Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][NH2:17])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[Br:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=1[CH2:37]Br.O>C1COCC1>[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]([CH2:37][C:30]2[CH:31]=[C:32]([O:35][CH3:36])[CH:33]=[CH:34][C:29]=2[Br:28])[NH2:17])=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NNc1ccc(OCc2ccccc2)cc1
Reactant: COc1ccc(Br)c(CBr)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Br)c(CN(N)c2ccc(OCc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
To a solution of [4-(benzyloxy)phenyl]hydrazine hydrochloride (2.0 g) in THF (25 mL) was added dropwise a THF solution (1.9 M, 8.4 ml) of sodium hexamethyldisilazide under ice-cooling, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 1-bromo-2-(bromomethyl)-4-methoxybenzene (2.23 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. 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 (1.56 g).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-])=O.I[CH2:14][CH3:15]>>[CH2:14]([N:7]1[CH:6]=[C:5]2[C:9]([CH:10]=[CH:11][CH:12]=[C:4]2[NH2:1])=[N:8]1)[CH3:15]
Reactant: CCI
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Product: CCn1cc2c(N)cccc2n1

Procedure:
In accordance with Example 4 (Steps 1 and 2), 4-nitro-1H-indazole was used instead of 5-nitro-1H-indazole, and 2-iodoethane was used instead of ethyl bromide-d5 to obtain 2-ethyl-2H-indazol-4-amine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1.[N:20]([O-])=O.[Na+]>C(O)(=O)C.O.[Zn]>[O:12]([C:8]1[CH:7]=[C:6]([N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:19])[NH2:20])[CH:11]=[CH:10][CH:9]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)CNc1cccc(Oc2ccccc2)c1
Reactant: O=N[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)CN(N)c1cccc(Oc2ccccc2)c1
Reaction time: 1 h
Yield: 25.5 %

Procedure:
N-(3-Phenoxyphenyl)glycine methyl ester (Intermediate 48; 10 g, 0.0389 mol) was dissolved in a mixture of glacial acetic acid (60 ml) and water (7 ml) and the solution was cooled to between 0° and 5° C. A solution of sodium nitrite (2.8 g, 0.0408 mol) in water (8.5 ml) was added to this over 15 min at the same low temperature. The solution was stirred for 1 h before being cooled to between 0° and -10° C. Zinc powder (9.9 g, 0.1517 mol) was gradually added at this temperature and the reaction was then stirred at 0° to 5° C. for 4 h. It was then poured into water (300 ml) and extracted with ethyl acetate (3×150 ml). The organic extract was washed with 8% sodium bicarbonate solution until effervescence had ceased. It was then dried and evaporated to give a dark brown oil. This was purified by FCC on deactivated silica (200 g) eluting with hexane-chloroform (2:1) to give the title compound as a brown oil (2.7 g, 25%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[C:11]([CH3:18])=[N:12][C:13]([CH3:17])=[CH:14][C:15]=2[CH3:16])[C:3]=1[N+:19]([O-:21])=[O:20].[CH2:22]([CH:24]([NH2:27])[CH2:25][CH3:26])[CH3:23]>C1COCC1>[CH2:22]([CH:24]([NH:27][C:2]1[C:3]([N+:19]([O-:21])=[O:20])=[C:4]([NH:9][C:10]2[C:11]([CH3:18])=[N:12][C:13]([CH3:17])=[CH:14][C:15]=2[CH3:16])[N:5]=[C:6]([CH3:8])[N:7]=1)[CH2:25][CH3:26])[CH3:23]
Reactant: Cc1cc(C)c(Nc2nc(C)nc(Cl)c2[N+](=O)[O-])c(C)n1
Reactant: CCC(N)CC
Solvent: C1CCOC1
Product: CCC(CC)Nc1nc(C)nc(Nc2c(C)cc(C)nc2C)c1[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
To a cooled solution of (6-chloro-2-methyl-5-nitro-pyrimidin-4-yl)-(2,4,6-trimethyl-pyridin-3-yl)-amine (88 mg, 0.29 mmol) in 1 ml of dry THF was added 1-ethyl-propyl-amine (80 mg, 0.92 mmol) at −78° C. The mixture was stirred at that temperature for 3 hrs, then warmed to −10° C. for 1 hour. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give the title compound (88 mg, 86%) as an orange solid, mp 151–152° C. 1H NMR (CDCl3) δ 9.16 (d, 1H), 6.92 (s, 1H), 4.35 (m, 1H), 2.50 (s, 3H), 2.39 (s, 3H), 2.18 (s, 3H), 2.16 (s, 3H), 1.5–1.80 (m, 4H), 0.94 (t, 6H) ppm.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[N:10]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])[C:11](=[O:14])[NH:12][CH2:13][C:3]=12.[CH3:23][N:24]([CH3:43])[C:25](=[O:42])[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[F:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[C:15]=1[N:10]1[C:4]2[N:5]=[C:6]([S:8][CH3:9])[N:7]=[C:2]([C:28]3[CH:27]=[C:26]([CH:31]=[CH:30][C:29]=3[CH3:32])[C:25]([N:24]([CH3:43])[CH3:23])=[O:42])[C:3]=2[CH2:13][NH:12][C:11]1=[O:14]
Reactant: CSc1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Reactant: Cc1ccc(C(=O)N(C)C)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CSc1nc(-c2cc(C(=O)N(C)C)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Temperature: 95 °C

