Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[C:31]([N+:32]([O-:34])=[O:33])=[CH:30][CH:29]=[CH:28][N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[C:31]([N+:32]([O-:34])=[O:33])=[CH:30][CH:29]=[CH:28][N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ncccc4[N+](=O)[O-])cc3CC[C@@H]12
Yield: 65.2 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-3-nitropyridine (73 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (90% ethyl acetate/hexanes eluent) to give 95 mg (65%) of the title compound as an amorphous foam. mp 80°-84°. FDMS: m/e=383. α[D]589 =+73.78 (c=0.49, chloroform).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.C(O)(=O)C.[O-:26][C:27]#[N:28].[Na+]>O>[NH2:14][C:11]1[N:10]=[C:9]([NH2:15])[C:8]([O:7][C:6]2[C:5]([CH:17]([CH3:19])[CH3:18])=[CH:4][C:3]([O:20][CH3:21])=[C:2]([NH:1][C:27]([NH2:28])=[O:26])[CH:16]=2)=[CH:13][N:12]=1
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1N
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1NC(N)=O
Reaction time: 0.5 h

Procedure:
To 5-(5-amino-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (314 mg, 1.09 mmol) suspended in water (3 mL) was added acetic acid (0.25 mL, 4.34 mmol). Once all solids had dissolved, sodium cyanate (71 mg, 1.09 mmol, dissolved in 1.5 mL water) was added dropwise. After 30 minutes, the reaction was concentrated and purified with silica gel column chromatography eluting with 92/8/0.1 dichloromethane/methanol/ammonium hydroxide to yield [5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-phenyl]-urea as an off-white solid (244 mg, 68%, M+H)+=333), which was converted to a hydrochloride salt:
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:14][C:13](=[O:15])[CH2:12][N:11]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[CH:22]=1.CN(C)C=O.Br[CH2:29][C:30]([O:32][CH3:33])=[O:31]>C1(C)C=CC=CC=1>[CH3:33][O:32][C:30](=[O:31])[CH2:29][N:14]1[C:8]2[CH:7]=[CH:6][C:5]([Cl:4])=[CH:22][C:9]=2[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:11][CH2:12][C:13]1=[O:15]
Reactant: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: COC(=O)CBr
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Reaction time: 8 h
Yield: 42 %

Procedure:
Sodium methoxide (5.95 g., 0.11 mole) is added to a solution of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (27 g., 0.1 mole) in 200 ml. of dimethylformamide and the mixture is stirred and heated on a steambath for about 20 minutes. To this mixture is added a solution of methyl bromoacetate (16.7 g., 0.11 mole) in 165 ml. of toluene during 1 hour while stirring and heating are continued. The mixture is heated for an additional 2 hours, allowed to stand overnight at room temperature (about 25° C.) and evaporated to dryness in vacuo. The residue is stirred with 500 ml. of water until a suspension results. The suspension is filtered and the solid thus obtained is crystallized first from ether and then from ethanol to give 14.5 g. (42% yield) of 7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-1-acetic acid methyl ester of melting point 137°-138° C.
Reaction SMILES: [OH:1][C:2]1([C:12]([F:21])([F:20])[C:13](O)([OH:18])[C:14]([F:17])([F:16])[F:15])[CH2:7][CH2:6][CH:5]([C:8](OC)=[O:9])[CH2:4][CH2:3]1.O>C1(C)C=CC=CC=1>[OH:1][C:2]1([C:12]([F:20])([F:21])[CH:13]([OH:18])[C:14]([F:15])([F:16])[F:17])[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]1
Reactant: COC(=O)C1CCC(O)(C(F)(F)C(O)(O)C(F)(F)F)CC1
Solvent: O
Solvent: Cc1ccccc1
Product: OCC1CCC(O)(C(F)(F)C(O)C(F)(F)F)CC1
Reaction time: 18 h
Yield: 80.3 %

