Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:22])[CH2:5][C:6]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])O[N:13]2[C:8]([C:9]([CH3:16])([CH3:15])[O:10][CH2:11][CH2:12]2)=[N:7]1)C.C(OCC)(=[O:25])C>CC1C=CC(C)=CC=1C.CCOCC>[OH:25][C:5]1[C:4](=[O:22])[N:13]2[C:8]([C:9]([CH3:15])([CH3:16])[O:10][CH2:11][CH2:12]2)=[N:7][C:6]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CC1(C(=O)OCC)N=C2N(CCOC2(C)C)O1
Reactant: CCOC(C)=O
Agent: Cc1ccc(C)c(C)c1
Solvent: CCOCC
Product: CCOC(=O)c1nc2n(c(=O)c1O)CCOC2(C)C
Yield: 18 %

Procedure:
A solution of intermediate 24, ethyl 2-(2-ethoxy-2-oxoethyl)-8,8-dimethyl-2,5,6,8-tetrahydro-[1,2,4]oxadiazolo[3,2-c][1,4]oxazine-2-carboxylate (31.16 g) in 1,2,4-trimethylbenzene (200 mL) was heated at 180° C. for 5 h. The resulting dark reaction solution was cooled then concentrated to give a dark brown paste which was taken up into ethyl acetate (250 mL) and extracted with 0.5 M aq Na2CO3 (4×50 mL). The organic layer was discarded and the aqueous layer acidified by carefully adding conc.HCl (20 mL) before being extracted with CH2Cl2 (4×50 mL). The combined CH2Cl2 layers were dried (Na2SO4), filtered and concentrated to give a dark paste which was dissolved in ether (100 mL) and allowed to stand at room temperature in a open flask. The brown/light yellow solid that formed was filtered to afford the title compound. The mother liquor that contained product was re-processed to afford additional material (combined yield ˜18–20% over two steps). 1H NMR (500 MHz, CDCl3) δ: 10.55 (1H, s), 4.45 (2H, q, J=7.0 Hz), 4.02 (4H, s), 1.61 (6H, s), 1.43 (3H, t, J=7.0 Hz). HRMS (M+H) calcd for C12H17N2O5: 269.1138. found: 269.1149. Anal calcd for C12H16N2O5: C, 53.72; H, 6.01; N, 10.44. Found: C, 53.71; H, 6.04; N, 10.30.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1)=[O:6].B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.[B]1OC2C(=CC=CC=2)O1>>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:5]([OH:6])[C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:8]2)[CH:20]=[CH:21][CH:22]=1.[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:5]([OH:6])[C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:8]2)[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(Cl)c2)C1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: [B]1Oc2ccccc2O1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](O)c2cccc(Cl)c2)C1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@H](O)c2cccc(Cl)c2)C1
Temperature: -15 °C
Reaction time: 0.33 h

Procedure:
To a solution of (R)-tert-butyl 3-(3-chlorobenzoyl)piperidine-1-carboxylate (5.60 g, 17.29 mmol) and (R)-2-methyl-CBS-oxazaborolidine (1 M in toluene, 9 mL, 9.00 mmol) cooled to −78° C. was added catecholborane (5.6 mL, 54.0 mmol) dropwise. After 20 min, the reaction temperature was allowed to warm to −15° C. and stirred overnight. The reaction was quenched at 0° C. by careful addition of water and diluted with ether. The resulting suspension was filtered through Celite and washed with ether. The filtrate was washed successively with 1 M aq NaOH (3×50 mL), 1 M aq HCl (3×50 mL), satd aq NaHCO3 and brine, and dried over Na2SO4. The solution was filtered, the filtrate was evaporated under vacuum, and the residue was purified by preparative HPLC to afford (R)-tert-butyl 3-((R)-(3-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (2.44 g) and (R)-tert-butyl 3-((S)-(3-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (1.21 g). MS: 348 (M+Na)+.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[CH:29]([C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1)([CH3:31])[CH3:30].[Cl-].[Na+]>C(OCC)C>[CH3:2][O:3][CH:4]=[CH:36][C:35]1[CH:38]=[CH:39][C:32]([CH:29]([CH3:31])[CH3:30])=[CH:33][CH:34]=1
Reactant: CC(C)c1ccc(C=O)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: COC=Cc1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.9 %

