Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[C:9](OC)(=[O:12])[CH2:10][CH3:11].ClCCl>CO>[NH:1]1[C:2]2[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]=2[CH:11]=[CH:10][C:9]1=[O:12]
Reactant: CCC(=O)OC
Reactant: NC1=CC(=O)CCC1
Solvent: CO
Solvent: ClCCl
Product: O=C1CCCc2[nH]c(=O)ccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
With stirring, 113.79 g (1.02 mol) of 3-aminocyclohex-2-en-1-one and 114.37 ml (1.19 mol) of methyl propionate were heated at 105° C. for 1 hour. The dark homogeneous solution formed was then slowly heated further to 170° C. After 20 min (temperature: 135° C.), a viscous material formed, and there was a marked evolution of gas. After a further 15 min (temperature: 160° C.), the reaction material became even more viscous while the evolution of gas subsided. After a total of 42 min, a temperature of 170° C. had been reached. After a further 13 min at this temperature, the reaction material was cooled to room temperature. 200 ml of dichloromethane were then added, the mixture was heated briefly and placed into an ultrasonic bath and the crystalline residue formed was filtered off. This procedure was repeated once more with a further 200 ml of dichloromethane. The crystalline residues obtained in this manner were combined, taken up in 1.6 liters of methanol and then heated with stirring until the solid had dissolved completely. This solution was then slowly cooled to room temperature and then stored in a fridge at about 4° C. for 2 days. The crystalline precipitate was filtered off and dried under reduced pressure. This gave 47.65 g (0.29 mol, 29% of theory) of the target product.
Reaction SMILES: S(Cl)(Cl)=O.[N:5]1([C:10]2[C:11]([CH3:23])=[C:12]([CH:16]=[CH:17][C:18]=2[S:19]([CH3:22])(=[O:21])=[O:20])[C:13](O)=[O:14])[CH:9]=[CH:8][CH:7]=[N:6]1.[CH3:24][N:25]1[C:29]([NH2:30])=[N:28][N:27]=[N:26]1.Cl>CN(C1C=CN=CC=1)C.N1C=CC=CC=1.O>[N:5]1([C:10]2[C:11]([CH3:23])=[C:12]([CH:16]=[CH:17][C:18]=2[S:19]([CH3:22])(=[O:21])=[O:20])[C:13]([NH:30][C:29]2[N:25]([CH3:24])[N:26]=[N:27][N:28]=2)=[O:14])[CH:9]=[CH:8][CH:7]=[N:6]1
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1-n1cccn1
Reactant: Cn1nnnc1N
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: Cc1c(C(=O)Nc2nnnn2C)ccc(S(C)(=O)=O)c1-n1cccn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
At RT, 178 mg (1.5 mmol) of thionyl chloride are added to 280 mg (1.0 mmol) of 3-(pyrazol-1-yl)-2-methyl-4-(methylsulfonyl)benzoic acid, 148 mg (1.5 mmol) of 1-methyl-5-aminotetrazole and 12 mg (0.1 mmol) of DMAP in 2 ml of pyridine. The mixture is stirred at RT for 12 h and, after having been checked by LCMS, stirred at 50° C. for 3 h. 0.1 ml of water is then added, the mixture is stirred at RT for 30 min and 2N HCl is added. The product is filtered off with suction and dried. Yield 134 mg (37%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[CH:4]([NH:5][C:6](=[O:22])[C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1.C[Si](C)(C(C)(C)C)O[C@H]1CC[C@@]2(C)C(C(=O)C[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2O[Si](C)(C)C(C)(C)C)C1.C[Si](C)(C(C)(C)C)O[C@@H]1CC[C@@]2(C)C(C(=O)C[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2O[Si](C)(C)C(C)(C)C)C1>>[CH3:13][C@:12]12[CH2:14][CH2:15][C@H:16]3[C@@H:7]([C:6](=[O:22])[NH:5][CH:4]4[C@:17]3([CH3:20])[CH2:18][CH2:19][C:2](=[O:1])[CH2:3]4)[C@@H:8]1[CH2:9][CH2:10][C:11]2=[O:21]
Reactant: C[C@]12CC[C@H](O)CC1NC(=O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@@]2(C)C(C1)C(=O)C[C@H]1[C@@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@]3(C)CC[C@@H]12
Agent: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)C(C1)C(=O)C[C@H]1[C@@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@]3(C)CC[C@@H]12
Product: C[C@]12CCC(=O)CC1NC(=O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 0.58 h
Yield: 75 %

