Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:9][CH:10]=[CH2:11])[CH2:4][CH2:5][CH2:6][C:7]#[N:8].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:1][CH2:2][CH:3]([CH2:9][CH:10]=[CH2:11])[CH2:4][CH2:5][CH2:6][C:7]#[N:8])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCC(CO)CCCC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC(CCCC#N)COS(C)(=O)=O
Reaction time: 3 h

Procedure:
To a solution of 2679 g of 6-hydroxy-5-(2-propenyl)-hexanenitrile in 25 L of methylene chloride is added 2681 mL of triethylamine. The mixture is cooled to -10° in an ice salt bath and a solution of 2103 g of methanesulfonyl chloride in 2 L of methylene chloride is added dropwise over 3 hours keeping the temperature at -5°. After addition is complete, the mixture is stirred for 3 hours in an ice salt bath and then overnight at 10°. The mixture is washed with water, saturated sodium bicarbonate solution, water and then brine, dried over sodium sulfate, evaporated to dryness, and dried at 45°/3 mm Hg to yield 6-methanesulfonyloxy-5-(2-propenyl)-hexanenitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[CH2:22][C:23]([OH:25])=O)=[O:15])=[CH:4][CH:3]=1.C(OC(Cl)=O)C(C)C.[F:34][C:35]1[CH:40]=[CH:39][C:38]([C:41](=[O:43])[CH3:42])=[CH:37][CH:36]=1.C([N-]C(C)C)(C)C.[Li+]>O1CCCC1.C(N(CC)CC)C>[F:34][C:35]1[CH:40]=[CH:39][C:38]([C:41](=[O:43])[CH2:42][C:23](=[O:25])[CH2:22][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][N:16]2[C:14]([C:9]2[N:10]=[C:11]([CH3:13])[S:12][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[O:15])=[CH:37][CH:36]=1
Reactant: Cc1nc(C(=O)N2CCCCC2CC(=O)O)c(-c2ccc(F)cc2)s1
Reactant: CC(=O)c1ccc(F)cc1
Agent: CC(C)COC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc(C(=O)N2CCCCC2CC(=O)CC(=O)c2ccc(F)cc2)c(-c2ccc(F)cc2)s1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
(1-{-[5-(4-fluorophenyl)-2-methylthiazol-4-yl]-methanoyl}-piperidin-2-yl)-acetic acid (0.500 g) was dissolved in dry tetrahydrofuran (15 ml) and cooled to −20° C. under an atmosphere of argon. Triethylamine (0.231 ml) and isobutylchloroformate (0.215 ml) were added and the solution was stirred at −20° C. for 1 hour. The solution was then cooled to −78° C. B. A solution of 4′-fluoroacetophenone (0.229 g) in THF (15 ml) was cooled to 20° C. under an atmosphere of argon. A solution of lithium diisopropylamide (0.830 ml; 2M solution in THF) was added and stirring continued at −20° C. for 30 minutes. The solution was then cooled to −78° C. C. The solution from part B was added to the stirred solution of part A by way of a cannula. Stirring was continued at −78° C. under an atmosphere of argon for 2 hours before being quenched by the addition of saturated ammonium chloride solution. After reaching room temperature, the reaction solution was partitioned between ethyl acetate and water. The organic solution was washed with brine, dried (MgSO4) and evaporated. The residue was chromatographed over silica gel, eluting with a gradient of 10 to 75% ethyl acetate in hexane. The title compound was obtained as a colourless oil (0.560 g) mass spectrum (API+) 483 [MH+], (API−) 481 [(M-H)−] C26H24F2N2O3S requires 482.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[OH:11].[C:12](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[O:11][CH3:12]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cccc(Br)c1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(Br)cccc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 89.8 %

