Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]([C:9]1[CH:34]=[CH:33][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([C:20]([C:23]3[CH:28]=[CH:27][C:26]([NH:29]C(=O)C)=[CH:25][CH:24]=3)([OH:22])[CH3:21])[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].Cl>C(O)C>[NH2:29][C:26]1[CH:27]=[CH:28][C:23]([C:20]([CH:17]2[CH2:16][CH2:15][N:14]([CH2:13][C:12]3[CH:33]=[CH:34][C:9]([C:3]([OH:8])([C:4]([F:7])([F:5])[F:6])[C:2]([F:1])([F:35])[F:36])=[CH:10][CH:11]=3)[CH2:19][CH2:18]2)([OH:22])[CH3:21])=[CH:24][CH:25]=1
Reactant: CC(=O)Nc1ccc(C(C)(O)C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Agent: Cl
Solvent: CCO
Product: CC(O)(c1ccc(N)cc1)C1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Temperature: 100 °C
Yield: 52.3 %

Procedure:
N-(4-(1-(1-(4-(1,1,1,3,3,3-Hexafluoro-2-hydroxypropan-2-yl)benzyl)piperidin-4-yl)-1-hydroxyethyl)phenyl)acetamide (0.482 mmol, 250 mg) was dissolved in ethanol (5 mL) and 2M hydrochloric acid (12.00 mmol, 6 mL) added. The mixture was heated to 100° C. for 5 hours then cooled. The mixture was purified by strong cation exchange column chromatography and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting with dichloromethane to 10% methanol/dichloromethane) to afford the title compound (120 mg). MS (ESI) m/z 477.2 [M+H]+
Reaction SMILES: [OH:1][CH:2]([CH2:17][OH:18])[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH-].[K+].[C:21]([O:38]C)(=O)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>>[OH:1][CH:2]([CH2:17][OH:18])[CH2:3][N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:21](=[O:38])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCCCCCC(=O)OC
Reactant: CCCCCCCCCCCCNCC(O)CO
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCC(=O)N(CCCCCCCCCCCC)CC(O)CO

Procedure:
N-(2,3-dihydroxypropyl)-N-dodecylamine (0.50 g, 0.0019 mole) and potassium hydroxide (0.01 g, 0.18 mmole) were heated to 85° C. under vacuum. Methyl palmitate (0.57 g, 0.0021 mole) was heated and added dropwise to the reaction. The reaction was heated under vacuum for 6 hours. A waxy off-white solid was obtained (crude yield=0.92 g) The waxy solid was recrystalized from hot hexane (yield=0.6 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][N:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2)#N.[H-].C([Al+]CC(C)C)C(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:24]>C1(C)C=CC=CC=1>[CH:1]([C:3]1[CH:4]=[CH:5][N:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2)=[O:24]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: N#Cc1ccn2c1CCC2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=Cc1ccn2c1CCC2
Temperature: -20 °C
Yield: 59 %

Procedure:
13.21 g (0.1 mol) of 7-cyano-2,3-dihydro-1H-pyrrolizine is dissolved in 150 ml of absolute toluene and cooled to -20° C. To this solution is added dropwise 108 ml (0.13 mol) of a 1.2-molar diisobutyl aluminum hydride solution in toluene; the mixture is then warmed to room temperature, stirred for another hour, and decomposed with 300 ml of 10% aqueous citric acid solution. The product is extracted with methylene chloride, the organic phase is dried, concentrated, and the residue recrystallized from ether, thus obtaining 8.0 g (59% of theory) of 7-formyl-2,3-dihydro-1H-pyrrolizine, mp 58° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13](O)[N:12]2[N:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:18]=[C:11]2[CH:10]=1.C(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:30])=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:30][C:13]1[N:12]2[N:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:18]=[C:11]2[CH:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(-c2ccc(Cl)cc2Cl)cc2nc(C(F)(F)F)nn12
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Product: FC(F)(F)c1nc2cc(-c3ccc(Cl)cc3Cl)nc(Cl)n2n1
Temperature: 120 °C
Reaction time: 12 h

