Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH2:3][CH3:4].Cl[SiH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:33])[F:32])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)[CH2:10][CH2:9]1>C1COCC1>[F:32][CH:31]([F:33])[O:30][C:27]1[CH:28]=[CH:29][C:24]([C@H:21]2[CH2:22][CH2:23][C@H:18]([CH2:17][CH2:16][CH2:15][CH2:14][C@H:11]3[CH2:12][CH2:13][Si@H:8]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:9][CH2:10]3)[CH2:19][CH2:20]2)=[CH:25][CH:26]=1
Reactant: CCCC[Mg]Cl
Reactant: FC(F)Oc1ccc([C@H]2CC[C@H](CCCCC3CC[SiH](Cl)CC3)CC2)cc1
Solvent: C1CCOC1
Product: CCCC[Si@H]1CC[C@H](CCCC[C@H]2CC[C@H](c3ccc(OC(F)F)cc3)CC2)CC1

Procedure:
50 ml (0.13 moles) of a THF solution of 2.5M of n-butylmagnesium chloride was dropped in a mixed solution of 41.5 g (0.1 mol) of 1-chloro-4-(4-(trans-4-(4-difluoromethoxyphenyl)cyclohexyl)butyl)-1-silacyclohexane and 30 ml of THF. The resultant product was found to be a mixture of trans and cis isomers with respect to the silacyclohexane ring. The product was subjected to ordinary aftertreatments, followed by isolation through chromatography to obtain 43.7 g (yield: 90%) of the intended trans isomer product.
Reaction SMILES: NCC(O)=O.[NH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24]>>[C:23]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:24])[CH:22]=[CH2:21].[C:12]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])(=[O:13])[CH:11]=[CH2:10]
Reactant: NCCCCCC(=O)O
Reactant: NCCCCCCCC(=O)O
Agent: NCC(=O)O
Product: C=CC(=O)NCCCCCC(=O)O
Product: C=CC(=O)NCCCCCCCC(=O)O

Procedure:
N-acryloyl 2-glycine (A2AGA), N-acryloyl 4-aminobutyeric acid (A4ABA), N-acryloyl 6-aminocaproic acid (A6ACA) and N-acryloyl 8-aminocaprylic acid (A8ACA) were synthesized from glycine (Fisher Scientific Inc), 4-aminobutyeric acid, 6-aminocaproic acid and 8-aminocaprylic acid (Acros Organics Inc) respectively.
Reaction SMILES: [CH2:1]([Al](C[CH:11]([CH3:13])[CH3:12])CC(C)C)[CH:2](C)[CH3:3].[CH2:14]=[CH2:15]>CCCCCCC>[CH2:1]=[CH:2][CH3:3].[CH2:14]=[CH2:15].[CH2:14]=[CH:13][CH2:11][CH3:12]
Reactant: CC(C)C[Al](CC(C)C)CC(C)C
Agent: C=C
Solvent: CCCCCCC
Product: C=CC
Product: C=CCC
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
20 mmol of triisobutylaluminum (TiBA, 10 ml of a 2 molar solution in heptane) were placed in a dry 10 l autoclave which had been flushed with N2. After addition of 150 mg of antistatic solution (Stadis® 450, Du Pont), 2000 g of liquid propene and 40 g of 1-butene (2% by weight) were metered in. At room temperature, 815 mg of the supported metallocene catalyst prepared in Example 1 were then blown in via a lock by means of N2. The autoclave was subsequently heated to 60° C. and polymerization was carried out for 90 minutes at this temperature. During the polymerization, 27 g/h of ethene were metered in continuously, i.e. a total of 40 g (2% by weight). After this reaction time had expired, the polymerization was stopped by blowing-off the remaining monomer mixture and the product was discharged via a bottom discharge valve. 1120 g of polymer powder were obtained (productivity: 1370 g of terpolymer/g of catalyst). The proportion of regioregular ′1-2′-inserted propene units in the terpolymer obtained corresponding to formula (1) is 99.24.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Si:20]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH2:45]O)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(C=P(CCCC)(CCCC)CCCC)#N.CO>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Si:20]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH2:45][CH:11]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[F:19])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])([C:33]([CH3:36])([CH3:35])[CH3:34])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: CC(C)(C)[Si](OCc1ccccc1CO)(c1ccccc1)c1ccccc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OCc1ccccc1CC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Yield: 86.4 %