Procedure:
2-Bromo-6-nitro-phenol 1b (46.55 g, 0.214 mol) was dissolved in 500 mL of acetone followed by addition of potassium carbonate (35.36 g, 0.26 mol) and iodomethane (20.1 mL, 0.32 mol). The reaction mixture was heated to reflux at 70° C. for 40 hours. The reaction mixture was concentrated under reduced pressure and diluted with 1300 mL of ethyl acetate and 500 mL of water. The aqueous layer was extracted with ethyl acetate (300 mL×2). The combined organic extracts were washed with 4 M hydrochloric acid and saturated sodium bicarbonate solution and then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 1-bromo-2-methoxy-3-nitro-benzene 1c (44.59 g, yield 90.0%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:16](Cl)(=[O:18])=[O:17])=[CH:4][C:5]2[C:6](=[O:15])[C:7]3[N:8]([CH2:11][CH2:12][CH2:13][N:14]=3)[C:9]=2[CH:10]=1.[CH3:20][O:21][CH2:22][C@@H:23]1[CH2:27][CH2:26][CH2:25][NH:24]1>C(Cl)Cl>[Cl:1][C:2]1[C:3]([S:16]([N:24]2[CH2:25][CH2:26][CH2:27][C@H:23]2[CH2:22][O:21][CH3:20])(=[O:18])=[O:17])=[CH:4][C:5]2[C:6](=[O:15])[C:7]3[N:8]([CH2:11][CH2:12][CH2:13][N:14]=3)[C:9]=2[CH:10]=1
Reactant: O=C1C2=NCCCN2c2cc(Cl)c(S(=O)(=O)Cl)cc21
Reactant: COC[C@@H]1CCCN1
Solvent: ClCCl
Product: COC[C@@H]1CCCN1S(=O)(=O)c1cc2c(cc1Cl)N1CCCN=C1C2=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.5 %

Procedure:
To a solution of 7-chloro-10-oxo-2,3,4,10-tetrahydropyrimido[1,2-a]indole-8-sulfonyl chloride (0.140 g, 0.439 mmol) in CH2Cl2 (10 mL) was added (S)-(+)-2-(methoxymethyl)pyrrolidine (0.119 g, 0.965 mmol, 2.2 eq) drop-wise with cooling in an ice bath under a dry N2 atmosphere. After stirring at room temperature for 1.5 hr, the mixture was quenched with H2O (10 mL) and extracted with EtOAc (3×). The combined organic extracts were dried over MgSO4, filtered, and concentrated to give a film on glass. The film was combined with the product of an earlier run and purified on Biotage KP silica gel eluting with a step gradient of 20/80 petroleum ether/EtOAc, followed by 100% EtOAc to give the title compound as a bright yellow solid (0.104 g, 52.3% yield). Anal. Calc'd. for C17H20ClN3O4S.0.2H2O: C, 50.86; H, 5.12; N, 10.47. Found, C, 50.82; H, 5.00; N, 10.31. NMR (400 MHz, DMSO-d6): consistent. MS: (ES−) m/z 396/398 [M−H] 1 chlorine pattern observed. m.p.: 127-130° C. HRMS: consistent ESI Adduct [M+H] Exact 398.09358, Expt'l 398.09411, mmu 0.53, ppm 1.34, RI % 100.
Reaction SMILES: [P:1]([O:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[CH:19]=[CH:18][C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:9][C@@H:8]1[OH:20])([OH:4])([OH:3])=[O:2].[Br:21]Br>N1C=CC=CC=1.C(O)(=O)C>[P:1]([O:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[CH:19]=[C:18]([Br:21])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:9][C@@H:8]1[OH:20])([OH:4])([OH:3])=[O:2]
Reactant: BrBr
Reactant: O=c1ccn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)O)O2)c(=O)[nH]1
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COP(=O)(O)O)O2)cc1Br
Reaction time: 20 h

Procedure:
5-Bromo-2′-deoxyuridine-5′-phosphate was prepared as follows: 2′-Deoxyuridine-5′-phosphate (6.2 g) was suspended in a mixture of 60 ml pyridine and 30 ml acetic acid. Bromine (0.84 ml) was added with stirring in an ice water bath and stirring continued for 20 hours at room temperature. The solution was concentrated by vacuum. After redissolution in a minimum of water a crude product was precipitated by addition of ethanol. The crude product was chromatographed on Dowex 50 (H+) and eluted with water. The free acid product was precipitated from the concentrated eluent by addition of ethanol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:11]1([CH3:19])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Mg]Cl>O1CCCC1>[OH:10][C:8]([C:4]1[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH3:19])[CH3:9]
Reactant: CC(=O)c1cccc(O)c1
Reactant: Cc1ccccc1[Mg]Cl
Solvent: C1CCOC1
Product: Cc1ccccc1C(C)(O)c1cccc(O)c1