Procedure:
In 300 ml of toluene was dissolved 30.0 g of methyl 4-hydroxy-4-(2,2-dihydroxy-1,1,3,3,3-pentafluoropropyl)-cyclohexanecarboxylate obtained in <6-1>. The solution was stirred and heated under reflux while the water formed was continuously removed. Under nitrogen atmosphere and with stirring, this solution was added dropwise to a solution of 5.0 g lithium aluminum hydride in 100 ml tetrahydrofuran. The mixture was stirred at 5° C. for one hour and then at room temperature for 18 hours. The reaction mixture was combined with 500 ml of 10% hydrochloric acid and extracted with ethyl acetate. Through conventional work-up including washing, drying and concentration, a crude product was obtained. Recrystallization from n-hexane gave 20.8 g (yield 80%) of the target compound.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][N:22]3[CH2:26][CH2:25][C@H:24]([NH:27][S:28]([C:31]4[CH:40]=[CH:39][C:38]5[C:33](=[CH:34][C:35]([O:41][CH3:42])=[CH:36][CH:37]=5)[CH:32]=4)(=[O:30])=[O:29])[C:23]3=[O:43])[CH:19]=2)[CH:14]=[CH:13][N:12]=1.Cl>C(Cl)Cl.O>[O:7]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][N:22]3[CH2:26][CH2:25][CH:24]([NH:27][S:28]([C:31]4[CH:40]=[CH:39][C:38]5[C:33](=[CH:34][C:35]([O:41][CH3:42])=[CH:36][CH:37]=5)[CH:32]=4)(=[O:29])=[O:30])[C:23]3=[O:43])[CH:19]=2)[CH:14]=[CH:13][N:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4ccc5ccnc(Cl)c5c4)C3=O)cc2c1
Reactant: Oc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc2ccc(S(=O)(=O)NC3CCN(Cc4ccc5ccnc(Oc6ccccc6)c5c4)C3=O)cc2c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
Phenol (6.81 g, 72.4 mmol) and potassium hydroxide ( 0.41 g, 7.31 mmol) are added to 7-methoxynaphthalene-2-sulfonic acid [1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide (1.8 g, 3.6 mmol) and heated to 90° C. until a homogeneous mixture is obtained. The mixture is stirred overnight at 90° C., then cooled to room temperature and diluted with methylene chloride (100 mL) and water. The aqueous layer is neutralized to pH 7 using 1 N HCl, then the two layers are separated and the aqueous layer is extracted with additional methylene chloride. The combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated. The residue is purified by column chromatography eluting with a gradient of 30% EtOAc/hexanes to 60% EtOAc/hexanes to give the product (1.66 g, 3 mmol) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[NH2:8].[C:10]([O:14][C:15]([NH:17][C:18](=NC(OC(C)(C)C)=O)SC)=[O:16])([CH3:13])([CH3:12])[CH3:11]>CO.C(O)(=O)C>[C:10]([O:14][C:15](=[O:16])[NH:17][C:18]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([OH:9])=[CH:3][C:2]=2[N:1]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: Nc1ccc(O)cc1N
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1nc2cc(O)ccc2[nH]1
Reaction time: 3 h
Yield: 61.8 %

Procedure:
5.75 g of 3,4-diaminophenol were combined with 15.5 g of 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea in 150 ml methanol and 22 ml acetic acid in a round bottom flask. The reaction mixture was heated to reflux with stirring for 3 hours. Solvents were then evaporated under reduce pressure yielding 7.13 g crude (5-hydroxy-1H-benzoimidazol-2-yl)-carbamic acid tert-butyl ester.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[C:8]([CH3:21])=[N:9][N:10]2[C:15](O)=[C:14]([CH2:17][CH2:18]O)[C:13]([CH3:20])=[N:12][C:11]=12.C[N:23](C)[C:24]1[CH:29]=[CH:28]C=[CH:26][CH:25]=1>C(OCC)(=O)C>[Br:6][C:7]1[C:8]([CH3:21])=[N:9][N:10]2[C:15]3[N:23]([CH:24]([CH2:29][CH3:28])[CH2:25][CH3:26])[CH2:18][CH2:17][C:14]=3[C:13]([CH3:20])=[N:12][C:11]=12
Reactant: CN(C)c1ccccc1
Reactant: Cc1nc2c(Br)c(C)nn2c(O)c1CCO
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCC(CC)N1CCc2c(C)nc3c(Br)c(C)nn3c21
Temperature: 120 °C
Reaction time: 0.33 h

Procedure:
Phosphorus oxychloride (3.3 mL) was added to a solution of 3-bromo-6-(2-hydroxyethyl)-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-ol (1.0 mg, 3.50 mmol) in N,N-dimethyaniline (5 mL), followed by stirring at 120° C. for 20 minutes. After cooling to room temperature, the mixture was added dropwise slowly into ice-water under vigorously stirring. Then, the mixture was stirred for two hours while raising a temperature gradually to room temperature, followed by diluting with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. 3-Aminopentane (10 mL) was added to a solution of the residue in acetonitrile (30 mL), followed by heating under reflux for three hours. The mixture was diluted with ethylacetate, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The resulting crystals were collected by filtration, to give the title compound (700 mg) as white crystals.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]([NH:9][C:10](=[S:27])[NH:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[NH:19][C:20]([NH:22][C:23]([O:25][CH3:26])=[O:24])=[S:21])[NH2:15])=[O:8].C(=O)(O)[O-].[Na+].O>CC(C)=O>[C:1]([NH:15][C:14]1[CH:16]=[CH:17][C:18]([NH:19][C:20]([NH:22][C:23]([O:25][CH3:26])=[O:24])=[S:21])=[C:12]([NH:11][C:10]([NH:9][C:7]([O:6][CH3:5])=[O:8])=[S:27])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)NC(=S)Nc1ccc(N)cc1NC(=S)NC(=O)OC
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)NC(=S)Nc1ccc(NC(C)=O)cc1NC(=S)NC(=O)OC
Reaction time: 6 h

