Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[O:5][C:6]=1[Cl:7].[CH3:12][N:13]1[C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:7][C:6]1[O:5][C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:3][C:2]=1[C:17]1[N:13]([CH3:12])[N:14]=[CH:15][CH:16]=1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(Br)c(Cl)o1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2ccnn2C)c(Cl)o1
Yield: 55.1 %

Procedure:
A solution of methyl 4-bromo-5-chloro-2-furancarboxylate (1.1 g, 4.59 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.05 g, 5.05 mmol)[prepared according to Preparation 7], potassium carbonate (3.17 g, 22.97 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.117 g, 0.23 mmol) in 1,4-dioxane (19.14 ml) and water (3.83 ml) was stirred at 80° C. in a sealed tube for 1 h. The reaction mixture was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 4-25% EtOAc in hexanes) yielding methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (800 mg, 2.53 mmol, 55% yield) as a yellow oil: LCMS m/e ES 240, 242 (M, M+2)+.
Reaction SMILES: [C:1]1([CH2:7][O:8][P:9]([CH2:26][C:27](O)=[O:28])([CH:11]([NH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(#N)C.[NH:33]1[CH2:47][CH2:46][CH2:45][C@H:34]1[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36]>C(OCC)(=O)C>[C:1]1([CH2:7][O:8][P:9]([CH2:26][C:27]([N:33]2[CH2:47][CH2:46][CH2:45][C@H:34]2[C:35]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36])=[O:28])([CH:11]([NH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)NC(CCc1ccccc1)P(=O)(CC(=O)O)OCc1ccccc1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)NC(CCc1ccccc1)P(=O)(CC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)OCc1ccccc1
Reaction time: 1 h

Procedure:
1,1-Carbonyldiimidazole (1.8 g., 0.011 mole) is added to a chilled (0°) solution of the product from part (c) (4.6 g., 0.011 mole) in 50 ml. of acetonitrile. The mixture is stirred for one hour at 0° and a solution of L-proline, benzyl ester (2.3 g., 0.011 mole) in 25 ml. of acetonitrile is added. The mixture is stirred at ambient temperature for 16 hours. The solvent is removed in vacuo. The residue is dissolved in 200 ml. of dichloromethane, washed with 5% potassium bisulfate, saturated sodium bicarbonate solution, brine, and dried (MgSO4). The solvent is removed in vacuo to give an oil residue of 6.5 g. Tlc, silica gel, ethyl acetate, shows a major spot at Rf 0.50 visualized with PMA. The residue is chromatographed on silica gel, eluted with dichloromethane/ethyl acetate (9:1) and (4:1) to give 5.4 g. of (±)-1-[(phenylmethoxy)[1-[(ethoxycarbonyl)amino]-3-phenylpropyl]phosphinyl]acetyl]-L-proline, phenylmethyl ester. Tlc shows a single spot at Rf 0.50.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>[Fe].C(O)C.O>[N:15]1([CH2:14][CH2:13][N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[C:4]([NH2:1])[CH:12]=3)[CH:8]=[N:9]2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1ccc2cnn(CCN3CCCC3)c2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc2cnn(CCN3CCCC3)c2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 6-nitro-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazole (1.60 g, 6.15 mmol), iron powder (3.40 g, 60.8 mmol), and ammonium chloride (166 mg, 3.13 mmol) in a 4:1 solution of ethanol/H2O was heated to reflux for 3 hours, cooled to room temperature, concentrated under reduced pressure. The residue was stirred in triethylamine/ethyl acetate (1/4, 30 mL) for 15 minutes, filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4), and the filtrate was concentrated under reduced pressure to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.66 (m, 4H), 2.50 (m, 4H), 2.85 (t, 2H, J=6.78), 4.27 (t, 2H, J=6.78), 5.30 (s, 2H), 6.49 (m, 2H), 7.35 (m, 1H), 7.70 (m, 1H); MS (DCI/NH3) m/z 231 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][C:5]([C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1)=O)=[N+:2]=[N-:3].[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[BH3-]C#N.[Na+]>>[N:1]([CH2:4][CH:5]([C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1)[NH:25][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[N+:2]=[N-:3]
Reactant: NC1CCCCC1
Reactant: COc1cc(C(=O)CN=[N+]=[N-])cc(OC)c1OC
Agent: [BH3-]C#N
Agent: [Na+]
Product: COc1cc(C(CN=[N+]=[N-])NC2CCCCC2)cc(OC)c1OC

