Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:21]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][CH2:17][CH:18]([F:20])[F:19])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:22]([O:26][C:27]([N:29]1[CH2:35][CH2:34][C:33]2[CH:36]=[CH:37][C:38]([NH2:40])=[CH:39][C:32]=2[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][C:27]([N:29]1[CH2:35][CH2:34][C:33]2[CH:36]=[CH:37][C:38]([NH:40][C:2]3[N:21]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=5[O:16][CH2:17][CH:18]([F:20])[F:19])=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:39][C:32]=2[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1
Reactant: FC(F)COc1ccccc1-c1cccn2nc(Cl)nc12
Product: CC(C)(C)OC(=O)N1CCc2ccc(Nc3nc4c(-c5ccccc5OCC(F)F)cccn4n3)cc2CC1

Procedure:
7-{8-[2-(2,2-Difluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-[2-(2,2-difluoro-ethoxy)-phenyl]-[1,2,4]-triazolo[1,5-a]pyridine (0.371 g, 1.20 mmol) and 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.471 g, 1.80 mmol) in a manner analogous to Example 311a and 311b to give product (0.388 g, 60%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.54 (s, 1H), 8.75 (d, 1H), 7.70 (m, 1H), 7.65 (m, 1H), 7.42 (m, 3H), 7.26 (m, 1H), 7.15 (m, 1H), 7.05 (m, 2H), 6.22 (br m, 1H), 4.39 (m, 2H), 3.45 (m, 4H), 2.76 (m, 4H), 1.41 (s, 9H). MS=536 (MH)+.
Reaction SMILES: [CH3:1][CH:2]1[CH:10]([CH2:11][CH2:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:14]([O-:16])=[O:15])[CH:8]=2)[N:3]1[CH2:17][C:18]([F:21])([F:20])[F:19].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CCOC(C)=O>[CH3:1][C:2]1[N:3]([CH2:17][C:18]([F:20])([F:19])[F:21])[C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][CH3:13])=[CH:8][C:7]([N+:14]([O-:16])=[O:15])=[CH:6][CH:5]=2
Reactant: CCCC1c2cc([N+](=O)[O-])ccc2N(CC(F)(F)F)C1C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Product: CCCc1c(C)n(CC(F)(F)F)c2ccc([N+](=O)[O-])cc12
Yield: 60.4 %

Procedure:
In a 10 ml round bottom flask, equipped with a magnetic stirrer and under a dry nitrogen atmosphere, 20 mg of 2-methyl-5-nitro-3-propyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-indole from last step was dissolved in EtOAc (3 mL), and 50 mg of DDQ was added to the solution and stirred at room temperature until TLC analysis (20% EtOAc in hexanes) showed no more starting material. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with saturated sodium bicarbonate solution, water, and then brine and dried over MgSO4. The organic layer was absorbed on silica gel and purified by flash column chromatography, eluting with 10% EtOAc in hexanes. 12 mg of 2-methyl-5-nitro-3-propyl-1-(2,2,2-trifluoroethyl)-1H-indole was obtained. 1H NMR (500 MHz, CDCl3) δ 8.50 (d, J=2.0 Hz, 1H), 8.14 (dd, J=9.3, 2.0 Hz, 1H), 7.36 (d, J=9.3 Hz, 1H), 4.69 (q, J=8.5 Hz, 2H), 2.76 (t, J=7.6 Hz, 2H), 2.44 (s, 3H), 1.72-1.64 (m, 2H), 2.96 (t, J=7.3 Hz, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[OH:6][C:7]1[CH:8]=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[C:11]([CH:14]=1)[CH:12]=[O:13].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>C(#N)C>[N+:15]([C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:2][CH2:3][CH2:4][OH:5])=[CH:14][C:11]=1[CH:12]=[O:13])([O-:17])=[O:16]
Reactant: OCCCBr
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: O=Cc1cc(OCCCO)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 95.7 %

