Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH:13]=O)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].[CH3:17][C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([CH3:31])[CH2:20][NH:19]1.O1CCCC1.C([BH3-])#N.[Na+]>CO.O.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)C>[C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13][N:19]3[CH2:20][C@@H:21]([CH3:31])[N:22]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:23][C@@H:18]3[CH3:17])=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1
Reactant: C[C@@H]1CN[C@@H](C)CN1C(=O)OC(C)(C)C
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CO
Solvent: O
Solvent: CCO
Product: C[C@@H]1CN(Cc2cncn2Cc2ccc(C#N)cc2)[C@@H](C)CN1C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a round bottom flask were added 1-(4-cyanobenzyl)-5-formylimidazole (250.0 mg, 1.2 mmole) along with titanium(IV)isopropoxide (1.0 ml, 3.65 mmol), (trans) 2,5-Dimethyl-4-tertbutyloxycarbonylpiprizine (253.7 mg, 1.2 mmol) (prepared as described in Step 1), and tetrahydrofuran (0.4 ml). The reaction was heated at 60° C. for 1.25 hour. The reaction was cooled and sodiumcyanoborohydride (95.0 mg, 1.5 mmol) was added along with ethanol (0.5 ml) and the reaction was stirred at RT for 18 hours. The reaction was diluted with methanol/water (3 ml/1 ml) and the mixture filtered through celite. The filtrate was then concentrated to an oil, dissolved into methanol and put through a High Pressure Liquid Chromatography column. The desired fractions were collected, concentrated, and lyophilized to give the ditrifluoroacetic acid salt of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][O:5][C:6]1[C:14]2[NH:13][C:12]3[CH2:15][CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][C:11]=3[C:10]=2[CH:9]=[CH:8][CH:7]=1>Cl>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][O:5][C:6]1[C:14]2[NH:13][C:12]3[CH2:15][CH2:16][NH:17][CH2:18][C:11]=3[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CN(C)CCOc1cccc2c3c([nH]c12)CCN(C(=O)OC(C)(C)C)C3
Agent: Cl
Product: CN(C)CCOc1cccc2c3c([nH]c12)CCNC3
Temperature: 25 °C
Reaction time: 19 h
Yield: 93 %

Procedure:
tert-Butyl 6-(2-(dimethylamino)ethoxy)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (304 mg, 0.85 mmol) was added to methanolic HCl (20 ml, reagent 10) at 0° C. under air. The resulting solution was stirred at room temperature for 19 hours. The solvent was removed under reduced pressure to afford N,N-dimethyl-2-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-6-yloxy)ethanamine (205 mg, 93%) as a yellow solid.
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[CH3:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26]I.[H-].[Na+]>C1COCC1.CCOCC>[CH3:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][O:1][CH:2]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)c2ccccc2)C1
Reactant: COCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCCCCOC(c1ccccc1)C1CCN(C(=O)OC(C)(C)C)C1
Yield: 17.5 %