Procedure:
6-Azaandrostane-3,7,17-trione was prepared from 3β-hydroxy-6-azaandrostane-7,17-dione by the procedure described above for the preparation of 3β,17β-di(dimethyltert-butylsilyloxy)androstane-6-one and 3α,17β-di(dimethyltert-butylsilyloxy)androstane-6-one (Prepn. 12). The mixture was stirred for 35 minutes, then SiO2 was added and evaporated to dryness. The mixture was purified by flash chromatography (SiO2, acetone/toluene 1/1) to give 6-azaandrostane-3,7,17-trione (75%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 7.34 (s, 1H), 3.31 (dd, 1H), 2.57-1.07 (m, 17H), 0.99 (s, 3H), 0.83 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:8][CH2:9][CH3:10])[CH:3]([OH:7])[CH2:4][C:5]#[CH:6].[CH2:12]([Si:14](Cl)([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:13].N1C=CN=C1>CN(C)C=O>[CH2:12]([Si:14]([O:7][CH:3]([C:2]([CH3:11])([CH3:1])[CH2:8][CH2:9][CH3:10])[CH2:4][C:5]#[CH:6])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:13]
Reactant: CC[Si](Cl)(CC)CC
Reactant: C#CCC(O)C(C)(C)CCC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C#CCC(O[Si](CC)(CC)CC)C(C)(C)CCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture containing 3 parts of 5,5-dimethyl-1-octyn-4(RS)-ol, 3.3 parts of triethylsilyl chloride, 3.4 parts of imidazole and 5 parts by volume of dimethylformamide is stirred at room temperature for about 1 hour, then is partitioned between water and ether. The ether solution is separated, washed several times with water, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to afford 5,5-dimethyl-1-octyn-4(RS)-ol triethylsilyl ether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([NH:17][C:18]([C:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[O:24][C:23]3[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=3[CH:21]=2)=[O:19])[CH:10]2[CH2:14][CH:13]([CH3:15])[C:12](=[O:16])[O:11]2)[CH:5]=[CH:6][CH:7]=1>C(N)CCC>[CH2:9]([NH:17][C:12]([CH:13]([CH3:15])[CH2:14][CH:10]([OH:11])[CH:9]([NH:17][C:18]([C:20]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][C:23]2[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=2[CH:21]=1)=[O:19])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)=[O:16])[CH2:8][CH2:4][CH3:3]
Reactant: CC1CC(C(Cc2cccc(F)c2)NC(=O)C2=Cc3ccccc3Oc3ccccc32)OC1=O
Solvent: CCCCN
Product: CCCCNC(=O)C(C)CC(O)C(Cc1cccc(F)c1)NC(=O)C1=Cc2ccccc2Oc2ccccc21
Reaction time: 16 h

Procedure:
Dibenzo[b,f]oxepine-10-carboxylic acid [2-(3-fluoro-phenyl)-1-(4-methyl-5-oxo-tetrahydrofuran-2-yl)-ethyl]-amide (50 mg) is dissolved in 2 ml butylamine and stirred for 16 h. The solution was concentrated in vacuo and the residual solid was recrystallised from EtOAc/hexane. Yield 25 mg (48%).
Reaction SMILES: B(Br)(Br)Br.[Cl:5][CH2:6][C:7]1([CH3:27])[O:11][N:10]=[C:9]([S:12][CH2:13][C:14]2[C:15]([C:23]([F:26])([F:25])[F:24])=[N:16][N:17]([CH2:21][CH3:22])[C:18]=2[O:19]C)[CH2:8]1.C(Cl)(Cl)Cl>ClCCl>[Cl:5][CH2:6][C:7]1([CH3:27])[O:11][N:10]=[C:9]([S:12][CH2:13][C:14]2[C:15]([C:23]([F:26])([F:25])[F:24])=[N:16][N:17]([CH2:21][CH3:22])[C:18]=2[OH:19])[CH2:8]1
Reactant: CCn1nc(C(F)(F)F)c(CSC2=NOC(C)(CCl)C2)c1OC
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCn1nc(C(F)(F)F)c(CSC2=NOC(C)(CCl)C2)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
10 ml of boron tribromide (2 M/liter of dichloromethane solution, 20.2 mmoles) was added, at −60° C., into a solution of 2.5 g (6.7 mmoles) of 5-chloromethyl-3-(1-ethyl-5-methoxy-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-meth-yl-2-isoxazoline dissolved in 30 ml of dichloromethane. The mixture was stirred at room temperature overnight to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into ice water and extraction with chloroform was conducted. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 1.6 g (yield: 66.7%) of 5-chloromethyl-3-(1-ethyl-5-hydroxy-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline.
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:19])[CH:9]=[C:10]([C:14]([O:16]CC)=[O:15])[NH:11]2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[OH-].[Na+]>>[CH2:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:19])[CH:9]=[C:10]([C:14]([OH:16])=[O:15])[NH:11]2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc2c(=O)cc(C(=O)OCC)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Product: CCCc1ccc2c(=O)cc(C(=O)O)[nH]c2c1
Yield: 89.7 %