Procedure:
27.7 g of methoxymethyltriphenylphosphonium chloride is introduced into 350 ml of diethyl ether under nitrogen. At 0° C., 38.8 ml of n-butyllithium solution (1.6 M in hexane) is added in drops, and it is stirred for one hour at room temperature. 12 g of 4-isopropylbenzaldehyde in 50 ml of diethyl ether is now added, and it is stirred for one more hour. Sodium chloride solution is added to the reaction mixture, extracted with ethyl acetate, dried on sodium sulfate and concentrated by evaporation. After chromatography on silica gel with ethyl acetate/hexane, 8.1 g of 1-methoxy-2-[4-(1-methylethyl)phenyl]-ethene 42 (E, Z-mixture) is obtained as a colorless oil, which is dissolved in 200 ml of acetone and stirred under nitrogen with 10 ml of 2N hydrochloric acid overnight. Sodium chloride solution is added, extracted with ethyl acetate, dried on sodium sulfate and concentrated by evaporation. Chromatographic purification on silica gel with ethyl acetate/hexane yields 5.1 g of title compound 43 as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:22]=[C:21]([C:29]#[N:30])[CH:20]=2)[C:12]=1[F:31])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[CH:22]=[C:21]([C:29]#[N:30])[CH:20]=2)[C:12]=1[F:31])=[O:8]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(C#N)cc(CC3CC3)c2)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(CC2CC2)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 76.1 %

Procedure:
4-chloro-N-[(4-chloro-3-{[3-cyano-5-(cyclopropylmethyl)phenyl]oxy}-2-fluorophenyl)methyl]-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (0.027 g, 0.046 mmol) dissolved in DCM (3 mL) was treated with TFA (3 mL) at 25° C. overnight with stirring. The reaction mixture was concentrated to dryness and the residue purified by mass-directed HPLC on a SunFire prep C-18 column eluted with 30 to 85% CH3CN/H2O (0.1% formic acid buffer). Appropriate fractions were combined, concentrated to dryness, chased twice with ethanol and twice with toluene to remove residual water to give 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(cyclopropylmethyl)phenyl]oxy}-2-fluorophenyl)methyl]-1H-imidazole-5-carboxamide (0.016 g, 0.035 mmol, 76% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 11.31 (br. s., 1H), 7.61 (s, 1H), 7.20-7.36 (m, 4H), 7.14 (s, 1H), 6.87 (s, 1H), 4.72 (d, J=5.91 Hz, 2H), 2.56 (d, J=6.96 Hz, 2H), 0.84-1.03 (m, 1H), 0.53-0.63 (m, 2H), 0.14-0.27 (m, 2H). LC-MS (ES−) m/z 457.14, 459.12 [M−1]. LC-MS (ES+) m/z 459.09, 461.07 [M+H].
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:7]=1[CH3:8].Br[CH2:16][CH:17]=O>>[CH3:8][C:7]1[C:2]2[N:3]([CH:16]=[CH:17][N:1]=2)[N:4]=[C:5]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=1
Reactant: O=CCBr
Reactant: Cc1cc(-c2ccccc2)nnc1N
Product: Cc1cc(-c2ccccc2)nn2ccnc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.2 g of 3-amino-4-methyl-6-phenylpyridazine are added to the filtrate (bromoacetaldehyde solution) and the mixture is stirred for 24 hours at room temperature.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C@H:5]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[NH:6][C:7]([C:9]1[S:10][C:11]([NH2:14])=[CH:12][CH:13]=1)=[O:8])[CH3:2].[CH3:23]CN(C(C)C)C(C)C.COS(OC)(=O)=O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:22])[C@H:5]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[NH:6][C:7]([C:9]1[S:10][C:11]([NH:14][CH3:23])=[CH:12][CH:13]=1)=[O:8])[CH3:2]
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(N)s1)C(=O)OCC
Reactant: CCN(C(C)C)C(C)C
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(NC)s1)C(=O)OCC
Temperature: 60 °C
Reaction time: 42 h
Yield: 15.5 %

