Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]1[C:7](=O)[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.C([NH2:23])C1C=CC=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:12]([O:11][C:9]([N:4]1[CH2:5][CH2:6][C@H:7]([NH2:23])[C@H:2]([F:1])[CH2:3]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.3 %

Procedure:
A mixture of (+/−)-tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (0.33 g, 1.52 mmol), benzylamine (0.16 mL, 1.52 mmol) and sodium triacetoxyborohydride (0.382 g, 1.8 mmol) in dry 1,2-dichloroethane (6 mL) was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aq. K2CO3 solution (25 mL) and extracted with ethyl acetate (2×40 mL). The combined organic extracts were dried over anhyd. Na2SO4 and concentrated under vacuum. The crude product obtained was purified by flash chromatography to give the cis isomer of the title compound (200 mg, 42.6%) as the major product and the trans isomer of the title compound (20 mg, 4.26%) as the minor product. Cis isomer: HPLC (condition D): retention time=10.20 min. LCMS (condition E): m/z 308.4 +ve with retention time=1.84 min. 1H-NMR (400 MHz, CDCl3) δ ppm: 7.32-7.37 (m, 4H), 7.24-7.29 (m, 2H), 4.69-4.82 (m, 1H), 4.32 (s, 1H), 4.11-4.16 (m, 1H), 3.88 (s 2H), 2.91-3.04 (dd, J=35.6 Hz, J=14 Hz, 1H), 2.66-2.80 (m, 2H), 1.78 (bs, 1H), 1.63-1.72 (m, 1H), 1.47 (s, 9H). 19F-NMR (400 MHz in CDCl3): δ ppm: −204.51 (1F). Trans isomer: HPLC (condition D): retention time=11.05 min. LCMS (condition E): m/z 308.4 +ve with retention time=1.99 min. 1H-NMR (400 MHz, CDCl3) δ ppm: 7.31-7.37 (m, 4H), 7.25-7.28 (m, 1H), 4.25-4.30 (m, 2H), 3.89-3.93 (d, J=13.6 Hz, 2H), 2.93 (bs, 1H), 2.80-2.89 (m, 2H), 1.96-2.01 (m, 1H), 1.48 (s, 9H), 1.37-1.40 (d, J=13 Hz, 1H). 19F-NMR (400 MHz in CDCl3): δ ppm: −189.58 (1F).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH2:9][CH2:8]2)#N.[OH-:12].[Na+].S(=O)(=O)(O)[OH:15]>>[NH:10]1[C:11]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[C:1]([OH:15])=[O:12])[CH2:8][CH2:9]1
Reactant: N#Cc1cccc2c1NCC2
Reactant: [OH-]
Reactant: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)c1cccc2c1NCC2
Temperature: 5 °C
Reaction time: 5.5 h

Procedure:
A mixture of 7-cyanoindoline (4.32 g) and 50% aqueous sulfuric acid (40 ml) was stirred at 110°-120° C. for 5.5 hours, cooled to 5° C. and adjusted to pH 7-8 with 24% aqueous sodium hydroxide. The mixture was washed with ethyl acetate and the aqueous layer was adjusted to pH 2.5-3.0 with 6N hydrochloric acid. The precipitates were collected by filtration to give indoline-7-carboxylic acid (3.25 g).
Reaction SMILES: C(O)C.[N+:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[O:15])=[CH:9][CH:8]=1)([O-:6])=[O:5].[CH2:16]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[CH2:17][CH3:18]>C(#N)C>[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([N:19]([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[CH2:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:12]=1)([O-:6])=[O:5]
Reactant: CCCNc1ccc(Cl)cc1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: CC#N
Product: CCCN(C(=O)Nc1ccc([N+](=O)[O-])cc1)c1ccc(Cl)cc1