Procedure:
950 mg (2.7 mmol) of 7-(2,4-dichlorophenyl)-2-(trifluoromethyl)[1,2,4]triazolo[1,5-c]pyrimidin-5-ol (Example 130A) are introduced into phosphoryl chloride (10 ml), 1.86 g (8.2 mmol) of benzyltriethylammonium chloride are added, and the reaction mixture is stirred at 120° C. for 12 h. The reaction mixture is slowly poured, with vigorous stirring, into saturated sodium bicarbonate solution and ice, and solid sodium bicarbonate (approx. 5 g) is added until a pH of 8 is reached. The solid is filtered off with suction. The reaction vessel is washed out with dichloromethane, and the organic phase is dried over magnesium sulphate, concentrated and combined with the filtered solid. The crude product is purified by silica gel chromatography (cyclohexane/ethyl acetate 10:1). 784 mg (78% of theory) of the product are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([N:16]1[C@@H:23]([C:24]#[CH:25])[CH2:22][CH2:21][C@H:17]1[C:18](O)=[O:19])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:27]1CCOCC1.ClC(OCC(C)C)=O.N.Cl>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([N:16]1[C@@H:23]([C:24]#[CH:25])[CH2:22][CH2:21][C@H:17]1[C:18]([NH2:27])=[O:19])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C#C[C@H]1CC[C@@H](C(=O)O)N1C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: N
Solvent: C1CCOC1
Product: C#C[C@H]1CC[C@@H](C(N)=O)N1C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of N-(tert-butoxycarbonyl)-L-leucyl-(5R)-5-ethynyl-L-proline (2.83 mmol) and N-methyl morpholine (0.39 mL, 3.50 mmol) in THF (15 mL) was added isobutyl chloroformate (0.42 mL, 3.25 mmol). The resulting cloudy white mixture was stirred at 0° C. for 30 minutes followed by the addition of a solution of ammonia (0.5 M in dioxane, 10.0 mL, 5.0 mmol). The solution was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was diluted by the addition of 1 M HCl (100 mL), and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried (sodium sulfate), filtered, and concentrated to provide the titled compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[CH:4][N:3]=1.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C>[CH:10]1([CH2:9][O:8][C:5]2[CH:6]=[CH:7][C:2]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])=[N:3][CH:4]=2)[CH2:12][CH2:11]1
Reactant: Brc1ccc(OCC2CC2)cn1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(OCC2CC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
A mixture of 2-bromo-5-(cyclopropylmethoxy)pyridine (1.145 g), bis(triphenylphosphine)palladium(II) dichloride (175 mg), copper(I) iodide (48 mg), trimethylsilylacetylene (737 mg), triethylamine (759 mg) and DMF (15 mL) was stirred at room temperature overnight under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and water, and the mixture was filtered through celite. The aqueous layer was separated from the organic layer. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a yellow oil (774 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8][N:7](N)[C:6]=2[CH:15]=1.[C:16]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CC.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8][N:7]3[C:6]=2[C:15]=1[C:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=13
Reactant: CN1CCc2ccc(F)cc2N(N)CC1
Reactant: O=C1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCCO
Product: CN1CCc2ccc(F)c3c4c(n(c23)CC1)CCCC4
Temperature: 25 °C
Yield: 24.6 %

Procedure:
To a solution of 9-fluoro-4-methyl-3,4,5,6-tetrahydro-2H-benzo[e][1,4]diazocin-1-ylamine (1.79 g, 8.5 mmole) in 1-propanol (100 mL) was added cyclohexanone (9 ml, 86.8 mmole), followed by p-toluenesulfonic acid monohydrate (3.5 g, 18.1 mmole), and the resulting reaction mixture was refluxed for 30 hours. The reaction mixture was cooled to room temperature and solvent removed in vacuo to produce a brown residue. The residue was diluted with methylene chloride (300 mL) and washed with saturated aqueous sodium bicarbonate (200 mL), saturated aqueous sodium chloride (200 mL), dried (sodium sulfate) and concentrated in vacuo. Purification by flash column chromatography (silica gel, ethyl acetate:hexanes 1:1) provided 0.57 g of the title compound. 50 mg of the free amine was treated with one equivalent of fumaric acid in ethanol to form a fumarate salt 63.7 mg, mp 206-208° C. MS (ESI) m/z 273 ([M+H]+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[C:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:3][CH:2]=1.[C:15]1(=O)[CH:20]=[CH:19][C:18](=[O:21])[CH:17]=[CH:16]1>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:16](=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=3)[N:9]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:8]=23)=[CH:3][CH:2]=1
Reactant: O=C1C=CC(=O)C=C1
Reactant: C(=C1CCCCCN1)c1ccncc1
Solvent: ClC(Cl)Cl
Product: Oc1ccc2c(-c3ccncc3)c3n(c2c1)CCCCC3
Reaction time: 24 h