Procedure:
By using 3′-hydroxyacetophenone (200 mg) and a 1 M solution of o-tolylmagnesium chloride in tetrahydrofuran (4.4 ml) as starting materials, the title compound (119.3 mg) was obtained in the same manner as that of Reference Example 69.
Reaction SMILES: [ClH:1].C(O[C:5](=[NH:15])/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)C.[NH3:16]>CO>[ClH:1].[F:14][C:11]1[CH:10]=[CH:9][C:8](/[CH:7]=[CH:6]/[C:5]([NH2:15])=[NH:16])=[CH:13][CH:12]=1
Reactant: CCOC(=N)/C=C/c1ccc(F)cc1
Reactant: N
Agent: Cl
Solvent: CO
Product: N=C(N)/C=C/c1ccc(F)cc1
Reaction time: 48 h
Yield: 99.9 %

Procedure:
A solution of E-3-(4-fluorophenyl)acrylimidic acid ethyl ester hyrochloride (0.86 g, 0.00374 moles) in dry methanol (20 ml) was treated with a solution of ammonia (0.064 g, 3.8 mmol) in dry methanol (0.51 ml) and the resulting solution was allowed to stand at room temperature for 48 h. The reaction mixture was evaporated to dryness, mixed with diethyl ether and evaporated to give E-3-(4-fluorophenyl)acrylamidine hydrochloride as a solid (0.75 g, 100%); 1H-NMR (d6-DMSO) 6.72, 6.79 (1H, d) 7.35 (2H, m), 7.67 (2H, m), 7.87, 7.94 (1H, d), 8.8, 9.15 (2×bs). MS (APCI+) M+1=165, C9H9FN2 requires 164.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][NH:21][C:15]=2[CH:14]=1.[CH3:23][N:24]([CH3:45])[C:25](=[O:44])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][C:29]=1[CH3:43]>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:31]3[CH:32]=[CH:33][C:28]([O:27][CH2:26][C:25]([N:24]([CH3:23])[CH3:45])=[O:44])=[C:29]([CH3:43])[CH:30]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(I)c3cn2)c1Cl
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1OCC(=O)N(C)C
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4ccc(OCC(=O)N(C)C)c(C)c4)c3cn2)c1Cl

Procedure:
This compound was prepared using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine and N,N-dimethyl-2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetamide. LCMS (M+H)+=515.1/517.1.
Reaction SMILES: [CH2:1]([S:8][CH2:9][CH:10]([C:16](=[O:21])[NH:17][CH2:18][C:19]#[N:20])[CH2:11][S:12][C:13](=O)[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[C:24]([C:26]1[CH:27]=C([CH:31]=[CH:32][CH:33]=1)CBr)#[N:25]>CN(C)C=O.O>[CH2:1]([S:8][CH2:9][CH:10]([CH2:11][S:12][CH2:13][C:14]1[CH:31]=[CH:32][CH:33]=[C:26]([C:24]#[N:25])[CH:27]=1)[C:16]([NH:17][CH2:18][C:19]#[N:20])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)SCC(CSCc1ccccc1)C(=O)NCC#N
Reactant: N#Cc1cccc(CBr)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCNC(=O)C(CSCc1ccccc1)CSCc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.8 %

