Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[O:7][C:6]([CH3:8])=[N:5][CH:4]=1.[NH:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[NH:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[CH3:8][C:6]1[O:7][C:3]([CH2:2][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]2)=[CH:4][N:5]=1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Reactant: Cc1ncc(CBr)o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2Cc2cnc(C)o2)CC1
Temperature: 80 °C
Reaction time: 18 h
Yield: 11.2 %

Procedure:
A mixture of 23 parts of 5-(bromomethyl)-2-methyloxazole, 57.6 parts of ethyl 4-[(1H-benzimidazol-2-yl)amino]-1-piperidinecarboxylate, 26.5 parts of sodium carbonate and 470 parts of N,N-dimethylformamide was stirred for 18 hours at 80° C. The reaction mixture was poured into water and the whole was extracted with 4-methyl-2-pentanone. The extract was washed with water, dried, filtered and evaporated. The residue was stirred in acetonitrile. The precipitate was filtered off and the filtrate was evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 90:10). The eluent of the desired fraction was evaporated, yielding 6 parts (11.2%) of ethyl 4-[[1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate (comp. 2).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:32])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH:25]([OH:30])[C:26]([F:29])([F:28])[F:27])[CH:23]=3)[N:18]([CH3:31])[N:17]=2)[CH2:9]1.[O:33]1[C:37]2[CH:38]=[CH:39][C:40]([CH:42]3[CH2:47][CH2:46][C:45](=O)[CH2:44][CH2:43]3)=[CH:41][C:36]=2[O:35][CH2:34]1>>[O:33]1[C:37]2[CH:38]=[CH:39][C:40]([CH:42]3[CH2:47][CH2:46][CH:45]([N:8]4[CH2:11][CH:10]([NH:12][C:13](=[O:32])[CH2:14][NH:15][C:16]5[C:24]6[C:19](=[CH:20][CH:21]=[C:22]([CH:25]([OH:30])[C:26]([F:29])([F:28])[F:27])[CH:23]=6)[N:18]([CH3:31])[N:17]=5)[CH2:9]4)[CH2:44][CH2:43]3)=[CH:41][C:36]=2[O:35][CH2:34]1
Reactant: O=C1CCC(c2ccc3c(c2)OCO3)CC1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(O)C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(NCC(=O)NC2CN(C3CCC(c4ccc5c(c4)OCO5)CC3)C2)c2cc(C(O)C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-[1-methyl-5-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-indazol-3-ylamino]-acetamide TFA salt (as prepared in Example 60, Step B) and 4-benzo[1,3]dioxol-5-yl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:38]2[CH2:50][CH2:49][N:41]3[C:42]4[CH2:43][CH2:44][CH2:45][CH2:46][C:47]=4[CH:48]=[C:40]3[C:39]2=[O:51])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]4[CH2:34][O:33][CH2:32]4)[CH2:27][C@H:26]3[CH3:35])=[CH:21][N:20]=2)[C:15](=[O:36])[N:14]([CH3:37])[CH:13]=1)(=O)C.O.[Li+].[OH-]>CC(O)C.O1CCCC1>[OH:4][CH2:5][C:6]1[C:7]([N:38]2[CH2:50][CH2:49][N:41]3[C:42]4[CH2:43][CH2:44][CH2:45][CH2:46][C:47]=4[CH:48]=[C:40]3[C:39]2=[O:51])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]4[CH2:34][O:33][CH2:32]4)[CH2:27][C@H:26]3[CH3:35])=[CH:21][N:20]=2)[C:15](=[O:36])[N:14]([CH3:37])[CH:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)C[C@H]4C)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CCCC6)C4=O)c3CO)cn(C)c2=O)nc1
Temperature: 30 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
To a solution of 137a (200 mg, 0.29 mmol) in propan-2-ol (8 mL), tetrahydrofuran (8 mL), and water (2.0 mL) was added LiOH (690 mg, 29 mmol). The mixture was stirred at 30° C. for 2 h. It was then evaporated and the residue was purified by reverse-phase prep-HPLC to afford 137 (143 mg, 76%) as a white solid. LCMS: (M+H)+ 651.4. 1H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J=2.0, 1H), 8.49 (d, J=5.0, 1H), 8.45 (s, 1H), 7.84 (d, J=2.5, 1H), 7.47 (d, J=2.0, 1H), 7.37-7.39 (m, 1H), 7.35 (d, J=5.5, 1H), 7.25 (d, J=9.5, 1H), 6.58 (s, 1H), 4.95 (t, J=4.0, 1H), 4.54-4.58 (m, 2H), 4.40-4.49 (m, 4H), 4.11-4.26 (m, 3H), 3.86-3.88 (m, 1H), 3.68 (s, 1H), 3.61 (s, 3H), 3.37-3.42 (m, 1H), 3.08-3.11 (m, 1H), 2.95 (t, J=9.0, 1H), 2.62-2.67 (m, 1H), 2.54-2.59 (m, 2H), 2.48 (t, J=6.0, 2H), 2.30-2.36 (m, 2H), 2.19 (t, J=8.0, 1H), 1.81 (s, 2H), 1.68-1.72 (m, 2H), 0.93 (d, J=6.0, 3H)
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][CH2:14][C:4]=2[N:5]=[C:6]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:7]=1.[CH2:17]([O:19][C:20](=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)[CH3:18]>>[CH:9]1([O:8][C:6]2[N:7]=[C:2]([NH:28][C:25]3[CH:24]=[CH:23][C:22]([CH2:21][C:20]([O:19][CH2:17][CH3:18])=[O:29])=[CH:27][CH:26]=3)[C:3]3[CH2:16][CH2:15][CH2:14][C:4]=3[N:5]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Clc1nc(OC2CCCC2)nc2c1CCC2
Reactant: CCOC(=O)Cc1ccc(N)cc1
Product: CCOC(=O)Cc1ccc(Nc2nc(OC3CCCC3)nc3c2CCC3)cc1
Yield: 93 %