Procedure:
To a stirred solution of tert-butyl 3-(hydroxy(phenyl)methyl)pyrrolidine-1-carboxylate (205 mg, 0.74 mmol) and 4-methoxybutyl iodide (750 mg, 3.5 mmol) in dry THF (5 mL) under N2 was added 60& NaH in oil (0.14 g, 3.5 mmol). H2 evolution occurred. The mixture was heated at reflux for 8 h. The mixture was cooled, diluted with ether (90 mL), and washed with water (25 mL) and brine (25 mL), and dried over MgSO4. Removal of the solvent left an oil which was purified by flash chromatography on a 12-g silica cartridge eluted with a 0 to 100% EtOAc in hexanes gradient to afford tert-butyl 3-((4-methoxybutoxy)(phenyl)methyl)pyrrolidine-1-carboxylate (47 mg, 17%) as an oil.
Reaction SMILES: [C:1]([C:3]1[C:4]([SH:12])=[N:5][C:6]([CH:9]([CH3:11])[CH3:10])=[CH:7][CH:8]=1)#[N:2].[O-]CC.[Na+].[C:17]([O:20][CH2:21][CH2:22]Br)(=[O:19])[CH3:18]>C(O)C>[NH2:2][C:1]1[C:3]2[C:4](=[N:5][C:6]([CH:9]([CH3:10])[CH3:11])=[CH:7][CH:8]=2)[S:12][C:18]=1[C:17]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CC(C)c1ccc(C#N)c(S)n1
Reactant: CC(=O)OCCBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1sc2nc(C(C)C)ccc2c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Cyano-6-isopropyl-2-mercaptopyridine (50 g) synthesized according to U.S. Pat. No. 5,001,137 (Mar. 19, 1991), sodium ethoxide (22.9 g) and bromoethyl acetate (34.2 ml) were added to ethanol (500 ml) and the mixture was stirred at room temperature for 1 hr and the solvent was evaporated. The residue was recrystallized from ethanol to give ethyl 3-amino-6-isopropylthieno[2,3-b]pyridine-2-carboxylate (69.3 g) (melting point: 161-162° C.). (2) This ester (30 g) and isoamyl nitrite (45.7 ml) were added to tetrahydrofuran (300 ml) and the mixture was stirred at 60° C. for 2 hr and the solvent was evaporated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase; chloroform) to give ethyl 6-isopropylthieno[2,3-b]pyridine-2-carboxylate (7.1 g). melting point: 73-74° C. (3) This was subjected to hydrolysis under basic conditions according to a conventional method to give the title compound (5.8 g). melting point: 218-220° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([O:17]C)=[CH:12][C:11]=2[F:19])=[O:9])=[CH:4][CH:3]=1>C(O)(=O)C.Br>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([OH:17])=[CH:12][C:11]=2[F:19])=[O:9])=[CH:6][CH:7]=1
Reactant: COc1cc(F)c(C(=O)c2ccc(Br)cc2)cc1F
Agent: Br
Solvent: CC(=O)O
Product: O=C(c1ccc(Br)cc1)c1cc(F)c(O)cc1F
Yield: 94.9 %

Procedure:
A solution of 22.9 g of (4-bromo-phenyl)-(2,5-difluoro-4-methoxy-phenyl)-methanone in 140 ml of acetic acid and 100 ml of 62% aqueous HBr solution is boiled under reflux for 13 hrs., subsequently evaporated, re-evaporated with toluene and taken up in ethyl acetate. The inorganic phase is washed with saturated sodium hydrogen carbonate solution and 10% sodium chloride solution and dried. After crystallization from methylene chloride/ether/pentane there are obtained 20.8 g of (4-bromo-phenyl)-(2,5-difluoro-4-hydroxy-phenyl)-methanone.
Reaction SMILES: [C:1]([C:5]1[CH2:9][C:8](=[O:10])[N:7]([CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][C:23]1[N:28]=[C:27]([CH2:29]O)[CH:26]=[CH:25][CH:24]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[C:1]([C:5]1[CH:9]=[C:8]([O:10][CH2:29][C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:22])[N:28]=2)[N:7]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(CN2N=C(C(C)(C)C)CC2=O)cc1
Reactant: Cc1cccc(CO)n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cn2nc(C(C)(C)C)cc2OCc2cccc(C)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
To a mixture of methyl 4-[(3-tert-butyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)methyl]benzoate (1.68 g, 5.83 mmol), (6-methylpyridin-2-yl)methanol (0.79 g, 6.4 mmol), tributylphosphine (2.90 mL, 11.6 mmol) and tetrahydrofuran (80 mL) was added 1,1′-(azodicarbonyl)dipiperidine (2.94 g, 11.7 mol), and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and diisopropyl ether was added to the residue. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=2:3) to give the title compound (2.14 g, yield 93%) as a yellow oil. 1H NMR (CDCl3) δ: 1.27 (9H, s), 2.54 (3H, s), 3.90 (3H, s), 5.11 (2H, s), 5.25 (2H, s), 5.47 (1H, s), 6.96 (1H, d, J=7.8 Hz), 7.06 (1H, d, J=7.8 Hz), 7.19 (2H, d, J=8.6 Hz), 7.51 (1H, t, J=7.7 Hz), 7.93-8.00 (2H, m).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)[N:7]=1)=[O:5].[CH3:19][Mg+].[Br-].O>C1COCC1>[N:13]1([C:8]2[N:7]=[C:6]([C:4](=[O:5])[CH3:19])[CH:11]=[C:10]([CH3:12])[N:9]=2)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: C[Mg+]
Reactant: CON(C)C(=O)c1cc(C)nc(-n2ccnc2)n1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cc(C)nc(-n2ccnc2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.4 %

