Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH2:18])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[Cl:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=1[N:30]=[C:31]=[O:32]>C(Cl)Cl>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH:18][C:31]([NH:30][C:21]2[CH:22]=[CH:23][C:24]([C:26]([F:27])([F:29])[F:28])=[CH:25][C:20]=2[Cl:19])=[O:32])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1Cl
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C(C)C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(C(F)(F)F)cc2Cl)cc1-c1c(Cl)cnn1C(C)C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
To a solution of 3-(4-chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.1 g, 0.433 mmol) in CH2Cl2, was added 2-chloro-4-trifluoromethyl-phenyl isocyanate (0.107 g, 0.476 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 57 as a colorless solid (0.085 g, 40%). LCMS m/z (%)=489 M+H+ (37Cl, 25), 488 M+H+ (35Cl37Cl, 25), 487 M+H+ (35Cl, 100), 1H NMR (400 MHz, acetone-d6) δ: 8.88 (bs, 1H), 8.544 (bs, 1H), 8.063 (s, 1H), 7.669 (d, J=1.54 Hz, 1H), 7.606 (d, J=2.69 Hz, 1H), 7.58 (t, 1H), 7.549 (d, J=1.51 Hz, 1H), 7.385 (d, J=2.68 Hz, 1H), 7.68-7.64 (m, 1H), 7.080 (d, J=8.98 Hz, 1H), 4.145 (m, 1H), 3.742 (s, 3H), 1.345 (d, J=6.61 Hz, 3H), 1.188 (d, J=6.61 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:19])OC2C=CC([N+]([O-])=O)=CC=2)=[CH:3][CH:2]=1.Cl.[NH2:21][C:22]1[C:23]2[C:33]([O:34][CH2:35][C@H:36]3[CH2:41][CH2:40][CH2:39][NH2+:38][CH2:37]3)=[CH:32][CH:31]=[CH:30][C:24]=2[NH:25][S:26](=[O:29])(=[O:28])[N:27]=1>>[NH2:21][C:22]1[C:23]2[C:33]([O:34][CH2:35][C@H:36]3[CH2:41][CH2:40][CH2:39][N:38]([C:8]([NH:7][C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[O:19])[CH2:37]3)=[CH:32][CH:31]=[CH:30][C:24]=2[NH:25][S:26](=[O:28])(=[O:29])[N:27]=1
Reactant: O=C(Nc1ccncc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCC[NH2+]C3)c21
Agent: Cl
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCN(C(=O)Nc4ccncc4)C3)c21

Procedure:
Prepared as in Example 29 from 4-nitrophenyl pyridin-4-ylcarbamate (Example 28a) and (S)-3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 2a). MS=431 (MH+).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Li]CCCC.[Sn:26](Cl)([CH2:35][CH2:36][CH2:37][CH3:38])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30]>C1COCC1.CCCCCC>[CH2:35]([Sn:26]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)[CH2:36][CH2:37][CH3:38]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)nc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.9 %

Procedure:
Into the solution of tert-butyl 4-(6-bromopyridin-3-yl)piperazine-1-carboxylate 7.13 (1.65 g, 4.8 mmol) in THF (30 mL) was added 1M solution of n-BuLi in hexane (5 mL) and n-Bu3SnCl (1.66 g, 5.1 mmol) at −70° C. After 30 min., the reaction was warmed up to rt. After stirring for 1 h., the reaction mixture was extracted with ethyl acetate and washed with brine. After drying with MgSO4, the organic solvent was removed under vaco., the residue was purified by silica gel chromatography to obtain 0.58 g of tert-butyl 4-(6-(tributylstannyl)pyridin-3-yl)piperazine-1-carboxylate 7.14. LCMS [M+H]+: 554.07.
Reaction SMILES: [N:1]1([C:7]2[C:8](=[O:14])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:16][C:17](=[O:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:19]=[C:17]([CH3:18])[CH2:16][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[C:8](=[O:14])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5]1
Reactant: CC(=O)CCl
Reactant: O=c1cccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)CN1CCN(c2cccccc2=O)CC1
Yield: 42 %