Procedure:
Following General Procedure B2, 4-chloro-2-(cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.075 g, 0.31 mmol) was reacted with 4-aminophenylacetic acid ethyl ester (0.084 g, 0.47 mmol) to afford the title compound (0.110 g, crude) as a white solid. MW=381.47. 1H NMR (CD3OD, 300 MHz) δ 7.61 (d, J=8.6 Hz, 2H), 7.18 (d, J=8.6 Hz, 2H), 5.55-5.45 (m, 1H), 4.13 (q, J=7.6 Hz, 2H), 3.57 (s, 2H), 2.79 (t, J=7.6 Hz, 2H), 2.71 (t, J=7.6 Hz, 2H), 2.14-1.95 (m, 4H), 1.89 (s, 1H), 1.87-1.76 (m, 4H), 1.72-1.61 (m, 2H), 1.24 (t, J=7.1 Hz, 1H); APCI MS m/z 382 [M+H]+.
Reaction SMILES: [C:1]([O:8]CC)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(OCC)(=O)C(OCC)=[O:13]>>[O:13]=[C:2]([CH2:3][CH2:4][CH2:5][CH3:6])[C:1]([OH:8])=[O:7]
Reactant: CCCCCC(=O)OCC
Reactant: CCOC(=O)C(=O)OCC
Product: CCCCC(=O)C(=O)O

Procedure:
Ethyl n-hexanoate and diethyl oxalate were subjected to Claisen condensation, and then hydrolyzed to form 2-oxo-n-hexanoic acid. This product was then condensed with diaminomaleonitrile to form 9.1 g (0.042 mole) of 2,3-dicyano-5-hydroxy-6-n-pentylpyrazine (m.p. 61°-64° C.). The product was dissolved in 120 g of phosphorus oxychloride, and 3.32 g (0.042 mole) of pyridine was added. The mixture was refluxed for 5 hours, and then worked up in the same way as in Example 3 and the resulting oily product was concentrated under reduced pressure. The resulting product was chromatographed on a silica gel column with benzene as an eluent to afford 6.0 g (yield 61%) of 2,3-dicyano-5-chloro-6-n-pentyl-pyrazine as a yellow liquid.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:23][C:22]([C:24]([O:26]C)=[O:25])=[CH:21][C:9]=3[N:10]([CH2:18][O:19][CH3:20])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CO>[CH:1]1([C:7]2[C:8]3[S:23][C:22]([C:24]([OH:26])=[O:25])=[CH:21][C:9]=3[N:10]([CH2:18][O:19][CH3:20])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COCn1c(-c2ccccc2)c(C2CCCCC2)c2sc(C(=O)OC)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COCn1c(-c2ccccc2)c(C2CCCCC2)c2sc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 21 h
Yield: 93 %