Procedure:
To a solution of 2-imidazol-1-yl-6-methyl-pyrimidine-4-carboxylic acid methoxy-methyl-amide (162 mg, 0.800 mmol) in THF (10 mL) at 0° C. was added MeMgBr (0.8 mL, 3M in Et2O, 2.40 mmol). The solution was warmed to rt and stirred for 20 min. Water was added and the mixture was extracted with ethyl acetate, washed with brine and dried over Na2SO4. Evaporation of the solvent gave 143 mg (88%) of 1-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-ethanone as a yellow solid. [M+H]+ 203.17.
Reaction SMILES: [CH3:1][N:2]([N:4]=[N:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[S:8][C:7]=1[C:17]([O:19]C)=[O:18])[CH3:3].[OH-].[Na+].Cl>CO.O>[CH3:3][N:2]([N:4]=[N:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[S:8][C:7]=1[C:17]([OH:19])=[O:18])[CH3:1]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N=NN(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)N=Nc1cc(-c2ccccc2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.2 %

Procedure:
To a solution of methyl 3-[(dimethylamino)diazenyl]-5-phenylthiophene-2-carboxylate (1.8 g, 6.22 mmol) in methanol (50 mL) was added a solution of sodium hydroxide (1.24 g, 31.1 mmol) in water (15 mL) and stirred at rt for 16 h. The mixture was diluted with ice cold water and acidified with dil. HCl. The mixture was stirred for 30 min and the precipitated solid was filtered, washed with water and dried. The solid was chromatographed over silica gel column using hexane-ethyl acetate (70:30) as eluents to give the product. The crude solid was recrystallized from hexane-chloroform to give the product as a pale pink color solid (1.1 g, 61%), mp 162-166° C. IR (neat)νmax. 2923, 2853, 1708, 1260, 1220, 1173, 1042, 1020, 879, 836 cm−1; 1H NMR (400 MHz, CDCl3): δ 12.15 (1H, br s), 7.58-7.60 (2H, m), 7.44 (1H, s), 7.32-7.40 (3H, m), 3.65 (3H, s), 3.25 (3H, s); 13C NMR (100 MHz, CDCl3): δ 162.8, 153.3, 149.7, 133.3, 129.1, 129.0, 125.9, 120.1, 113.4, 44.3, 37.0; LC-MS (positive ion mode): m/z 298 (M+Na)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:23]([CH3:33])=[C:22]([C:34](O)=[O:35])[C:17]=3[N:18]=[C:19]([CH3:21])[N:20]=2)[CH2:3][CH2:2]1.[NH2:37][CH:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:23]([CH3:33])=[C:22]([C:34]([NH:37][CH:38]4[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:42][CH2:43]4)=[O:35])[C:17]=3[N:18]=[C:19]([CH3:21])[N:20]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1cc(OCC2CC2)c(-c2nc(C)nc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)cc1F
Product: COc1cc(OCC2CC2)c(-c2nc(C)nc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2,6-dimethyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c17) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as colorless foam.
Reaction SMILES: [C:1]([C:5]1(C(OCC)=O)[O:9][NH:8][CH:7]=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O.[O:18]1CCC[CH2:19]1>C(O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([CH2:19][OH:18])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CCOC1
Reactant: CCOC(=O)C1(C(C)(C)C)C=CNO1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(CO)no1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
1.83 g of ethyl 5-t-butyl-isoxazole-5-carboxylate was dissolved in 18 ml of tetrahydrofuran, and 0.70 g of sodium borohydride in 10 ml of ethanol was then added. The mixture was stirred at room temperature for 10 hours. After 5 ml of water was added, the reaction mixture was concentrated to 5 ml under reduced pressure. The concentrated solution was extracted with methyl-t-butyl ether. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 0.62 g of (5-t-butyl-isoxazol-3-yl)methanol.
Reaction SMILES: [OH-].[NH4+:2].Cl.[C:4]([CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH3:20])([CH3:19])[C:11]1=[NH:21])(OCC)=[O:5]>C(O)C>[C:4]([CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH3:20])([CH3:19])[C:11]1=[NH:21])(=[O:5])[NH2:2]
Reactant: CCOC(=O)CN1C(=N)C(C)(C)c2ccccc21
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: CC1(C)C(=N)N(CC(N)=O)c2ccccc21