Procedure:
Acetyl chloride (1.66 g; 0.0212 mole) was added dropwise during five minutes to a stirred suspension of 3,4-bis-(3-methoxycarbonyl-2-thioureido)aniline (4.0 g; 0.0112 mole) and sodium bicarbonate (1.78 g; 0.0212 mole) in dry acetone (50 ml). The temperature of the reaction mixture rose spontaneously to 30° C. After completion of the addition, the mixture was refluxed with stirring for 6 hours, cooled and poured into water. The solid which separated was filtered off, washed well with water and crystallised from ethanol to give 4-acetamido-1,2-bis-(3-methoxycarbonyl-2-thioureido)benzene, m.p. 183°-185° C. (with decomposition).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>ClCCl>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][N:30]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 40 °C
Reaction time: 17 h
Yield: 25.8 %

Procedure:
To a suspension of 5-(2-benzyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (80 mg, 0.17 mmol) in dichloromethane (1 mL) was added methanesulfonyl chloride (15 μL, 0.19 mmol) and triethylamine (73 μL, 0.52 mmol). The reaction was stirred at 40° C. for 17 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 50% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 22 mg (25%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.90 (s, 1 H), 7.80 (d, 1 H), 7.59 (s, 1 H), 7.28-7.39 (m, 5 H), 7.15 (d, 1 H), 6.64 (s, 1 H), 5.65 (s, 2 H), 3.66 (d, 2 H), 3.19-3.30 (m, 1 H), 2.85-2.95 (m, 5 H), 2.11 (d, 2 H), 1.69-1.80 (m, 2 H); ES-MS m/z 502.31 [M+H]+, HPLC RT (min) 2.73.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([S:15][CH2:22][C:21]4[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=4)=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: Sc1nnc(-c2ccc3c(c2)CCO3)o1
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(CSc2nnc(-c3ccc4c(c3)CCO4)o2)cc1
Yield: 56 %

Procedure:
In the same manner as in Example 1 and using 5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 4-methoxybenzyl chloride instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 56%) was obtained as colorless crystals.
Reaction SMILES: C(Cl)CCl.[CH3:5][C:6]1[O:7][CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=1.C[O:15][C:16](=[O:67])[C@@H:17]([NH:34][C:35]([C@@H:37]1[CH2:46][C:45]2[CH:44]=[C:43]3[O:47][CH2:48][C@H:49]([C:51]4[CH:56]=[CH:55][C:54]([O:57][CH2:58][C:59]5[CH:64]=[CH:63][C:62]([Cl:65])=[C:61]([Cl:66])[CH:60]=5)=[CH:53][CH:52]=4)[O:50][C:42]3=[CH:41][C:40]=2[CH2:39][NH:38]1)=[O:36])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[C:27]=2[CH3:33])=[CH:21][CH:20]=1>C(Cl)Cl>[Cl:66][C:61]1[CH:60]=[C:59]([CH:64]=[CH:63][C:62]=1[Cl:65])[CH2:58][O:57][C:54]1[CH:55]=[CH:56][C:51]([C@H:49]2[CH2:48][O:47][C:43]3=[CH:44][C:45]4[CH2:46][C@@H:37]([C:35]([NH:34][C@@H:17]([CH2:18][C:19]5[CH:24]=[CH:23][C:22]([O:25][C:26]6[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[C:27]=6[CH3:33])=[CH:21][CH:20]=5)[C:16]([OH:67])=[O:15])=[O:36])[N:38]([C:11]([C:9]5[N:10]=[C:6]([CH3:5])[O:7][CH:8]=5)=[O:13])[CH2:39][C:40]=4[CH:41]=[C:42]3[O:50]2)=[CH:52][CH:53]=1
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: Cc1nc(C(=O)O)co1
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1nc(C(=O)N2Cc3cc4c(cc3C[C@H]2C(=O)N[C@@H](Cc2ccc(Oc3ccnc(C)c3C)cc2)C(=O)O)OC[C@H](c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)O4)co1
Reaction time: 0.67 h