Procedure:
A solution (0.1 M) of methyl 6-cyclohexyl-4-(methoxymethyl)-5-phenyl-4H-thieno[3,2-b]pyrrole-2-carboxylate in THF/MeOH (1:1) was treated with aqueous NaOH (1 N solution, 5 eq.). The mixture was stirred at RT for 21 h then concentrated and acidified to pH 4-5 with aqueous HCl (1 N) and extracted with AcOEt. The combined organic phase was dried and concentrated to give a residue that was triturated with MeCN/Et2O (20:1) and filtered to afford the title compound (93%) as a solid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=[O:17])=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:21]=[C:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=[CH:24][C:25]=1C(O)=O.[CH3:35]O>>[CH3:19][C:20]1[CH:21]=[C:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=[CH:24][C:25]=1[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([O:18][CH3:35])=[O:17])=[O:7]
Reactant: CO
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Cc1cc(-c2ccccc2)ccc1C(=O)O
Product: CON=C1C[C@@H](C(=O)OC)N(C(=O)c2ccc(-c3ccccc3)cc2C)C1

Procedure:
Following the general method as outlined in Example 11, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 3-methyl[1,1′-biphenyl]-4-carboxylic acid, and methanol, the title compound isolated as a mixture of two isomers in 82.3% purity by HPLC.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH2:5][CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>C(O)C>[CH:6]1([CH2:5][CH:4]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[C:3]([OH:23])=[O:2])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCCCC1)c1ccc(S(C)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(CC2CCCCCC2)C(=O)O)cc1
Yield: 85.9 %

Procedure:
A solution of 3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-propionic acid methyl ester (95 mg, 0.28 mmol) in ethanol (2 mL) was treated with a 1N aqueous sodium hydroxide solution (1.5 mL). The solution was heated at 45–50° C. for 15 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was concentrated in vacuo to remove ethanol. The residue was diluted with water (10 mL) and extracted with diethyl ether (1×20 mL) to remove any neutral impurities. The aqueous layer was then acidified with a 1N aqueous hydrochloric acid solution, and the resulting acid was extracted into ethyl acetate (2×15 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-propionic acid (78 mg, 86%) as a white solid: EI-HRMS m/e calcd for C17H24O4S (M+H)+ 325.1474, found 325.1478.
Reaction SMILES: C([O:8][N:9]1[CH2:13][CH2:12][NH:11][C:10]1=[N:14][C:15]1[C:20]([Cl:21])=[CH:19][C:18]([O:22][CH3:23])=[CH:17][C:16]=1[Cl:24])C1C=CC=CC=1.C(O)(=O)C.C(Cl)C1C=CC=CC=1>C(O)C.[Pt]=O>[Cl:21][C:20]1[CH:19]=[C:18]([O:22][CH3:23])[CH:17]=[C:16]([Cl:24])[C:15]=1[N:14]=[C:10]1[NH:11][CH2:12][CH2:13][N:9]1[OH:8]
Reactant: COc1cc(Cl)c(N=C2NCCN2OCc2ccccc2)c(Cl)c1
Agent: O=[Pt]
Solvent: CCO
Solvent: ClCc1ccccc1
Solvent: CC(=O)O
Product: COc1cc(Cl)c(N=C2NCCN2O)c(Cl)c1

