Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][N:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1.[CH3:15][S:16]([N:19]=[C:20](SC)[S:21][CH3:22])(=[O:18])=[O:17]>C(OCC)(=O)C>[CH3:13][N:12]([CH2:11][C:9]1[O:10][C:6]([CH2:5][S:4][CH2:3][CH2:2][NH:1][C:20]([S:21][CH3:22])=[N:19][S:16]([CH3:15])(=[O:18])=[O:17])=[CH:7][CH:8]=1)[CH3:14]
Reactant: CSC(=NS(C)(=O)=O)SC
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: CCOC(C)=O
Product: CSC(=NS(C)(=O)=O)NCCSCc1ccc(CN(C)C)o1
Yield: 79 %

Procedure:
A mixture of 5-[[(2-aminoethyl)thio]methyl]-N,N-dimethyl-furanmethanamine (2.97 g) and methylsulphonylcarbonimidodithioic acid, dimethyl ester (4.0 g) in ethyl acetate (250 ml) was refluxed for 18 hours. The mixture was washed with acetic acid (0.126 ml) in water (20 ml) three times, the aqueous extracts combined and the pH adjusted to 9 with 8% aqueous potassium carbonate. The oily suspension was extracted with ethyl acetate (3×125 ml), the combined extracts dried (magnesium sulphate) and evaporated to dryness to give the title compound (4 g) as a yellow oil.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23](O)=[O:24])[CH:18]=2)[CH2:13][CH2:12]1.[N:26]1([CH2:31][CH2:32][CH2:33][CH:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[NH:36][CH2:35]2)[CH2:30][CH2:29][CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[N:26]1([CH2:31][CH2:32][CH2:33][CH:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]([C:23]([C:19]3[N:20]=[CH:21][N:22]=[C:17]([N:14]4[CH2:13][CH2:12][CH:11]([N:3]5[C:4]6[C:5](=[N:6][CH:7]=[CH:8][CH:9]=6)[NH:10][C:2]5=[O:1])[CH2:16][CH2:15]4)[CH:18]=3)=[O:24])[CH2:35]2)[CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Reactant: c1ccc2c(c1)NCC2CCCN1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)N1CC(CCCN2CCCC2)c2ccccc21

Procedure:
140 mg (0.41 mmol) 6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 94.4 mg (0.41 mmol) 3-(3-pyrrolidin-1-yl-propyl)-2,3-dihydro-1H-indole, 138.2 mg (0.43 mmol) TBTU and 112 μL (0.8 mmol) triethylamine in 4 mL DMF were stirred overnight at RT. The mixture was separated by preparative HPLC. The product fractions were combined and lyophilised.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH3:6])[CH2:3][OH:4].[C:7](=O)([O:13]C(C)(C)C)[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C>C1COCC1>[OH:4][CH2:3][C@@H:2]([NH:1][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][CH3:6]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CC[C@H](N)CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-2-aminobutan-1-ol (1 eq) in THF (0.26 M) at 0° C. was added di-tert-butyl carbonate (1 eq) and triethylamine (1 eq). The reaction was stirred at room temperature for 3 hours. The reaction mixture was concentrated en vaccuo; and the residue was diluted in ethyl acetate. The organic solution was washed with water (2×), brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The material was carried onto the next step without further purification.
Reaction SMILES: [K].CC(C)([O-])C.[OH:7][C:8]1[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=1[CH2:10]P(=O)(OCC)OCC.[C:23]1([CH3:45])[CH:28]=[CH:27][C:26]([N:29]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=2)[C:30]2[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=2)=[CH:25][CH:24]=1.Cl>O1CCCC1.O>[OH:7][C:8]1[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=1[CH:10]=[CH:44][C:41]1[CH:40]=[CH:39][C:38]([N:29]([C:30]2[CH:37]=[CH:36][C:33]([CH3:34])=[CH:32][CH:31]=2)[C:26]2[CH:27]=[CH:28][C:23]([CH3:45])=[CH:24][CH:25]=2)=[CH:43][CH:42]=1
Reactant: CCOP(=O)(Cc1ccccc1O)OCC
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=O)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=Cc3ccccc3O)cc2)cc1
Reaction time: 2 h
Yield: 72 %

