Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C@@H:14]1[CH2:19][CH2:18][O:17][C:15]1=[O:16].[F:20][C:21]([F:30])([F:29])[C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:20][C:21]([F:30])([F:29])[C:22]1[CH:27]=[CH:26][C:25]([O:13][C@H:14]2[CH2:19][CH2:18][O:17][C:15]2=[O:16])=[CH:24][CH:23]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: O=C1OCC[C@H]1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1OCC[C@@H]1Oc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Diethyl azodicarboxylate (2.31 ml, 14.7 mmol) is slowly added to a solution of (R)-(+)-α-hydroxy-γ-butyrolactone (1 g, 9.8 mmol), 4-trifluoromethylphenol (1.58 g, 9.8 mmol) and triphenylphosphine (3.86 g, 14.7 mmol) in anhydrous THF (80 ml) cooled to 0° C. After stirring for 5 minutes at 0° C. and overnight at room temperature, the solvent is evaporated off and the triphenylphosphine oxide is then precipitated from ether and filtered off. The filtrate is then washed with water, dried over magnesium sulphate and evaporated. After purification by flash chromatography (3/1 heptane/EtOAc), the expected compound is obtained in the form of a white powder (1.14 g, 47%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][C:12]#[N:13])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[BH4-].[Na+]>CC(O)C>[NH:1]1[C:2]2[C:7](=[C:6]([CH:10]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:11][C:12]#[N:13])[CH:5]=[CH:4][CH:3]=2)[CH:8]=[CH:9]1
Reactant: N#CC=C(c1ccccc1)c1ccc2[nH]ccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: N#CCC(c1ccccc1)c1cccc2[nH]ccc12
Temperature: 25 °C

Procedure:
To a stirring suspension of 3-(1H-indol-5-yl)-3-phenyl-acrylonitrile VII (2.8 g, 11.5 mmol) in 2-propanol (60 ml) at room temperature, under N2 was added NaBH4 (2.8 g, 74 mmol) portionwise over 90 min period. The mixture was refluxed for 20 hours and additional 2-propanol (25 ml) was added to facilitate the stirring. After 40 hours at reflux, additional NaBH4 (0.5 g, 13.2 mmol) was added. After 60 hours at reflux, additional NaBH4 (1 g, 26.4 mmol) and 2-propanol (20 ml) were added. After 110 hours at reflux, the mixture was cooled to room temperature, concentrated and the residue was partitioned between H2O and Et2O. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated. The waxy dark yellow solid was re-subjected to the NaBH4 reduction conditions at reflux for 40 hours. The reaction was cooled to room temperature and worked up as above affording 3-(1H-indol-4-yl)-3-phenyl-propionitrile VIII as a yellow-brown solid which was used as crude mixture for the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])[CH2:7][N:6]1[C:24](=S)[CH2:25][C:26](=O)[CH3:27])=[O:4].[Cl:30][C:31]1[CH:36]=[C:35]([NH:37][NH2:38])[CH:34]=[CH:33][N:32]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[C:20]([F:23])([F:21])[F:22])(=[O:12])=[O:11])[CH2:7][N:6]1[C:24]1[N:37]([C:35]2[CH:34]=[CH:33][N:32]=[C:31]([Cl:30])[CH:36]=2)[N:38]=[C:26]([CH3:27])[CH:25]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1C(=S)CC(C)=O
Reactant: NNc1ccnc(Cl)c1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1c1cc(C)nn1-c1ccnc(Cl)c1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with (2-chloro-pyridin-4-yl)-hydrazine (CAS Reg. No. 700811-29-6) to give the title compound as colorless solid. MS (ESI): m/z=547.2 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](O)=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B#B>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCCCCCc1ccccc1
Agent: B#B
Solvent: C1CCOC1
Product: OCCCCCCCCc1ccccc1