Procedure:
44.3 g of 1-(benzyloxy)-2-[(2,6-dichloro-4-methoxyphenyl)imino]imidazoline are dissolved in 350 ml of ethanol and 350 ml of acetic acid and treated with 13.8 ml of benzyl chloride. The mixture is hydrogenated in the presence of 1 g of platinum oxide under normal pressure. After completion of the hydrogen uptake, the catalyst is removed by filtration and the solution is evaporated. The residue is treated with water and washed with ether. The aqueous phase is made alkaline and extracted with ethyl acetate. After drying and evaporating the organic extracts and recrystallization of the residue from ethyl acetate/methanol, there is obtained 2-[(2,6-dichloro-4-methoxyphenyl)imino]-1-hydroxyimidazolidine of melting point 199°-201°.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][C:14]#[N:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][CH2:14][NH2:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCc1ccccc1-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCCc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine 2-phenylphenylacetonitrile (4.69 g, 24.26 mmol) and diethyl ether (10 ml) and add dropwise to a cooled (−10°) solution of LiAlH4 (2.76 g, 72.81 mmol) in diethyl ether (100 ml). Warm to ambient temperature. After 2 hours, quench with saturated sodium sulfate (100 mL/mol). Filter to remove the precipitate, dry (Na2SO4) the filtrate, filter, and concentrate to residue. Chromatograph the residue on silica gel eluting with dichloromethane/2N NH3(methanol) (95/5) to give the title compound as a yellow oil. Prepare the HCl salt in diethyl ether: mp 197-199° C. MS (ACPI): m/e 198.1 (M+1). Analysis for C14H16ClN: Calcd: C, 71.94; H, 6.90; N, 5.99. found: C, 72.15; H, 6.84; N, 6.09.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:7][C:8]=2O)[C:3]=1[S:17]([OH:20])(=[O:19])=[O:18].FC1N=NN=C(F)C=1F.N1CCOCC1>>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:7][C:6]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:5][C:4]=2[C:3]=1[S:17]([OH:20])(=[O:19])=[O:18]
Reactant: Nc1ccc2c(O)cc(S(=O)(=O)O)cc2c1S(=O)(=O)O
Agent: Fc1nnnc(F)c1F
Solvent: C1COCCN1
Product: Nc1ccc2c(S(=O)(=O)O)cc(S(=O)(=O)O)cc2c1S(=O)(=O)O
Yield: 200 %

Procedure:
31.9 g of 2-amino-5-hydroxynaphthalene-1,7-disulphonic acid are condensed by the procedure of Example 1 with trifluorotriazine and then with morpholine. A diazo compound obtained in the usual manner by direct diazotisation of 38.3 g of 2-aminonaphthalene-1,5,7-trisulphonic acid is added to the resulting suspension of the monofluorotriazinyl compound at 5° to 10°, while simultaneously maintaining the pH at 7.0 to 7.5 by sprinkling in sodium bicarbonate. After coupling is complete, the dyestuff of the formula ##STR17## is salted out, filtered off with suction, dried and milled.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[C:18]3[C:17]([NH:19][C@H:20]([C:22]4[N:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:26](=[O:34])[C:25]5=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]5[N:23]=4)[CH3:21])=[N:16][CH:15]=[N:14][C:13]=3[N:12](COCC[Si](C)(C)C)[CH:11]=2)[CH:6]=[CH:7][CH:8]=1.FC(F)(F)C(O)=O.N>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[C:18]3[C:17]([NH:19][C@H:20]([C:22]4[N:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:26](=[O:34])[C:25]5=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]5[N:23]=4)[CH3:21])=[N:16][CH:15]=[N:14][C:13]=3[NH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(Sc2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(Sc2c[nH]c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Yield: 186.2 %

Procedure:
(S)-2-(1-((5-((3-Methoxyphenyl)thio)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (10.2 mg, 0.02 mmol) was treated with trifluoroacetic acid (1 mL, 12.98 mmol) and a solution of ammonia (7N in methanol, 1 mL, 7 mmol) according to the method described in Example 27 to give 19.5 mg (83% yield) of the title compound. Purity 100%.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[C:16]([F:18])[C:15](Br)=[CH:14][C:13]=2[F:20])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[OH-].[NH4+].O.ClCCl.[CH3:27][N:28](C)C=O>>[C:27]([C:15]1[C:16]([F:18])=[CH:17][C:12]([C:9]2[CH2:8][CH2:7][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH:10]=2)=[C:13]([F:20])[CH:14]=1)#[N:28]
Reactant: CN(C)C=O
Reactant: CCOC(=O)N1CC=C(c2cc(F)c(Br)cc2F)CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)N1CC=C(c2cc(F)c(C#N)cc2F)CC1