Procedure:
5-chloro-1-(2,6-difluorophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.102 g, 0.298 mmol), N,N,4-trimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide from above, (0.129 g, 0.447 mmol), and K2CO3 (0.123 g, 0.894 mmol), were taken up in dioxane (6 mL) and water (1.2 mL). The mixture was degassed with argon for 30 min and tetrakis(triphenyl-phosphine)palladium(0) (0.026 g, 0.022 mmol) was added. The mixture was then heated under argon at 95° C. for 18 h. The solvents were pumped off, and after aqueous workup, the crude material was flashed on silica gel (15 g), eluted with a EtOAc/CH2Cl2 gradient to give the title compound as a white amorphous solid. mp 144-147° C. LC-MS m/z 470 (M+H)+, 2.02 min (ret time).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:18][CH3:19])[CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[N+:15]([O-])=O.CO>[C].[Pd].C(O)(=O)C>[NH2:15][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:5]=1[CH2:4][CH:3]([O:18][CH3:19])[O:2][CH3:1])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1ccc(CC(OC)OC)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CC(OC)OC)c(N)c1
Yield: 106.7 %

Procedure:
To a mixture of 4.40 g (16.3 mmol) of methyl 4-(2,2-dimethoxyethyl)-3-nitrobenzoate in a solvent mixture of 200 ml of methanol and 2 ml of acetic acid was added 0.50 g of 5% palladium-carbon to perform catalytic hydrogenation at ambient temperature under normal pressure and then treat the reaction mixture in a conventional manner. Thus, 4.16 g of methyl 3-amino-4-(2,2-dimethoxyethyl)benzoate was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C[O:16][C:17](OC)(N(C)C)[CH3:18]>CC(N(C)C)=O>[N+:12]([C:3]1[C:2]([CH2:1][C:17](=[O:16])[CH3:18])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])([O-:14])=[O:13]
Reactant: COC(C)(OC)N(C)C
Reactant: COC(=O)c1cccc(C)c1[N+](=O)[O-]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cccc(CC(C)=O)c1[N+](=O)[O-]
Yield: 23 %

Procedure:
A solution of methyl 3-methyl-2-nitrobenzoate (1.5 g) and N,N-dimethylacetamide dimethyl acetal (3 ml) in dimethylacetamide (5 ml) was heated at 140° C. for 3 hours. After evaporation of the solvent, the resulting brown syrup was dissolved in ethyl acetate. The solution was washed with water, dried and concentrated to dryness. The residue was purified by column chromatography on silica gel to give a pale brown syrup (0.42 g, 23%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=1.[C:16](=[O:18])=[O:17]>>[CH:13]1([C:9]2[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=2)[C:16]([OH:18])=[O:17])[CH2:15][CH2:14]1
Reactant: Brc1cccc(C2CC2)c1
Reactant: O=C=O
Agent: [Li]CCCC
Product: O=C(O)c1cccc(C2CC2)c1
Reaction time: 1 h

Procedure:
1.6 M n-Butyllithium in hexanes (3.2 mL, 5.1 mmol) was added drop-wise to a solution of 1-bromo-3-cyclopropyl-benzene at −78° C. and stirred for 1 hour. This reaction mixture was then transferred via canula to a 250 mL round bottom flask equipped with a stirrer bar approximately ¼ full of solid carbon dioxide and stirred and for 1 hour. The reaction mixture was concentrated and then the residue was diluted with water. The aqueous layer was washed with dichloromethane (3×), acidified with 1 N HCl to pH˜2, and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford 3-cyclopropyl-benzoic (356 mg, 43%, white solid).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[N:7][CH:8]=3)[N:3]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Nc1ccc2cnccc2n1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1ccc2cnccc2n1)c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 19.1 %