Procedure:
In a manner similar to Preparation 21 react 2-azido-1-(3,4,5-trimethoxyphenyl)ethanone with cyclohexanamine and NaCNBH3 to obtain the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:5]([NH2:10])=[N:6][CH:7]=[CH:8][CH:9]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(O)(=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH:1][CH2:2][CH2:3][C:4]2[C:5]([NH2:10])=[N:6][CH:7]=[CH:8][CH:9]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NCCc1cccnc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(NCCc2cccnc2N)CC1
Yield: 42.2 %

Procedure:
A solution of 3-(2-aminoethyl)-2-aminopyridine (0.122 g, 0.88 mmol) and 1-t-butoxycarbonyl 4-piperidone (0.177 g, 0.88 mmol) in dichloroethane (3 mL) containing 2 drops of acetic acid was treated with sodium triacetoxyborohydride (0.28 g, 1.33 mmol) at 20-75° C. until starting material was no longer consumed. The reaction was worked up with saturated sodium bicarbonate and methylene chloride, and dried over sodium sulfate. The crude product was purified by chromatography (silica gel, 0-10% {0.1% ammonium hydroxide in methanol) in methylene chloride, gradient elution) to produce the title compound (0.119 g) as a yellow oil. MS 321 (M+1).
Reaction SMILES: [Cl-].[CH3:2][N:3]([CH3:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S+:13]=[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[CH:6][CH:5]=1.C(O)C.[CH3:32][N:33]([C:35]1[CH:36]=[CH:37][C:38]([N:41]=[N:42][C:43]2[CH:44]=[CH:45][C:46]([S:49]([OH:52])(=[O:51])=[O:50])=[CH:47][CH:48]=2)=[CH:39][CH:40]=1)[CH3:34]>O>[CH3:32][N:33]([CH3:34])[C:35]1[CH:36]=[CH:37][C:38]([N:41]=[N:42][C:43]2[CH:48]=[CH:47][C:46]([S:49]([O-:52])(=[O:51])=[O:50])=[CH:45][CH:44]=2)=[CH:39][CH:40]=1.[CH3:2][N:3]([CH3:28])[C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[S+:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:15]=2)=[CH:8][CH:9]=1
Reactant: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)O)cc2)cc1
Agent: CN(C)c1ccc(-c2cc(-c3ccccc3)[s+]c(-c3ccccc3)c2)cc1
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)[O-])cc2)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 4-(4'-dimethylaminophenyl)-2,6-diphenylthiapyrylium chloride, 8.07 g, in a hot mixture of water, 400 mls, and ethanol, 100 mls, is added a solution of Methyl Orange, E. K. 432, 6.8 g, in hot water, 200 mls, with stirring. The mixture is stirred for 10 minutes and then is cooled and filtered, the filtrate being orange-red in color. The solid product is taken up in boiling nitromethane, filtered hot, evaporated down somewhat, and diluted with ethanol. The solid which crystallizes out overnight is filtered off. Yield: 9.3 g. of product having structural formula II noted above and exhibiting light absorption maxima (when dissolved in ethanol) at 582 and 427 nm.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[F:21][C:22]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=O>>[F:21][C:22]1[C:30]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[CH:7]2)[N:16]=1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(O)c1cccc(C(F)(F)F)c1F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cccc(C(F)(F)F)c3F)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 2-fluoro-3-(trifluoromethyl)benzoic acid: MS (ESI): m/z 455 (M+1).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][C:15]([CH3:18])([CH3:17])[N:14]=[C:13]([CH:19]3[S:24][CH2:23][CH2:22][CH2:21][S:20]3)[C:12]=2[CH:25]=1>O.CO>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][C:15]([CH3:17])([CH3:18])[N:14]=[C:13]([CH:19]3[S:20][CH2:21][CH2:22][CH2:23][S:24]3=[O:2])[C:12]=2[CH:25]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC1(C)N=C(C2SCCCS2)c2cc(Br)ccc2O1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1(C)N=C(C2SCCCS2=O)c2cc(Br)ccc2O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.8 %