Procedure:
One hundred and forty-one grams (0.75 mole) of 2-(4-picolinylidene)1,3,4,5,6,7-hexahydroazepine were dissolved in 1000 ml of chloroform and mixed under ice cooling with a solution of 89 g (0.83 mole) of 1,4-benzoquinone in 1000 ml of chloroform added dropwise. After the mixture stood for 24 hours at room temperature, the precipitate formed was filtered, suspended in 500 ml of dimethylformamide, and then heated for two hours to 100° C. After cooling, the suspension was suction filtered and washed with dimethylformamide and acetone, whereby the pure 2-hydroxy-isomer was obtained.
Reaction SMILES: C=CC1C=CC=CC=1.[C:9]([OH:24])(=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CCCCCC>>[CH2:9]1[O:24][CH:10]1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCCCCCCCCCCCCC(=O)O
Solvent: C=Cc1ccccc1
Product: c1ccc(C2CO2)cc1
Yield: 16.5 %

Procedure:
To a stirred suspension (at room temperature) of immobilized C. antarctica lipase (370 mg, according to example 1) in styrene (4.15 ml, 36.1 mmol) containing myristic acid (823 mg, 3.6 mmol) hydrogen peroxide (3 ml, 52.5 mmol) was added in six equal portions after 0, 0.5, 1.0, 1.5, 2.0 and 3.0 hours. After 1.5 hours 16.5% styrene oxide was formed as determined by gas chromatography.
Reaction SMILES: [C:1]([C:3]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH2:16][CH:17]=C)[CH2:4][C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=[O:6])#[N:2].CSC>C(Cl)Cl>[C:1]([C:3]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:16]=[CH:17][N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[C:5](=[O:6])[CH2:4]1)#[N:2]
Reactant: C=CCC(C#N)(CC(=O)NCc1ccc(F)cc1)c1ccccc1
Solvent: ClCCl
Solvent: CSC
Product: N#CC1(c2ccccc2)C=CN(Cc2ccc(F)cc2)C(=O)C1
Reaction time: 0.17 h

Procedure:
Into a cooled (−78° C.) solution of 3-cyano-N-(4-fluorobenzyl)-3-phenylhex-5-enamide (8.00 g, 24.8 mmol) in CH2Cl2 (500 mL) was bubbled ozone until a blue color persisted. The mixture was stirred for 10 min, then dimethyl sulfide (84.6 g, 1.36 mol) was added. After stirring for 48 hours at room temperature, the mixture was concentrated under vacuum. The residue was partitioned between EtOAc and water. The organic extract was dried with Na2SO4, filtered, and concentrated under vacuum. The residual material was purified using silica gel column chromatography eluting with 0-40% EtOAc in hexanes. The appropriate fractions were combined and concentrated to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.45 (m, 5H), 7.29 (m, 2H), 7.15 (t, J=8.9 Hz, 2H), 6.78 (d, J=7.7 Hz, 1H), 5.50 (d, J=7.7 Hz, 1H), 4.72 (s, 2H), 3.17 (q, J=16 Hz, 2H) ppm. ES MS M+1=307.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:36]1([NH2:40])[CH2:39][CH2:38][CH2:37]1>>[CH:36]1([NH:40][CH2:24][C:21]2[N:20]=[C:19]([C@H:10]([CH2:9][CH2:8][CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[O:23][N:22]=2)[CH2:39][CH2:38][CH2:37]1
Reactant: NC1CCC1
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CNC2CCC2)no1

Procedure:
Method as for preparation 5 using tert-butyl (3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (500 mg, 0.99 mmol) and cyclobutylamine (250 μl, 2.96 mmol) as starting materials.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH2:9][CH3:10])[CH:3]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19].O>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18](=[O:20])[CH3:19])=[C:4]([CH2:9][CH3:10])[CH:3]=1
Reactant: CCc1cc(Br)ccc1N
Reactant: CC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cc(Br)ccc1NC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
To a solution of 4-bromo-2-ethylaniline (50 g, 0.25 mol) in dichloromethane (250 ml) is added triethylamine (63.24 g, 0.62 mol) and the mixture is stirred at room temperature for 30 minutes. The reaction mixture is cooled to 0° C. and acetyl chloride (39.25 g, 0.5 mol) is added dropwise. The reaction mixture is stirred at 25-30° C. for 60 minutes, then poured into water, and the two phases separated. The organic phase is washed with water, dried over anhydrous sodium sulfate, filtered and the filtrate is evaporated under reduced pressure to yield N-(4-bromo-2-ethylphenyl)acetamide (40 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([CH2:23][CH2:24][CH:25]=[O:26])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S([CH2:37][N:38]=[C:39]=O)(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)(=[O:15])=[O:14])[CH:11]([CH2:23][CH2:24][C:25]3[O:26][CH:39]=[N:38][CH:37]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCC=O)CC[C@H]2c2ccc(F)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)CN=C=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2C(CCc3cnco3)CCC2c2ccc(F)cc2)cc1
Yield: 24 %