Procedure:
A solution of thioacetic acid S-[3-benzylsulfanyl-2-(cyanomethyl-carbamoyl)propyl] ester (0.105 g) in dimethylformamide (1 mL) and water (0.8 mL) was cooled on ice and treated with 1 N aqueous potassium hydroxide (0.65 mL). 3-Cyanobenzylbromide (0.129 g) in dimethylformamide (0.8 mL) was added. The reaction mixture was allowed to warm to room temperature while stirring overnight. The reaction mixture was then poured into ice water and extracted with ethyl acetate (50 mL) and washed with water and saturated aqueous sodium chloride. The solution was dried over magnesium sulfate and evaporated to give 2-benzylsulfanylmethyl-3-(3-cyano-benzylsulfanyl)-N-cyanomethyl-propionamide (0.135 g).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]2[C:12]([OH:13])=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:10][C:9]=2[N:20]=1)([CH3:4])[CH3:3].[C:21]([O-])(=[O:23])[CH3:22].[Na+]>C(OC(=O)C)(=O)C>[C:21]([O:13][C:12]1[C:8]2[CH:7]=[CH:6][C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[N:20][C:9]=2[S:10][C:11]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)c1ccc2c(O)c(-c3ccccc3)sc2n1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1c(-c2ccccc2)sc2nc(C(C)(C)C)ccc12
Yield: 91.6 %

Procedure:
A solution of 1.42 g (5 mmol) of 6-(1,1-dimethylethyl)-3-hydroxy-2-phenyl-7-azabenzo[b]-thiophene and 1.42 g sodium acetate in 20 mL of acetic anhydride was heated at reflux for 1 hour. The solution was concentrated and the residue was partitioned between ether and water. The ether layer was washed with sodium bicarbonate solution and brine, dried and concentrated. The residue was crystallized from ether-hexane to afford 1.49 g (91%) of fine white needles, m.p. 128°-9° C.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:10]([CH2:11][OH:12])[O:9][C@H:8]2[C@H:4]([N:5]=[C:6]([N:13]([CH2:21][CH2:22][F:23])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[S:7]2)[C@H:3]1[OH:24].[C:25]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[Si:29]([O:12][CH2:11][C@H:10]1[O:9][C@H:8]2[C@H:4]([N:5]=[C:6]([N:13]([CH2:21][CH2:22][F:23])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18])[S:7]2)[C@@H:3]([OH:24])[C@@H:2]1[OH:1])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N(CCF)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCF)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 6 h
Yield: 47.6 %

Procedure:
To a solution of tert-butyl (3aR,5R,6S,7R,7aR)-6,7-dihydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(2-fluoroethyl)carbamate (16 g, 43.7 mmol) in dichloromethane (100 mL) was added tert-butylchlorodimethylsilane (7.6 g, 50.7 mmol), 4-dimethylaminopyridine (530 mg, 4.34 mmol) and triethylamine (6.6 g, 65 mmol). After stirred for 6 h at room temperature, the resulting mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column, eluting with 20% petroleum in ethyl acetate to give compound 69 as pale yellow oil (10 g, 48%). (ES, m/z) [M+H]+ 481.0; 1H NMR (300 MHz, CDCl3) δ 6.17-6.19 (d, J=6.3 Hz, 1H), 4.42-4.74 (m, 3H), 3.52-4.26 (m, 7H), 1.56 (s, 9H), 0.92 (s, 9H), 0.10 (s, 6H).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[C:15]#[N:16])[CH:6]=1)=[O:4].[NH4+].[OH-].[H][H]>[Ni].CCO>[CH3:1][N:2]([CH3:17])[C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH2:15][NH2:16])[CH:6]=1)=[O:4]
Reactant: [H][H]
Reactant: CN(C)C(=O)c1ccc2c(C#N)cccc2c1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)C(=O)c1ccc2c(CN)cccc2c1
Yield: 97 %