Procedure:
2-Amino-1,6-naphthyridine (200 mg, Production Example 25b) was dissolved in dichloromethane (6.0 ml), to which were then added triethylamine (0.20 ml) and 4-chlorobenzenesulfonyl chloride (0.31 g), followed by stirring at 40° C. for 1.5 hours. An aqueous saturated sodium bicarbonate was added thereto, followed by extracting with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column, to give the title compound (84 mg, 21.44%) as pale yellow crystals.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][CH2:16][C@H:17]([OH:30])[CH2:18][O:19][C:20]1[C:28]2[NH:27][C:26](=[O:29])[NH:25][C:24]=2[CH:23]=[CH:22][CH:21]=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:52]=[CH:53][C:54]=1[O:55][CH3:56])[C:36]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH2:50][CH2:49][C:48](=O)[CH2:47][CH2:46]2)=[CH:41][CH:40]=1)=[O:37].C(O)(=O)C>CN(C)C=O>[OH:30][C@H:17]([CH2:18][O:19][C:20]1[C:28]2[NH:27][C:26](=[O:29])[NH:25][C:24]=2[CH:23]=[CH:22][CH:21]=1)[CH2:16][NH:15][CH:48]1[CH2:47][CH2:46][N:45]([C:42]2[CH:43]=[CH:44][C:39]([NH:38][C:36](=[O:37])[C:35]3[CH:52]=[CH:53][C:54]([O:55][CH3:56])=[C:33]([O:32][CH3:31])[CH:34]=3)=[CH:40][CH:41]=2)[CH2:50][CH2:49]1
Reactant: COc1ccc(C(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1OC
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)cc1OC
Reaction time: 2 h

Procedure:
Sodium triacetoxyborohydride (0.044 g, 2.1 mmol) was added to a solution of 4-((2S)-3-amino-2-hydroxy-propoxy)-1,3-dihydro-benzoimidazol-2-one (U.S. Pat. No. 5,786,356) (0.23 g, 1.05 mmol), 3,4-dimethoxy-N-[4-(4-oxo-piperidine-1-yl)-phenyl]-benzamide (which was obtained in Example 369) (0.41 g, 1.16 mmol), and acetic acid (0.07 mL, 1.16 mmol) in anhydrous dimethylforamide (8 mL). The reaction was stirred for 2 hours. The reaction was quenched with 50% water/saturated aqueous NaHCO3(20 mL). The solids were captured on a filter and washed with ethyl acetate, diethyl ether, and hexanes to afford 0.31 g of the desired product as a brown solid; 1H NMR (300 MHz, DMSO-d6) δ 1.32 (m, 2H), 1.89 (m, 2H), 2.54 (m, 1H), 2.65 (m, 2H), 2.84 (m, 2H), 3.56 (m, 2H), 3.83 (s, 3H), 3.84 (s, 3H), 3.95 (m, 2H), 4.02 (s, 1H), 5.06 (brs, 1H), 6.52 (d, 1H, J=7.1), 6.51 (d, 1H, J=8.1Hz), 6.88 (m, 2H), 7.08 (d, 1H, J=8.7 Hz), 7.58 (m, 5H), 8.87 (s, 1H), 10.59 (brs, 1H), 10.72 (brs, 1H); MS (ES) m/z: 561.2 (MH+).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:39](=[O:38])[CH2:40][OH:41])[CH2:33][CH2:34]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1
Reactant: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)cc1F
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCN(C(=O)CO)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2-methyl-N-piperidin-4-yl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f26) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([NH:18][NH2:19])(=O)[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.[OH-].[Na+].Cl>C(O)C.O>[C:1]1([N:7]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[N:18][N:19]=[C:8]2[SH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=C=Nc1ccccc1
Reactant: NNC(=O)c1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Sc1nnc(-c2ccncc2)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A one liter round bottomed flask, fitted with a reflux condenser, nitrogen inlet and magnetic stirrer bar, is charged with 40.5 g (0.30 mol) of phenyl isothiocyanate and 41.845 g (0.30 mol) of isonicotinic acid hydrazide in 300 ml of absolute ethanol. The mixture is heated to reflux for 3 hours. The resulting solid is filtered and washed with ethanol and then added to an aqueous solution of sodium hydroxide (prepared by dissolving 16.8 g, 0.42 mol, of sodium hydroxide in 240 ml of water). The mixture is heated to reflux for 5 hours and then stirred at ambient temperature for 18 hours. The solution is treated with 100 ml of distilled water to dissolve the gel which has formed. The solution is made acidic (to pH 2) with concentrated HCl and cooled with ice. The solid is filtered, taken up in 600 ml of warm absolute ethanol and filtered again to afford approximately 70 g (92%) of slightly wet titled product with a melting point of 288°-290° C. IR (nujol shows a peak at 1900 cm-1 ; UV (95% ethanol) shows peaks at 257 nm and 317 nm; NMR (DMSO-d6 δ) 8.5 and 7.2-7.6; the mass spectra shows a strong molecular ion peak at m/e 254, with fragment ions at 253, 195 and 149.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:15][CH2:16][CH2:17][N:18]1[C:22]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:21][S:20][C:19]1=[N:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=1[O:38][CH3:39])[CH2:9][C:10](OCC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].O>O1CCCC1>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([N:30]=[C:19]2[N:18]([CH2:17][CH2:16][CH2:15][N:8]([CH2:9][CH2:10][OH:11])[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:22]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)=[CH:21][S:20]2)=[C:32]([O:38][CH3:39])[CH:33]=1
Reactant: CCOC(=O)CN(CCCn1c(-c2ccc(F)cc2)csc1=Nc1ccc(Cl)cc1OC)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Cl)ccc1N=c1scc(-c2ccc(F)cc2)n1CCCN(CCO)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound (3 g) obtained in the above (1) in tetrahydrofuran (20 ml) was added lithium borohydride (170 mg), and the mixture was stirred at room temperature overnight. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [n-hexane:ethyl acetate (1:1)] to give the title compound (2.14 g) as amorphous.
Reaction SMILES: [C:1]([CH:3](P(=O)(OCC)OCC)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].[H-].[Na+].[C:20]12([CH:30]=O)[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2.O>C1COCC1>[C:20]12([CH:30]=[C:3]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:1]#[N:2])[CH2:21][CH:22]3[CH2:28][CH:26]([CH2:25][CH:24]([CH2:23]3)[CH2:29]1)[CH2:27]2
Reactant: O=CC12CC3CC(CC(C3)C1)C2
Reactant: CCOP(=O)(OCC)C(C#N)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC(=CC12CC3CC(CC(C3)C1)C2)c1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 28.3 %