Procedure:
To a solution of 25 ml. of 32% ammonium hydroxide and 15 ml. of ethanol, 4.5 g. of 1-carbethoxymethyl-3,3-dimethyl-2-iminoindoline hydrochloride are added. After 15 hours the reaction mixture is evaporated to dryness and the residue is crystallized from chloroform giving 3,5 g. of the product of the title, melting at 167°-173° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[CH:24]1[CH2:29][C:28](=[O:30])[CH:27]=[C:26]([CH3:31])[CH2:25]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:22])([CH3:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[C@H:24]1[CH2:25][C@@H:26]([CH3:31])[CH2:27][C:28](=[O:30])[CH2:29]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCC(C)(C)c1ccc(C2CC(=O)C=C(C)C2)c(OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Product: CCCCCCC(C)(C)c1ccc([C@@H]2CC(=O)C[C@H](C)C2)c(OCc2ccccc2)c1
Reaction time: 0.5 h
Yield: 32.1 %

Procedure:
A mixture of 5-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-3-methyl-2-cyclohexen-1-one (1.00 g, 2.39 mmole) and 500 mg of 5% palladium on carbon-50% water was stirred under one atmosphere of hydrogen for one hour. A second 500 mg portion of catalyst was added and stirring continued for 30 minutes. A third 500 mg portion of catalyst was added and stirring continued for 13 minutes. The reaction mixture was then filtered through sodium bicarbonate and magnesium sulfate and the filtrate evaporated. The residue was purified via column chromatography on 140 g of silica gel eluted with 10% ether-petroleum ether to yield 323 mg (32%) of the title compound as an oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].C1COCC1.C(N(C(C)C)CC)(C)C.[Cl-].[CH3:33][Si:34]([CH3:40])([CH3:39])[CH2:35][CH2:36][O:37][CH3:38]>O>[C:14]([C:11]1[CH:10]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:12]=1[O:13][CH2:38][O:37][CH2:36][CH2:35][Si:34]([CH3:40])([CH3:39])[CH3:33])[CH:8]=[O:9])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: COCC[Si](C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1OCOCC[Si](C)(C)C