Procedure:
A mixture of 2-(1-piperazinyl)-2,4,6-cycloheptatrien-1-one (12.4 g), described in Example 2), 1-chloro-2-propanone (5.55 g), potassium carbonate (11.04 g) and acetonitrile (120 ml) was refluxed for 4 hr and filtered. Chloroform and water were added to the filtrate. The organic phase was separated, washed with water, dried and evaporated. The residue was chromatographed on silica gel using methanol-ethyl acetate and the eluates were evaporated to give an oil (6.21 g) of 2-[4-(2-oxopropyl)-1-piperazinyl]-2,4,6-cycloheptatrien-1-one (VII; R1, R2, R3 and R4 =H and Alk=C--CH2): ir(CHCl3) 3660, 3360, 1720, 1710, 1660 and 1560 cm-1 ; uv max(MeOH) 351 (ε=9310), 255 (ε=13915) and 221 nm(ε=11750); nmr(CDCl3) δ2.12 (s, 3H), 2.62 (t, 4H), 3.21 (s, 2H), 3.35 (s, 4H) and 6.40-7.10 (m, 5H); and Anal. Calcd for C14H18N2O2 : C, 68.26% H, 7.37% N, 11.37% and Found: C, 67.33% H, 7.59% N, 11.44%.
Reaction SMILES: C[O:2][C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[Cl-].[Li+].O.Cl>CN(C)C=O>[OH:2][C:3]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: COc1cc(C(F)(F)F)ccc1C=O
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(C(F)(F)F)cc1O
Yield: 97.1 %

Procedure:
A mixture of 2-methoxy-4-trifluoromethyl benzaldehyde (Description 96; 18 g, 88 mmol) and lithium chloride (11.19 g; 264 mmol) in anhydrous N,N-dimethylformamide (100 ml) was heated at reflux for 3 hours. The mixture was cooled and poured into water (200 ml), then acidified by the addition of 1N HCl. The mixture was extracted with ether (3×200 ml) then the combined ether layers washed with water (2×500 ml), sat NaCl (100 ml), dried over Na2SO4, filtered and evaporated to give the title compound (16.25 g, 97%).
Reaction SMILES: [NH2:1][C:2](=[S:14])[NH:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5].Br[CH2:16][C:17]([C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[C:22]([OH:28])=[C:21]([OH:29])[CH:20]=1)=O>C(O)C>[OH:29][C:21]1[CH:20]=[C:19]([C:17]2[N:1]=[C:2]([NH:3][S:4]([C:7]3[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=3)(=[O:5])=[O:6])[S:14][CH:16]=2)[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[C:22]=1[OH:28]
Reactant: Cc1ccc(S(=O)(=O)NC(N)=S)cc1
Reactant: O=C(CBr)c1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3cc(O)c(O)c([N+](=O)[O-])c3)cs2)cc1

Procedure:
A mixture of 0.24 g of N-(aminothioxomethyl)-4-methyl-benzenesulfonamide and 0.2 g of 2-bromo-1-(3,4-dihydroxy-5-nitrophenyl)ethanone was dissolved in 5 ml of ethanol and boiled under reflux for 1 h. 0.26 g of N-[4-(3,4-dihydroxy-5-nitro-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide separated as red crystals upon cooling.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[C:16]([NH:25][C:26]3[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=3)[N:17]=[C:18]2[O:21][CH:22]([CH3:24])[CH3:23])=[CH:13][C:12]=1[O:32][CH3:33]>>[CH:22]([O:21][C:18]1[C:19]2[C:14](=[CH:13][C:12]([O:32][CH3:33])=[C:11]([O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:20]=2)[CH:15]=[C:16]([NH:25][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)[N:17]=1)([CH3:24])[CH3:23]
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(OC(C)C)c2cc1F
Reactant: OCCN1CCCCC1
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(OC(C)C)c2cc1OCCN1CCCCC1

Procedure:
Similar procedure as described in example 378 was used, starting from 2-Piperidin-1-yl-ethanol and (7-Fluoro-1-isopropoxy-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-Isopropoxy-6-methoxy-7-(2-piperidin-1-yl-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 440(MH+).
Reaction SMILES: COC[N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]([CH3:22])[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl.C(O)C>O>[CH3:22][N:13]([S:14]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)(=[O:15])=[O:16])[C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[NH:4][C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:6]2
Reactant: CCOC(=O)c1cc2cccc(N(C)S(=O)(=O)c3cccs3)c2n1COC
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc2cccc(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Yield: 45.5 %