Procedure:
A solution of sodium periodate (430 mg) in water (6 ml) was added to a solution of Compound 105 (600 mg) in methanol (18 ml) and the mixture was stirred at room temperature for 18 hours. The methanol was distilled off under reduced pressure and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue was purified by chromatography on silica gel to obtain a solid. The solid was recrystallized from ethyl acetate to obtain 2-(6-bromo-2,2-dimethyl-2H-1,3-benzoxazin-4-yl)-1,3-dithian-1-oxide (331 mg) (Compound 111).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]([O:15]C)=[O:14])[CH2:11][O:10][C:9]1([CH3:18])[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]([OH:15])=[O:14])[CH2:11][O:10][C:9]1([CH3:18])[CH3:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H](C(=O)O)COC1(C)C
Reaction time: 3 h
Yield: 47.9 %

Procedure:
Methyl 3-tert-butoxycarbonyl-2,2-dimethyloxazolidine-4-(R)-carboxylate (3.0 g) is dissolved in a mixture of tetrahydrofurane (THF)/H2O (3/1; 30 ml), and LiOH.H2O (684 mg) is added. After being subjected to agitation for 3 hours at room temperature, the reaction mixture is acidified with citric acid 1N (11 ml). THF is concentrated and the aqueous phase is extracted with ethyl acetate. The organic phase is dried on MgSO4, filtered and concentrated to obtain the expected product as a viscous orange oil (1.36 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[F:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1>ClCCl>[F:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([CH:23]2[CH2:24][CH:19]([NH:18][C:10]3[N:9]([CH2:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[N:11]=3)[CH2:20][CH2:21][N:22]2[CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:37])=[CH:34][CH:33]=1
Reactant: Fc1ccc(Cn2c(NC3CCN(C4CCNCC4)CC3)nc3ccccc32)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)C1CC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CCN1C1CCNCC1
Reaction time: 1 h

Procedure:
To a stirred mixture of 4 parts of N-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-[1,4'-bipiperidine]-4-amine, 1 part ofN,N-diethylethanamine and 91 parts of dichloromethane was added dropwise a solution of 1.6 parts of 4-fluorobenzoyl chloride in 39 parts of dichloromethane: slightly exothermic reaction, the temperature rises from 25° C. to 30° C. Upon completion, stirring was continued for one hour at room temperature. The reaction mixture was purified by high performance liquid chromatography using a mixture of trichloromethane, hexane and methanol (45:45:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 1.8 parts (34%) of 1'-(4-fluorobenzoyl-N-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-[1,4'-bipiperidine]-4-amine; mp. 194.3° C.; (compound 18).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][CH:17]2[CH2:20][N:19](C(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:18]2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].CCOC(C)=O>[Pd].CO>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][CH:17]2[CH2:18][NH:19][CH2:20]2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2c(c1)OC(C)(C)C2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc(OC2CNC2)c2c(c1)OC(C)(C)C2
Reaction time: 8 h
Yield: 113.6 %