Procedure:
The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (600 mg, 1.98 mmol) obtained in Example 5 and [2-[(t-butyldiphenylsilyloxy)methyl]phenyl]methanol (1.00 g, 2.66 mmol) were dissolved in toluene (20 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (640 mg, 2.65 mmol). Under an argon atmosphere, the resulting mixture was heated under reflux for 14 hours. After the reaction mixture was allowed to cool down, 2-[(t-butyldiphenylsilyloxy)methyl]phenyl]methanol (400 mg, 1.06 mmol) and cyanomethylenetri-n-butylphosphorane (400 mg, 1.66 mmol) were added. Under an argon atmosphere, the resulting mixture was heated under reflux for 14 hours. After the reaction mixture was allowed to cool down, the residue obtained by concentrating the mixture under reduced pressure was subjected to flash silica gel chromatography. The fraction obtained from the hexane:ethyl acetate=15:1 eluate was concentrated under reduced pressure, whereby the title compound (1.13 g, 1.71 mmol, 86%) was obtained as a pale yellowish brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([Cl:13])=[CH:6][C:4]=1[NH2:5].[Cl-:14]>C1C=CC=CC=1.N1C=CC=CC=1.O>[Cl:14][CH2:6][CH2:4][C:3]([NH:5][C:4]1[CH:6]=[C:7]([Cl:13])[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:3]=1[O:2][CH3:1])=[O:2]
Reactant: COc1cc([N+](=O)[O-])c(Cl)cc1N
Reactant: [Cl-]
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: O
Product: COc1cc([N+](=O)[O-])c(Cl)cc1NC(=O)CCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
17.2 g of 2 -methoxy 4 -nitro 5 -chloroaniline dissolved in 150 ml benzene are added with 11.1 g of β chloropropionly chloride dissolved in 40 ml benzene and 2 ml pyridine. The reaction mixture is kept under stirring at room temperature for two hours then diluted with 250 ml water. The benzenic phase is separated while the aqueous phase is extracted twice with benzene. The benzenic solutions are united, washed with 2N hydrochloric acid then with water, dried on sodium sulphate, filtered and evaporated to dryness. The dry residue is recristallised from isopropyl ether and 21.1 g of 1(β chloropropionylamino) 2 -methoxy 4 -nitro 5 -chlorobenzene are recovered (yield 40-50%). It melts at 101°-110° (dec)
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:13]([NH2:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[ClH:1].[CH2:13]([NH:25][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: Oc1cccc2c(Cl)ccnc12
Reactant: CCCCCCCCCCCCN
Product: CCCCCCCCCCCCNc1ccnc2c(O)cccc12
Product: Cl

Procedure:
In a manner similar to that described in Example 49, Part B, 4-chloroquinolin-8-ol and n-dodecylamine were transformed into the title compound: m.p. 189°-190° C.; m/e 328 (molecular ion); NMR spectum consistent with assigned structure.
Reaction SMILES: [C:1]([C:3](O)([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:7][CH:6]=1)[CH3:4])#[N:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.P12SP3(SP(SP(S3)(S1)=S)(=S)S2)=S>C1(C)C=CC=CC=1>[C:1]([CH:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:9][CH:10]=1)[CH3:4])#[N:2].[CH2:11]([C:8]1[CH:7]=[CH:6][C:5]([C:3](=[CH2:4])[C:1]#[N:2])=[CH:10][CH:9]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)Cc1ccc(C(C)(O)C#N)cc1
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: S=P12SP3SP(=S)(S1)SP(=S)(S3)S2
Solvent: Cc1ccccc1
Product: C=C(C#N)c1ccc(CC(C)C)cc1
Product: CC(C)Cc1ccc(C(C)C#N)cc1
Temperature: 85 °C

Procedure:
A crude solution of 410 mg (2.0 mmol) of 1-cyano-1-hydroxy-1-(4-isobutylphenyl)ethane (IBACH) in 5 mL of toluene was treated under nitrogen with 450 mg (1.0 mmol) of a finely-ground commercial phosphorus pentasulfide which is a mixture of tetraphosphorus decasulfide and tetraphosphorus nonasulfide. The reaction mixture was stirred well and heated in an 85° C. bath for one hour. GC analysis of the crude reaction product indicated that the reaction resulted in the formation of 1-cyano-1-(4-isobutylphenyl)ethane (PN) and 2-(4-isobutylphenyl)acrylonitrile (UN) in a ratio of 2/1.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9](O)[CH:8]=[C:7]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:18].O>C1(C)C=CC=CC=1.CN(C)C=O>[C:1]([C:5]1[N:10]=[C:9]([Cl:18])[CH:8]=[C:7]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(O)cc(C2CCC2)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1nc(Cl)cc(C2CCC2)n1
Reaction time: 3 h
Yield: 100.1 %

Procedure:
9.9 g of 2-tert-butyl-4-hydroxy-6-cyclobutyl-pyrimidine (48 mmol) were dissolved in 80 ml of toluene and 1 ml of dimethylformamide. 10.7 ml of POCl3 (114.8 mmol) were added dropwise at 10° C. Stirring was continued for 3 h at room temperature. The reaction mixture was poured into water, and the aqueous layer extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and then concentrated to dryness to give 10.8 g of a yellowish oil (quant.).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[CH2:19][C@H:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.C(O)(=O)C.[OH-].[OH-].[Pd+2]>[NH2:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[CH2:19][C@H:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1Cc1cccc2ccc(N(Cc3ccccc3)Cc3ccccc3)cc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1Cc1cccc2ccc(N)cc12
Reaction time: 8 h
Yield: 84.1 %