Procedure:
A mixture of ethyl 1-(methoxymethyl)-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (1.06 g), concentrated hydrochloric acid (1 ml) and ethanol (5 ml) was heated overnight under reflux. Water was added to the reaction mixture, and the resulting crystals were collected by filtration, washed with water, and dried. The obtained crystals were subjected to silica gel column chromatography to give the title compound (0.43 g, yield 46%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 164-165° C.
Reaction SMILES: [C:1]1(=O)[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9]([NH2:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:9]([N:17]1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1=[O:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=C1CCCCCO1
Reactant: CCCCCCCCN
Product: CCCCCCCCN1CCCCCC1=O

Procedure:
Alternatively, equimolar amounts of 6-hexanolactone and n-octylamine were heated at 190° for 20 hours. In this time, water was distilled off slowly. The residue was distilled to obtain 1-octyl-azacycloheptan-2-one.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:21][CH2:22][CH3:23])[NH:8][C:9]=1[C:10]([O:12][CH2:13][O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:11])([CH3:4])[CH3:3].[C:24]([N:43]1[C:47]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[C:54]2[CH:61]=[CH:60][C:57]([CH2:58]Br)=[CH:56][CH:55]=2)=[N:46][N:45]=[N:44]1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>>[OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:21][CH2:22][CH3:23])[N:8]([CH2:58][C:57]2[CH:56]=[CH:55][C:54]([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=3[C:47]3[N:43]([C:24]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:44]=[N:45][N:46]=3)=[CH:61][CH:60]=2)[C:9]=1[C:10]([O:12][CH2:13][O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:11])([CH3:4])[CH3:3]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCOC(=O)C(C)(C)C)[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCOC(=O)C(C)(C)C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 48.8 %

Procedure:
Following a procedure similar to that described in Example 61(a), but using 0.85 g of pivaloyloxymethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate [prepared as described in Preparation 22(ii)], 1.52 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide and 0.72 g of potassium carbonate, 1.02 g of the title compound were obtained as an amorphous solid.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:29][C:30]1[CH:35]=[CH:34][C:33](B2OC3C=CC=CC=3O2)=[CH:32][CH:31]=1>>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:12]2[N:13]([CH:18]([CH3:19])[CH3:20])[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)=[CH:32][CH:31]=1
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: Clc1ccc(B2Oc3ccccc3O2)cc1
Product: CC(C)n1nc2c(c1-c1ccc(Cl)cc1)CCNCC2
Yield: 59 %

Procedure:
The title compound (82 mg) was prepared as in Example 177, Steps C and D, using 205 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 332 mg of 2-(4-chloro-phenyl)-benzo[1,3,2]dioxaborole. MS (ESI): exact mass calculated for C16H20ClN3, 289.13; found, m/z 290.4 [M+H]+, 292.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.57 (d, J=8.5 Hz, 2H), 7.33 (d, J=8.5 Hz, 2H), 4.36 (m, 1H), 3.44-3.40 (m, 2H), 3.20-3.18 (m, 2H), 2.81-2.76 (m, 2H), 1.40 (d, J=6.6 Hz, 6H).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].CO[C:8](=[O:42])[CH2:9][CH2:10][C:11]1[S:15][C:14]([CH:16]([NH:21][C:22](=[O:41])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])=[O:32])=[CH:26][CH:25]=2)[CH2:17][CH:18]([CH3:20])[CH3:19])=[N:13][CH:12]=1.Cl>CO>[OH:3][NH:2][C:8](=[O:42])[CH2:9][CH2:10][C:11]1[S:15][C:14]([CH:16]([NH:21][C:22](=[O:41])[CH2:23][C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:31]([NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])=[O:32])=[CH:28][CH:29]=2)[CH2:17][CH:18]([CH3:19])[CH3:20])=[N:13][CH:12]=1
Reactant: COC(=O)CCc1cnc(C(CC(C)C)NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)cc2)s1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)NC(CC(C)C)c2ncc(CCC(=O)NO)s2)cc1
Temperature: 90 °C
Yield: 21.8 %