Procedure:
EDC (5 eq.) and 2-methyl-oxazole-4-carboxylic acid (10 equiv) were dissolved in DCM and stirred 40 min. To this solution was added (S)-2-({(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester and stirred for 12 h. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH to 1:1 hexanes EtOAc+2% MeOH to 1:1 hexanes EtOAc+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (12 mg). LCMS (m/z): 866.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[F:18][C:19]([F:29])([F:28])[O:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24].Cl>O.C(O)C>[ClH:1].[F:18][C:19]([F:28])([F:29])[O:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH:24][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Reactant: Nc1cccc(OC(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: FC(F)(F)Oc1cccc(Nc2cc(C(F)(F)F)nc(-c3ccccn3)n2)c1
Temperature: 25 °C
Yield: 54.9 %

Procedure:
A mixture of 4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (25 mg, 0.096 mmol), 3-trifluoromethoxyaniline (19 μl, 0.144 mmol), and 2N HCl (75 μl) in water:ethanol (2:1, 5 ml) was refluxed for 24 h. The mixture was cooled to room temperature and the resulting precipitate was filtered, washed with water, water:ethanol (2:1) and dried to give a yellow solid (23 mg, 59%). 1H NMR (CDCl3): 8.88-8.85 (m, 1H), 8.59-8.55 (m, 1H), 7.93-7.87 (m, 1H), 7.59 (s, 1H), 7.48 (t, J=8.3 Hz, 1H), 7.45 (dd, J=1.2, 7.5 Hz, 1H), 7.36 (s, 1H), 7.30-7.29 (m, 1H), 7.16-7.10 (m, 1H), 7.05 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([OH:22])=O.FC1C=CC(C2(C3C=CC(F)=CC=3)CCN(CC(O)=O)C2=O)=CC=1.O[NH:48]/[C:49](=[N:60]\[H])/[C:50]1[CH:55]=[CH:54][C:53]([C:56]([F:59])([F:58])[F:57])=[N:52][CH:51]=1.ON/C(=N\[H])/C1C=CC(C(F)(F)F)=CC=1>>[C:7]1([C:6]2([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:5][CH2:4][N:3]([CH2:19][C:20]3[O:22][N:60]=[C:49]([C:50]4[CH:51]=[N:52][C:53]([C:56]([F:59])([F:57])[F:58])=[CH:54][CH:55]=4)[N:48]=3)[C:2]2=[O:1])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: [H]/N=C(\NO)c1ccc(C(F)(F)F)nc1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: [H]/N=C(\NO)c1ccc(C(F)(F)F)cc1
Product: O=C1N(Cc2nc(-c3ccc(C(F)(F)F)nc3)no2)CCC1(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared using the procedure described in Example 190 substituting 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid from Example 1C for 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid and (Z)—N-hydroxy-6-(trifluoromethyl)nicotinimidamide for (Z)—N-hydroxy-4-(trifluoromethyl)benzimidamide. 1H NMR (300 MHz, CDCl3) δ ppm 9.33 (s, 1H), 8.43 (dd, J=1.5, 8.2, 1H), 7.80 (dd, J=0.5, 8.2, 1H), 7.44-7.26 (m, 10H), 4.93 (s, 2H), 3.59 (t, J=6.5, 2H), 2.90 (t, J=6.5, 2H); MS (DCI) m/z 465.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:13]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][CH:15]=3)=[N:10][CH:11]=1)=[O:5])C.[OH-].[K+].CO.Cl>O>[F:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:13]2[C:14]3[C:19](=[CH:18][C:17]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:16][CH:15]=3)[CH:20]=[C:12]2[C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH3:1])=[O:5])=[CH:11][N:10]=2)=[CH:31][CH:30]=1
Reactant: CCOC(=O)c1ccc(-c2cc3cc(S(C)(=O)=O)ccc3n2Cc2ccc(F)cc2)nc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(-c2cc3cc(S(C)(=O)=O)ccc3n2Cc2ccc(F)cc2)nc1
Temperature: 22.5 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-(5-ethoxycarbonylpyridin-2-yl)-1-(4-fluorobenzyl)-5-methanesulfonylindole (0.68 g), potassium hydroxide (0.24 g) and methanol (45 ml) was stirred at 15 to 30° C. for 30 minutes under nitrogen atmosphere. To the reaction solution was added water and the mixture was neutralized with hydrochloric acid. The precipitated crystal was filtered off. The resulting crude crystal was recrystallized (methanol) to obtain 0.44 g of the desired. product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C:8](OC(=O)C)(=[O:10])[CH3:9].C(Cl)(=O)C>C(O)C>[N:5]1[CH:6]=[CH:7][C:2]([CH2:1][C:8](=[O:10])[CH3:9])=[CH:3][CH:4]=1
Reactant: Cc1ccncc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)Cl
Solvent: CCO
Product: CC(=O)Cc1ccncc1
Temperature: 50 °C
Reaction time: 0.12 h