Procedure:
A mixture of 7-dibenzylamino-1-(1-t-butoxycarbonyl-pyrrolidin-2-(R)-ylmethyl)-naphthalene (0.68 g, 1.34 mmol) and 20% palladium hydroxide on carbon (0.25 g) in ethanol (20 mL) and acetic acid (20 mL) was hydrogenated at 50 psi for 8 hours. Additional 20% palladium hydroxide on carbon (0.25 g) was added and hydrogenation was continued overnight. The catalyst (0.3 g) was added a third time and hydrogenation was continued 24 hours more. The reaction was filtered through celite and the pad was washed with ethanol. The filtrate was concentrated and the residue was taken up in ether. This organic phase was extracted with saturated aqueous sodium bicarbonate, water and brine, then it was dried and concentrated to give 0.368 g (84%) of the title compound as a tan foam. A sample recrystallized from ether/hexane as a light tan solid had mp 157°-158.5° C. Analysis calculated for C20H26N2O2 : C, 73.59; H, 8.03; N, 8.58. Found: C, 73.47; H, 7.93; N, 8.37.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([CH3:14])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[C:15]([Cu])#[N:16]>CN(C=O)C.N1C=CC=CC=1>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[N:5]([CH3:14])[CH:4]=[N:3][C:2]=2[C:15]#[N:16])=[CH:8][CH:9]=1
Reactant: Cn1cnc(Br)c1-c1ccc(Cl)cc1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1cnc(C#N)c1-c1ccc(Cl)cc1
Temperature: 200 °C

Procedure:
To 4-bromo-5-(4-chlorophenyl)-1-methyl-1H-imidazole (1.3 g, 4.79 mmol) in DMF (8.4 mL) and pyridine (1.6 mL) was added CuCN (1.3 g, 14.4 mmol). The reaction was heated in a microwave reactor at 200° C. for 35 min. After cooling to ambient temperature, the reaction was quenched by addition of a 3:1 solution of NH4OH/saturated aqueous NH4Cl (60 mL). The reaction was extracted with EtOAc, organics separated, washed with saturated aqueous NaHCO3, and dried with saturated aqueous NaCl. Solvents were removed in vacuo and the residue purified by column chromatography on silica to provide desired product and recovered starting material. The recovered starting material was resubjected to the reaction conditions and purified as above to provide additional desired product. MS (m/z) 218.3 [M+H]+.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[C:5]([F:12])[CH:4]=1.C(=O)([O-])O.[K+].O.Br[CH2:20][C:21]([C:23]1[N:24]([CH:28]([CH3:30])[CH3:29])[N:25]=[CH:26][N:27]=1)=O>C1COCC1>[Br:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]2[NH:9][CH:20]=[C:21]([C:23]3[N:24]([CH:28]([CH3:30])[CH3:29])[N:25]=[CH:26][N:27]=3)[N:8]=2)=[C:5]([F:12])[CH:4]=1
Reactant: CC(C)n1ncnc1C(=O)CBr
Reactant: N=C(N)c1ccc(Br)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1c[nH]c(-c2ccc(Br)cc2F)n1
Reaction time: 18 h
Yield: 74.3 %

Procedure:
To a rapidly stirred mixture of 4-bromo-2-fluoro-benzamidine hydrochloride (9.84 g, 38.8 mmol), potassium hydrogen carbonate (15.6 g, 154.8 mmol), THF (98 mL) and water (16 mL) at reflux was added a solution of 2-bromo-1-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-ethanone (9.0 g, 38.8 mmol) in THF (19 mL) over 15 min. The resulting mixture was stirred for 18 h at reflux before concentrating in vacuo. The resultant residue was treated with water and the solid formed collected by filtration, washed (water, then 1:1 diethyl ether: cyclohexane then diethyl ether) to give 5-[2-(4-Bromo-2-fluoro-phenyl)-1H-imidazol-4-yl]-1-isopropyl-1H-[1,2,4]triazole as a brown solid (10.1 g, 74%). 1H NMR δ (ppm) (CDCl3): 8.21-8.14 (1H, m), 7.90 (1H, s), 7.80 (1H, s), 7.47-7.38 (2H, m), 7.26 (1H, s), 5.91 (1H, br, s), 1.59 (6H, d, J=6.63 Hz).
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7](O)=[O:8])=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:19])=O>C(Cl)Cl.CN(C=O)C>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7]([Cl:19])=[O:8])=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(-c2ccccc2)cc1
Yield: 46 %