Procedure:
Palladium on carbon (108 mg) was added to a solution of 4-(1-benzhydryl-azetidin-3-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (193b) (740 mg, 1.67 mmol) in 1:1 EtOAc and MeOH. The mixture was stirred under H2 balloon overnight. The mixture was filtered through Celite and concentrated to give a pale yellow solid (526 mg, 100% yield). LCMS for C15H19NO4 m/z 278.10 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:14][C:13](=[O:15])[C:10]3([CH2:12][CH2:11]3)[C:9]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]1([CH2:7][N:8]2[CH2:14][CH:13]([OH:15])[C:10]3([CH2:11][CH2:12]3)[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CN(Cc2ccccc2)C(=O)C12CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1CN(Cc2ccccc2)CC12CC2
Temperature: 65 °C
Reaction time: 0.08 h
Yield: 104.4 %

Procedure:
5-(Phenylmethyl)-5-azaspiro[2.4]heptane-4,7-dione (997.4 mg, 4.63 mmol) was dissolved in 46 mL of THF and LiAlH4 (997 mg) was added portion wise with stirring. The mixture was heated to 65° C. for 5 hours, then cooled to 0° C. The reaction was quenched with Na2SO4.H2O and was stirred at room temperature overnight. The contents were filtered through Celite, and the Celite pad was washed with EtOAc. The Celite filter cake was suspended in EtOAc (200 mL) and boiled for 5 min. The suspension was filtered, and the combined organic filtrates were then concentrated in vacuo to provide 5-(phenylmethyl)-5-azaspiro[2.4]heptan-7-ol (983 mg, >100%). LCMS: (M+H)+: 204.1
Reaction SMILES: [NH2:1][C:2]1[C:18]([F:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:3]=1[C:4]([OH:14])([C:9]#[C:10][CH:11]1[CH2:13][CH2:12]1)[C:5]([F:8])([F:7])[F:6].C(N(CC)CC)C.[C:28](Cl)(Cl)=[O:29]>C1(C)C=CC=CC=1>[Cl:20][C:16]1[CH:17]=[C:18]([F:19])[C:2]2[NH:1][C:28](=[O:29])[O:14][C:4]([C:9]#[C:10][CH:11]3[CH2:13][CH2:12]3)([C:5]([F:6])([F:7])[F:8])[C:3]=2[CH:15]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1c(F)cc(Cl)cc1C(O)(C#CC1CC1)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1Nc2c(F)cc(Cl)cc2C(C#CC2CC2)(C(F)(F)F)O1
Temperature: -25 °C
Reaction time: 0.5 h

Procedure:
To a stirred, cooled (−25° C.) solution of 144 mg (0.47 mmol) of (+/−)-2-amino-5-chloro-3-fluoro-α-(cyclopropylethynyl)-α-(trifluoromethyl)benzyl alcohol in 6 mL of toluene was added 0.28 mL (2.0 mmol) of triethylamine followed by 0.62 mL(1.2 mmol) of a 1.93 M solution of phosgene in toluene over 3 min. The solution was stirred an additional 30 min. at −25° C. after which time it was warmed to ambient temperatue and quenched with 0.5 N aq. citric acid. The mixture was extracted once with ether and once with ethyl acetate, and the combined organic extracts were washed sequentially with sat'd aq. NaHCO3, water, and brine. The solution was dried (MgSO4), and concentrated under reduced pressure to afford a tan solid. The crude product was chromatographed on silica gel(elution with 3:1 hexanes-ether) to afford, after concentration, 90 mg (58%) of (+/−)-6-chloro-4-(cyclopropylethynyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one as an off-white solid. 1H NMR (300 MHz, CDCl3) δ7.65(br s, 1H); 7.32-7.34(m, 1H); 7.22(d, 1H, J=2.2 Hz); 1.36-1.43(m, 1H); 0.82-0.98(m, 4H). 19F NMR (282 MHz, CDCl3) δ−132.5(s, 1F), −81.1(s, 3F). High resolution mass spec: calculated for C14H9NO2ClF4(M+H)+: 334.0258, found: 334.0244.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:7]([N+:17]([O-])=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(COC)OC.[H][H]>[Pd].CO>[NH2:17][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=[CH:9][C:8]=1[N:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: [H][H]
Reactant: CC(C)(C)c1ccc(N2CCOCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: COCCOC
Solvent: CO
Product: CC(C)(C)c1ccc(N2CCOCC2)c(N)c1
Reaction time: 3 h
Yield: 97.8 %