Procedure:
A solution of diethyl 1-cyano-1-phenylmethylphosphonate (10.97 g, 43.3 mmol) in dry THF (60 mL) at 0° C. was treated with NaH (60% dispersion in oil, 1.7 g, 43.3 mmol), stirred at 0° C. for 40 min, warmed to room temperature for 20 min, treated with a solution of 1-adamantanecarboxaldehyde (3.56 g, 21.7 mmol) in dry THF (10 mL) and heated at 60° C. for 16 h. The reaction mixture was cooled, treated with water (50 mL), extracted with EtOAc (3×20 mL), the extracts washed with brine (40 mL), dried (MgSO4) and concentrated in vacuo. The resulting brown oil was purified by chromatography [SiO2, heptane-EtOAc (9:1)] and recrystallised (heptane) to give the product (1.62 g, 28%) as a white solid: mp 107-108° C; IR νmax (Nujol)/cm−1 2924, 2852, 2218, 1497, 1448, 1377, 1343, 1101, 910, 762, 750 and 689; NMR δH (400 MHz, CDCl3) 1.76 (6H, m), 1.99 (6H, m), 2.07 (3H, m), 6.50 (1H, s), 7.37 (3H, m) and 7.51 (2H, m); Anal. Calcd for C19H21N: C, 86.65; H, 8.04; N, 5.32. Found: C, 86.58; H, 8.09; N, 5.33.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]=2[N:3]=1.[NH:19]1[CH:23]=[C:22](B(O)O)[CH:21]=[N:20]1>>[CH2:14]([C@H:6]1[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]2[N:3]=[C:2]([C:22]3[CH:23]=[N:19][NH:20][CH:21]=3)[N:11]=[CH:10][C:9]=2[N:8]([CH3:12])[C:7]1=[O:13])[CH3:15]
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C(C)C
Reactant: OB(O)c1cn[nH]c1
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3cn[nH]c3)nc2N1C(C)C