Procedure:
Hydroxylamine hydrochloride (6.96 g) was suspended in methanol ( 35 mL) and heated to 90° C. This solution was added to potassium hydroxide (8.34 g) dissolved in methanol (21 mL) After 15 minutes of stirring, the solution was filtered and 3-[2-(3-methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-thiazol-5-yl]propionic acid methyl ester (0.80 g, 1.53 mmol) was added. The reaction was stirred at room temperature for 15 minutes, 1N HCl (50 mL) was added, and the methanol was removed in vacuo. The residue was partitioned between ethyl acetate and hydrochloric acid (1N). The organic portion was dried over sodium sulfate and the solvent removed in vacuo. The title compound (0.175 g, 17%) was isolated by crystallization from a mixture of ethyl acetate and methanol. MS [M+1] 524.1.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH2:37][CH2:38][NH:39][CH2:40][CH:41]=2)=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:39]1[CH2:38][CH:37]=[C:36]([C:33]2[CH:34]=[CH:35][C:30]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:31][CH:32]=2)[CH2:41][CH2:40]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCCCBr)Nc1ccccc1Cc1ccccc1
Reactant: C1=C(c2ccc(Oc3ccccc3)cc2)CCNC1
Product: O=C(CCCCCN1CC=C(c2ccc(Oc3ccccc3)cc2)CC1)Nc1ccccc1Cc1ccccc1

Procedure:
The compound (12) synthesized in Reference Example 12 and the compound (3) synthesized in Reference Example 3 were used to produce the above compound in the same way as Example 1.
Reaction SMILES: BrC[C:3]1[CH:8]=[CH:7][C:6]([C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.[C:17]([O-:20])(=[O:19])[CH3:18].[K+]>CN1CCCC1=O.O.[I-].[K+]>[C:17]([O:20][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=1)(=[O:19])[CH3:18]
Reactant: COC=C(C(=O)OC)c1ccc(CBr)cc1
Reactant: CC(=O)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC=C(C(=O)OC)c1ccc(OC(C)=O)cc1
Reaction time: 3 h
Yield: 82.9 %

Procedure:
3 g (10.5 mmol) of methyl 2-(p-bromomethylphenyl)-3-methoxyacrylate (prepared similarly to EP 226 917), 1.1 g (11.2 mmol) of potassium acetate and 50 mg of potassium iodide in 70 ml of N-methylpyrrolidone are stirred for 3 hours at 70°-80° C. The reaction mixture is diluted with water and extracted three times with ether. The combined ether phases are washed with water, dried over MgSO4 and evaporated down. Purification of the residue by column chromatography gives 2.3 g (8.7 mmol, 83%) of the title compound as colorless crystals (mp.= 69°-70° C.).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:4][C:3]1=2.[CH3:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[CH3:20][C:21]1[CH:26]=[C:25]([C:6]2[CH:7]=[C:8]3[C:3](=[CH:4][CH:5]=2)[C:2](=[O:1])[CH2:11][CH2:10][CH2:9]3)[CH:24]=[CH:23][CH:22]=1
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: Cc1cccc(B(O)O)c1
Product: Cc1cccc(-c2ccc3c(c2)CCCC3=O)c1

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester and 3-methylphenyl boronic acid according to the coupling procedure as described in example 6. MS (ESI) m/z 237.
Reaction SMILES: [OH-].[K+].[C:3]([O:7][C:8](=[O:31])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:12][CH:11]=1)([CH3:6])([CH3:5])[CH3:4].[CH2:32]([O:34][C:35](=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:42]Br)[CH3:33]>CS(C)=O>[CH2:32]([O:34][C:35](=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:42][N:9]([C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:31])[C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:14][CH:15]=1)[CH3:33]
Reactant: CCOC(=O)c1ccccc1CBr
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(NC(=O)OC(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCOC(=O)c1ccccc1CN(C(=O)OC(C)(C)C)c1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Reaction time: 2.5 h
Yield: 94 %