Procedure:
Treatment of ethyl 7-propyl-4-oxo-1,4-dihydroquinoline-2 carboxylate (0.5 g, Example 1b) with sodium hydroxide (0.309 g), as described in Example 1c, gave 7-propyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (0.4 g), mp>240° C. δ (360 MHz, DMSO-d6) 0.92 (3H, t, CH3), 1.64 (2H, dt, CH2CH3) 2.66 (2H, t, CH2CH2CH3), 6.59 (1H, s, 3-H), 7.20 (1H, dd, 6-H), 7.74 (1H, s, 8-H) and 7.98 (1H, d, 5-H), (Found: C, 64.66; H, 6.08; N, 6.22%. C13H13NO3. 0.6H2O requires C, 64.51; H, 5.91; N, 5.79%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[C:4]([N+:16]([O-])=O)[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.C(O)C.O.[Fe]>[NH2:16][C:4]1[CH:3]=[C:2]([Cl:1])[CH:15]=[CH:14][C:5]=1[O:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Oc1ccc(O)cc1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Nc1cc(Cl)ccc1Oc1ccc(O)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
A mixture of the product of Example 151A (400 mg, 1.506 mmol) and iron powder (336 mg, 6.02 mmol) in acetic acid (10 mL) and ethanol (10 mL) was heated at reflux under a nitrogen atmosphere for 25 minutes. The reaction was cooled to room temperature, diluted with water (50 mL), and treated with solid sodium carbonate until the pH was 6. Extracted with ethyl acetate (2×50 mL) and washed the organic with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation under vacuum. Co-evaporating the resulting oil with methylene chloride/hexanes provided the title compound as a tan solid (355 mg, 100%).
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:25])[CH2:6][CH2:7][CH2:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=[C:10]1[CH2:22][CH2:23][CH3:24])[CH2:2][CH3:3].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:38].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1(C)C=CC=CC=1.ClCCl>[NH2:38][C:13]1[C:12]2[N:11]=[C:10]([CH2:22][CH2:23][CH3:24])[N:9]([CH2:8][CH2:7][CH2:6][C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[O:25])[C:21]=2[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1
Reactant: CCCNC(=O)CCCn1c(CCC)nc2cnc3ccccc3c21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCNC(=O)CCCn1c(CCC)nc2c(N)nc3ccccc3c21

Procedure:
N-Propyl-4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butanamide (5.6 g, 15 mmol) was treated with mCPBA (8.5 g, 38 mmol), concentrated ammonium hydroxide (100 mL), and p-toluenesulfonyl chloride (4.9 g, 26 mmol) according to the method described in Part F of Example 1. The crude product was dissolved in hot toluene (25 mL) and dichloromethane. A precipitate slowly formed, was isolated by filtration, and was washed with toluene (15 mL). The solid was recrystallized twice from 4:1 methanol:water (25 mL), and the crystals were heated at reflux in chloroform in the presence of charcoal (1 g). The mixture was filtered through a layer of CELITE filter agent, and the filtrate was concentrated under reduced pressure. The residue was recrystallized twice from methanol:water and twice from toluene (15 mL) and dried overnight in a vacuum even to provide 0.74 g of 4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-N-propylbutanamide as a grey solid, mp 161-163° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[CH2:9]([OH:14])[C:10]([F:13])([F:12])[F:11].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:11][C:10]([F:13])([F:12])[CH2:9][O:14][C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1
Reactant: OCC(F)(F)F
Reactant: O=Cc1ccc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCC(F)(F)F)s1
Temperature: 100 °C
Reaction time: 20 h
Yield: 66.4 %