Procedure:
3-Bromo-1-propanol (3.34 g, 24 mmol) was refluxed in 80 ml of anhydrous acetonitrile with 5-hydroxy-2-nitrobenzaldehyde (3.34 g, 20 mmol), K2CO3 (3.5 g), and KI (100 mg) overnight (15 hr). The reaction mixture was cooled to room temperature and 150 ml of methylene chloride was added. The mixture was filtered and the solid residue was washed with methylene chloride. The combined organic solution was evaporated to dryness and redissolved in 100 ml methylene chloride. The resulted solution was washed with saturated NaCl solution and dried over sodium sulfate. 4.31 g (96%) of desired product was obtained after removal of the solvent in vacuo.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]([C:6]1[N:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:8]2[C:14]([CH2:15][C:16]#[N:17])=[C:13]([F:18])[CH:12]=[CH:11][C:9]=2[N:10]=1)[CH3:5].[NH2:25][C:26]1[C:31]([C:32]#[N:33])=[C:30](Cl)[N:29]=[CH:28][N:27]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:25][C:26]1[C:31]([C:32]#[N:33])=[C:30]([NH:3][C@H:4]([C:6]2[N:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]3[C:14]([CH2:15][C:16]#[N:17])=[C:13]([F:18])[CH:12]=[CH:11][C:9]=3[N:10]=2)[CH3:5])[N:29]=[CH:28][N:27]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: C[C@H](N)c1nc2ccc(F)c(CC#N)c2n1-c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(CC#N)c2n1-c1ccccc1
Temperature: 90 °C
Yield: 106.9 %

Procedure:
To a solution of [2-((S)-1-aminoethyl)-5-fluoro-3-phenyl-3H-benzoimidazol-4-yl]acetonitrile dihydrochloride (100 mg, 0.27 mmol) in IPA (2 mL) was added 4-amino-6-chloropyrimidine-5-carbonitrile (44 mg, 0.28 mmol) and DIPEA (139 μL, 0.82 mmol) and the reaction mixture heated at 90° C. for 16 h. The reaction mixture was concentrated in vacuo and the resultant residue purified by prep HPLC (C18 phenomenex column, 10-90% MeCN in water 0.1% formic acid, 20 min gradient) to give 345 as a white solid (119 mg, 66%). 1H NMR 400 MHz δ (d6-DMSO): 7.73 (1H, dd, J=8.8, 4.8 Hz), 7.67 (1H, d, J=7.2 Hz), 7.63-7.58 (1H, m), 7.56-7.45 (4H, m), 7.18 (1H, dd, J=10.6, 8.8 Hz), 7.14 (2H, br s), 5.22 (1H, quin, J=5.2 Hz), 3.38-3.21 (2H, m), 1.47 (3H, d, J=6.8 Hz), LCMS (Method K): RT=3.56 min, [M+H]+=413
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[F:55][C:56]([F:69])([F:68])[O:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[S:64](Cl)(=[O:66])=[O:65]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:64]([C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][C:58]=2[O:57][C:56]([F:55])([F:68])[F:69])(=[O:66])=[O:65])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(S(=O)(=O)c2ccccc2OC(F)(F)F)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 16 %

Procedure:
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2-(trifluoromethoxy)benzenesulfonyl chloride as starting materials in 16% yield. LCMS for C31H30ClF3N7O4S (M+H)+: m/z=688.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([C:14]([CH:16]1[CH2:18][CH2:17]1)=O)[C:6](=O)[C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1)[CH3:2].Cl.[NH2:21][NH2:22]>>[CH2:1]([O:3][C:4]([C:5]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[N:11][CH:12]=2)=[N:21][NH:22][C:14]=1[CH:16]1[CH2:18][CH2:17]1)=[O:19])[CH3:2]
Reactant: CCOC(=O)C(C(=O)c1cncnc1)C(=O)C1CC1
Reactant: NN
Agent: Cl
Product: CCOC(=O)c1c(-c2cncnc2)n[nH]c1C1CC1
Yield: 39 %

Procedure:
In analogy to the procedure described in Example 162B], 2-cyclopropanecarbonyl-3-oxo-3-pyrimidin-5-yl-propionic acid ethyl ester and hydrazine.hydrochloride gave the title compound as white solid (39%). MS: 259.1 (MH+).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[C:8](=[O:23])[C:7]1=[O:24].FC(F)(F)C(O)=O.[C:38]1(OC)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C1(C(C2C=CC=CC=2)=[N+]=[N-])C=CC=CC=1>C(OCC)(=O)C.CO>[O:23]=[C:8]1[C:7](=[O:24])[NH:6][CH2:11][CH2:10][N:9]1[CH2:12][C:13]([O:15][CH:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:14]
Reactant: COc1ccc(CN2CCN(CC(=O)OCc3ccccc3)C(=O)C2=O)c(OC)c1
Reactant: COc1ccccc1
Agent: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C(CN1CCNC(=O)C1=O)OC(c1ccccc1)c1ccccc1