Procedure:
12.3 g (52 mmol) of 3,5-di-tert-butyl-4-hydroxybenzaldehyde and 100 ml of THF are introduced into a round-bottomed flask. 10 ml (58 mmol) of diisopropylethylamine and 10.3 ml (58 mmol) of 2-trimethylsilylethoxymethane chloride are added successively and the mixture is refluxed for three hours. The reaction medium is poured into water and extracted with ethyl ether, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of ethyl acetate and hexane (3/97% by volume). After evaporation of the solvents, 15.6 g (82%) of the expected product are collected in the form of a colourless oil.
Reaction SMILES: [CH:1]1([C:4]#[C:5][Si:6]([CH3:9])([CH3:8])[CH3:7])[CH2:3][CH2:2]1.[Li][CH2:11]CCC.S(OC)(OC)(=O)=O>CCOCC>[CH3:7][Si:6]([CH3:9])([CH3:8])[C:5]#[C:4][C:1]1([CH3:11])[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)C#CC1CC1
Reactant: [Li]CCCC
Solvent: COS(=O)(=O)OC
Solvent: CCOCC
Product: CC1(C#C[Si](C)(C)C)CC1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
To a solution of cyclopropylethynyl-trimethyl-silane (3.0 g, 22 mmol) in ether (20 mL) was added dropwise n-BuLi (8.6 mL, 21.7 mol, 2.5 M solution in hexane) at 0° C. The reaction mixture was stirred at ambient temperature for 24 h before dimethyl sulfate (6.85 g, 54.3 mmol) was added dropwise at −10° C. The resulting solution was stirred at 10° C. and then at 20° C. for 30 min each. The reaction was quenched by adding a mixture of sat. aq. NH4Cl and 25% aq. ammonia (1:3, 100 mL). The mixture was then stirred at ambient temperature for 1 h. The aqueous phase was extracted with diethyl ether (3×50 mL) and the combined organic layers were washed successively with 5% aqueous hydrochloric acid (100 mL), 5% aq. NaHCO3 solution (100 mL), and water (100 mL). The organics were dried over anhydrous NaSO4 and concentrated at ambient pressure. After fractional distillation under reduced pressure, trimethyl-(1-methyl-cyclopropylethynyl)-silane (1.7 g, 52%) was obtained as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ 1.25 (s, 3H), 0.92-0.86 (m, 2H), 0.58-0.56 (m, 2H), 0.15 (s, 9H).
Reaction SMILES: Cl.[CH3:2][CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:4]([C:6]([OH:8])=[O:7])[NH2:5].Cl.[CH2:16]=O.[OH-].[Na+]>O>[CH3:2][CH:3]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:16][NH:5][CH:4]1[C:6]([OH:8])=[O:7]
Reactant: C=O
Reactant: CC(c1ccccc1)C(N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1c2ccccc2CNC1C(=O)O
Reaction time: 3.5 h

Procedure:
β-Methyl(dl)phenylalanine hydrochloride (4 g), concentrated hydrochloric acid (20 ml) and formaldehyde (6 ml) were heated with stirring in an oil bath at 100° for 3.5 h and then evaporated to dryness to give a white froth which was dissolved in water (20 ml) and the pH adjusted to 4 with 5M NaOH, under nitrogen. The reaction mixture was stored at 5° for 60 h after which a precipitated white solid was recovered by filtration, washed with a small quantity of water and dried to yield the title compound (1.965 g) m.p. >260° (decomp).
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=1[Cl:14])[NH2:10].[CH:15]([S:17]([F:20])(=[O:19])=[O:18])=[CH2:16]>O>[Cl:6][C:7]1[CH:8]=[C:9]([NH:10][CH2:16][CH2:15][S:17]([F:20])(=[O:19])=[O:18])[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: C=CS(=O)(=O)F
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(F)CCNc1ccc(Cl)c(Cl)c1

Procedure:
A N,N-dimethylformamide solution (DMF, 100 ml) of 3,4-dichloroaniline (6.48 g, 40 mmol) and ethenesulfonyl fluoride (6.7 g, 57.9 mmol) was warmed to 110° C. for three hours. The cooled dark solution was diluted to 400 ml with water and the resulting dark oily precipate was decanted from the supernatant layer. This layer was extracted with ether (4×50 ml). The combined ether extracts were added to the oily precipitate and this dark solution was washed with brine and dried over MgSO4. The organic solution was evaporated to give the crude 2-[(3,4-dichlorophenyl)amino]ethanesulfonyl fluoride as a dark liquid in quantitative yield.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14](CCC(OC(C)(C)C)=O)[C:15]([OH:17])=[O:16])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>>[CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:15]([OH:17])=[O:16])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)OC(=O)CC[C@@H](CC[C@H](Cc1ccccc1)C(=O)O)C(=O)O
Product: CC(C)(C)OC(=O)C[C@@H](CC[C@H](Cc1ccccc1)C(=O)O)C(=O)O