Procedure:
4-(4-tert-Butyl-2-nitrophenyl)morpholine (15 g.; 57 mmoles) was dissolved in a mixture of 150 ml. of monoglyme and 150 ml. of methanol. The mixture was then hydrogenated in the presence of 1.4 g. of Pd on carbon catalyst (10%) with an initial pressure of 39 p.s.i. hydrogen. After 3 hours, the resultant mixture was filtered to remove the catalyst and the filtrate evaporated to dryness to give the product (13 g.; 97.8% yield) as tan crystals, m.p. 165°-166° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[CH:5]([OH:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:2].CCN(CC)CC.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH2:14]([N:3]([CH2:1][CH3:2])[C:4]([C@@H:5]([O:12][S:24]([CH3:23])(=[O:26])=[O:25])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:13])[CH3:15]
Reactant: CCN(CC)C(=O)C(O)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)[C@@H](OS(C)(=O)=O)c1ccccc1

Procedure:
To a solution of N,N-diethyl-2-hydroxy-2-phenyl-acetamide (0.18 g, 0.9 mmol), Et3N (0.36 mL, 2.6 mmol), and CH2Cl2 (10 mL) at 0° C. was added methane sulfonyl chloride (0.08 mL, 1.0 mmol). After stirring for an hour, the reaction mixture was quenched with H2O (5 mL) and extracted with CH2Cl2 (3×25 mL). The orgranic extracts were combined, dried (Na2SO4), and the solvent was evaporated under reduced pressure. Chromatography of the resulting residue (Si02: EtOAc:Hex) yielded the title compound.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:32])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH:25]([OH:30])[C:26]([F:29])([F:28])[F:27])[CH:23]=3)[N:18]([CH3:31])[N:17]=2)[CH2:9]1.[CH2:33]([O:35][C:36]([CH:38]1[CH2:43][CH2:42][C:41](=O)[CH2:40][CH2:39]1)=[O:37])[CH3:34]>>[CH2:33]([O:35][C:36]([CH:38]1[CH2:43][CH2:42][CH:41]([N:8]2[CH2:11][CH:10]([NH:12][C:13](=[O:32])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([CH:25]([OH:30])[C:26]([F:29])([F:28])[F:27])[CH:23]=4)[N:18]([CH3:31])[N:17]=3)[CH2:9]2)[CH2:40][CH2:39]1)=[O:37])[CH3:34]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(O)C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CCC(N2CC(NC(=O)CNc3nn(C)c4ccc(C(O)C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-[1-methyl-5-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-indazol-3-ylamino]-acetamide TFA salt (as prepared in the previous step) and 4-oxo-cyclohexanecarboxylic acid ethyl ester using the procedure described in Step E of Example 1.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9](CO)[OH:10])[OH:8])[OH:6])[OH:4].OP([O-])(O)=O.[K+].[O-]S([O-])(=O)=O.[Mg+2]>>[CH2:9]([OH:10])[C@@H:7]([OH:8])[CH:5]([OH:6])[C@H:3]([OH:4])[CH2:2][OH:1]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Product: OC[C@@H](O)C(O)[C@H](O)CO
Temperature: 120 °C
Yield: 36 %