Procedure:
14.8 g of kalium-tert-butoxide and 50 ml of tetrahydrofuran were put in a reaction reservoir having a mixer, a thermometer and a dropping funnel. Under a nitrogen stream, a solution wherein 9.90 g of the diethyl 2-hydroxybenzylphosphonate and 5.44 g of 4-(di-para-tolylamino)benzaldehyde were dissolved in tetrahydrofuran was slowly dropped therein at a room temperature, and the reaction therein is further performed for 2 hrs at the same temperature. Then, water was added therein while cooling the reaction product with water, a hydrochloric acid solution having a normal concentration of 2 was added therein to acidize the reaction product, and the tetrahydrofuran was removed by an evaporator to extract a crude product with toluene. The toluene phase was washed with water, a sodium hydrogen carbonate solution and a saturated saline in this order, and magnesium sulfate was further added thereto to dehydrate the toluene phase. After filtered, the toluene was removed therefrom to prepare an oily crude product, and the oily crude product was further column-refined with silica gel to crystallize 5.09 g of 2-hydroxy-4′-(di-para-tolylamino)stilbene in hexane at a yield of 72%, having a boiling point of 136.0 to 138.0° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][CH2:17][CH2:18]Br>C1CCCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:14])[N:7]([CH2:18][CH2:17][O:16][CH3:15])[CH:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCBr
Reactant: CC(C)(C)OC(=O)NC1CC=CCC1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: COCCN(C(=O)OC(C)(C)C)C1CC=CCC1
Yield: 31 %

Procedure:
Cyclohex-3-enyl-carbamic acid tert-butyl ester (Kampferer, P.; Vasella, A. Helvetica Chimica Acta 2004, 87, 2764-2789) (3 g, 15.2 mmol) and 2-bromoethyl methyl ether (1.43 ml, 15.2 mmol) were treated overnight to the method of Example 7 Step A. After work up and chromatography of the reaction mixture (silica, cyclohexane/ethyl acetate=7/1) the title compound (Rf=0.33, 1.2 g, 31% yield) was obtained as colorless solid.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][O:7][CH2:8][C:9]1([CH2:18][CH2:19]O)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][O:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)(O)[C:51]#[N:52].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.CCOCC>[F:27][C:24]([F:26])([F:25])[C:22]1[CH:21]=[C:5]([CH:4]=[C:3]([C:2]([F:28])([F:29])[F:1])[CH:23]=1)[CH2:6][O:7][CH2:8][C:9]1([CH2:18][CH2:19][C:51]#[N:52])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][O:10]1
Reactant: CC(C)(O)C#N
Reactant: OCCC1(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)OCc2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#CCCC1(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)OCc2ccccc21
Temperature: 25 °C

