Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[CH3:10][C:11]1[O:15][N:14]=[C:13]([C:16](Cl)=[O:17])[CH:12]=1>>[CH3:10][C:11]1[O:15][N:14]=[C:13]([C:16]([NH:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[NH2:1])=[O:17])[CH:12]=1
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: NCc1ccccc1N
Product: Cc1cc(C(=O)NCc2ccccc2N)no1

Procedure:
2-Aminobenzylamine (490 mg, 4.01 mmol) and 5-methyl-3-isoxazoyl chloride (437 mg, 3.01 mmol) were converted to the title compound by the procedure of Preparation 1 to yield 250 mg. (36%). MS(FD) m/z 231 (M+). 1H NMR consistent with desired product.
Reaction SMILES: C([N:9]1[CH2:18][C:17]2[C:16](=[O:19])[NH:15][C:14]3[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=3[C:12]=2[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.CC(O)C>O.OS(O)(=O)=O>[CH2:11]1[CH2:10][NH:9][CH2:18][C:17]2[C:16](=[O:19])[NH:15][C:14]3[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=3[C:12]1=2
Reactant: O=C(c1ccccc1)N1CCc2c(c(=O)[nH]c3ccccc23)C1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: O
Product: O=c1[nH]c2ccccc2c2c1CNCC2

Procedure:
A solution of 7.7 g (0.025 m) of 3-benzoyl-1,2,3,4-tetrahydrobenzo[c][2,7]naphthyridin-5(6H)-one in 30 ml of water, 10 ml of H2SO4, and 200 ml of 2-propanol was refluxed for 20 hr. After cooling, the solid was filtered and recrystallized from water, mp 292°-295° C. By analysis, this material contains 0.7 mole of H2SO4 per mole of base and was used as is for alkylation.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:32])[C:7]([CH3:31])([CH3:30])[CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:18][C:19]2[C:20]3[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:21]=3[S:22][CH:23]=2)[C:10]1=[O:29].Cl>O.O1CCOCC1>[CH3:30][C:7]([CH3:31])([CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:18][C:19]2[C:20]3[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:21]=3[S:22][CH:23]=2)[C:10]1=[O:29])[C:6]([OH:32])=[O:5]
Reactant: COC(=O)C(C)(C)Cn1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc2scc(Cn3c(=O)n(CC(C)(C)C(=O)O)c4ccccc43)c12
Reaction time: 60 h
Yield: 91.8 %

Procedure:
Lithium hydroxide monohydrate (4.3 mg, 0.10 mmol) is dissolved in water (1.0 mL) and it is added into the solution of 2,2-Dimethyl-3-[3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-propionic acid methyl ester (28 mg, 0.069 mmol) in 1,4-dioxane (2.0 mL) at room temperature. The mixture is stirred for 60 hr and LCMS then 1.0 M HCl solution (1.0 mL) is added followed by water (15 mL). Then the mixture is extracted with EtOAc (3×30 mL) and the organic layers are combined, dried over MgSO4 and concentrated to give 25 mg (90%) of 2,2-Dimethyl-3-[3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3dihydro-benzimidazol-1-yl]propionic acid. LCMS (ESMS): m/z 395.17 (M+H+).
Reaction SMILES: O=[C:2]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH2:3][C:4]#[N:5].[CH3:12][NH:13][NH2:14]>C(O)C>[CH3:12][N:13]1[C:2]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)=[CH:3][C:4]([NH2:5])=[N:14]1
Reactant: N#CCC(=O)c1cccnc1
Reactant: CNN
Solvent: CCO
Product: Cn1nc(N)cc1-c1cccnc1
Temperature: 25 °C
Yield: 6.1 %