Procedure:
The title compound was prepared similarly to the methods described in Example 5, using Intermediate C instead of Intermediate B and pyrazol-4-ylboronic acid instead of pyridin-4-ylboronic acid. 1H NMR (CDCl3) δ: 8.23 (broad, 2H), 7.85 (s, 1H), 4.63 (m, 1H), 4.33 (m, 1H), 3.36 (s, 3H), 1.95 (m, 1H), 1.75 (m, 1H), 1.44 (dd, 6H) and 0.87 ppm (t, 3H); LCMS: 301.2 m/z (M+H)+; ret. Time: 1.30 min (Analytical Method E).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:18][CH:19]([C:21]1[N:25]=[C:24]([CH3:26])[O:23][N:22]=1)[NH2:20].CO>CCCCCCC>[CH3:26][C:24]1[O:23][N:22]=[C:21]([CH:19]([NH:20][C:15]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[CH3:18])[N:25]=1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: Cc1nc(C(C)N)no1
Solvent: CO
Solvent: CCCCCCC
Product: Cc1nc(C(C)NC(=O)c2ccc(C3CC3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and α,5-dimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153834-40-2) as starting materials. The product was isolated by chiral chromatography on Chiralpak AD using heptane/20% ethanol as eluent. The (−)-enantiomer was isolated. LC-MS (UV peak area/ESI) 98.1%, 343.1767 (M+H)+, αD20 (MeOH)=−28.2°.
Reaction SMILES: [CH3:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[CH:6]=1)=[O:4].BrBr.[NH2:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18]>C(Cl)Cl.C(OCC)C>[Cl:11][C:9]1[CH:10]=[C:5]([C:3]2([OH:4])[O:18][CH2:17][C:16]([CH3:20])([CH3:19])[NH:15][CH:2]2[CH3:1])[CH:6]=[C:7]([Cl:12])[CH:8]=1
Reactant: CC(C)(N)CO
Reactant: CCC(=O)c1cc(Cl)cc(Cl)c1
Agent: BrBr
Solvent: ClCCl
Solvent: CCOCC
Product: CC1NC(C)(C)COC1(O)c1cc(Cl)cc(Cl)c1
Reaction time: 8 h
Yield: 46 %

Procedure:
To a stirred solution of 3,5-dichloropropiophenone (8m, 3.81 g, 0.0188 mol) in CH2Cl2 (28 mL) was added bromine (0.986 mL, 19.1 mmol) dropwise. The bromine was immediately consumed upon addition of each drop until the end of addition when it had a consistent brownish color, indicative of excess bromine. The reaction was immediately quenched with saturated aqueous NaHCO3, extracted three times with CH2Cl2. The organic layer was separated, combined and concentrated under reduced pressure, without drying to afford a yellow oil. The oil was dissolved in anhydrous diethyl ether (50 mL) and 2-amino-2-methyl-1-propanol (6.7 g, 0.075 mol) was added. The reaction mixture was stirred overnight and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted three times with CH2Cl2, and the organic layers concentrated to afford another yellow oil. Purification by column chromatography on silica gel afforded 2.51 g (46%) of the title compound. The hemi-fumarate salt was prepared by dissolving the free base in methanol and adding 1.0 g of fumaric acid to form the title compound: mp 188-190° C.; 1H NMR (DMSO-d6) δ 7.58-7.57 (m, 1H), 7.47 (m, 2H), 6.67 (s, 0.5H), 4.09 (d, 1H, J=11.9 Hz), 3.53 (d, 1H, J=12.0 Hz), 3.41-3.37 (m, 1H), 1.53 (s, 3H), 1.28 (s, 3H), 1.02 (d, 3H, 6.6 Hz); 13C NMR (DMSO-d6) δ 134.9, 133.6, 127.7, 125.2, 94.7, 67.2, 52.5, 50.1, 25.0, 21.6, 14.6; Anal. (C15H19Cl2NO4.0.25H2O) calcd: C, 51.08; H, 5.57; N, 3.97. found: C, 51.13; H, 5.64; N, 3.90.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)[OH:4].[C:23]1([C:34](O)=[O:35])[CH:24]=[CH:25][CH:26]=[C:27]2[CH2:33][CH2:32][CH2:31][CH:30]=[CH:29][C:28]=12.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:7]1[CH:6]=[C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:34]([C:23]2[CH:24]=[CH:25][CH:26]=[C:27]3[CH2:33][CH2:32][CH2:31][CH:30]=[CH:29][C:28]=23)=[O:35])[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:18]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc(F)c1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(3-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (167 mg, 0.53 mmol) in acetonitrile (20 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (100 mg, 0.53 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (153 mg, 0.80 mmol) and 1-hydroxy-1H-benzotriazole (81 mg, 0.53 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (209 mg, 81%).