Procedure:
A solution containing N-(5-aminothiophene-2-carbonyl)-L-glutamic acid diethyl ester (III-3 where R2 is H) (1.78 g, 5.42 mmol), (i-Pr)2NEt (1.0 mL, 0.74 g, 5.7 mmol), and Me2SO4 (0.59 mL, 0.79 g, 6.2 mmol) in 20 mL N,N-dimethylformamide (DMF) was warmed at 60° C. for 2 hours, then left at 20°-25° C. for 42 hours. The solution was evaporated in vacuo (1 mm, bath 25°-30° C.), and the residue was dissolved in EtOAc-cyclohexane (1:1 by volume) for application to a silica gel column. Elution by the same solvent system afforded fractions homogeneous by TLC of the product. Fractions were combined and evaporated to afford 16% yield (287 mg) of N-[5-(methylamino)thiophene-2-carbonyl]-L-glutamic acid diethyl ester (III-3) R2 =CH3 as an amber oil.
Reaction SMILES: [C:1]([C:3]1[C:4](=O)[NH:5][C:6]([CH3:15])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1)#[N:2].C1(P(Cl)([Cl:25])=O)C=CC=CC=1>>[Cl:25][C:4]1[C:3]([C:1]#[N:2])=[CH:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([CH3:15])[N:5]=1
Reactant: Cc1[nH]c(=O)c(C#N)cc1-c1ccccc1
Reactant: O=P(Cl)(Cl)c1ccccc1
Product: Cc1nc(Cl)c(C#N)cc1-c1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
A mixture of 100.34 g 3-cyano-6-methyl-5-phenyl-1H-pyridin-2-one [Walker and Weaver, J. Org. Chem. 26, 4441 (1961)] and 192 ml phenylphosphonic dichloride (C6H5POCl2) was warmed to 160°-170° C. and kept at that temperature for about 16 hours. The reaction mixture was cooled and poured into ice water. The solid product was collected, dried in a vacuum oven and extracted with ether. The ether solution was concentrated, and the residue was washed with hexane and extracted with 300 ml 15% aqueous potassium bicarbonate. The resulting solid was dried in a vacuum oven to give 92.71 g (85%) 2-chloro-3-cyano-6-methyl-5-phenylpyridine, m.p. 134°-135° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[F:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[N:23]1[CH2:28][CH2:27][CH:26]([C:29]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:30])[CH2:25][CH2:24]1.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:34]2[CH2:35][CH2:36][N:31]([C:29]([CH:26]3[CH2:27][CH2:28][N:23]([C:22]4[CH:21]=[CH:20][N:19]=[CH:18][C:17]=4[F:16])[CH2:24][CH2:25]3)=[O:30])[CH2:32][CH2:33]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=C(C1CCN(c2ccncc2F)CC1)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C1CCN(c2ccncc2F)CC1)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.3 %

Procedure:
4-Trifluoromethylphenylsulphonyl chloride (0.97 g) was added to a mixture 1-[1-(3-fluoro-4-pyridyl)piperidin-4-ylcarbonyl]piperazine hydrochloride (1.22 g) and triethylamine (3.70 ml) in dichloromethane (45 ml) at 0° C. The solution was stirred at ambient temperature for 18 hours. The solution was diluted with dichloromethane and washed with water, dried (Na2SO4) and evaporated. The residue was purified by chromatography eluting with 2% methanol in dichloromethane. Recrystallisation from ethyl acetate/hexane gave 1-(4-trifluoromethylphenylsulphonyl)-4-[1-(3-fluoro-4-pyridyl)piperidin-4-ylcarbonyl]piperazine (0.99 g) as a solid.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:19]=[C:18]3[C:12]([CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)=[N:11]2)=[CH:6][CH:5]=1.[CH3:21][CH:22]([CH3:25])[CH:23]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.CO>[CH3:1][NH:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:19]=[C:18]3[C:12]([CH2:13][CH2:14][N:15]([CH2:21][CH:22]([CH3:25])[CH3:23])[CH2:16][CH2:17]3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: CNC(=O)c1ccc(-n2cc3c(n2)CCNCC3)cc1
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)c1ccc(-n2cc3c(n2)CCN(CC(C)C)CC3)cc1
Temperature: 25 °C

Procedure:
A solution of N-methyl-4-(5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)benzamide (may be prepared as described in Description 25) (30.0 mg, 0.11 mmol) in dichloromethane (3 ml) was treated with 2-methylpropanal (20.0 μl, 0.22 mmol) and acetic acid (1 drop) and stirred at room temperature. Sodium triacetoxyborohydride (47.0 mg, 0.22 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was diluted with methanol and passed down a SCX cartridge eluting with methanol and then a 2M solution of ammonia in methanol. The basic fractions were combined and evaporated to afford the title compound (E5); MS (ES+) m/e 327 [M+NH3]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=O)[C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.C(Cl)(=O)OCC.[NH2:22][CH:23]1[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([NH:22][CH:23]2[CH:28]3[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]3)[CH2:24]2)=[O:15])[C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1
Reactant: O=C1COc2c(cc(Cl)cc2C(=O)O)N1
Reactant: NC1CN2CCC1CC2
Agent: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cl
Product: O=C1COc2c(cc(Cl)cc2C(=O)NC2CN3CCC2CC3)N1