Procedure:
A culture medium (pH=6.0) containing 10% of D-glucose, 0.5% of peptone, 0.1% of KH2PO4, 0.05% of MgSO4, and 0.2% of yeast extract was sterilized by heating at 120° C. for 15 minutes. After sterilization, 2%(w/v) of CaCO3 sterilized separately was added thereto, in order to prevent the decrease of the medium pH during the progress of culturing. Onto the culture medium, the above-mentioned culture solution was inoculated in an amount of 10%(v/v), and was cultured at 30° C. On the third day of the culturing, D-arabitol had been formed at a concentration of 3.6 g/dl (36% yield based on the D-glucose).
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[C:9]2[CH:10]=[C:11]([C:13]([O:15]C)=[O:14])[O:12][C:8]=2[CH:7]=[C:6]([N+:17]([O-:19])=[O:18])[C:5]=1[O:20][CH3:21]>CO.O>[Cl:3][C:4]1[C:9]2[CH:10]=[C:11]([C:13]([OH:15])=[O:14])[O:12][C:8]=2[CH:7]=[C:6]([N+:17]([O-:19])=[O:18])[C:5]=1[O:20][CH3:21]
Reactant: COC(=O)c1cc2c(Cl)c(OC)c([N+](=O)[O-])cc2o1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1c([N+](=O)[O-])cc2oc(C(=O)O)cc2c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.5 %

Procedure:
Lithium hydroxide (0.9 g, 21.0 mmol) was added to a stirred suspension of methyl 4-chloro-5-methoxy-6-nitrobenzofuran-2-carboxylate (2.0 g, 7.0 mmol) in methanol-water (3:1) (40 mL). The reaction was allowed to stir for 3 h at room temperature. The reaction was then concentrated under reduced pressure and the resulting residue was dissolved in water and washed with diethyl ether. The aqueous phase was acidified by the addition of 2M aqueous hydrochloric acid then extracted with ethyl acetate. The combined organic extracts were passed through a phase separation cartridge and evaporated to afford a white solid (1.17 g, 61%), which was taken through to the next step with no further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C@@H:15]2[CH2:19][CH2:18][C:17]([C:20]3[NH:29][C:28](=[O:30])[C:27]4[CH2:26][C:25]5([CH2:32][CH2:31]5)[CH2:24][CH2:23][C:22]=4[N:21]=3)=[CH:16]2)[CH2:11][CH2:10]1.[C:33]([Zn]C#N)#[N:34]>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C@@H:15]2[CH2:19][CH2:18][C:17]([C:20]3[NH:29][C:28](=[O:30])[C:27]4[CH2:26][C:25]5([CH2:32][CH2:31]5)[CH2:24][CH2:23][C:22]=4[N:21]=3)=[CH:16]2)[CH2:11][CH2:10]1)[C:33]#[N:34]
Reactant: O=c1[nH]c(C2=C[C@H](N3CCN(c4ccc(I)cc4F)CC3)CC2)nc2c1CC1(CC2)CC1
Reactant: N#C[Zn]C#N
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2CCN([C@H]3C=C(c4nc5c(c(=O)[nH]4)CC4(CC5)CC4)CC3)CC2)c(F)c1
Temperature: 117.5 °C
Yield: 34.5 %

Procedure:
To a stirred solution of (R)-2′-(3-(4-(2-fluoro-4-iodophenyl)piperazin-1-yl)cyclopent-1-en-1-yl)-7′,8′-dihydro-3′H-spiro[cyclopropane-1,6′-quinazolin]-4′(5′H)-one (synthesis from (R)-3-aminocyclopent-1-enecarbonitrile and 2-fluoro-4-iodoaniline as described in example 11) (0.160 g, 0.293 mmol) in N,N-dimethylformamide (10 ml) was added dicyanozinc (0.344 g, 2.93 mmol) at 25° C. The reaction mixture was heated to 115-120° C. for 4 h. Progress of the reaction was monitored by TLC. After completion of reaction, reaction mixture was cooled and solvent was evaporated under reduced pressure to obtain crude product. Crude product was purified by flash column chromatography over silica gel (110-200 mesh) using 6% methanol in in dichloromethane as eluent to obtain title compound (0.045 g, 34.5%).