Procedure:
To ethanol (8.53 ml) was added 3-oxo-3-(pyridin-3-yl)propanenitrile (0.82 g, 5.61 mmol) and methylhydrazine (0.25 g, 5.61 mmol) and stirred at reflux for 2 hours. The reaction was cooled to room temperature and concentrated to dryness. The crude material was purified by silica gel chromatography by eluting with 0-20% MeOH/dichloromethane to yield two products—1-methyl-5-(pyridin-3-yl)-1H-pyrazol-3-amine (0.060 g; 6.14%): 1H NMR (300 MHz, CDCl3) δ 8.72 (s, 1H), 8.53 (d, 1H), 7.76-7.63 (m, 1H), 7.43-7.33 (m, 1H), 5.75 (s, 1H), 3.76-3.57 (m, 5H) and 1-methyl-3-(pyridin-3-yl)-1H-pyrazol-5-amine (0.150 g, 15.35%): 1H NMR (300 MHz, CDCl3) δ 8.88 (s, 1H), 8.48 (d, 1H), 7.99 (d, 1H), 7.38-7.07 (m, 1H), 585 (s, 1H), 3.80-3.59 (m, 5H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:12](=O)([O-])[O-].[Cs+].[Cs+]>[Cl-].C1([N+](C)(C)C)C=CC=CC=1.C(#N)C>[CH3:12][O:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cncc(O)c1
Reactant: O=C([O-])[O-]
Agent: C[N+](C)(C)c1ccccc1
Agent: [Cl-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1cncc(OC)c1
Temperature: 80 °C

Procedure:
A mixture of 0.5 g of methyl 5-hydroxynicotinate, 1.2 g (2 equiv) of phenyltrimethylammonium chloride, 4.8 g (3 equiv) of cesium carbonate, and 5 mL of anhydrous acetonitrile was heated to 80° C. for 6 h, cooled, filtered and concentrated under reduced pressure. The residue was taken up in 25 mL of ethyl acetate, filtered and concentrated. Purification by flash chromatography (0-50% ethyl acetate in hexane) gave the product as white crystalline solid: MS (m+1)=168.1; 1H NMR (400 MHz, CDCl3) 8.72 (s, 1H), 8.4 (s, 1H), 7.67 (s, 1H), 3.83 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[N-:12]=[N+]=[N-].[Na+].S(=O)(=O)(O)O>C(Cl)(Cl)Cl>[NH:12]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3][CH2:2][C:1]1=[O:11]
Reactant: O=C1CCCc2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C1CCCc2ccccc2N1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To an ice bath cooled solution of 3,4-dihydronaphthalen-1(2H)-one (20 mL, 150 mmol) in chloroform (300 mL) was added sodium azide (14.62 g, 225 mmol) and then concentrated sulfuric acid (80 mL, 1499 mmol) was added dropwise over 30 minutes, and the mixture was stirred at room temperature for 24 hours. The biphasic solution was poured into ice, and the product was extracted twice with ethyl acetate. The organic layer was washed with water, dried over Na2SO4 and concentrated to give the crude product which was purified by silica gel chromatography (Analogix IntelliFlash™ 280, SF 25-120) loading with dichloromethane and eluting with 30% ethyl acetate/hexanes to obtain the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 9.50 (s, 1H), 7.28-7.14 (m, 2H), 7.07 (td, J=7.4, 1.2, 1H), 7.00-6.85 (m, 1H), 2.67 (t, J=6.9, 2H), 2.20-2.03 (m, 4H); MS (ESI−) m/z 160.1 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([N:21]1[CH2:30][C@H:29]([OH:31])[CH2:28][C@@H:22]1[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[C:36]([O:44][C:45]([F:48])([F:47])[F:46])[CH:35]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:40]([C:37]1[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][C:36]=1[O:44][C:45]([F:46])([F:47])[F:48])(=[O:42])=[O:41])[C:6](=[O:11])[C:5]2([N:21]1[CH2:30][C@H:29]([OH:31])[CH2:28][C@@H:22]1[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Reactant: COc1ccc(C)cc1C1(N2C[C@H](O)C[C@@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(C)ccc3OC)(N3C[C@H](O)C[C@@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1