Procedure:
To a solution of 2-(1-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-1,3-dihydroisobenzofuran-1-yl)ethanol (250 mg, 0.60 mmol) and triphenylphosphine (390 mg, 1.5 mmol) in tetrahydrofuran (2.5 mL) at 0° C. was added acetone cyanohydrin (0.163 mL, 1.8 mmol), followed immediately by the addition of diethyl azodicarboxylate (0.234 mL, 1.5 mmol). The reaction was allowed to gradually warm to room temperature in the dewar overnight. The reaction was diluted with ether, washed with water, then saturated sodium bicarbonate, then water, then brine, dried over magnesium sulfate, and concentrated. Column chromatography (12%-->19% EtOAc/Hex) gave 214 mg (84%) as a colorless oil. 1H-NMR (CDCl3, 300 MHz) δ 7.77 (s, 1H), 7.66 (s, 2H), 7.35 (m, 2H), 7.25 (m, 1H), 7.18 (d, J=6.7 Hz, 1H), 5.14 (s, 2H), 4.64 (s, 2H), 3.65 (s, 2H), 2.38 (m, 2H), 2.22 (m, 1H), 2.07 (m, 1H); 13C-NMR (CDCl3, 126 MHz) δ 140.9, 140.0, 139.4, 131.8 (q, J=33.6 Hz), 128.9, 128.0, 127.2, 123.4 (q, J=273 Hz), 121.7, 121.6, 121.5, 119.7, 88.9, 76.2, 73.1, 72.1, 32.4, 11.8. Mass spec.: 430.09 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[CH2:9][C@H:8]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[C@@H:7]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][O:23][CH2:24][CH2:25][CH2:26][NH2:27])[CH2:18][CH2:17]2)[CH2:6]1.[C:33](OC(=O)C)(=[O:35])[CH3:34].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[CH2:9][C@H:8]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[C@@H:7]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][O:23][CH2:24][CH2:25][CH2:26][NH:27][C:33](=[O:35])[CH3:34])[CH2:18][CH2:17]2)[CH2:6]1
Reactant: CC(=O)OC(C)=O
Reactant: NCCCOCC1CCN(C[C@H]2CN(Cc3ccc(Cl)cc3Cl)C[C@@H]2c2ccsc2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NCCCOCC1CCN(C[C@H]2CN(Cc3ccc(Cl)cc3Cl)C[C@@H]2c2ccsc2)CC1

Procedure:
A solution of 0.03 g (0.06 mmol) of 1-(2,4-dichlorobenzyl)-3-(S)-(4-(3-aminopropyloxymethyl)piperidinylmethyl)-4-(S)-(3-thienyl)pyrrolidine, 0.02 mL (0.12 mmol) of acetic anhydride, 0.025 mL (0.3 mmol) of pyridine and a catalytic amount of DMAP in 0.5 mL of CH2Cl2 was stirred at rt for 18 h. The reaction mixture was concentrated and the residue was purified by chromatography (silica, CH2Cl2:methanol, 9:1) to give the title compound. Mass Spectrum (ESI) m/e=538 (M+1 35Cl, 35Cl), 540 (M+1 35Cl, 37Cl), and 542 (M+1 37Cl, 37Cl).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[C:17]([NH:29][CH3:30])[N:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31]I>>[CH2:1]([N:8]([C:9]1[CH:10]=[C:11]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[C:17]([NH:29][CH3:30])[N:16]=2)[CH:12]=[CH:13][CH:14]=1)[CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CNc1nc(-c2cccc(NCc3ccccc3)c2)c2cc(OC)c(OC)cc2n1
Product: CNc1nc(-c2cccc(N(C)Cc3ccccc3)c2)c2cc(OC)c(OC)cc2n1
Yield: 33.8 %

Procedure:
Starting from 100 mg of 4-(3-benzylaminophenyl)-6,7-dimethoxy-2-methylaminoquinazoline obtained in Example 38 and 71.0 mg of methyl iodide, 35.0 mg of the title compound was obtained as a pale yellow oil in the same manner as in Example 38.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O>C1C=CC=CC=1>[Cl:1][C:2]1[C:11]([CH2:12][Br:13])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Cl)ccc2cccnc12
Solvent: c1ccccc1
Product: Clc1ccc2cccnc2c1CBr