Procedure:
1.09 g of 2-chlorobenzoylisocyanate was added to a solution of 2.00 g of N-(4-aminophenyl)-N'-(4-chlorophenyl)-N'-propylurea in 50 ml of acetonitrile while stirring at room temperature. After stirring for 1.5 hours at room temperature the formed precipate was sucked off, washed with diethyl ether, and dried. According to PMR the product had the desired structure; the product melted at 170° C. The starting aniline was obtained from the corresponding nitro compound by reduction with hydrogen under the influence of Raney nickel as a catalyst; in this reaction ethanol was used as a solvent. N-(4-nitrophenyl)-N'-(4-chlorophenyl)-N'-propylurea was prepared by a coupling of p-nitrophenylisocyanate with N-propyl-4-chloroaniline in acetonitrile as a solvent. In a corresponding manner, in which, if desired, instead of acetonitrile diethyl ether was used as a solvent for the first-mentioned reaction, the following compounds were prepared; the compound numbers corresponding again with the numbers given before in the specification:
Reaction SMILES: [CH2:1]([OH:12])[CH:2]1[O:7][CH:6]([OH:8])[CH:5]([OH:9])[CH:4]([OH:10])[CH:3]1[OH:11].C(O)C(O)C(O)C(O)C=O.[NH3:23]>C(O)C>[C:6]([O-:8])(=[O:7])[CH:5]([CH3:4])[OH:9].[NH4+:23].[CH2:1]([OH:12])[CH:2]1[O:7][CH:6]([OH:8])[CH:5]([OH:9])[CH:4]([OH:10])[CH:3]1[OH:11]
Reactant: N
Agent: O=CC(O)C(O)C(O)CO
Agent: OCC1OC(O)C(O)C(O)C1O
Solvent: CCO
Product: CC(O)C(=O)[O-]
Product: [NH4+]

Procedure:
Accordingly, hetero-lactic fermentation of a mixture containing hexose and pentose may be performed. Hetero-lactic fermentation is conducted while neutralizing with ammonia to produce ammonium lactate and ethanol from hexose, and to produce ammonium lactate and ammonium acetate from pentose. Ammonium lactate and ammonium acetate are esterified with ethanol (if amount of ethanol obtained by fermentation is not enough, ethanol might be further added) to yield ethyl lactate and ethyl acetate, respectively. Ammonia generated at the time of esterification is recovered. Unreacted ethanol is distilled off, and purification of ethyl lactate is conducted by distillation with removing and recovering ethyl acetate.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C@H:17]3[CH2:22][CH2:21][C@H:20]([CH:23]=[CH2:24])[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)[CH:5]=[CH:4][C:3]=1[OH:25].[CH2:26]([C@H:28]1[CH2:33][CH2:32][C@H:31]([CH2:34]Br)[CH2:30][CH2:29]1)[CH3:27].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>COCCOC.C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][C@H:11]2[CH2:12][CH2:13][C@H:14]([C@H:17]3[CH2:22][CH2:21][C@H:20]([CH:23]=[CH2:24])[CH2:19][CH2:18]3)[CH2:15][CH2:16]2)[CH:5]=[CH:4][C:3]=1[O:25][CH2:34][C@H:31]1[CH2:32][CH2:33][C@H:28]([CH2:26][CH3:27])[CH2:29][CH2:30]1
Reactant: CC[C@H]1CC[C@H](CBr)CC1
Reactant: C=C[C@H]1CC[C@H]([C@H]2CC[C@H](COc3ccc(O)c(F)c3F)CC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: C=C[C@H]1CC[C@H]([C@H]2CC[C@H](COc3ccc(OC[C@H]4CC[C@H](CC)CC4)c(F)c3F)CC2)CC1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
6.5 g of 2,3-difluoro-4-(trans-4-(trans-4-vinylcyclohexyl)cyclohexyl)methoxyphenol was dissolved in 35 mL of DME, and 4.9 g of (trans-4-ethylcyclohexyl)methyl bromide and 6.4 g of tripotassium phosphate were added thereto, and then stirred for 2 hours at 80 to 100° C. Water and toluene were added thereto, and the organic layer was fractioned. The resultant product was washed with saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by recrystallization and column chromatography, to thereby obtain 3.8 g of 2,3-difluoro-1-(trans-4-ethylcyclohexyl)methoxy-4-(trans-4-(trans-4-vinylcyclohexyl)cyclohexyl)methoxybenzene (1a) in the form of colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH:25]4[CH2:27][CH2:26]4)=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[O:28]=[C:29]1[NH:33][C@H:32]([CH2:34][O:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:31][O:30]1>>[C:36]([O:35][CH2:34][C@@H:32]1[CH2:31][O:30][C:29](=[O:28])[N:33]1[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH:25]4[CH2:27][CH2:26]4)=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([C:7]#[N:8])[CH:9]=1)(=[O:43])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2C#N)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3COC(=O)c3ccccc3)cc2C#N)CC1
Yield: 74.2 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 91 and using 5-bromo-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (1.58 g) described in Preparation Example 194 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (906 mg), the title compound (1.56 g) was obtained.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:19])[C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[C:10]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[NH:3][N:2]=1)=[O:19])[CH3:5]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)CCC=C(C)C
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(CCC=C(C)C)[nH]n1