Procedure:
With 700 mg of the compound obtained in Step 133-1 and 505 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, respectively 219 mg (Isomer A: colorless amorphous) and 314 mg (Isomer B: colorless amorphous) of two species of diastereoisomers of the title compound were obtained by a similar method to Example 2.
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([NH2:12])[CH:9]=[N:8]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:23]2[O:27][C:26]([CH3:28])=[N:25][C:24]=2[C:29](O)=[O:30])[CH:20]=[CH:21][CH:22]=1>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([NH:12][C:29]([C:24]2[N:25]=[C:26]([CH3:28])[O:27][C:23]=2[C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([O:16][CH3:15])[CH:18]=2)=[O:30])[CH:9]=[N:8]1
Reactant: CC(F)(F)CCCCn1cc(N)cn1
Reactant: COc1cccc(-c2oc(C)nc2C(=O)O)c1
Product: COc1cccc(-c2oc(C)nc2C(=O)Nc2cnn(CCCCC(C)(F)F)c2)c1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-4-ylamine and 5-(3-methoxy-phenyl)-2-methyl-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.15 min; [M+H]+=419.22.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][N:11]([CH3:19])[C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1.CC(O)=O>CCO>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[N:18]/[C:15]2[CH:16]=[CH:17][C:12]([N:11]([CH3:19])[CH3:10])=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CN(C)c1ccc(N)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: CN(C)c1ccc(/N=C/c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 73.5 %

Procedure:
To a mixture of 4-chloro-benzaldehyde (1.55 g, 11.0 mmol) and N,N-dimethyl-benzene-1,4-diamine (1.5 g, 11.0 mmol) in EtOH (15 ml) was added a catalytic amount of AcOH (0.063 ml, 1.1 mmol) at RT. The reaction mixture was heated at reflux and stirred for 14 h during which time precipitation took place. After cooling to RT, the slurry was filtered and washed with heptane. The solid was collected and dried under high vacuum to yield the title compound (2.09 g, 8.08 mmol, 73%) as a brownish solid. 1H NMR (400 MHz, CDCl3): 3.01 (s, 6H), 6.78 (m, 2H), 7.29 (m, 2H), 7.44 (m, 2H), 7.84 (m, 2H), 8.49 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:14])=[C:4]([NH:8][C:9](=[O:13])[CH:10]=NO)[CH:5]=[CH:6][CH:7]=1.[OH:15]S(O)(=O)=O>>[Br:1][C:2]1[C:3]([CH3:14])=[C:4]2[C:5]([C:10](=[O:15])[C:9](=[O:13])[NH:8]2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1c(Br)cccc1NC(=O)C=NO
Product: Cc1c(Br)ccc2c1NC(=O)C2=O
Temperature: 0 °C

Procedure:
A mixture of N-(3-Bromo-2-methyl-phenyl)-2-hydroxyimino-acetamide (18.0 g, 0.07 mol), conc.H2SO4 (150 mL) is stirred at 80° C. for 1 h. After reaction, poured the reaction mixture to ice water (2 L) the mixture is filtered and the solid is dried under vacuum to give product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:12][C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:16][O:15][C:13]([CH2:12][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:14]
Reactant: COC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)COc1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-nitrophenol, methyl bromoacetate and caesium carbonate analogously to Example XVIIIa.
Reaction SMILES: P(Br)(Br)[Br:2].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[S:13]([N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[CH2:22][CH2:23][CH2:24]O)(=[O:15])=[O:14]>CN(C=O)C.O>[Br:2][CH2:24][CH2:23][CH2:22][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][N:16]1[S:13]([C:7]1[C:8]([CH3:12])=[CH:9][CH:10]=[CH:11][C:6]=1[Cl:5])(=[O:15])=[O:14]
Reactant: Cc1cccc(Cl)c1S(=O)(=O)N1CCCCC1CCCO
Reactant: BrP(Br)Br
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(Cl)c1S(=O)(=O)N1CCCCC1CCCBr
Reaction time: 0.5 h
Yield: 25 %