Procedure:
A solution of 8-phenyloctanoic acid (19.8 mmol) in sieve dried tetrahydrofuran (5 ml) was reduced with diborane in tetrahydrofuran (30 ml, 29.1 mmol) at 0° C. for 4 hours to give 8-phenyloctanol. To an ice cold solution of the octanol (ca. 19.8 mmol) and carbon tetrabromide (21.98 mmol) in methylene chloride (50 ml) was added triphenylphosphine (22.30 mmol) in methylene chloride (50 ml) and the resulting solution was stirred for 2.5 hours. The volatiles were evaporated and the residue was taken up in ether (100 ml), cooled in ice, and filtered. The filtrate was evaporated and distilled to afford 8-phenyloctyl bromide as an oil.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][CH:3]=1.Cl[C:17]1[N:22]=[N:21][C:20]([N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[C:37]4[C:32](=[CH:33][CH:34]=[C:35]([F:38])[CH:36]=4)[CH2:31][CH2:30]3)[CH2:25][CH2:24]2)=[CH:19][CH:18]=1>>[F:38][C:35]1[CH:36]=[C:37]2[C:32]([CH2:31][CH2:30][N:29]2[CH:26]2[CH2:27][CH2:28][N:23]([C:20]3[N:21]=[N:22][C:17]([C:5]4[S:6][C:2]([CH3:1])=[CH:3][CH:4]=4)=[CH:18][CH:19]=3)[CH2:24][CH2:25]2)=[CH:33][CH:34]=1
Reactant: Fc1ccc2c(c1)N(C1CCN(c3ccc(Cl)nn3)CC1)CC2
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: Cc1ccc(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)s1

Procedure:
The title compound was prepared following the procedure as described in Example 1, Method A, STEP 4, reacting 5-methylthiophene-2-boronic acid pinacol ester and 1-(1-(6-chloropyridazin-3-yl)piperidin-4-yl)-6-fluoroindoline.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[O:14][C:15](=[O:29])[C:16]4[C:21]([C:22]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:9]=[C:10](I)[C:3]=12.[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[C:35]([OH:37])[CH:36]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[O:14][C:15](=[O:29])[C:16]4[C:21]([C:22]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:9]=[C:10]([C:33]3[CH:34]=[C:35]([OH:37])[CH:36]=[C:31]([F:30])[CH:32]=3)[C:3]=12
Reactant: OB(O)c1cc(O)cc(F)c1
Reactant: Nc1ncnc2c1c(I)nn2Cc1oc(=O)c2ccccc2c1-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1cc(O)cc(F)c1)nn2Cc1oc(=O)c2ccccc2c1-c1ccccc1
Yield: 12.4 %

Procedure:
3-((4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-4-phenyl-1H-isochromen-1-one (intermediate D1, 50 mg, 0.101 mmol), 3-fluoro-5-hydroxyphenylboronic acid (32 mg, 0.201 mmol), Cs2CO3 (69 mg, 0.202 mmol), Pd(PPh3)4 (9.3 mg, 8.0 umol), were reacted in DMF (0.5 mL) at 110° C. under mw irradiation. The resulting crude was straightforward purified via reverse phase chromatography using a Biotage C18 30 g SNAP with a gradient of water and acetonitrile to give the title compound (6 mg, 12%).
Reaction SMILES: C([C@H:3]([S:7]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[N:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]3[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[CH:30]=3)=[O:28])[CH:21]=2)[CH:17]=1)=[O:11])=[O:8])[C:4]([O-:6])=O)C.[NH2:42][CH2:43][CH:44]([OH:47])[CH2:45][OH:46]>>[OH:47][CH:44]([CH2:45][OH:46])[CH2:43][NH:42][C:4](=[O:6])[CH2:3][S:7](=[O:8])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[N:9][C:10](=[O:11])[C:12]1[CH:17]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]3[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[CH:30]=3)=[O:28])[CH:21]=2)[CH:15]=[N:14][CH:13]=1
Reactant: NCC(O)CO
Reactant: CC[C@@H](C(=O)[O-])S(=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3cc(C)nn3C)c2)c1)c1ccccc1
Product: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)N=S(=O)(CC(=O)NCC(O)CO)c4ccccc4)c3)c2)n(C)n1

Procedure:
In a manner similar to that described in Example 534, (S)-Ethyl[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate and 3-amino-1,2-propanediol were reacted to give the title compound.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[CH2:14][NH:13][C:12]2=[O:15])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:17]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].[H-].[Na+].C(OCC)(=O)C>CN(C)C=O>[CH2:21]([O:20][C:18]([CH:17]([N:13]1[CH2:14][CH:11]([NH:10][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:12]1=[O:15])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(Cc1ccccc1)NC1CNC1=O
Reactant: O=C(OCc1ccccc1)C(Br)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1)NC1CN(C(C(=O)OCc2ccccc2)c2ccccc2)C1=O