Procedure:
A stirred mixture of (2RS,5S)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionaldehyde (375 mg, 1.0 mmol, prepared from the corresponding alcohol by oxidation in accordance with the general method of example 29a), tosylmethyl-isocyanate (199 mg, 1.0 mmol), potassium carbonate (207 mg, 1.5 mmol) and MeOH (10 ml) was heated under reflux conditions for 35 h, evaporated and purified by column chromato-graphy on silica gel (ethyl acetate/hexane 4:1) to give the title compound (100 mg, 24%) as a light yellow oil, MS: m/e=415.3 (M+H+).
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:18]4[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=4[C:16]=3[CH:33]=O)[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.O1CCCC1.[CH3:40][NH:41][CH3:42].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:18]4[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=4[C:16]=3[CH2:33][N:41]([CH3:42])[CH3:40])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:13])[F:14])[CH2:2][CH2:3]1
Reactant: CNC
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CC3)c2)c(C=O)c2c(=O)[nH]ncc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cn[nH]c(=O)c12
Reaction time: 0.17 h
Yield: 53 %

Procedure:
To 133 mg (0.270 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-formyl-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 10-(a) and 112 mg of Molecular sieve (3A) was added 5 ml of tetrahydrofuran solution containing 2M dimethylamine at room temperature, and the mixture was stirred for 10 minutes. Then, 156 mg (0.740 mmol) of sodium triacetoxyborohydride was added to the mixture, and the mixture was stirred for further 17 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed successively with water and then with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; ethyl acetate→chloroform:methanol=4:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 74 mg of the title compound as a pale yellowish solid. (Yield: 53%)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C(Cl)(Cl)Cl>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH2:2][NH:1][C:18](=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:4][CH:5]=1)#[N:8]
Reactant: N#Cc1ccc(CN)cc1
Reactant: CCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCC(=O)NCc1ccc(C#N)cc1
Reaction time: 0.17 h
Yield: 98.5 %

Procedure:
To a solution of 4-(aminomethyl)benzonitrile (5.0 g, 0.038 moles) in 100 mL chloroform is added 3.82 g (0.038 moles) triethylamine. A solution of nonanoyl chloride (6.68 g, 0.038 moles) in 10 mL chloroform is then added dropwise with stirring over a 10 min period and the final mixture stirred at room temperature for 18 hrs. The mixture is extracted with water (100 mL), saturated NaHCO3 (50 mL), 2N HCl (50 mL), dried over Na2SO4 and evaporated to leave 10.2 g crude N-(4-cyanobenzyl)nonanamide. This crude product is taken up in 50 mL dimethylformamide, to which is added 2.47 g (0.038 moles) sodium azide and 2.03 g (0.038 moles) ammonium chloride. The final mixture is heated at 90°-110° C. for 4 hrs after cooling, the mixture is diluted with water (350 mL) and the resultant precipitate recovered by suction filtration, washed with water, and vacuum dried. Recrystallization from ethyl acetate left N-[[4-(1H-tetrazol-5-yl)phenyl]methyl]nonanamide (2.6 g), m.p. 185°-187° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:14]>CO>[NH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[C:3](=[O:14])[CH2:4]2
Reactant: CN1C(=O)Cc2cc([N+](=O)[O-])ccc21
Solvent: CO
Product: CN1C(=O)Cc2cc(N)ccc21