Procedure:
To 10 g of 4-methylpyridine and 32.75 g acetic anhydride, maintained at room temperature, was added 1 ml of acetyl chloride, dropwise over 5-10 min. The solution was then warmed to 50° C. for 6-16 hours. The black reaction mixture was then cooled to 0° C. and 100 mls of ethanol, was added dropwise. The reaction mixture was stirred for 1 hour after the addition, then refluxed for 4-12 hours. The alcohol was removed under reduced pressure and the residue taken up in 100-150 ml methylene chloride. The methylene chloride was washed 2 times with saturated 50 ml portions of sodium carbonate solution then dried over sodium sulfate and evaporated under reduced pressure. Toluene was added to the residue and the excess 4-methylpyridine removed by azeotropic distillation under reduced pressure. Yield: 4.3 gm of 4-pyridinyl-2-propanone.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([N:11]=O)[C:7]([CH3:14])([CH3:13])[CH2:6]1)(=[O:4])=[O:3].[NH2+]([O-])(=O)C(N)=S.C(O)C.[OH-].[Na+]>O>[NH2:11][N:8]1[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][C:7]1([CH3:14])[CH3:13]
Reactant: CC1(C)CN(S(C)(=O)=O)CCN1N=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)CN(S(C)(=O)=O)CCN1N

Procedure:
A mixture of 84.2 g of 4-methanesulphonyl-2,2-dimethyl-1-nitrosopiperazine, 90.5 g of thiourea dioxide, 200 ml of ethanol and 200 ml of water is cautiously treated with 85 g of caustic soda and heated to reflux for 30 hours. After cooling, the mixture is filtered and the product is isolated from the filtrate by extraction with methylene chloride. After drying over sodium sulphate and concentrating the methylene chloride solution, the oil which remains is dissolved in a little ethanol and precipitated as the hydrochloride by addition of ethanolic hydrochloric acid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[O:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH2:18])[CH2:13][CH2:12]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[NH2:1][C:2]1[CH:9]=[C:8]([NH:18][CH2:17][CH:14]2[CH2:15][CH2:16][O:11][CH2:12][CH2:13]2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: NCC1CCOCC1
Reactant: N#Cc1cnc(N)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: N#Cc1cnc(N)cc1NCC1CCOCC1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
6-amino-4-fluoronicotinonitrile (intermediate 21, 50 mg, 0.365 mmol) and (tetrahydro-2H-pyran-4-yl)methanamine (84 mg, 0.729 mmol) were dissolved in NMP (1 ml) and treated at room temperature with DIPEA (0.219 ml, 1.09 mmol). The reaction mixture was then stirred at 50° C. for 4 h and at 90° C. for 4 h. The reaction mixture was cooled to room temperature, quenched with water and diluted with EtOAc. The layers were separated and organic layer was washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) to give the title compound as an off-white solid. (UPLC-MS 3) tR 0.40 min; ESI-MS 233.1 [M+H]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:8][N:9]([CH3:19])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])=[O:11].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:1][S:2]([O:6][CH:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:8][N:9]([CH3:19])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])=[O:11])(=[O:4])=[O:3]
Reactant: CN(CC(O)c1ccccc1)S(=O)(=O)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(CC(OS(C)(=O)=O)c1ccccc1)S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
Methanesulfonyl chloride (0.028 mL, 41 mg, 0.36 mmol) was added dropwise over 5 min to a 0° C. solution of N-(2-hydroxy-2-phenylethyl)-N-methylbenzenesulfonamide (100 mg, 0.357 mmol) and triethylamine (0.075 mL, 54 mg, 0.054 mmol) in 1.0 mL of ethyl acetate. After 15 min., the resulting suspension was poured into 40 mL of ice cold ethyl acetate and washed succesively with 20 mL of ice water, 20 mL of ice cold 2.0 N HCl, 20 mL of ice water and 20 mL of brine. The ethyl acetate layer was dried over sodium sulfate and evaporated to give 128 mg of crude N-(2-methanesulfonyloxy-2-phenylethyl)-N-methylbenzenesulfonamide.