Procedure:
A suspension of 5-cyano-naphthalene-2-carboxylic acid dimethylamide, 4, (18.93 g, 84.51 mmol), 28% NH4OH (24 mL) and EtOH (500 mL) is reacted with hydrogen (1 atmosphere) in the presence of Ra—Ni (8 g) catalyst for 4 days. The catalyst is removed by filtration and the filtrate is concentrated in vacuo to afford 18.66 g (97% yield) of the desired product. 1H NMR (300 MHz, CD3OD): δ 8.23 (d, J=8.7 Hz, 1H), 8.70-8.11 (m, 2H), 7.63-7.78 (m, 3H), 4.69 (s, 2H), 3.20, (s, 3H), 3.09 (s, 3H). LRMS: 228.99 (M+1), 211.96 (M+1-NH3).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[Br:29][C:30]1[CH:31]=[CH:32][C:33]2[C:39](=O)[CH2:38][CH2:37][CH2:36][O:35][C:34]=2[CH:41]=1>C1COCC1>[Br:29][C:30]1[CH:31]=[CH:32][C:33]2[C:39](=[CH:2][O:3][CH3:4])[CH2:38][CH2:37][CH2:36][O:35][C:34]=2[CH:41]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCCOc2cc(Br)ccc21
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC=C1CCCOc2cc(Br)ccc21
Temperature: -75 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
14.27 g (1.6 eq.) of (methoxymethyl)triphenylphosphonium chloride was suspended in 50 ml of abs. THF and deprotonated at a temperature of −10° C. and −5° C. by adding via syringe 25.2 ml of 1.6 M n-butyllithium (1.55 eq., in hexane). The resultant red ylide solution was cooled to −75° C. and treated with 6.20 g (26.0 mmol) of 8-bromo-3,4-dihydro-2H-benzo[b]oxepin-5-one dissolved in 13 ml of abs. THF. The mixture was then kept for 0.2 h at −78° C. and for 1 h at room temperature, poured onto crushed ice and extracted with diethylether. The organic phase was washed with water and dried over magnesium sulfate, filtrated and the solvent evaporated to yield a crude product which was purified by flash chromatography (SiO2, hexane/ethylacetate=95/5). Thereby, 5.85 g of 8-bromo-5-methoxymethylene-2,3,4,5-tetrahydrobenzo[b]oxepine was obtained as E/Z-mixture which was hydrolyzed as follows:
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]2[C:22]2[CH:23]=[N:24][C:25](Cl)=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2].[CH3:29]B1OB(C)OB(C)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[CH:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]2[C:22]2[CH:23]=[N:24][C:25]([CH3:29])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)c1ccc(-n2c(-c3ccc(Cl)nc3)nc3ccccc3c2=O)cc1
Reactant: CB1OB(C)OB(C)O1
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: [K+]
Solvent: C1COCCO1
Product: CCC(C)c1ccc(-n2c(-c3ccc(C)nc3)nc3ccccc3c2=O)cc1
Temperature: 25 °C
Yield: 59.3 %

Procedure:
3-(4-sec-butylphenyl)-2-(6-chloropyridin-3-yl)quinazolin-4(3H)-one (0.345 g, 0.89 mmol), trimethyboroxine (0.124 mL, 0.89 mmol), Pd(PPh3)4 (0.102 g, 0.09 mmol), and K2CO3 (0.368 g, 2.67 mmol) were combined in dioxane (10 mL) and heated at reflux under nitrogen for 5 hours. The reaction mixture was cooled to room temperature, filtered through Celite®, with THF washings, concentrated, and purified by flash chromatography on silica gel, eluting with 50% ethyl acetate/heptane to 100% ethyl acetate, to afford the title compound as a white solid (0.195 g, 59%). 1H-NMR (300 MHz, DMSO-6): δ 8.43 (d, J=2.0 Hz, 1H), 8.20 (d, J=6.9 Hz, 1H), 7.89-7.94 (m, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.55-7.65 (m, 2H), 7.13-7.27 (m, 4H), 7.07 (d, J=8.1 Hz, 1H), 2.55-2.60 (m, 1H), 2.36 (s, 3H), 1.37-1.58 (m, 2H), 1.15 (d, J=6.9 Hz, 3H), 0.66 (t, J=7.3 Hz, 3H). MS (APCI) m/z: 370 (M+H)+.
Reaction SMILES: [CH2:1]([NH:13][CH:14]=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].P(Cl)(Cl)(Cl)(Cl)Cl.[CH:22]([NH:25][CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23].[OH-].[Na+]>C1C=CC=CC=1.O>[CH:22]([N:25]([CH:26]([CH3:28])[CH3:27])[CH:14]=[N:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])([CH3:24])[CH3:23]
Reactant: CCCCCCCCCCCCNC=O
Reactant: CC(C)NC(C)C
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCCCCCCN=CN(C(C)C)C(C)C
Reaction time: 12 h