Procedure:
A mixture of 27.60 g (79.8 mmol) 1-ethoxycarbonyl-4-(4-bromo-2,5-difluorophenyl)-1,2,3,6-tetrahydropyridine and 9.00 g (89.6 mmol) cuprous cyanide in 300 ml N,N-dimethylformamide was stirred at reflux for 20 hours. The mixture was cooled and shaken with 800 ml concentrated ammonium hydroxide, 800 ml water and 1,000 ml of dichloromethane. The organic layer was washed with water, dried (MgSO4) and evaporated. The product was purified by chromatography on silica gel and crystallization from hexane to give the title compound, mp 85°-87° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:13][C@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1[C:20]([NH:22][C@@H:23]([CH2:27][CH2:28][C:29]([NH2:31])=O)[C:24]([NH2:26])=O)=[O:21])=[O:12].FC(F)(F)C(OC(=O)C(F)(F)F)=O.Cl>N1C=CC=CC=1.C(Cl)Cl>[C:24]([CH:23]([NH:22][C:20]([C@@H:15]1[CH2:16][CH2:17][CH2:18][CH2:19][C@@H:14]1[NH:13][C:11]([C:3]1[N:2]([CH3:1])[C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:12])=[O:21])[CH2:27][CH2:28][C:29]#[N:31])#[N:26]
Reactant: Cn1c(C(=O)N[C@H]2CCCC[C@H]2C(=O)N[C@@H](CCC(N)=O)C(N)=O)cc2ccccc21
Agent: Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1c(C(=O)N[C@H]2CCCC[C@H]2C(=O)NC(C#N)CCC#N)cc2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91.5 %

Procedure:
To a 0° C. suspension of (S)-2-({(1R,2S)-2-[(1-Methyl-1H-indole-2-carbonyl)-amino]-cyclohexanecarbonyl}-amino)-pentanedioic acid diamide (0.53 g, 1.2 mmol) in 30 mL of anhydrous pyridine and 30 mL of CH2Cl2 was slowly added trifluoroacetic anhydride dropwise. The resulting yellow reaction mixture was stirred at 0° C. for 15 min, and poured into a slurry of ice and a 1N HCl solution. The mixture was extracted with 250 mL of ethyl acetate, washed with a 1N solution of HCl (3×250 mL), water (250 mL), and dried with sodium sulfate, filtered, concentrated and purified by column chromatography (5:95, MeOH/CH2Cl2) to give 430 mg (89%) of 1-methyl-1H-indole-2-carboxylic acid [(1S,2R)-2-(1,3-dicyano-propylcarbamoyl)-cyclohexyl]-amide as a light-yellow liquid, which was determined to be a 38:62 ratio of epimers by 1H NMR spectroscopy. MS: 392 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5](OC)[C:4]=1/[CH:11]=[N:12]/[CH:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH3:2].[CH:20]([Li])([CH2:22][CH3:23])[CH3:21]>>[CH:20]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1/[CH:11]=[N:12]/[CH:13]([CH:14]([CH3:15])[CH3:16])[CH:17]([CH3:19])[CH3:18])([CH2:22][CH3:23])[CH3:21]
Reactant: [Li]C(C)CC
Reactant: CCc1cccc(OC)c1/C=N/C(C(C)C)C(C)C
Product: CCc1cccc(C(C)CC)c1/C=N/C(C(C)C)C(C)C