Procedure:
7-Chloro-8-methylquinoline (1 g.) [Bradford et al., J. Chem. Soc., p. 437 (1947)] is dissolved in 20 ml. of benzene and brominated with one equivalent of N-bromosuccinimide in the presence of catalytic amounts of peroxide. The product, 7-chloro-8-(bromomethyl)quinoline is isolated by evaporation.
Reaction SMILES: C([O:8][C:9](=O)[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[N:17]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:18](=[O:26])[CH2:19][C:20]1[O:24][N:23]=[C:22]([CH3:25])[CH:21]=1)C1C=CC=CC=1.[H-].[Na+].CCOC(C)=O>CN(C=O)C>[CH2:27]([N:17]1[C:11]2[C:10](=[CH:15][C:14]([Cl:16])=[CH:13][CH:12]=2)[C:9]([OH:8])=[C:19]([C:20]2[O:24][N:23]=[C:22]([CH3:25])[CH:21]=2)[C:18]1=[O:26])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1cc(CC(=O)N(Cc2ccccc2)c2ccc(Cl)cc2C(=O)OCc2ccccc2)on1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(-c2c(O)c3cc(Cl)ccc3n(Cc3ccccc3)c2=O)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-{benzyl-[2-(3-methyl-isoxazol-5-yl)-acetyl]-amino}-5-chloro-benzoic acid benzyl ester (3.30 g, 7.58 mmol) in 25 ml of DMF at 0° C. was added NaH (340 mg). The mixture was stirred at rt for 1 h under Ar. Treated with 200 ml of EtOAc, the mixture was extracted with H2O (4×50 ml). The combined aqueous layers were neutralized to pH=6 with 1N HCl and extracted with EtOAc (4×50 ml). The combined org. layers were washed with H2O (2×50 ml), brine (50 ml) and dried (Na2SO4). Removal of the solvent under reduced pressure gave. 2.35 g (92%) of product as a white solid: 1H-NMR (CD3OD, 400 MHz) δ 9.49 (s, 1H), 8.21 (d, 1H, J=2.6 Hz), 7.48 (dd, 1H, J=9.0, 2.6 Hz), 7.17-7.36 (m, 7H), 5.60 (s, 2H), 2.43 (s, 3H), 2.54 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C20H15ClN203, 367.1 (M+H), found 367.0.
Reaction SMILES: [Br-:1].[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([C:11]#[C:12]/[C:13](/[CH3:35])=[CH:14]\[CH2:15][P+:16]([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)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([CH3:36])[C:5]=1[CH3:37].O.[H][H]>CO>[Br-:1].[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7](/[CH:11]=[CH:12]\[C:13](\[CH3:35])=[CH:14]/[CH2:15][P+:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:6]([CH3:36])[C:5]=1[CH3:37]
Reactant: [H][H]
Reactant: COc1cc(C)c(C#C/C(C)=C\C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1C
Agent: [Br-]
Solvent: CO
Solvent: O
Product: COc1cc(C)c(/C=C\C(C)=C/C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1C
Yield: 89 %

Procedure:
In a manner analogous to Example 2, a solution of 3.42 g of (Z)-[5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2-penten-4-ynyl]triphenylphosphonium bromide in 240 ml of methanol was hydrogenated in the presence of 1.8 g of water-moist Raney-nickel. 188 ml of hydrogen were taken up within 28 hours. The crude product (3.4 g), which contained 89.4% of (2Z,4Z)-[5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2,4-pentadienyl]triphenylphosphonium bromide (yield 89%), obtained after filtration and evaporation was dissolved in 20 ml of methylene chloride and crystallized by the dropwise addition of 50 ml of ethyl acetate while stirring. The suspension was left to stand at 0° C. overnight, filtered and the product, washed with a small amount of ethyl acetate/methylene chloride (volume ratio 5:1), was dried at 40°C./0.01 mbar. There were obtained 1.8 g of 99.6% (2Z,4Z)-[5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2,4-pentadienyl]triphenylphosphonium bromide as white crystals of melting point 202°-204° C.; yield 52.5%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.C([O:14][CH2:15][CH:16]1[CH2:24][CH:23]2[CH:19]([CH2:20][N:21]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:22]2)[C:18](=[O:32])[CH2:17]1)(=O)C.[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1>[CH2:25]([N:21]1[CH2:20][CH:19]2[CH:23]([CH2:24][CH:16]([CH2:15][OH:14])[CH2:17][C:18]2([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[OH:32])[CH2:22]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(=O)OCC1CC(=O)C2CN(Cc3ccccc3)CC2C1
Reactant: COc1ccccc1[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccccc1C1(O)CC(CO)CC2CN(Cc3ccccc3)CC21
Temperature: 20 °C
Reaction time: 20 h
Yield: 37.9 %