Procedure:
To a suspension of 1-methyl-5-nitroindolin-2-one (92 mg, 0.48 mmol) in 20 mL MeOH, was Pd(C) (9.2 mg, 10 weight %) added. The round bottom flask was capped with a rubber septum and put under a hydrogen atmosphere. After 18 h the hydrogen gas was evacuated by introducing argon to the round bottom flask. The reaction mixture was filtered through celite. The celite was washed with EtOAc (2×30 ml). The volatiles were evaporated to afford the title compound in quantitative yield.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH:17]=[O:18])[CH:13]=3)[O:8][CH:7]=2)=[N:4][N:3]=[N:2]1.[BH4-].[Na+].[Na]>CO>[OH:18][CH2:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]=[C:6]([C:5]1[NH:4][N:3]=[N:2][N:1]=1)[C:15]2=[O:16]
Reactant: O=Cc1ccc2occ(-c3nnn[nH]3)c(=O)c2c1
Agent: [BH4-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: O=c1c(-c2nnn[nH]2)coc2ccc(CO)cc12

Procedure:
A suspension of 0.242 part of 3-(1H-tetrazol-5-yl)chromone-6-carboxaldehyde in 5 parts by volume of methanol was heated to dissolve the starting compound as much as possible. To the solution under stirring was added little by little 0.038 part of sodium borohydride under warming to obtain a nearly homogeneous solution. The resulting solution was again heated to dissolve completely, and then to the resulting solution was further added little by little 0.019 part of sodium horohydride under warming. The solvent was distilled off, and to the residue was added 20 parts by volume of 1N-hydrochloric acid. The resulting pale yellow precipitates were recovered by filtration and recrystallized from ethanol to obtain 0.090 part of 6-hydroxymethyl-3-(1H-tetrazol-5-yl)chromone as pale yellow crystals. Melting point: 264°-266° C(decomposition)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[CH3:13]O.S(=O)(=O)(O)O>O>[CH3:13][O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C(O)Cc1ccc(O)c(Cl)c1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)Cc1ccc(O)c(Cl)c1

Procedure:
A mixture of 50 g of 3-chloro-4-hydroxybenzeneacetic acid, 250 ml of methyl alcohol and 10 ml of concentrated sulfuric acid is heated at reflux temperature for 23.5 hours. The cooled solution is diluted with water and extracted with methylene chloride. The organic layer is washed with saturated sodium bicarbonate and saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel:30% ethyl acetate/hexane) to give 49.9 g of the desired product.
Reaction SMILES: [CH:1]1([CH:4]=O)[CH2:3][CH2:2]1.[NH2:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[C:20](=[O:24])[NH:19][CH:18]=[CH:17]3)[CH2:9][CH2:8]1>>[CH:1]1([CH2:4][NH:6][C@@H:7]2[CH2:8][CH2:9][C@H:10]([O:13][C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[NH:19][CH:18]=[CH:17]4)[CH2:11][CH2:12]2)[CH2:3][CH2:2]1
Reactant: N[C@H]1CC[C@@H](Oc2ccc3c(=O)[nH]ccc3c2)CC1
Reactant: O=CC1CC1
Product: O=c1[nH]ccc2cc(O[C@H]3CC[C@@H](NCC4CC4)CC3)ccc12

Procedure:
125 was obtained as hydrochloride using the previously described general method employing cyclopropane carbaldehyde and cis-6-(4-amino-cyclohexyloxy)-2H-isoquinolin-1-one (28) as starting materials. Rt=1.04 min (Method B). Detected mass: 313.2 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([CH2:11][CH:12]([O:15][CH3:16])[O:13][CH3:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH2:18]([O:25][C:26]1[CH:27]=[C:28]([Cl:35])[C:29]([CH2:33]Br)=[C:30]([Cl:32])[CH:31]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>C1COCC1>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:33][C:29]1[C:28]([Cl:35])=[CH:27][C:26]([O:25][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:31][C:30]=1[Cl:32])([CH2:11][CH:12]([O:13][CH3:14])[O:15][CH3:16])[C:4]([O:3][CH2:1][CH3:2])=[O:17])[CH3:10]
Reactant: Clc1cc(OCc2ccccc2)cc(Cl)c1CBr
Reactant: CCOC(=O)C(CC(OC)OC)C(=O)OCC
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)(CC(OC)OC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.6 %

Procedure:
Cool 2-(2,2-Dimethoxy-ethyl)-malonic acid diethyl ester (4.5 g, 16.3 mmol) in 50 mL THF to −78° C. and add lithium hexamethylsilane amide (1M, 17 mL) drop wise. After 15 min, add 5-benzyloxy-2-bromomethyl-1,3-dichloro-benzene (17.9 mmol 6.2 g) in 10 mL THF. Warm this mixture to ambient temperature, acidify with 1N HCl, and extract with ethyl acetate. Concentrate the organics and purify by normal phase column chromatography to afford the title compound as a white solid (7.0 g, 80%).