Procedure:
PBr3 (3.8 mmol, 1.5 eq) was added dropwise to a solution of 3-(1-(2-chloro-6-methylphenylsulfonyl)piperidin-2-yl)propan-1-ol (2.53 mmol, 1 eq) in DMF (6 ml) at 0° C. and the mixture was stirred for 30 min. The reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (2×20 ml). The combined organic phases were washed with water (30 ml) and saturated sodium chloride solution (20 ml), dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (30% ethyl acetate in hexane). Yield: 25%
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([N:9]1[C:13](=[O:14])[C:12]([NH:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[CH2:22][NH:21][CH2:20][CH2:19]3)=[C:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:10]1(=[O:33])=[O:32])[CH2:6][CH2:7][CH3:8].CCOC(C)=O>C1COCC1>[C:1]([N:21]1[CH2:20][CH2:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]([NH:15][C:12]3[C:13](=[O:14])[N:9]([CH2:5][CH2:6][CH2:7][CH3:8])[S:10](=[O:32])(=[O:33])[C:11]=3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:17]=2)[CH2:22]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCCCN1C(=O)C(Nc2ccc3c(c2)CCNC3)=C(c2ccccc2)S1(=O)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCN1C(=O)C(Nc2ccc3c(c2)CCN(C(C)=O)C3)=C(c2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 64.4 %

Procedure:
Acetyl chloride (0.020 ml, 0.243 mmol) was added to a solution of 2-butyl-5-phenyl-4-(1,2,3,4-tetrahydroisoquinolin-6-ylamino)isothiazol-3(2H)-one 1,1-dioxide (example 60) (0.100 g, 0.243 mmol) and TEA (0.040 mmol, 0.267 mmol) in dry THF (2 ml) and the reaction mixture was stirred at rt for 40 mins. EtOAc was added and the mixture was washed with brine and evaporated. The residue was purified by silica gel column chromatography using a 1:5 mixture of EtOAc/petroleum ether 40-60° C. mixture as eluent, to give the title compound (0.071 g, 64%). 1H NMR (500 MHz CDCl3); δ 7.30-7.22 (m, 2H), 7.22-7.14 (m, 4H), 6.88, 6.68 (dd, 1H), 6.68 (td, 1H), 6.36, 6.31 (d, 1H), 4.58, 4.47 (s, 2H), 3.79 (t, 2H), 3.63, 3.48 (t, 2H), 2.43, 2.39 (t, 2H), 2.16, 2.15 (s, 3H), 1.94-1.84 (m, 2H), 1.56-1.44 (m, 2H), 1.01 (t, 3H); 13C NMR (125 MHz CDCl3): δ 169.8, 159.6, 135.8, 134.4, 131.0, 130.8, 129.6, 129.4, 128.3, 127.0, 126.2, 126.0, 122.6, 122.2, 120.4, 120.0, 111.4, 111.2, 47.8, 43.9, 40.5, 39.4, 30.5, 29.3, 26.8, 22.0, 21.8, 20.3, 13.8; Mass Spectrum M+H+ 454.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[F:42].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[F:42])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2ccccc2F)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.23 g), potassium carbonate (0.96 g), 1-(bromomethyl)-2-fluorobenzene (0.66 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.93 g, 59%).
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][N:5]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([NH:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)=[O:16])[CH:10]=[CH:11]2)=[N:6]1.CC(O)=O.[NH:35]1[CH2:40][CH2:39][CH2:38][CH:37]([CH2:41][OH:42])[CH2:36]1>CO>[OH:42][CH2:41][CH:37]1[CH2:38][CH2:39][CH2:40][N:35]([CH2:2][CH2:3][CH2:4][N:5]2[CH:13]=[C:12]3[C:7]([CH:8]=[C:9]([NH:14][C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[CH:20][CH:19]=4)=[O:16])[CH:10]=[CH:11]3)=[N:6]2)[CH2:36]1
Reactant: O=CCCn1cc2ccc(NC(=O)Nc3ccc(Oc4ccccc4)cc3)cc2n1
Reactant: OCC1CCCNC1
Solvent: CC(=O)O
Solvent: CO
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)Nc1ccc2cn(CCCN3CCCC(CO)C3)nc2c1
Reaction time: 18 h

