diameter column containing silica (0.063-0.2 mm; 75 g) by eluting with mixtures of cyclohexane and ethyl acetate and collecting 200-cc fractions. The first 2 fractions from the elution with a mixture of cyclohexane and ethyl acetate (50:50 by volume) are rejected. The next 3 fractions from the elution with a mixture of cyclohexane and ethyl acetate (50:50 by volume) and the following fraction from the elution with pure ethyl acetate, are combined and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 60° C. 2-[-5-(3-Pyridyl)-1H,3H-pyrrolo[1,2-c]thiazol-7-yl]acetonitrile (6 g) is thus obtained in the form of light yellow crystals melting at 92° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17](O)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[NH2:25][C:26]1[CH:34]=[C:33]2[C:29]([C:30](=[O:43])[N:31]([CH3:42])[N:32]2[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:25][C:26]3[CH:34]=[C:33]4[C:29]([C:30](=[O:43])[N:31]([CH3:42])[N:32]4[C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])=[CH:28][CH:27]=3)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: Cn1c(=O)c2ccc(N)cc2n1C(=O)OC(C)(C)C
Product: CCC(C(=O)Nc1ccc2c(=O)n(C)n(C(=O)OC(C)(C)C)c2c1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
87 mg (0.25 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 74 mg (0.27 mmol, 1.1 eq.) of tert-butyl 6-amino-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate were reacted according to General Method 5A. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 112 mg (77% of theory)
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.O[NH:38][C:39](=[NH:48])[C:40]1[CH:45]=[CH:44][C:43]([CH2:46][OH:47])=[CH:42][CH:41]=1>CN(C=O)C.O>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:13]1[O:15][N:48]=[C:39]([C:40]2[CH:45]=[CH:44][C:43]([CH2:46][OH:47])=[CH:42][CH:41]=2)[N:38]=1
Reactant: Nc1c(C(=O)O)cnn1-c1ccccc1
Reactant: N=C(NO)c1ccc(CO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(-c2nc(-c3ccc(CO)cc3)no2)cnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
5-Amino-1-phenyl-1H-pyrazole-4-carboxylic acid (1.8 g, 8.86 mmol), HOBt (1.357 g, 8.86 mmol) and EDCI (1.698 g, 8.86 mmol) were dissolved in DMF (12 mL) under nitrogen at room temperature. The resulting clear, pale yellow solution was stirred for 30 minutes then N-hydroxy-4-(hydroxymethyl)benzimidamide (1.472 g, 8.86 mmol) was added in several portions. The reaction was placed in an oil bath set to 130° C. After 4 hours, the solution was cooled to RT and then added to rapidly stirring water (50 mL). The initial precipitate was stirred and sonicated to give a yellow solid which was collected by filtration, washed with water, air dried and then dried under vacuum to afford (4-(5-(5-amino-1-phenyl-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)methanol (1.5 g 4.05 mmol).