Procedure:
3-(2-Phenylacetamido)-2-azetidinone (816 mg.) and benzyl 2-bromo-2-phenylacetate (1.22 g.) were dissolved in N,N-dimethylformamide (20 ml.), and to the solution was added sodium hydride (50% oily) (210 mg.) in nitrogen atmosphere under ice-cooling while stirring, and then the reaction mixture was stirred for an hour at the same temperature. Ethyl acetate (150 ml.) was added to the reaction mixture, and the solution was washed with water, a sodium bicarbonate-saturated-aqueous solution and water respectively, and then dried over anhydrous magnesium sulfate. The solution was evaporated to dryness under reduced pressure to give the yellow oily material (1.7 g.). The material was subjected to column chromatography using silica-gel (developer: chloroform) to give two isomers of 1-(α-benzyloxycarbonylbenzyl)-3-(2-phenyl)acetamido-2-azetidinone. Yield of the isomer A is 26 mg. and it of the isomer B is 65 mg.
Reaction SMILES: [Na].C([CH:4]1[CH2:9][CH2:8][C:7](=[N:10]O)[CH2:6][CH2:5]1)C.O.[CH2:13](O)[CH3:14]>>[CH2:13]([NH:10][CH:7]1[CH2:6][CH2:5][CH2:4][CH2:9][CH2:8]1)[CH3:14]
Reactant: CCO
Reactant: CCC1CCC(=NO)CC1
Agent: [Na]
Solvent: O
Product: CCNC1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium (45 g, 1.96 mol) was slowly added to a solution of 4-ethylcyclohexanone oxime (33 g, 0.23 mol) (prepared according to lit. R. O. Hutchins et al. J. Org. Chem. 60 (1995) 7396-7405)) in 99.9% ethanol (500 mL) while keeping the temperature below 65° C. The reaction mixture was heated at reflux temperature for 1½ h and then stirred at room temperature for further 16 h. A mixture of water (500 mL) and ethanol (100 mL) was added and the mixture was extracted with diethyl ether (3×250 mL). The combined organic phases was washed with brine (150 mL), dried over anhydrous magnesium sulphate and evaporated to dryness. The residue was dissolved in ethanol (100 mL), pH was adjusted to approx. 3 with 4 N hydrochloric acid (60 mL) and the solution was evaporated to dryness in vacuo to give crude ethylcyclohexylamine. The product was purified by recrystallization from ethanol/acetonitrile (4:1) to give 4-trans-ethylcyclohexylamine, hydrochloride as white crystalls.
Reaction SMILES: [Mg].II.Br[CH2:5][CH3:6].[F:7][C:8]([F:18])([F:17])[C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1.Cl>C(Cl)Cl.O1CCCC1>[F:7][C:8]([F:17])([F:18])[C:9]1[CH:10]=[CH:11][C:12]([CH:13]([OH:14])[CH2:5][CH3:6])=[CH:15][CH:16]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CCBr
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCC(O)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C