Procedure:
A mixture of 10.0 g of benzyl [4-(2,4-dimethoxybenzyl)-2,3-dioxopiperazin- 1-yl]acetate, 40 ml of trifluoroacetic acid and 20 ml of anisole was refluxed for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and 20 ml of ethyl acetate and 10 ml of diethyl ether were added to the resulting residue, and the solid was collected by filtration. The solid obtained was dissolved in a mixed solvent of 9 ml of ethyl acetate and 1 ml of methanol, followed by adding thereto 25 ml of a 1M solution of diphenyldiazomethane in ethyl acetate, and the resulting mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent; chloroform: methanol=10:1) to obtain 6.8 g of diphenylmethyl (2,3-dioxopiperazin-1-yl)acetate as a white foamy substance.
Reaction SMILES: [OH:1][CH:2]([C:17]1[N:18]=[CH:19][N:20]([C:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([NH:15][CH3:16])=[O:14])[CH:7]=[CH:6]2.CN(C)C(=O)C>[O-2].[O-2].[Mn+4].C(OCC)(=O)C>[CH3:16][NH:15][C:13]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:2]([C:17]3[N:18]=[CH:19][N:20]([C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:21]=3)=[O:1])[CH:4]=2)[CH:9]=1)=[O:14]
Reactant: CNC(=O)c1ccc2cc(C(O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
6-[Hydroxy(1-trityl-1H-imidazol-4-yl)methyl]-N-methyl-2-naphthamide (10.0 g, 19.1 mmol) and manganese dioxide (6.6 g, 75.9 mmol) were added to N,N-dimethylacetamide (85 mL), and the mixture was stirred at 60° C. for 2 hr. The insoluble material was filtered off at the same temperature, and washed with N,N-dimethylacetamide (40 mL). The filtrate and washing were combined and cooled to 40° C., water (60 mL) was added dropwise thereto, and the mixture was stirred at room temperature. The obtained crystals were collected by filtration, and washed with water (50 mL). The wet crystals were dried under reduced pressure to give crude crystals (9.5 g). Ethyl acetate (100 mL) was warmed to 40° C., and the crude crystals (9.5 g) were added thereto. The obtained mixture was warmed to 50° C., and stirred for 0.5 hr. The solvent (20 mL) was evaporated under reduced pressure. The residue was allowed to cool to room temperature, and diisopropyl ether (80 mL) was added dropwise thereto, and the mixture was stirred at the same temperature. The obtained crystals were collected by filtration, and washed with a mixed solvent (30 mL) of diisopropyl ether/ethyl acetate (1:1, volume ratio). The obtained wet crystals were dried under reduced pressure to give N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide (8.9 g, 17.1 mmol). yield 89%.
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:4].[O:19]([C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.C>O1CCOCC1.C(O)(C)C>[O:19]([C:26]1[CH:27]=[C:28]([NH:29][C:3]([C:5]2[CH:6]=[CH:7][N:8]3[C:12]=2[CH2:11][S:10][CH:9]3[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:4])[CH:30]=[CH:31][CH:32]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Reactant: Nc1cccc(Oc2ccccc2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(Oc2ccccc2)c1)c1ccn2c1CSC2c1cccnc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 34 %

Procedure:
7-chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (4.5 g) is added, at a temperature between 60° C. and 68° C., to a solution of 3-phenoxyaniline (2.8 g) and triethylamine (3.05 g) in dioxane (100 cc) heated to a temperature in the vicinity of 60° C., in the course of 5 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 6 hours and 15 minutes and is then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. The residue is dissolved in methylene chloride (250 cc) and the solution obtained is washed twice with distilled water (200 cc in total), twice with an aqueous 4N sodium hydroxide solution (200 cc in total) and twice with distilled water (200 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolourizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 50° C. Crude product (6.7 g) is thereby obtained. This product is dissolved in boiling isopropanol (25 cc). Decolourizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 4° C. for 3 hours. The crystals formed are separated by filtration, washed 4 times with ispropanol (20 cc in total) and then 3 times with diethyl ether (75 cc in total) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-(3-phenoxyphenyl)-3(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (2.1 g) in the form of creamcoloured crystals, m.p. 144° C., is thereby obtained.
Reaction SMILES: C([O:6][C:7]([C:9]1[CH:10]=[CH:11][C-:12](C)[CH:13]=1)=[O:8])(=O)CCC.[CH-:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.[Fe+2:20].[OH-:21].[K+]>C(O)C>[C-:15]1([C:12]([CH2:11][CH2:10][CH2:9][C:7]([OH:6])=[O:8])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16]1.[CH-:9]1[CH:10]=[CH:11][CH:12]=[CH:13]1.[Fe+2:20]
Reactant: [OH-]
Reactant: CCCC(=O)OC(=O)c1cc[c-](C)c1
Agent: [Fe+2]
Agent: [K+]
Agent: c1cc[cH-]c1
Solvent: CCO
Product: O=C(O)CCCC(=O)[c-]1cccc1
Yield: 194.7 %