Procedure:
A solution of 4.6 g of 6-chloro-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid in 50 ml of tetrahydrofuran is cooled to below 0° C. and 5 ml of triethylamine is added under stirring thereto. Further, 2.5 g of ethyl chlorocarbonate is added and the mixture is stirred for an hour. To the resultant mixture is added 3.0 g of 3-aminoquinuclidine and the mixture stirred for 3 hours. After completion of the reaction, aqueous sodium hydrogen carbonate and ethyl acetate are added. The organic layer is separated, washed with water and dried over magnesium sulfate. The solvent is distilled off and the residue is recrystallized from ethanol-water followed by treating with ethanolic hydrochloric acid to give 6-chloro-3,4-dihydro-3-oxo-N-(3quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide hydrochloride, melting at 227°-229° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][OH:4].S(=O)(=O)(O)[OH:12].[K].S(=O)(O)[O-].[Na+]>CCOCC.O>[CH3:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:3]([OH:12])=[O:4]
Reactant: CCCCCCC(C)CO
Reactant: O=S(=O)(O)O
Agent: O=S([O-])O
Agent: [K]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCCCCCC(C)C(=O)O
Temperature: 0 °C
Yield: 71 %

Procedure:
To 21.2 g (147 mmol) of (-)-2-methyloctanol were added an aqueous solution of 330 ml of water and 46.4 g of concentrated sulfuric acid, which was stirred to form an emulsion. To this emulsion was added dropwise 63.4 g (401 mmol) of potassium permaganate over 7 hours. Then, the reaction mixture was added with 51.5 g of sodium bisulfite and poured into 270 ml of ice water together with 70 ml of ice water and 200 ml of ether. After the separation into two layers, the reaction product was extracted from the aqueous layer with ether, which was further extracted with a 10% aqueous solution of sodium hydroxide, added with ice and further with a concentrated hydrochloric acid to adjust the pH to not more than 1. Thereafter, the extraction with chloroform on the aqueous layer was performed, which was washed with water, dried on magnesium sulfate and filtered. The filtrate was concentrated and distilled under a reduced pressure to obtain 16.5 g (yield: 71%) of a colorless and transparent liquid of (+)-2-methyl octanoic acid.
Reaction SMILES: [C:1]1([C@H:7]([N:9]2[C:13](=[O:14])[CH2:12][C@@H:11]([C:15]([OH:17])=O)[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](Cl)(=[O:22])C(Cl)=O.[CH2:24]([N:26](CC)CC)C>CN(C)C=O.ClCCl>[CH3:24][N:26]([O:22][CH3:18])[C:15]([C@@H:11]1[CH2:12][C:13](=[O:14])[N:9]([C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH3:8])[CH2:10]1)=[O:17]
Reactant: C[C@H](c1ccccc1)N1C[C@H](C(=O)O)CC1=O
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CON(C)C(=O)[C@@H]1CC(=O)N([C@H](C)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a dichloromethane solution (200 ml) of 1-[1-(R)-phenylethyl]-5-oxopyrrolidine-3-(R)-carboxylic acid (11.66 g, 0.05 mol) were added oxalyl chloride (6.54 ml, 0.075 mol) and dimethylformamide (3 drops) under ice cooling, followed by stirring at room temperature overnight. After removal of the solvent under reduced pressure, toluene (100 ml) was added thereto and the solvent was again removed under reduced pressure. To the residue were added dichloromethane (200 ml) and N,O-methylhydroxylamine hydrochloride (5.47 g, 0.055 mol), and then a dichloromethane solution (50 ml) of triethylamine (17.4 ml, 0.125 mol) was added thereto under ice cooling and stirring over a period of 15 minutes. After stirring under ice cooling for 30 minutes, the mixture was stirred at room temperature for 3 hours. The reaction solution was washed with 10% citric acid aqueous solution (100 ml), water (100 ml) and saturated sodium hydrogen carbonate aqueous solution (100 ml), successively, and then dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the residue was subjected to silica gel column chromatography. Elution with chloroform/methanol of 50/1 to 20/1 afforded the title compound (11.32 g, 82%) as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].Cl.[Cl:12][CH2:13][C:14](=N)OCC>C(O)C>[Cl:12][CH2:13][C:14]1[NH:1][C:2]2[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=2[N:10]=1
Reactant: CCOC(=N)CCl
Reactant: N#Cc1ccc(N)c(N)c1
Agent: Cl
Solvent: CCO
Product: N#Cc1ccc2nc(CCl)[nH]c2c1
Yield: 54.9 %