Procedure:
Hydrazine hydrate (0.41 mL, 8.48 mmol) was added to a stirring room temperature solution of 49 (0.1.9190 g, 8.48 mmol) in EtOH (8.5 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by HPLC (1/2 h): The reaction was concentrated and purified by silica gel chromatography (Combiflash column, 96:4 Hexanes:2N NH3 in EtOH): 1H (CDCl3, 400 MHz): δ 12.73 (1H, broad s), 6.57 (1H, s), 5.09 (1H, t, J=6.8 Hz), 4.32 (2H, q, J=7.1 Hz), 2.70 (2H, t, J=7.5 Hz), 2.29 (2H, q, J=7.5 Hz), 1.63 (3H, s), 1.52 (3H, s), 1.30 (3H, t, J=7.1 Hz) ppm. Partial 13C (CDCl3, 100 MHz): δ 162.27, 106.11, 60.65, 31.49, 27.53, 25.52, 17.51, 13.10 ppm. HPLC: 9.986 min.
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]([S:6]([C:9]1[CH:37]=[CH:36][C:12]([O:13][C:14]2[C:28]([CH2:29][C:30](N(OC)C)=[O:31])=[CH:27][C:17]3[NH:18][C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[N:20][C:16]=3[CH:15]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:5].[Cl-].[NH4+]>O1CCCC1>[CH2:4]([S:6]([C:9]1[CH:37]=[CH:36][C:12]([O:13][C:14]2[C:28]([CH2:29][C:30]([CH3:1])=[O:31])=[CH:27][C:17]3[NH:18][C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[N:20][C:16]=3[CH:15]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:5]
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2CC(=O)N(C)OC)cc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2CC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
With cooling with ice, 14 μl of a tetrahydrofuran solution of 3.0 M methylmagnesium bromide was added to a tetrahydrofuran (500 μl) solution of 8.7 mg of the compound obtained from Example 138, and stirred at room temperature for 30 minutes. then, 14 μl of a tetrahydrofuran solution of 3.0 M methylmagnesium bromide was added to it, and stirred at room temperature for 5 minutes. With cooling with ice, aqueous saturated ammonium chloride solution was added to it, extracted with chloroform, and the organic layer was washed with saturated saline water. After dried, the solvent was evaporated away under reduced pressure, and the residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=20/1) to obtain 4.0 mg of the entitled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:17]([C:18]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][N:22]4[CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[CH3:34][Mg]Br.[Cl-].[NH4+]>C1COCC1.O>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[CH:12][C:13]([CH:14]([OH:15])[CH3:34])=[CH:16][C:17]=2[C:18]2[N:26]=[C:25]([CH3:27])[N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][N:22]3[CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)=[CH:5][CH:4]=1
Reactant: C[Mg]Br
Reactant: COc1ccc(Nc2ncc(C=O)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Nc2ncc(C(C)O)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.1 %