Procedure:
An amount of 25.8 g of methyl-4-ferrocenoyl butyrate prepared according to the method of Preparation Example 1 (1) was reacted in ethanol with 11.5 g of potassium hydroxide, to obtain 24.0 g of 4-ferrocenoyl butyric acid represented by the following formula: ##STR58##
Reaction SMILES: [C:1]([C:3]([CH3:10])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])#[N:2].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.Cl>N1C=CC=CC=1>[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17]([O:5][CH2:4][C:3]([C:1]#[N:2])([CH3:10])[CH2:6][CH2:7][CH2:8][CH3:9])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCC(C)(C#N)CO
Agent: Cl
Solvent: c1ccncc1
Product: CCCCC(C)(C#N)COS(=O)(=O)c1ccc(C)cc1
Yield: 66.8 %

Procedure:
535 mg (3.8 mM) of (-)-2-cyano-2-methylhexanol ([α]435 -1.9 degree (c=2.393, methylene chloride)) and 911 mg (11.4 mM) of dry pyridine were stirred at room temperature, followed by addition of 724 mg (3.8 mM) of p-toluenesulfonyl chloride and 7 hours of reaction. After the reaction, 6 ml of 2M-hydrochloric acid was added and extraction with ether was effected. The organic layer was washed with a small amount of 2M-hydrochloric acid and distilled water, followed by drying on sodium sulfate and distilling-off of the solvent under reduced pressure The product was then purified by thin layer chromatography (developer solvent: hexane/methylene chloride=1/5) to obtain 748 mg of (+) 2-cyano-2-methylhexyl p-toluenesulfonate. Yield: 63.3%, [α]D +10.7 degrees (c 2.182, benzene).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9]([NH:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)=[N:10][CH:11]=[C:12]([C:15]#[N:16])[C:13]=3[S:14][C:4]=2[CH:3]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/B(O)O)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(O)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:27][C:28]1[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:2]2[CH:7]=[CH:6][C:5]3[C:8]4[C:9]([NH:17][CH2:18][C:19]5[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=5)=[N:10][CH:11]=[C:12]([C:15]#[N:16])[C:13]=4[S:14][C:4]=3[CH:3]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(CNc2ncc(C#N)c3sc4cc(Br)ccc4c23)cc1
Reactant: OB(O)/C=C/c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Product: COc1ccc(CNc2ncc(C#N)c3sc4cc(/C=C/c5ccc(F)cc5)ccc4c23)cc1
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 7-bromo-1-[(4-methoxybenzyl)amino][1]benzothieno[3,2-c]pyridine-4-carbonitrile (Example 12, Step 9) in 1-propanol (0.1 M) was added [(E)-2-(4-fluorophenyl)vinyl]boronic acid (1.5 equiv), 2.0 M aqueous Na2CO3 solution (2.5 equiv), and a 3:1 mixture of Ph3P:Pd(OAc)2 (0.1 equiv). The mixture was degassed and then stirred at 100° C. for 2.5 h, and was then partitioned between EtOAc/THF and H2O. The organic layer was washed with H2O and brine, and was then dried (MgSO4), filtered, and evaporated. The crude material was purified by flash chromatography, eluting with 1:1 Et2O:hexanes. The product was stirred with 1:10 EtOAc:hexanes containing trace acetone to yield the title compound as a pale yellow solid after filtration.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:15][C:16]([CH3:18])=[CH2:17])[CH2:12]C=C)(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[CH3:18][C:16]1[CH:17]=[CH:12][N:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])[CH:15]=1
Reactant: C=CCN(CC(=C)C)S(=O)(=O)c1ccc(C)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2ccc(C)c2)cc1
Temperature: 80 °C