Procedure:
Dry tetrahydrofuran (700 mL), magnesium turnings (16.75 g, 0.69 mol, 1.2 eq), and a iodine crystal were placed in a flask and the mixture was stirred intensively at 0° C. Bromoethane (68 g, 46.7 mL, 0.69 mol, 1.1 eq) was added dropwise and the resulting mixture was allowed to stir for 30 min. Then the reaction mixture was treated with 4-trifluoromethylbenzaldehyde (100 g, 0.57 mol, 1 eq). After stirring at room temperature for 2 h, the reaction mixture was cooled to 0° C. and poured carefully to a mixture of 1N HCl (750 mL) and ice cooled to 0° C. and poured carefully to a mixture of 1N HCl (750 mL) and ice with CH2Cl2. The organic layer was washed with 5% aqueous NaHCO3 and with CH2Cl2. The organic layer was washed with 5% aqueous NaHCO3 and brine, then dried over anhydrous Na2SO4, the drying agent was filtered and
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]([NH2:16])=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](OCC)(OCC)(OCC)[CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>CCO>[CH2:1]([N:8]1[C:9]2[C:10](=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[N:16]=[C:17]1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nc(Cl)ccc1NCc1ccccc1
Reactant: CCOC(C)(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1nc2nc(Cl)ccc2n1Cc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of N3-benzyl-6-chloropyridine-2,3-diamine (2.56 g, 11.0 mmol, from Step 1), triethyl orthoacetate (15.7 mL, 85.6 mmol, Aldrich) and p-toluenesulfonic acid (0.59 g, 3.4 mmol, Aldrich) in EtOH (55 mL) was heated to reflux for 1.5 hours. The reaction was cooled to room temperature and solvent was evaporated. The residue was partitioned between EtOAc and water. The organic layer was washed with saturated NaHCO3 solution, and brine, dried over sodium sulfate, filtered and concentrated. The product began to crystallize and was triturated with hexanes over the weekend. The white solid was isolated by filtration (2.0 g, 71%).
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=O)=[N:5]1)([CH3:3])[CH3:2].[NH2:16][C@H:17]1[CH2:22][N:21]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:20]([CH2:30][CH2:31][OH:32])[CH2:19][CH2:18]1.C(N(CC)C(C)C)(C)C.C(P(=O)(OCC)OCC)#N>CN(C)C=O>[CH2:23]([N:21]1[C@H:20]([CH2:30][CH2:31][OH:32])[CH2:19][CH2:18][C@H:17]([NH:16][C:13]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=2)=[O:15])[CH2:22]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)n1nc(C(=O)O)c2ccccc21
Reactant: N[C@@H]1CC[C@H](CCO)N(Cc2ccccc2)C1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)n1nc(C(=O)N[C@H]2CC[C@@H](CCO)N(Cc3ccccc3)C2)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.1 %

Procedure:
To a stirred solution of 1-isopropyl-1H-indazole-3-carboxylic acid (235 mg, 1.15 mmol), 2-[cis-5-amino-1-benzylpiperidin-2-yl]ethanol (322 mg, 1.37 mmol, step 8 of Example 1), N,N-diisopropylethylamine (177 mg, 1.37 mmol) in N,N-dimethylformamide (3 mL) was added diethyl cyanophosphonate (223 mg, 1.37 mmol) at room temperature. After stirring at room temperature for 20 h, the mixture was concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with dichloromethane/methanol/25% ammonium hydroxide (10:1:0.2) to give 276 mg (52%) of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([O:15]C(C)(C)C)=[O:14])[CH:9]=2)[N:4]=1.FC(F)(F)C(O)=O>ClCCl>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([OH:15])=[O:14])[CH:9]=2)[N:4]=1
Reactant: CC(C)(C)OC(=O)c1ccc2nc(C(F)(F)F)ccc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc2nc(C(F)(F)F)ccc2c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 93.6 %

Procedure:
To a solution of tert-butyl 2-trifluoromethylquinoline-6-carboxylate (2 g, 7 mmol) in dichloromethane (50 mL), cooled to 0° C., was added trifluoroacetic acid (5.18 mL, 67.2 mmol) and the reaction mixture allowed to warm to room temperature and stirred for 36 h. The reaction mixture was concentrated under reduced pressure and the crude product obtained triturated with heptane (4×10 mL) to give 2-trifluoromethylquinoline-6-carboxylic acid (1.58 g, 98%). 1H NMR (400 MHz, CD3OD) δ 7.93 (1H, d), 8.24 (1H, d), 8.42 (1H, dd), 8.73 (1H, d), 8.78 (1H, d). LCMS: Retention time: 1.38 min. MS (ESI) m/z 242 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:11]=[C:12]([S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23])[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])C>C(O)C>[C:2]1([NH:1][CH:11]=[C:12]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:14])=[O:15])[S:22]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)(=[O:24])=[O:23])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC=C(S(=O)(=O)c1ccccc1)S(=O)(=O)c1ccccc1
Reactant: Nc1ccccc1
Solvent: CCO
Product: O=S(=O)(C(=CNc1ccccc1)S(=O)(=O)c1ccccc1)c1ccccc1
Yield: 80.7 %