Procedure:
To a suspension of 3.41 g of powdered KOH in 110 ml of DMSO was added at 22° C. 6.00 g of {4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-carbamic acid tert-butyl ester and the suspension was stirred for 25 min. A solution of 7.40 g of 2-bromomethyl-benzoic acid ethyl ester in 10 ml of DMSO was added slowly keeping the temperature at 15-20° C. and stirring was continued at 22° C. for 2.5 h. The dark mixture was partitioned between 500 ml of a saturated aqueous NH4Cl and 200 ml of AcOEt, the organic layer was washed with saturated aqueous NH4Cl and water, dried and evaporated. The residue was purified by chromatography (SiO2, n-hexane/AcOEt 4:1) to give 7.96 g of the title compound as a pale yellow oil. MS: (M+H)+ 557.3.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([N:13]2[C:17]([CH3:18])=[N:16][N:15]=[N:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH:19][CH2:20][C:21]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.[H-].[Na+]>CN(C)C=O.O>[CH3:18][C:17]1[N:13]([C:5]2[CH:4]=[C:3]([CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)[CH2:2][O:19][CH2:20][C:21]2([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[N:14]=[N:15][N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Reactant: Cc1nnnn1-c1cc(CBr)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nnnn1-c1cc(COCC2(c3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-(3-(Bromomethyl)-5-(trifluoromethyl)phenyl)-5-methyl-1H-tetrazole (30.0 mg, 0.09 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (29.0 mg, 0.1 mmol) were combined in dimethylformamide (2 mL) and cooled to 0° C. The reaction was treated with sodium hydride (2.4 mg, 0.1 mmol), stirred at 0° C. for 1 hr and at room temperature for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (40% ethyl acetate/hexanes) gave 40 mg (81%). LC/MS (HPLC method 3): tR=3.14 min, 532.24 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([CH3:18])=[C:16](I)[C:15]([CH3:20])=[N:14]1.[CH:21]([Sn](CCCC)(CCCC)CCCC)=[CH2:22]>CN(C)C=O.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>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([CH3:18])=[C:16]([CH:21]=[CH2:22])[C:15]([CH3:20])=[N:14]1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(C)c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1c(C)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C
Temperature: 75 °C
Reaction time: 2 h

Procedure:
A solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3,5-dimethyl4-iodopyrazole (1 g) in dimethylformamide (10 ml) containing yinyltri-n-butyltin (2 ml) and tetrakis(triphenylphosphine)palladium(0) (0.1 g) was stirred at 75° C. for 2 hours then left overnight at room temperature. The mixture was again heated at 75° C. for 2 hours then vinyltri-n-butyltin (2 ml) was added and the mixture heated at 75° C. for 2 hours. Tetrakis(triphenylphosphine)palladium(0) (0.1 g) was added and heating continued for a further 2 hours. The reaction mixture was evaporated and the residue partitioned between water and dichloromethane. The organic layer was separated, washed with water (×2), then brine, dried (Na2SO4) and evaporated. The residue was adsorbed onto silica gel (20 g) and purified by column chromatography on silica gel (150 g) eluted with hexane, then hexane with increasing amounts of dichloromethane and finally dichloromethane. Combination and evaporation of suitable fractions provided the title compound as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH3:15]
Reactant: Oc1ccccc1Cl
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccccc1Cl

Procedure:
The title compound was prepared by reacting 2-chloro-phenol, with ethyl 2-bromoacetate and K2CO3 in DMF. Yield, 97%, colourless oil; 1H NMR (CDCl3): 1.29 (3H, t, J=6.3, CH2CH3), 4.29 (2H, q, J=6.3, CH2CH3), 4.72 (2H, s, OCH2), 6.76 (1H, d, J=8.2, H-6), 6.95 (1H, m, H-4), 7.20 (1H, m, H-5), 7.40 (1H, dd, J=8.2, H-3).
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH:4]=[C:5]1[C:9]2=[N:10][C:11]3[CH:12]=[CH:13][C:14]([C:19]([OH:21])=[O:20])=[CH:15][C:16]=3[C:17](=[O:18])[N:8]2[CH2:7][CH2:6]1.[CH2:26](I)[CH3:27].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH:4]=[C:5]1[C:9]2=[N:10][C:11]3[CH:12]=[CH:13][C:14]([C:19]([O:21][CH2:26][CH3:27])=[O:20])=[CH:15][C:16]=3[C:17](=[O:18])[N:8]2[CH2:7][CH2:6]1
Reactant: Cc1ccccc1C=C1CCn2c1nc1ccc(C(=O)O)cc1c2=O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2nc3n(c(=O)c2c1)CCC3=Cc1ccccc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-pyrrolo[2,1-b]quinazoline-7-carboxylic acid (1 g) was reacted with ethyl iodide (0.93 g) and anhydrous K2CO3 (0.83 g) in dimethylformamide (10 ml) under stirring at room temperature for 16 hours. After dilution with ice water the precipitate was filtered and washed with water until neutral: crystallization from chloroform-ethanol gave 0.9 g of 3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-pyrrolo[2,1-b]quinazoline-7-carboxylic acid, ethyl ester, m.p. 184°-185° C.