Procedure:
A solution of 213 g of dodecylformamide (1.0 mole) in 500 ml of anhydrous benzene is added dropwise at 20°-30° to a suspension of 208 g of phosphorus pentachloride (1.0 mole) in 750 ml of anhydrous benezne. After a further 12 hours of stirring at 30°, the reaction mixture is concentrated in vacuo to dryness. The residue is then dissolved in 100 ml of anhydrous benzene, and 202 g of di-isopropylamine (2.0 moles) added dropwise at 40°-50°. The whole is heated for 2 hours at 50°; water and ice are added, and the mixture rendered alkaline with aqueous sodium hydroxide solution. The organic layer is then separated and concentrated by evaporation. The N1,N 1 -diisopropyl-N2 -dodecyl-formamidine obtained as residue boils at 125°-128°C and 0.03 Torr.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]=O)=[CH:4][CH:3]=1.Cl.[O:13]([NH2:15])[CH3:14]>>[CH3:14][O:13][N:15]=[CH:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1
Reactant: CON
Reactant: O=CCCc1ccc(F)cc1
Agent: Cl
Product: CON=CCCc1ccc(F)cc1
Yield: 97 %

Procedure:
Reaction of 3-(4-fluorophenyl)-propionaldehyde (Dickinson, R. P.; Dack, K. N.; Steele, J.; Tute, M. S. Bioorg. Med. Chem. Lett., 6, 14, 1996, 1691-1696) with methoxylamine hydrochloride as described in the preparation of compound 3-A gave the title oxime ether as a clear oil (97% yield), bp 65-75° C./1.5 torr (bulb to bulb distillation, air bath temperature). 1HNMR indicated a 6:4 mixture of E- and Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.51 and 2.65 (2H, 2 m, CH2), 2.8 (2H, m, CH2), 3.84 and 3.88 (3H, 2 s, OCH3), 6.67 (t, J=5.5 Hz, CH), 7.0 (2H, m, aromatics), 7.16 (2H, m, aromatics), 7.40 (t, J=4.2 Hz, CH).
Reaction SMILES: Br[CH2:2][C:3]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7](=[O:19])[NH:6][CH:5]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=2[S:28]([CH3:31])(=[O:30])=[O:29])[C:4]=1[C:32](OCC)=[O:33].[CH2:37]([NH2:39])[CH3:38]>C(#N)C>[CH2:37]([N:39]1[C:32](=[O:33])[C:4]2[CH:5]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=3[S:28]([CH3:31])(=[O:29])=[O:30])[NH:6][C:7](=[O:19])[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:10]=3)[C:3]=2[CH2:2]1)[CH3:38]
Reactant: CCN
Reactant: CCOC(=O)C1=C(CBr)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1S(C)(=O)=O
Solvent: CC#N
Product: CCN1CC2=C(C1=O)C(c1ccc(C#N)cc1S(C)(=O)=O)NC(=O)N2c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(rac)-Ethyl 6-(bromomethyl)-4-[4-cyano-2-(methylsulfonyl)phenyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (200 mg, 0.34 mmol; Example 13A) was dissolved in acetonitrile (5 ml), ethylamine (46.1 mg, 1.02 mmol) was added and the mixture was stirred at RT overnight. The reaction mixture was then purified directly by preparative HPLC (column: Kromasil C18, 125 mm×20 mm, 5 μm, 100 Å; mobile phase A: water with 0.01% formic acid, mobile phase B: acetonitrile; gradient: 0 min 10% B→2 min 10% B→9 min 90% B→12 min 90% B→12.1 min 10% B→15 min 10% B; flow rate: 0.35 ml/min; UV detection: 254 nm). This gave 120 mg (70% of theory) of the title compound.