Procedure:
To a solution of 5-bromothiophene-2-carbaldehyde (909 mg, 4.76 mmol) and trifluoroethanol (0.69 mL, 9.52 mmol) in 10 mL dimethylformamide was added potassium carbonate (1.38 g, 10.00 mmol). The resulting suspension was stirred at 100° C. for 20 h before being cooled to room temperature and poured into 50 mL water. Organics were extracted with ether (3×50 mL), washed with water and brine (50 mL each), dried over magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel with gradient elution (10-20% ethyl acetate in hexanes) to give 5-(2,2,2-trifluoroethoxyl)thiophene-2-carbaldehyde (664 mg, 66%) as an off-white solid. Used without further characterization.
Reaction SMILES: [N:1]1([C:6]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][C:9]=3[S:8](=[O:21])(=[O:20])[N:7]=2)[CH:5]=[CH:4]N=C1.[CH:22]1(CN)C[CH2:23]1>>[CH:4]1([CH2:5][NH:1][C:6]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([C:16]([F:17])([F:19])[F:18])=[CH:15][C:9]=3[S:8](=[O:20])(=[O:21])[N:7]=2)[CH2:23][CH2:22]1
Reactant: NCC1CC1
Reactant: O=S1(=O)N=C(n2ccnc2)Nc2ccc(C(F)(F)F)cc21
Product: O=S1(=O)N=C(NCC2CC2)Nc2ccc(C(F)(F)F)cc21

Procedure:
3-(Imidazol-1-yl)-7-trifluoromethyl-4H-1,2,4-benzothiadiazine 1,1-dioxide was treated with cyclopropylmethylamine according to the general procedure Method D to give the title compound; m.p. 266-268° C.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:29]=[CH:28][C:17]2[N:18]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:20][C:16]=2[CH:15]=1>>[CH3:12][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:13][C:14]2[CH:29]=[CH:28][C:17]3[NH:18][C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:20][C:16]=3[CH:15]=2)=[O:9])=[CH:10][CH:11]=1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Reactant: Nc1ccc2nc(Nc3ccccc3)[nH]c2c1
Product: CN(C)c1ccc(C(=O)Nc2ccc3[nH]c(Nc4ccccc4)nc3c2)cc1