Procedure:
6-(6-Methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)nicotinaldehyde (641.5 mg, 1.440 mmol) was suspended in THF (14 mL) and the reaction was cooled in an ice bath under nitrogen. Then, methylmagnesium bromide (3.0 M solution in diethyl ether, 1.65 mL, 4.95 mmol) was added via syringe, and the reaction was allowed to warm up to room temperature. After 1 h and 45 min, the reaction was cooled in an ice bath and the reaction was treated with saturated ammonium chloride, dropwise at first as gas evolution was observed. Then, the reaction was warmed to room temperature and diluted with water (15 mL). The layers were separated, and the aqueous phase was extracted with 10:1 DCM/MeOH. The organic layer and the organic extracts were combined, concentrated, and dried under high vacuum to give 1-(6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethanol (725 mg). 1H NMR (CDCl3, 400 MHz) δ 12.52 (s, 1H), 9.81 (s, 1H), 8.43 (s, 1H), 8.36-8.19 (m, 3H), 6.83-6.77 (m, 1H), 5.88 (d, J=9.00 Hz, 1H), 5.01 (d, J=5.87 Hz, 1H), 4.21 (d, J=10.95 Hz, 1H), 3.89-3.81 (m, 1H), 2.91 (s, 3H), 2.21-1.65 (m, 6H), 1.63-1.61 (m, 3H). m/z (ESI, pos. ion) 462 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH:3]=1.[NH:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:31][C:30]3[CH:32]=[N:33][CH:34]=[CH:35][C:29]=3[NH:28][C:27]2=[O:36])[CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:10]([C:8]([C:4]1[N:5]=[CH:6][N:7]=[C:2]([N:20]3[CH2:21][CH2:22][CH:23]([N:26]4[CH2:31][C:30]5[CH:32]=[N:33][CH:34]=[CH:35][C:29]=5[NH:28][C:27]4=[O:36])[CH2:24][CH2:25]3)[CH:3]=1)=[O:9])[CH2:11][CH2:12]2
Reactant: O=C1Nc2ccncc2CN1C1CCNCC1
Reactant: O=C(c1cc(Cl)ncn1)N1CCc2cc(F)ccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(N2CCC(N3Cc4cnccc4NC3=O)CC2)ncn1)N1CCc2cc(F)ccc21

Procedure:
70 mg (0.25 mmol) (6-chloro-pyrimidin-4-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone, 60 mg (0.26 mmol) 3-piperidin-4-yl-3,4-dihydro-1H-pyrido[4,3-d]pyrimidin-2-one and 50 μL (0.30 mmol) DIPEA in 5.0 mL DMF were shaken for 2 h at RT. Then the reaction mixture was poured onto water, stirred and the precipitate formed was suction filtered. This was washed with diisopropylether and dried.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([NH:6][C:7]2[CH:19]=[C:18]([CH:20]=[CH2:21])[CH:17]=[CH:16][C:8]=2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.Br[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1.C(N(CCCC)CCCC)CCC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.CN(C)C(=O)C>[F:1][C:2]1[CH:23]=[CH:22][C:5]([NH:6][C:7]2[CH:19]=[C:18](/[CH:20]=[CH:21]/[C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[CH:17]=[CH:16][C:8]=2[C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])=[CH:4][CH:3]=1
Reactant: Brc1cccnc1
Reactant: C=Cc1ccc(C(=O)OC(C)(C)C)c(Nc2ccc(F)cc2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: CCCCN(CCCC)CCCC
Product: CC(C)(C)OC(=O)c1ccc(/C=C/c2cccnc2)cc1Nc1ccc(F)cc1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To N,N-dimethylacetamide 3.0 mL solution of tert-butyl 2-(4-fluoroanilino)-4-vinylbenzoate 0.15 g were added 3-bromopyridine 70 μL, tributylamine 0.23 mL and palladium acetate 11 mg at room temperature, and it was stirred at 110° C. for 24 hours. After the reaction mixture was cooled to room temperature, palladium acetate 11 mg was added to it, and it was stirred at 110° C. for 24 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 10% citric acid aqueous solution, saturated sodium thiosulfate aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=4:1] to give tert-butyl 2-(4-fluoroanilino)-4-((E)-2-(pyridin-3-yl)vinyl)benzoate.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[N:4]([Si](C(C)C)(C(C)C)C(C)C)[CH:3]=1.C([Mg]Cl)(C)C.C(OC(=O)[N:34]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[Cl:51])[C:35]1[CH:40]=[CH:39][C:38]([CH:41]=O)=[C:37]([F:43])[N:36]=1)(C)(C)C.[Cl-].[NH4+]>O1CCCC1>[Cl:51][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=1[CH2:44][NH:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=3)[NH:4][CH:3]=2)=[C:37]([F:43])[N:36]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1Cl)c1ccc(C=O)c(F)n1
Reactant: COc1cnc2c(c1)c(I)cn2[Si](C(C)C)(C(C)C)C(C)C
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cnc2[nH]cc(Cc3ccc(NCc4ccccc4Cl)nc3F)c2c1
Temperature: 5 °C
Yield: 160 %