Procedure:
To a solution of 1-[2-(3-oxopropyl)-2H-indazol-6-yl]-3-(4-phenoxyphenyl)urea (20 mg, 0.05 mmol) in Methanol containing 2% v/v AcOH (1 mL) was added 3-piperidinemethanol (10 mg, 0.10 mmol) and MS-CNBH3 (52 mg, 0.065 mmol). The reaction was shaken vigorously at 40 C for 18h. The reaction was filtered, eluting with additional Methanol (3×0.5 mL). The sample was directly purified by RP-HPLC to afford the titled product. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.15 (m, 1 H), 1.65 (m, 2 H), 1.83 (m, 2 H), 2.30 (m, 2 H), 2.63 (m, 1 H), 2.77 (m, 1 H), 3.10 (m, 2 H), 3.24 (dd, J=10.68, 6.61 Hz, 1 H), 3.36 (m, 1 H), 3.44 (m, 2 H), 4.47 (t, J=6.27 Hz, 2 H), 6.97 (m, 5 H), 7.09 (m, 1 H), 7.36 (m, 2 H), 7.49 (m, 2 H), 7.62 (m, 1 H), 7.90 (s, 1 H), 8.29 (s, 1 H), 8.76 (m, 2 H) and 9.16 (s, 1 H); MS (ESI) 500 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:18]#[N:19])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11](Br)[CH:10]=2)=[O:5])[CH3:2].[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:18]#[N:19])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([NH:27][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([F:20])=[CH:22][CH:23]=1)[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2cc(Br)ccc2c1O
Reactant: NC(=O)c1ccc(F)cc1
Product: CCOC(=O)c1nc(C#N)c2cc(NC(=O)c3ccc(F)cc3)ccc2c1O

Procedure:
1-Cyano-7-(4-fluoro-benzoylamino)-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester was prepared from 7-Bromo-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester under conditions analogous to Example 116(a) using 4-fluorobenzamide. 1H NMR (200 MHz, DMSO): δ ppm=10.85 (s, 1H), 8.83 (s, 1H), 8.39 (m, 2H), 8.11 (m, 2H), 7.37 (m, 3H) 4.49 (q, 2H), 1.41 (t, 3H.)
Reaction SMILES: [CH2:1]=[C:2]([C:7](OS(F)(=O)=O)([F:9])[F:8])[C:3]([F:6])([F:5])[F:4].[I-:15].[Na+].COCCOCCOC>O>[F:4][C:3]([F:6])([F:5])[C:2]([C:7]([F:9])([F:8])[I:15])=[CH2:1]
Reactant: C=C(C(F)(F)F)C(F)(F)OS(=O)(=O)F
Reactant: [I-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: O
Product: C=C(C(F)(F)F)C(F)(F)I
Reaction time: 8 h
Yield: 55.2 %

Procedure:
CH2═C(CF3)CF2OSO2F (10 g, 0.04 mole) is added gradually to a mixture of dry sodium iodide (NaI) (7 g, 0.047 mole) and dry diglyme (20 ml) at 10° C. with stirring. The reaction mixture is kept overnight and then poured into water. The organic layer is separated, washed with aqueous sodium bicarbonate solution and then with water and then dried over MgSO4. Distillation gives a mixture (6 g, 54%) of 2-trifluoromethyl−3,3,-difluoro−3-iodopropene (CH2═C(CF3)CF2I) (10%) and 1,1-difluoro−2-trifluoromethyl−3-iodopropene (CF2═C(CF3)CH2I) (90%), as shown by GC-MS and 19F NMR. B.pt. 98–99° C. The difluoromethylene isomer CF2═C(CF3)CH2I predominates in this example. The experience with chloride as nucleophile (Example 17), indicates that reaction conditions, time in the case of Example 17, can be varied to control the ratio of methylene to difluoromethylene isomer. Simple experimentation should identify conditions at which iodide as nucleophile will yield higher amounts of methylene monomer.
Reaction SMILES: [NH:1]([C:8]1[CH:9]=[C:10]([C:24]([OH:26])=[O:25])[C:11](=[CH:15][C:16]=1[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[NH:17]([C:16]1[CH:15]=[C:11]2[C:12](=[O:14])[O:26][C:24](=[O:25])[C:10]2=[CH:9][C:8]=1[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cc(Nc2ccccc2)c(Nc2ccccc2)cc1C(=O)O
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2cc(Nc3ccccc3)c(Nc3ccccc3)cc21