Procedure:
Compound 180 was prepared according to the procedure similar to that described in Scheme III from 4-dimethylaminobenzoic acid and 5-amino-2-phenylaminobenzimidazole. [M+H]+ calcd for C22H22N5O: 372.18; found: 371.95.
Reaction SMILES: FC(OC(=O)C)(F)F.Cl[C:10]1[N:15]=[CH:14][C:13]([CH2:16][C:17]2[C:26]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[N:20]=[C:19]([C:27]([NH:29][C@H:30]3[CH2:35][CH2:34][CH2:33][CH2:32][C@@H:31]3[OH:36])=[O:28])[CH:18]=2)=[CH:12][CH:11]=1.[CH3:37][S-:38].[Na+]>CS(C)=O.C(OCC)(=O)C>[OH:36][C@H:31]1[CH2:32][CH2:33][CH2:34][CH2:35][C@@H:30]1[NH:29][C:27]([C:19]1[CH:18]=[C:17]([CH2:16][C:13]2[CH:14]=[N:15][C:10]([S:38][CH3:37])=[CH:11][CH:12]=2)[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[N:20]=1)=[O:28]
Reactant: C[S-]
Reactant: O=C(N[C@H]1CCCC[C@@H]1O)c1cc(Cc2ccc(Cl)nc2)c2c(n1)CCCC2
Agent: CC(=O)OC(F)(F)F
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CSc1ccc(Cc2cc(C(=O)N[C@H]3CCCC[C@@H]3O)nc3c2CCCC3)cn1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
To a solution of 4-[(6-chloropyridin-3-yl)methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-5,6,7,8-tetrahydroquinoline-2-carboxamide trifluoromethyl acetate (0.060 g, 0.18 mmol) in 1 mL of DMSO was added sodium thiomethoxide (9.8 mg, 0.14 mmol). The mixture was heated at 80° C. for 1 h, at 90° C. for 1 h, then cooled to rt. After 15 h, additional sodium thiomethoxide (9.3 mg, 0.14 mmol) was added and the mixture was heated at 100° C. for 1 h, then cooled to rt. The mixture was diluted with ethyl acetate, washed 2× with water and 1× with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 35-85% ethyl acetate in hexanes, to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 412.0 for [M+H]+: 1H NMR (400 MHz, d6-DMSO) δ 8.32 (s, 1H), 8.14 (d, J=8.0 Hz, 1H), 7.53 (s, 1H), 5.43-7.40 (m, 1H), 7.25 (d, J=8.2 Hz, 1H), 4.67 (d, J=5.5 Hz, 1H), 4.02 (s, 2H), 3.54-3.48 (m, 1H), 3.43-3.37 (m, 1H), 3.00 (br s, 2H), 2.72 (br s, 2H), 1.91-1.87 (m, 2H), 1.79 (s, 3H), 1.65-1.59 (m, 2H), 1.24-1.17 (m, 3H).
Reaction SMILES: Cl.Cl[C:3]1[C:8]([Cl:9])=[CH:7][N:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[NH:17]1[CH2:25][CH2:24][CH:20]([C:21]([NH2:23])=[O:22])[CH2:19][CH2:18]1.C(=O)([O-])O.[Na+]>CN(C=O)C>[Cl:9][C:8]1[C:3]([N:17]2[CH2:25][CH2:24][CH:20]([C:21]([NH2:23])=[O:22])[CH2:19][CH2:18]2)=[N:4][CH:5]=[N:6][CH:7]=1
Reactant: NC(=O)C1CCNCC1
Reactant: Clc1cncnc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)C1CCN(c2ncncc2Cl)CC1
Reaction time: 0.5 h
Yield: 19.3 %

Procedure:
To a solution of 4,5-dichloropyrimidne hydrochloride 20 (0.20 g, 1.1 mmol) in DMF (4 mL) was added triethylamine (1.5 mL, 10 mmol). After stirring for 30 min, a solution of isonipecotamide (0.42 mg, 3.3 mmol) in DMF (4 mL) was added and the mixture was stirred at r.t. for a further 16 h. The mixture was poured into a saturated solution of sodium hydrogen carbonate (50 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were washed with water (25 mL), brine (25 mL), dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (CH2Cl2, MeOH, gradient 98:2-96:4) to furnish the title compound as a white solid (51 mg, 20%), m.p. 201-202° C.; umax (CHCl3)/cm−1 3023, 3014, 1724, 1682, 1448, 1360, 1219, 1037; m/z (ESI) C10H14CN4O requires 241.0851, found [M+H]+ 241.0851.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[C:16]3[N:15]=[C:14]([CH3:17])[C:13](=[O:18])[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[S:21][CH3:22].[C:23]([C:27]1[CH:31]=[C:30]([N:32]=[C:33]=[O:34])[N:29]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33]([NH:1][C:2]2[CH:20]=[CH:19][C:5]([O:6][C:7]3[C:16]4[N:15]=[C:14]([CH3:17])[C:13](=[O:18])[NH:12][C:11]=4[N:10]=[CH:9][CH:8]=3)=[CH:4][C:3]=2[S:21][CH3:22])=[O:34])[N:29]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CSc1cc(Oc2ccnc3[nH]c(=O)c(C)nc23)ccc1N
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccccc2)n1
Product: CSc1cc(Oc2ccnc3[nH]c(=O)c(C)nc23)ccc1NC(=O)Nc1cc(C(C)(C)C)nn1-c1ccccc1
Yield: 51 %

Procedure:
Method F2 was used with 8-(4-amino-3-(methylthio)phenoxy)-2-methylpyrido[2,3-b]pyrazin-3(4H)-one and 3-tert-butyl-5-isocyanato-1-phenyl-1H-pyrazole to afford the title compound (45 mg, 51%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:25]([O:27]CC)=[O:26])[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].O.[OH-].[Li+]>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:25]([OH:27])=[O:26])[CH:5]=[C:6]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)[C:7]=1[O:8][CH2:9][C:10]([F:12])([F:13])[F:11]
Reactant: CCOC(=O)C(CC(C)C)c1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(C(=O)O)c1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.5 %