Procedure:
To 3-iodo-5-methoxy-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (5, 0.49 g, 1.14 mmol) in 6.8 mL of tetrahydrofuran at −50° C. under nitrogen, isopropylmagnesium chloride (0.569 mL, 2.0 M in tetrahydrofuran, 1.14 mmol) was added slowly. The reaction was allowed to warm to 5° C. over 70 minutes, then cooled to −60° C. and (2-chloro-benzyl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (48, 0.23 g, 0.63 mmol) in 30.0 mL of tetrahydrofuran was added. The reaction was allowed to warm to room temperature over 1 hour, then poured into aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 20-100% ethyl acetate in hexane. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound as a white solid (176, 0.400 g). MS (ESI) [M+H+]+=669.4.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:18][O:19][CH3:20].[Li]CCCC.CN([CH:29]=[O:30])C.[NH4+].[Cl-].C[CH2:34][O:35]CC>C1COCC1>[CH3:20][O:19][CH2:18][O:17][C:12]1[C:13]([CH:34]=[O:35])=[CH:14][CH:15]=[CH:16][C:11]=1[C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([CH:29]=[O:30])[C:5]=1[O:4][CH2:3][O:2][CH3:1]
Reactant: COCOc1ccccc1-c1ccccc1OCOC
Reactant: CN(C)C=O
Reactant: CCOCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCOc1c(C=O)cccc1-c1cccc(C=O)c1OCOC
Temperature: 0 °C
Yield: 47 %