Procedure:
3.42 g of 3, 4-diaminobenzonitrile and 4.06 g of ethyl chloroacetoimidate hydrochloride were dissolved in 100 ml of ethanol, and the solution was refluxed under heating for 3 hours. After cooling and distilling off the solvent, the resulting residue was dissolved in ethyl acetate, washed with water, and then dried. After distilling off the solvent, the crystals thus precipitated were collected by filtration to obtain 2.7 g of 2-chloromethyl-5-benzimidazolecarbonitrile.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C@@H:25]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26]3)=[N:23][N:24]=2)[CH:21]=1.N>CN(C=O)C.CO.C(Cl)Cl>[CH3:30][N:27]1[CH2:28][CH2:29][C@@H:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26]1
Reactant: CN1CC[C@@H](c2nnc3ccc(F)cn23)C1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: CN1CC[C@@H](c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)C1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of Intermediate A (203 mg, 1.24 mmol) in dry DMF (3 mL) under N2 was added NaH (60% dispersion in oil, 83.0 mg, 2.07 mmol) (CARE: gas evolution) and the resulting opaque brown solution stirred at RT for 45 min. A solution of Intermediate 90d (228 mg, 1.03 mmol) in dry DMF (2 mL) was added and the dark brown solution stirred at 60° C. under N2 for 90 min. The cooled solution was concentrated in vacuo, redissolved in MeOH (2 mL) and AcOH (0.1 mL), applied to and SCX-2 cartridge (20 g) and washed with MeOH (75 mL). The product was eluted with 2M NH3 in MeOH (50 mL); concentration in vacuo gave a dark brown solid. FCC, using 5-15% (2M NH3 in MeOH) in DCM, gave the title compound as a light brown powder after freeze-drying (299 mg, 80%). LCMS (Method 3): Rt 0.44 min, m/z 364 [MH+].
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].Cl.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](Cl)=[N:27][OH:28])=[CH:21][CH:20]=1.C(N(CC)CC)C>O1CCCC1>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=3)[O:28][N:27]=2)=[CH:21][CH:20]=1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1ccc(CCc2ccccn2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(CCc3ccccn3)cc2)no1
Temperature: 60 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
To an anhydrous tetrahydrofuran (5 mL) solution of 3-ethynyl-pyridin-2-ylamine (39 mg, 0.33 mmol) described in Manufacturing Example 1-2-3 was added (4-(2-pyridin-2-yl-ethyl)-phenyl)-acetohydroximoyl chloride hydrochloride (310 mg, 1.0 mmol) described in Manufacturing Example 93-1-8 under nitrogen atmosphere at room temperature. Triethylamine (0.42 mL, 3.0 mmol) was then added dropwise, and stirred for 2 hours at 60° C. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=3:7 then 4:6), and the resulting crude product was further purified by silica gel thin-layer chromatography (ethyl acetate) to obtain the title compound (21.2 mg, 18%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([F:11])[CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccc(F)c1
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN(Nc1cccc(F)c1)C(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 39.2 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 570 mg, 4.1 mmol), 3-fluorophenylboronic acid (Aldrich; 673 mg, 4.6 mmol), copper(II) acetate (750 mg, 4.1 mmol) and triethylamine (1.4 mL, 10.0 mmol) in 1,2-dichloroethane (20 mL) was heated in an oil bath at 60° C. for 1.5 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 120 g column, eluting with 10-20% ethyl acetate/hexanes, to give N′-(3-fluoro-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (386 mg, 39%) as a pale yellow oil.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=2)[N:3]1[CH2:16][C:17]([OH:19])=[O:18].CO>[Pd]>[O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:14])([F:13])[F:15])[CH:8]=2)[N:3]1[CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C(O)Cn1c(=O)ccc2cc(C(F)(F)F)ccc21
Agent: [Pd]
Solvent: CO
Product: O=C(O)CN1C(=O)CCc2cc(C(F)(F)F)ccc21

Procedure:
To a stirring mixture of 2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid in Pd/C was added MeOH. The reaction mixture was placed under an atmosphere of hydrogen (balloon) for several hours. The product mixture was filtered through a plug of celite. The plug was washed several times with EtOAc. The mixture was concentrated under reduced pressure and the crude amine was taken directly to the next reaction without further purification. Retention time (min)=1.841, method [1], MS (ESI) 274.1 (M+H).