Procedure:
To a suspension of 2-methoxyphenylmagnesium bromide (prepared from 24.9 cm3 of 2-bromoanisole and 4.86 g of magnesium) in 200 cm3 of anhydrous tetrahydrofuran is added a solution of 8.0 g of (3aRS,6SR,7aSR)-6-acetoxymethyl-2-benzyl-4-perhydroisoindolone in 60 cm3 of anhydrous tetrahydrofuran. The reaction mixture is stirred for 20 hours at 20° C. and then cooled to +5° C. and treated with 120 cm3 of saturated aqueous ammonium chloride solution and 100 cm3 of ethyl acetate. After filtration of the mixture, the organic phase is washed with brine and then dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.06-0.200 mm, height 40 cm) in a mixture of 1,2-dichloroethane and methanol (95/5 by volume). After recrystallization in ethyl ether, 3.2 g of (3aRS,4RS,6SR, 7aSR)-2-benzyl-6-hydroxymethyl-4-(2-methoxyphenyl)-4-perhydroisoindolol are obtained, in the form of a white solid melting at 110° C.
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH2:10][CH:9]([C:13]2[C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][CH2:15][C:14]=2[CH3:21])[CH2:8][C:7]1=[O:22])(=O)[CH2:2][CH2:3][CH3:4].[Cl-].[CH2:24]([O:27][NH3+:28])[CH:25]=[CH2:26].C([O-])(=O)C.[Na+]>C(O)C>[CH2:24]([O:27][NH:28][C:1](=[C:6]1[C:7](=[O:22])[CH2:8][CH:9]([C:13]2[C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][CH2:15][C:14]=2[CH3:21])[CH2:10][C:11]1=[O:12])[CH2:2][CH2:3][CH3:4])[CH:25]=[CH2:26]
Reactant: C=CCO[NH3+]
Reactant: CCCC(=O)C1C(=O)CC(C2=C(C)CCCC2(C)C)CC1=O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: C=CCONC(CCC)=C1C(=O)CC(C2=C(C)CCCC2(C)C)CC1=O

Procedure:
8.0 parts by weight of 2-butyryl-5-(1,3,3-trimethylcyclohex-1-en-2-yl)-cyclohexane-1,3-dione are reacted with 2.9 parts by weight of allyloxyammonium chloride and 2.4 parts by weight of sodium acetate in 100 parts by volume of ethanol and the mixture is worked up, by a procedure similar to that of Example 1. 9.0 parts by weight of 2-(1-allyloxyaminobutylidene)-5-(1,3,3-trimethylcyclohex-1-en-2-yl)-cyclohexane-1,3-dione are obtained as a viscous oil (active ingredient No.2).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26](C)([CH3:28])[CH3:27])=[CH:17][CH:16]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:7]=1)[CH3:2].C(N(CC)CC)C.ClC(O[C:42]1[CH:47]=CC=C[CH:43]=1)=O>Cl.CO>[CH2:1]([C:3]1[N:4]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]3[CH:27]=[CH:47][CH:42]=[CH:43][CH:28]=3)=[CH:19][CH:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:7]=1)[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCc1nc(-c2ccc(F)cc2)cn1-c1ccc(CCNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCc1nc(-c2ccc(F)cc2)cn1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Reaction time: 1 h
Yield: 82.7 %