Procedure:
2,2′-Bis-(methoxymethoxy)bibenzene (7.5 g, 27.4 mmol) was dissolved in 300 mL of anhydrous Et2O in a 500 mL of three-necked bottle, while stirring, 80 mmol (50 mL, 1.6M solution in hexane) of nBuLi was added dropwise under Ar atmosphere, the mixture was stirred at room temperature for 2 h. After cooled to 0° C., DMF (20 mL, 260 mmol) in THF (20 mL) was added, and the solution was stirred at room temperature for another 4 h. Saturated NH4Cl (150 mL) was added to quench the reaction. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (100 mL×3). The combined organic phase was washed with water (100 mL) and brine (100 mL) successively and dried over anhydrous MgSO4. Concentration with a rotary evaporator and subsequent chromatography on silica gel eluted with petroleum ether/ethyl acetate (3:1) afforded the product 3.925 g (47% yield) as a yellow oil. 1HNMR (300 MHz, CDCl3) δ (ppm) 3.15 (s, 6H), 4.81 (s, 4H), 7.37 (dd, J=0.9, 8.4 Hz, 2H), 7.67 (dd, J=1.8, 7.5 Hz, 2H), 7.93 (dd, J=1.8, 7.8 Hz, 2H), 10.44 (s, 2H). Physical data of the compound was consistent with that reported in literature.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[C:4](C1C=CC(C)=CC=1)=[O:5].ClC1C=CC=C(C(OO)=[O:26])C=1.P([O-])([O-])(O)=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>ClCCl.O>[CH3:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[C:4]([OH:5])=[O:26]
Reactant: Cc1ccc(C(=O)c2ccc(F)cc2C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(F)ccc1C(=O)O
Temperature: 40 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
2.3 g (10 mmol) of 2-methyl-4-fluoro-4'-methylbenzophenone were added dropwise at 20° C., under inert gas, to 3.8 g (12 mmol) of 3-chloroperbenzoic acid (55%) in 40 ml of dichloromethane and 14.2 g (0.1 mol) of disodium hydrogenphosphate and the reaction mixture was then heated for 8 h at 40° C. It was monitored by gas chromatography and, if the conversion was incomplete, a further 2.5 g (8 mmol) of 3-chloroperbenzoic acid were added. 100 g of water were added 4 hours later and the mixture was neutralized with sodium hydrogencarbonate solution. The phases were separated, the aqueous phase was extracted with dichloromethane and the solvent was distilled off. The residue was boiled for 4 h with 100 g of 70% sulfuric acid and then poured on to 200 g of ice. Extraction and crystallization gave 1.15 g (7.5 mmol, 5%) of 2-methyl-4-fluorobenzoic acid. If the reaction is carried out under these conditions with 9.2 g (15 mmol) of ®Oxone (=potassium peroxomonosulfate) instead of with 3-chloroperbenzoic acid, essentially the same result is obtained.
Reaction SMILES: [O:1]=[C:2]1[O:6][CH:5]([CH:7]([NH:20]C(=O)OC(C)(C)C)[CH2:8][CH2:9][CH2:10][CH:11]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13](OC)=[N:12]2)[CH2:4][O:3]1.[Cl-:28].[NH4+:29].Cl.CCOC(C)=O>CO>[ClH:28].[ClH:28].[NH2:20][CH:7]([CH:5]1[CH2:4][O:3][C:2](=[O:1])[O:6]1)[CH2:8][CH2:9][CH2:10][CH:11]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13](=[NH:29])[NH:12]1
Reactant: [Cl-]
Reactant: COC1=NC(CCCC(NC(=O)OC(C)(C)C)C2COC(=O)O2)CCCC1
Reactant: [NH4+]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: N=C1CCCCC(CCCC(N)C2COC(=O)O2)N1

Procedure:
The product of EXAMPLE 271 in MeOH is reacted with ammonium chloride by the method of EXAMPLE 27. This product is then treated with 3M HCl/EtOAc to generate the title material.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[N:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(N(CC)CC)C>ClCCCl.CC(O)C>[C:15]([O:14][C:12]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[C:3]3[CH:11]=[CH:10][CH:9]=[N:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:21][CH2:20]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ncnc2ncccc12
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3ncccc23)CC1
Yield: 90.8 %

Procedure:
To a solution of 4-chloropyrido[2,3-d]pyrimidine (0.72 g, 4.4 mmol) and 1-Boc piperazine (0.84 g, 4.5 mmol) in DCE (10 mL) and IPA (10 mL) was added triethylamine (4 mL). The mixture was refluxed for 4 hours. After cooling, the solvent was removed. The residue was subject to column chromatography by ethyl acetate to give 4-pyrido[2,3-d]pyrimidin-4-yl-piperazine-1-carboxylic acid tert-butyl ester (1.26 g, 92%). 1H NMR (CDCl3, 400 MHz) δ 9.07 (dd, J=4.30 Hz, J=1.98 Hz, 1H), 8.88 (s, 1H), 8.25 (dd, J=7.99 Hz, J=1.98 Hz, 1H), 7.41 (dd, J=8.18 Hz, J=3.74 Hz, 1H), 3.82 (m, 4H), 3.65 (m, 4H), 1.50 (s, 9H). MS (APCI+) [M+H]+316.