Procedure:
A mixture of aniline (1.0 g) and 2-ethoxy-1,1-bis(phenylsulphonyl)ethene (3.5 g) was heated at 160°-180° C. for 30 minutes, allowing any ethanol evolved to escape. After cooling, the residue was recrystallised by dissolving in a minimum of hot choroform and diluting with between 3 and 4 volumes of ethanol to give 1-phenylamino-2,2-bis(phenylsulphonyl)ethene (3.2 g), m.p. 199°-202° C.
Reaction SMILES: [NH2:1]N.[Br:3][C:4]1[CH:16]=[CH:15][C:7]([C:8](/[N:10]=[CH:11]/[N:12](C)C)=O)=[C:6]([F:17])[CH:5]=1>C(O)(=O)C>[Br:3][C:4]1[CH:16]=[CH:15][C:7]([C:8]2[NH:1][N:12]=[CH:11][N:10]=2)=[C:6]([F:17])[CH:5]=1
Reactant: CN(C)/C=N/C(=O)c1ccc(Br)cc1F
Reactant: NN
Solvent: CC(=O)O
Product: Fc1cc(Br)ccc1-c1ncn[nH]1
Temperature: 97.5 °C
Reaction time: 2 h
Yield: 114 %

Procedure:
Hydrazine (0.14 mL, 4.4 mmol) was added to a solution of (E)-4-bromo-N-((dimethylamino)methylene)-2-fluorobenzamide (1.105 g, 4.046 mmol) in acetic acid (11 mL). The resulting white suspension was heated to 95-100° C. The resulting solution was stirred at 95-100° C. for 2 hours. The reaction mixture was cooled to ambient temperature and the acetic acid was azeotropically removed in vacuo with multiple additions of heptane. Heptane (10 mL) was added to the residue. The resulting suspension was cooled to 0-5° C. and stirred for 1 hour. The solids were collected by vacuum filtration, rinsed with excess heptane, and dried to afford 5-(4-bromo-2-fluorophenyl)-1H-1,2,4-triazole (1.116 g, 114%) as an off-white solid which was carried on without further purification.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:27]=[CH:26][C:10]([CH2:11][C:12]2[NH:13][C:14](=[O:25])[C:15]3[N:20]([CH3:21])[N:19]=[C:18]([CH2:22][CH2:23][CH3:24])[C:16]=3[N:17]=2)=[CH:9][CH:8]=1>N1C=CC=CC=1>[CH3:21][N:20]1[C:15]2[C:14](=[O:25])[NH:13][C:12]([CH2:11][C:10]3[CH:26]=[CH:27][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:8][CH:9]=3)=[N:17][C:16]=2[C:18]([CH2:22][CH2:23][CH3:24])=[N:19]1
Reactant: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(N)cc3)nc12
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(NS(C)(=O)=O)cc3)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride (43 μl, 0.00055 mol) was added to a solution of 5-(4-aminobenzyl)-1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one (150 mg, 0.0005 mol) in pyridine (5 ml), and the reaction stirred at room temperature, under a nitrogen atmosphere for 2 hours.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][N:6]=[CH:7][C:8]1[N:9]=[C:10]([CH2:13][CH2:14][CH3:15])[NH:11][CH:12]=1)C.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH2:13]([C:10]1[N:9]2[C:4](=[O:3])[NH:5][N:6]=[CH:7][C:8]2=[CH:12][N:11]=1)[CH2:14][CH3:15]
Reactant: CCCc1nc(C=NNC(=O)OCC)c[nH]1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCc1ncc2cn[nH]c(=O)n12

Procedure:
An 8.75 gm. portion of 3-(2-n-propyl-4-imidazolylmethylene)carbazic acid ethyl ester in 50 ml. of diphenyl ether is reacted as described in Example 70 giving the desired product, m.p. 159°-162.5° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:9]=[C:8]([Cl:10])[S:7][C:6]=1[Cl:11])=[O:4].[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[CH3:1][NH:2][C:3]([C:5]1[C:9]([N+:12]([O-:14])=[O:13])=[C:8]([Cl:10])[S:7][C:6]=1[Cl:11])=[O:4]
Reactant: O=[N+]([O-])O
Reactant: CNC(=O)c1cc(Cl)sc1Cl
Agent: O=S(=O)(O)O
Product: CNC(=O)c1c(Cl)sc(Cl)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
An ice-cold mixture of 2,5-dichloro-thiophene-3-carboxylic acid methylamide (475 mg) in H2SO4 (20 mL, 95-98%) was treated with fuming HNO3 (25 mL). The mixture was stirred for 1 hour and slowly poured onto ice, extracted with ethyl acetate three times, and dried over sodium sulfate. Filtration and concentration provided 2,5-dichloro-4-nitro-thiophene-3-carboxylic acid methylamide (565 mg): 1H NMR (300 MHz, CDCl3) δ 6.0 (bs, 1H), 3.0 (d, 3H).
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[N:8][N:9]=1)(=O)C.Cl>>[NH2:4][C:5]1[S:6][C:7]([S:10]([N:13]([CH3:15])[CH3:14])(=[O:11])=[O:12])=[N:8][N:9]=1
Reactant: CC(=O)Nc1nnc(S(=O)(=O)N(C)C)s1
Agent: Cl
Product: CN(C)S(=O)(=O)c1nnc(N)s1
Temperature: 25 °C