Procedure:
A solution of tert-butyl 2-{4-[2-ethyl-4-(4-fluorophenyl)-1H-imidazol-1-yl]phenyl}ethylcarbamate (1.1 g, 2.6 mmol) in 10% HCl-MeOH (20 mL) was heated at 50° C. for 2 h. After cooling, the volatile components were removed by evaporation and the resulting amorphous was dried under reduced pressure. Then, the amorphous was suspended in dichloromethane at 0° C. To the cooled mixture was added triethylamine (1.4 mL, 10 mmol) and phenyl chloroformate (380 μL, 3.0 mmol). After 1 h, the reaction mixture was partitioned between ethyl acetate (30 mL) and water (10 mL). The aqueous phase was extracted with ethyl acetate (3×30 mL) and the combined organic phase was dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (gradient elution from 3:1 to 2:1) afforded 924 mg (85%) of the title compound as colorless amorphous. MS (ESI) m/z 430 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[C:5]2[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15](=[O:24])[C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])[C:6]=2[O:7][C:8]=1[CH3:9])(=[O:3])[CH3:2].[CH3:25][Mg]Br.[Cl-].[NH4+].O>O1CCCC1>[Cl:22][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:23])[C:16]=1[C:15]([NH:14][C:10]1[C:6]2[O:7][C:8]([CH3:9])=[C:4]([C:1]([OH:3])([CH3:25])[CH3:2])[C:5]=2[CH:13]=[CH:12][CH:11]=1)=[O:24]
Reactant: C[Mg]Br
Reactant: CC(=O)c1c(C)oc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1C(C)(C)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-acetyl-7-(2,6-dichlorobenzoylamino)-2-methylbenzo[b]furan (100 mg) in tetrahydrofuran (3 ml) was added a 1M solution of methylmagnesium bromide in tetrahydrofuran (0.7 ml) dropwise with ice cooling. The solution was stirred at ambient temperature for 2 hours and to the solution was added aqueous saturated ammonium chloride. Then, the mixture was poured into water and the separated oil was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by colimn chromatography on silica gel and the obtained oil was crystallized from a mixture of diisopropyl ether and hexane to give 7-(2,6-dichlorobenzoylamino)-3-(1-hydroxy-1-methylethyl)-2-methylbenzo[b]furan (75 mg).
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[C:14]3[C:15]4[CH:21]=[CH:20][C:19]([C:22]5[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=5)=[CH:18][C:16]=4[S:17][C:13]=3[C:12]([C:32]#[N:33])=[CH:11][N:10]=2)=CC=1.[OH:36]S(O)(=O)=O.C([O-])(O)=O.[Na+].[Na+].[Cl-]>C1COCC1.CCOC(C)=O>[NH2:8][C:9]1[C:14]2[C:15]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=4)=[CH:18][C:16]=3[S:17][C:13]=2[C:12]([C:32]([NH2:33])=[O:36])=[CH:11][N:10]=1
Reactant: COc1ccc(CNc2ncc(C#N)c3sc4cc(-c5ccc(C(F)(F)F)cc5)ccc4c23)cc1
Reactant: O=S(=O)(O)O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1cnc(N)c2c1sc1cc(-c3ccc(C(F)(F)F)cc3)ccc12

Procedure:
1-[(4-Methoxybenzyl)amino]-7-[4-(trifluoromethyl)phenyl][1]benzothieno[3,2-c]pyridine-4-carbonitrile was placed in a flask cooled to 0° C. before conc. H2SO4 (excess) was added dropwise under vigorous stirring. The final mixture was warmed to room temperature and, after 1 h, poured into THF/EtOAc and aqueous NaHCO3 previously saturated with NaCl solid. After separation of the organic phase, the aqueous phase was extracted again with THF/EtOAc, and the combined organic phases were dried over MgSO4 and filtered. After evaporation of the organic solvents, the crude material was purified by a wash with Et2O to provide the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][C@H:3]1[C:23]([O:25][CH3:26])=[O:24].[O:27]1[C:36]2[CH:35]=[C:34]([CH:37]=O)[N:33]=[CH:32][C:31]=2[O:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[C:19]2[C:14]=1[CH:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][C@@H:2]([NH:1][CH2:37][C:34]2[N:33]=[CH:32][C:31]3[O:30][CH2:29][CH2:28][O:27][C:36]=3[CH:35]=2)[C@H:3]([C:23]([O:25][CH3:26])=[O:24])[CH2:4]1
Reactant: COC(=O)[C@@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1N
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COC(=O)[C@@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1NCc1cc2c(cn1)OCCO2
Yield: 79.2 %

Procedure:
Methyl(3R,4R)-4-amino-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidine-3-carboxylate (Intermediate 38) (195 mg, 0.53 mmol), 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (88 mg, 0.53 mmol) and sodium triacetoxy borohydride (339 mg, 1.6 mmol) were reacted as described for Example 14 to give 216 mg (79%) of product as a colorless hard foam.