Procedure:
rac-(E)-[1-(2-sec-Butyl-6-ethyl-phenyl)-methylidene]-(1-isopropyl-2-methyl-propyl)-amine was prepared from (E)-[1-(2-ethyl-6-methoxy-phenyl)-methylidene]-(1-isopropyl-2-methyl-propyl)-amine (Example 3 a) and sec.-butyl lithium in analogy to procedure Example 5 a): colourless liquid: MS (ISP): 288.1 ((M+H)+.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11](=[CH:12][CH:13]=1)[O:10][CH2:9][C:6]1([CH2:8][CH2:7]1)[C:5]2([NH:19][C:20]([NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[S:21])[C:14]([F:18])([F:17])[CH2:15]O.ClC(N(C)C)=C(C)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]3([C:14]([F:17])([F:18])[CH2:15][S:21][C:20]([NH:22][C:23](=[O:30])[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[N:19]3)[C:6]3([CH2:7][CH2:8]3)[CH2:9][O:10][C:11]2=[CH:12][CH:13]=1
Reactant: O=C(NC(=S)NC1(C(F)(F)CO)c2cc(Br)ccc2OCC12CC2)c1ccccc1
Agent: CC(C)=C(Cl)N(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(NC1=NC2(c3cc(Br)ccc3OCC23CC3)C(F)(F)CS1)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 60.4 %

Procedure:
Under ice cooling, to a solution of N-{[6-bromo-4-(1,1-difluoro-2-hydroxyethyl)-4H spiro[chromene-3,1′-cyclopropan]-4-yl]carbamothioyl}benzamide (340 mg, 0.684 mmol) in CH2Cl2 (9 mL) was added 1-chloro-N,N,2-trimethylprop-1-en-1-amine (206 mg, 1.54 mmol), and the mixture was stirred for 17 hours at room temperature. Ice was added and the mixture was neutralized by 10% aqueous K2CO3 and extracted with CH2Cl2. The organic layer was washed with brine and dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (EtOAc/hexane=1:99-40:60) to afford N-(6′-bromo-5″,5″-difluoro-5″,6″-dihydrodispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]thiazin]-2″-yl)benzamide (198 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH:15][C:16](=[O:33])[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)[CH:21]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=4)[CH:21]=3)[CH2:17][C:16](=[O:33])[NH:15][C:9]=2[CH:10]=1
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)ccc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-c2cccc(C3=Nc4ccc(Cl)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from (4-chloro-2-{3-[3-(6-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M28) (282 mg, 0.59 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (163 mg).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:7][O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]1[C:28](=[O:29])[C:27]3([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:26][C:25]1=[O:35])[CH2:13][O:14]2.[C:36](O)(=O)[C:37](O)=O>>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:1]([N:19]([CH2:20][CH2:21][CH2:22][CH2:23][N:24]1[C:28](=[O:29])[C:27]2([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:26][C:25]1=[O:35])[CH:12]1[CH2:11][C:10]2[C:15](=[CH:16][CH:17]=[CH:18][C:9]=2[O:8][CH3:7])[O:14][CH2:13]1)[CH2:36][CH3:37]
Reactant: COc1cccc2c1CC(NCCCCN1C(=O)CC3(CCCCC3)C1=O)CO2
Agent: O=C(O)C(=O)O
Product: CCCN(CCCCN1C(=O)CC2(CCCCC2)C1=O)C1COc2cccc(OC)c2C1

Procedure:
Using the procedure described in Example 10, but replacing the compound of Example 9 by the compound of Example 28, the product of the title is obtained. It is salified with oxalic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](O)=[O:11])=[C:7]([CH2:13][CH3:14])[C:6]=2[CH:15]=1.CO>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][OH:11])=[C:7]([CH2:13][CH3:14])[C:6]=2[CH:15]=1
Reactant: CCc1c(C(=O)O)oc2ccc(Br)cc12
Solvent: C1CCOC1
Solvent: CO
Product: CCc1c(CO)oc2ccc(Br)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a stirred solution of 5-bromo-3-ethylbenzofuran-2-carboxylic acid (1.91 g) in dry tetrahydrofuran (70 ml) at 0° C. under an atmosphere of dry nitrogen was added dropwise borane-tetrahydrofuran complex (25 ml of 1M solution). The solution was stirred at 0° C. for 1 hour and then at room temperature for 24 hours. Methanol was added continuously to decompose the excess borane complex and then the solution was evaporated. The residue was dissolved in ether and the solution was washed with water and dried (Na2SO4). Evaporation of the ether gave a solid which was chromatographed on silica gel. Elution with chloroform gave a solid which was crystallised from ethyl acetate/petrol to give 5-bromo-3-ethyl-2-hydroxymethylbenzofuran (1.05 g), m.p. 93°-94°.