Procedure:
(2R,5R)-2-Benzyl-5-(2-tert-butoxy-2-oxoethyl)hexanedioic acid (33 mg, 0.094 mmol) was synthesized as described for the preparation of Intermediate 7 using tert-butyl bromoacetate in step A.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:3]=1[C:4]([NH:6][C:7](=[O:25])[NH:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]1)=[O:5].[OH-].[Na+:33].O>C(O)(C)C>[Na+:33].[Cl:1][C:2]1[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:3]=1[C:4]([NH:6][C:7](=[O:25])[NH:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH2:17][CH2:18][CH:19]([C:22]([O-:24])=[O:23])[CH2:20][CH2:21]1)=[O:5]
Reactant: O=C(NC(=O)c1cc(F)c(F)cc1Cl)Nc1cc(F)ccc1N1CCC(C(=O)O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=C(NC(=O)c1cc(F)c(F)cc1Cl)Nc1cc(F)ccc1N1CCC(C(=O)[O-])CC1

Procedure:
The solution of 100 mg of 1-{2-[3-(2-chloro-4,5-difluorobenzoyl)ureido]-4-fluoro-phenyl}piperidine-4-carboxylic acid in 8 ml of isopropanol at 60° C. is admixed with the equimolar amount of 2N sodium hydroxide solution and, after the addition of 20 ml of water, cooled slowly with stirring. The precipitated product is filtered off with suction, washed with isopropanol and water and dried under reduced pressure.
Reaction SMILES: C([N:8]1[CH2:14][CH2:13][NH:12][CH:11]([CH3:15])[C:10]2[C:16](=[O:21])[N:17]([CH3:20])[N:18]=[CH:19][C:9]1=2)C1C=CC=CC=1.C1CCCCC=1>[Pd].C(O)C>[CH3:15][CH:11]1[NH:12][CH2:13][CH2:14][NH:8][C:9]2[CH:19]=[N:18][N:17]([CH3:20])[C:16](=[O:21])[C:10]1=2
Reactant: CC1NCCN(Cc2ccccc2)c2cnn(C)c(=O)c21
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CC1NCCNc2cnn(C)c(=O)c21

Procedure:
0.38 g (2 mmol) of 1-benzyl-5,7-dimethyl-2,3,4,5-tetrahydro-6(7H)-pyridazino[4,5-b][1,5]diazepinone, 10 ml of abs. ethanol, 2 ml of cyclohexene and 0.20 g of Pd/C are warmed for 2 hours at 80° C. After cooling the mixture is filtered. The filtrate is evaporated and the residue is taken up in 10 ml of water, then it is shaken with 4×10 ml of ethyl acetate. The ethyl acetate phase is dried with anhydrous sodium sulphate and evaporated. The crystalline material obtained is recrystallized from 2 ml of ethyl acetate.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.CN(C)C=O.C(NC(C)C)(C)C.[CH:35]([NH:38][CH2:39][CH2:40][OH:41])([CH3:37])[CH3:36]>>[OH:41][CH2:40][CH2:39][N:38]([CH:35]([CH3:37])[CH3:36])[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:3]=[N:2][NH:1][CH:5]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:20]
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: CC(C)NCCO
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Temperature: 50 °C
Yield: 15.1 %

Procedure:
To a solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (363.8 mg, 1.161 mmol) in N,N-dimethylformamide (39-60 equiv.) and N,N-Diisopropylamine (1.5 equiv.) was added 2-(isopropylamino)ethanol (133.1 mg, 1.29 mmol) followed by the addition of N,N,N′N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uranium hexafluorophosphate (1.1 equiv.). The reaction mixture was heated at 50° C. for 2 hrs to 24 hours depending on when complete by LCMS. Reaction mixture was concentrated on the genevac and purified by HPLC or diluted with ethyl acetate, washed with brine, dried over sodium sulfate and concentrated in vacuo prior to purification by HPLC to give 103 (70 mg, 15% yield, M+1 399.1)