Procedure:
A mixture of ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (0.6 g, 1.21 mmol) and lithium hydroxide monohydrate (0.509 g, 12.1 mmol) in MeOH/THF/Water a solvent mixture (10 mL/10 mL/10 mL) was stirred for 4 h at room temperature. After completion of reaction volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×20 mL). The combined organic layers washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methyl pentanoic acid (0.4 g, 72% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2.[N+:26]([C:29]1[N:30]=[CH:31][NH:32][CH:33]=1)([O-])=O>C(Cl)Cl.CO>[N:32]1[CH:33]=[C:29]([NH:26][C:23]([C:20]2[CH:21]=[CH:22][C:13]([C:3]3[C:4]([Cl:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=3[Cl:1])=[C:14]3[C:19]=2[N:18]=[CH:17][CH:16]=[CH:15]3)=[O:24])[NH:30][CH:31]=1
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3ncccc23)c1Cl
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3cnc[nH]3)c3ncccc23)c1Cl
Temperature: 70 °C
Reaction time: 3 h

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but using 5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (Step 159.1), stirring the reaction mixture for 3 h at 70° C., and using 4-nitro-imidazole instead of 2-nitroimidazole in Step 14.3. The title compound: ESI-MS: 442.9 [M+H]+; tR=3.93 min (System 1); TLC: Rf=0.17 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].I[CH3:20]>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH3:20])[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: CI
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(CC(F)(F)F)nc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (1 g) in DMF (20 mL) was added sodium hydride (230 mg of 60% in oil dispersion). The resulting mixture was stirred at room temperature for 5 min. To the dark green solution was added iodomethane (815 mg) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (5%-25% EtOAc/hexanes) to yield the title compound as an orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:20]=[CH:19][C:14]([O:15][CH2:16][CH2:17]O)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.S(Cl)([Cl:23])=O>>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:20]=[CH:19][C:14]([O:15][CH2:16][CH2:17][Cl:23])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: OCCOc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1
Reactant: O=S(Cl)Cl
Product: ClCCOc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1

Procedure:
2-[4-(6-Bromo-3H-imidazo[4,5-b]pyridin-2-yl)phenoxy]ethanol (2.0 g, 6 mmol) was dissolved and refluxed in thionyl chloride (30 ml) for 3 h. The excess thionyl chloride was evaporated off and the residue was co-evaporated twice with toluene affording the title product in quantitative yield.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]([NH:18][C:19]1[N:24]=[C:23]([CH2:25]Cl)[CH:22]=[C:21]([O:27][CH3:28])[N:20]=1)=[O:17])(=[O:14])=[O:13])(=[O:5])=[O:4].O.O.[Na+].[CH3:33][N:34]([CH3:38])[C:35](=[S:37])[S-:36]>C(#N)C.O>[CH3:1][N:2]([CH3:29])[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]([NH:18][C:19]1[N:20]=[C:21]([O:27][CH3:28])[CH:22]=[C:23]([CH2:25][S:37][C:35](=[S:36])[N:34]([CH3:38])[CH3:33])[N:24]=1)=[O:17])(=[O:14])=[O:13])(=[O:5])=[O:4]
Reactant: CN(C)C(=S)[S-]
Reactant: COc1cc(CCl)nc(NC(=O)NS(=O)(=O)c2ccccc2S(=O)(=O)N(C)C)n1
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1cc(CSC(=S)N(C)C)nc(NC(=O)NS(=O)(=O)c2ccccc2S(=O)(=O)N(C)C)n1

Procedure:
A mixture of 9.3 g of N-(2-dimethylsulfamoylphenylsulfonyl)-N'-(4-chloromethyl-6-methoxy-pyrimidin-2-yl)-urea and 3.7 g of dimethyldithiocarbamic acid sodium salt dihydrate is stirred in 100 ml of acetonitrile at 20°-25° C. for 3 hours. In further processing, the reaction mixture is diluted with 1 liter of water, and the precipitated product is separated. The yield is 10.0 g (91% of theory) of N-(2-dimethylsulfamoylphenyl-sulfonyl)-N'-(4-methoxy-6-dimethylthiocarbamoylthiomethyl-pyrimidin-2-yl)-urea m.p. 181°-183° C. (decomp.).