Procedure:
2-Acetamido-5-(N,N-dimethylaminosulfonyl)-1,3,4-thiadiazole (250 grams) and concentrated hydrochloric acid (1 L) were charged into a glass reaction vessel fitted with a mechanical stirrer, reflux condenser and thermometer. This mixture was refluxed for a period of about 2 hours. It was then cooled to room temperature, filtered and the solvent stripped from the filtrate using a rotary evaporator. The solid residue was washed with 10% aqueous sodium carbonate (200 ml), air dried, then crystallized from isopropanol. These crystals were the desired product 2-amino-5-(N,N-dimethylaminosulfonyl)-1,3,4-thiadiazole and having a melting point of 188°-190° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.Cl.CN.[CH2:15]([N:17](CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([NH:8][C:9]([NH:17][CH3:15])=[S:10])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1N=C=S
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CNC(=S)Nc1cc(Cl)ccc1C
Temperature: 25 °C
Yield: 96.9 %

Procedure:
5-Chloro-2-methylphenyl isothiocyanate (36.6 g; 0.2 mol) was added to the solution of methylamine hydrochloride (26.8 g; 0.4 mol) in chloroform (300 mL). Triethylamine (65 mL; 0.47 mol) was added dropwise while stirring at ambient temperature. The mixture was stirred for 18 hours. The solvent was evaporated. The residue was treated with ethyl acetate (800 mL) and water (400 mL). The organic phase was separated, washed with water (2×300 mL), dried over magnesium sulfate and evaporated to dryness to give 41.6 g of N-(5-chloro-2-methylphenyl)-N′-methylthiourea, m.p. 139–140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:29][C:30]2[CH:35]=[CH:34][C:33](=[O:36])[N:32]([CH3:37])[CH:31]=2)[C:9]2[C:10]([C:24]([O:26]CC)=[O:25])=[N:11][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:13]=2[CH3:14])=[CH:4][CH:3]=1.O[Li].O>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:29][C:30]2[CH:35]=[CH:34][C:33](=[O:36])[N:32]([CH3:37])[CH:31]=2)[C:9]2[C:10]([C:24]([OH:26])=[O:25])=[N:11][N:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[C:13]=2[CH3:14])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nn(Cc2ccc(OC)cc2)c(C)c1C(Nc1ccc(=O)n(C)c1)c1ccc(Cl)cc1
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Cn2nc(C(=O)O)c(C(Nc3ccc(=O)n(C)c3)c3ccc(Cl)cc3)c2C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.7 %

Procedure:
In a 25-mL flask was introduced ethyl 4-((4-chlorophenyl)(1-methyl-6-oxo-1,6-dihydropyridin-3-ylamino)methyl)-1-(4-methoxybenzyl)-5-methyl-1H-pyrazole-3-carboxylate (Step 1.4) (140 mg, 0.269 mmol) and LiOH.H2O (33.8 mg, 0.806 mmol) in dioxane (2.5 mL) and H2O (1.0 mL). The reaction mixture was stirred for 3 hr at rt, quenched with 0.5N HCl (50 mL), and extracted with EtOAc. The combined organic layers were washed with 0.5N HCl, dried over Na2SO4, and evaporated to dryness to afford the title product (128 mg, 0.260 mmol, 97% yield) as a green solid. tR: 3.94 min (HPLC 1); tR: 0.90 min (LC-MS 2); ESI-MS: 493 [M+H]+ (LC-MS 2).