Procedure:
A steady stream of argon is passed through a suspension of 23.4 g (67.18 mmol) of 4,5-bis(anilino)phthalic acid in 250 ml of toluene, and 19.0 m1(201.5 mmol, 3 eq) of acetic anhydride is added. The reaction mixture is heated to 60°-65° for 90 minutes with vigorous stirring. The reaction mixture is cooled to 10° for 30 minutes, and the yellow to orange crystals are filtered off and washed with toluene/hexane to yield the title compound in the form of yellow crystals, FAB-MS: 331 [M+ +H].
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:17]=[N:18][N:19]=2)[CH:5]=[C:6]([C:8]2[S:12][C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[N:10][CH:9]=2)[CH:7]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CCO.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>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[C:3]2[N:4]([CH:17]=[N:18][N:19]=2)[CH:5]=[C:6]([C:8]2[S:12][C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[N:10][CH:9]=2)[CH:7]=1
Reactant: CC(C)Nc1ncc(-c2cc(Br)c3nncn3c2)s1
Reactant: OB(O)c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)Nc1ncc(-c2cc(-c3ccccc3F)c3nncn3c2)s1
Temperature: 100 °C
Yield: 47 %

Procedure:
A mixture of 5-(8-bromo-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-N-isopropylthiazol-2-amine (19.6 mg, 0.0579 mmol) and 2-fluorophenylboronic acid (12.7 mg, 0.081 mmol) in toluene (0.58 mL) was degassed via nitrogen bubble, then was added Pd(PPh3)4 (3.3 mg, 0.003 mmol), aqueous K3PO4 (2 M, 58 μL, 0.116 mmol) and ethanol (84 μL). The reaction mixture was heated to 100° C. overnight, cooled to rt, diluted with EtOH (1 mL), filtered and concentrated. The residues were purified directly by reverse phase preparative HPLC and the product containing fractions were concentrated and neutralized with aqueous NaHCO3 to precipitate the product. The solids were filtered, washed and dried to give (9.7 mg, 47% yield).
Reaction SMILES: NC(N)=[S:3].CO.Cl.[CH2:8]([O:15][C:16]1[C:17]([CH3:26])=[N:18][CH:19]=[C:20]([CH:24]=[CH2:25])[C:21]=1[CH2:22]Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>O>[CH3:26][C:17]1[C:16]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:21]([CH2:22][SH:3])[C:20]([CH:24]=[CH2:25])=[CH:19][N:18]=1
Reactant: NC(N)=S
Reactant: C=Cc1cnc(C)c(OCc2ccccc2)c1CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=Cc1cnc(C)c(OCc2ccccc2)c1CS

Procedure:
To a well stirred solution of 0.11 mole of thiourea in 250 ml. methanol, under N2 is added 0.1 mole of 3-benzyloxy-4-chloromethyl-2-methyl-5-vinylpyridine hydrochloride. The mixture is refluxed for 1 hour and then cooled. A solution of 0.4 mole of sodium hydroxide in 50 ml. of water is added, and the resulting mixture refluxed for 30 minutes. After concentration in vacuo the reaction mixture is taken up between benzene and water and enough acetic acid added to neutralize the mixture. The organic layer is separated, washed well with water, dried, and concentrated to give 2-methyl-3-benzyloxy-4-mercaptomethyl-5-vinylpyridine.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)(=O)=O.[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[S:10]1[CH:11]=[CH:12][C:8]([CH2:7][CH2:6][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)=[CH:9]1
Reactant: c1nc[nH]n1
Reactant: CS(=O)(=O)OCCc1ccsc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ncn(CCc2ccsc2)n1
Yield: 82.7 %

Procedure:
A mixture of 3-thiopheneethanol methanesulfonate (ester) (0.286 mol), 1,2,4-triazole (0.571 mol) and potassium carbonate (39.47 g) in acetonitrile (1100 ml) was refluxed overnight. The mixture was filtered off and the filtrate was evaporated. The residue was taken up in water and extracted with dichloromethane. The organic layer was dried (MgSO4), filtered off and evaporated. The residue (49.08 g) was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH/NH4OH 99/1/0.1 to 97/3/0.1) (35-70 μm). The pure fractions were collected and evaporated, yielding 42.4 g (83%) of 1-[2-(3-thienyl)ethyl]-1H-1,2,4-triazole (interm. 1).