Procedure:
A solution of the compound obtained in Step B (15.2 g, 57.3 mmol) in toluene (550 mL) is heated at 80° C. in the presence of (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)-dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium (Grubbs' catalyst, 2nd generation) (150 mg, 0.18 mmol) for 1 hour. 2,3-Dichloro-5,6-dicyano-p-benzoquinone (16.1 g, 70.9 mmol) is then added in one portion, and the solution is heated at 80° C. for 24 hours. The solution is filtered over Celite, and the filtrate is concentrated in vacuo. The product is purified by chromatography over silica gel using ethyl acetate and heptane as eluants to obtain the expected compound in the form of a solid.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][N:18]=2)[CH2:12][CH2:11]1)=O)(C)(C)C.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28].ClCl>>[F:30][C:29]([F:32])([F:31])[C:27]([OH:33])=[O:28].[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][N:18]=2)[CH2:12][CH2:11]1
Reactant: COC(=O)c1ccc(CN2CCC(CNC(=O)OC(C)(C)C)CC2)nc1
Agent: ClCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(CN2CCC(CN)CC2)nc1
Temperature: 40 °C

Procedure:
A solution containing 1.7 g (0.0046 mole) of the product of example 33, 15 ml of CF3COOH and 15 ml of CH2 Cl2 is heated at 40° C. for 3 hours. The solvent is evaporated off under vacuum, concentrated ammonia is added, and then an extraction with ethyl acetate carried out. The solvent is evaporated off and the named product obtained: M. P. 193-195° C.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].S(=O)(=O)(O)O.NS(O)(=O)=O.[C:26]([OH:30])(=[O:29])[CH:27]=[CH2:28]>O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Pd+2]>[Cl:15][C:13]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH:28]=[CH:27][C:26]([OH:30])=[O:29])[CH:14]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: C=CC(=O)O
Agent: [Pd+2]
Agent: CC(=O)/C=C(/C)[O-]
Agent: NS(=O)(=O)O
Solvent: O
Product: O=C(O)C=Cc1cc(Cl)ccc1C(=O)O
Reaction time: 4 h
Yield: 88.1 %

Procedure:
At 2° C., a solution of 2.98 g of sodium nitrite in 5.65 ml of water is added to a mixture of 6.43 g of 2-amino-4-chlorobenzoic acid, 29.5 ml of water and 14.3 ml of concentrated sulfuric acid. 0.4 g of amidosulfonic acid are subsequently added, and this reaction mixture is then added dropwise to 2.7 g of acrylic acid and 28.5 mg of palladium acetylacetonate. After 4 hours at 40° C., the precipitated solid is filtered off, giving 7.48 g of 4-chloro-2-(3-hydroxy-3-oxo-1-propenyl)-benzoic acid of melting point 200-202° C.
Reaction SMILES: O[CH2:2][N:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4]1.S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl>[Cl:19][CH2:2][N:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4]1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1cn(CO)cc1C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(CCl)cc1C(F)(F)F
Temperature: 0 °C

Procedure:
The obtained 1-hydroxymethyl-4-trifluoromethyl-3-ethoxycarbonyl-1H-pyrole was dissolved to 3 ml of chloroform, and 4 ml of thionyl chloride was added, followed by refluxing for 30 minutes. After the reaction mixture was cooled to 0° C., it was poured into ice-water. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 225 mg of 1-chloromethyl-4-trifluoromethyl-3-ethoxycarbonyl-1H-pyrole.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[N:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:3]=1.O.[SH2:17].[Na]>CO>[SH:17][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[N:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:3]=1
Reactant: S
Reactant: COC(=O)c1cc(Cl)n2nc(C)nc2n1
Agent: [Na]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(S)n2nc(C)nc2n1
Temperature: 60 °C
Reaction time: 5 h
Yield: 83.4 %

Procedure:
Methyl 7-chloro-2-methyl-s-triazolo[1,5-a]pyrimidine-5-carboxylate (0.80 g) (3.53 mmol) are suspended in 35 ml of methanol and treated with 0.78 g (10.6 mmol) of sodium hydrogen sulphide hydrate. After stirring at 60° C. for 5 hours the mixture is concentrated and the residue is dissolved in 20 ml of water. The solution is acidified to pH 3 with 3N aqueous hydrochloric acid. The precipitated product is filtered off under suction and washed with water and methanol. After recrystallization from methanol/dichloromethane there is obtained 0.66 g of methyl 7-mercapto-2-methyl-s-triazolo[1,5-a]pyrimidine-5-carboxylate as yellow crystals of melting point 237° C. (dec.).