Procedure:
To a solution of biphenyl-4-carboxylic acid (2.1 mmol) in dry CH2Cl2 (5.3 mL) and dry DMF (1 mL), kept at 0° C. under N2, was added oxalyl chloride (0.3 mL, 3.13 mmol). The mixture was reacted 20 min at 0° C. and 2 h at room temperature, then concentrated to give crude biphenyl-4-carbonyl chloride as a light-yellow solid. An amount of his sample (2 mmol) were dissolved in dry THF (20 mL) and the resulting solution added dropwise, at 0° C., to a suspension obtained by mixing 3 (1.3 mmol), Et3N (1.143 mL, 8.2 mmol) and dry THF (3 mL) at 0° C. under N2. The ensuing mixture was reacted at 0° C. for 30 min and at room temperature for 3 h, then evaporated. Purification by flash-chromatography (cyclohexane/EtOAc 1:1) and recrystallization gave pure URB894 as an ivory coloured solid. Yield 46%. Mp 218-220° C. (acetone/petroleum ether; sealed capillary tube; decomposition of the sample with changing of colour and shrinking of the mass was noted starting from 146° C.); [α]D20=−20° (c 0.55, CH3CN). MS (EI): m/z 267 (M+), 222, 181, 167 (100). IR (Nujol) 3270, 1827, 1641, 1540 cm−1; 1H NMR (d6-acetone) δ 4.53-4.65 (m, 2H), 4.50-4.59 (m, 1H), 7.38-7.55 (m, 3H), 7.70-7.84 (m, 4H), 8.00-8.07 (m, 2H), 8.68 (br d, 1H, J=7 Hz) ppm. 13C NMR (d6-acetone): δ 58.8, 65.1, 126.9, 127.0, 128.0, 128.1, 129.0, 131.9, 139.7, 144.4, 166.4, 169.2 ppm.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1.[Br:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH:27]=[O:28].[Cl-].[NH4+]>CCCCCC.C1COCC1>[Br:23][C:24]1[CH:25]=[C:26]([CH:27]([OH:28])[C:13]2([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]2)[CH:29]=[CH:30][C:31]=1[Cl:32]
Reactant: CC(C)(C)OC(=O)C1CC1
Reactant: O=Cc1ccc(Cl)c(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)C1(C(O)c2ccc(Cl)c(Br)c2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
42.2 ml (105.5 mmol) of a 2.5 M solution of n-butyllithium in hexane were added dropwise to a solution, cooled to from −20° C. to −30° C., of 14.8 ml (105.5 mmol) of diisopropylamine in 60 ml of abs. THF. After the addition had ended, the mixture was stirred at from −20° C. to −30° C. for another 30 min. The mixture was then cooled to −78° C., and a solution of 12.0 g (84.4 mmol) of tert-butyl cyclopropanecarboxylate in 60 ml of abs. THF was added dropwise at this temperature. After 4 h at −78° C., a solution of 15.4 g (70.3 mmol) of 3-bromo-4-chlorobenzaldehyde in 60 ml of abs. THF was added. The reaction mixture was slowly warmed to RT overnight, saturated aqueous ammonium chloride solution was then added and the mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 40:1→10:1). This gave 16.2 g of the target compound (52.5% of theory).
Reaction SMILES: NC1C=CC([C:6]([NH:8]CCC)=[O:7])=CC=1.[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][NH:15]1.Cl.[CH2:24]1[C:32]2C(=C[C:29]([C:33]([O:35][CH3:36])=[O:34])=[CH:30][CH:31]=2)C[NH:25]1>>[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][N:15]1[C:6]([NH:8][C:32]1[CH:31]=[CH:30][C:29]([C:33]([O:35][CH3:36])=[O:34])=[N:25][CH:24]=1)=[O:7]
Reactant: c1ccc2c(c1)CNC2
Reactant: CCCNC(=O)c1ccc(N)cc1
Reactant: COC(=O)c1ccc2c(c1)CNC2
Agent: Cl
Product: COC(=O)c1ccc(NC(=O)N2Cc3ccccc3C2)cn1

Procedure:
The title compound was prepared as described in Example 272B, substituting methyl 5-aminopicolinate for 4-amino-N-propylbenzamide and isoindoline for methyl isoindoline-5-carboxylate hydrochloride.
Reaction SMILES: C([Mg]Cl)CCCCCCC.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].[O:17]=[C:18]1[N:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:21]([C:30]([O:32][CH3:33])=[O:31])[CH2:20][CH2:19]1>O1CCCC1>[C:26]([O:25][C:23]([NH:22][C@@H:21]([CH2:20][CH2:19][C:18](=[O:17])[C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])[C:30]([O:32][CH3:33])=[O:31])=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Agent: CCCCCCCC[Mg]Cl
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCC(=O)C#C[Si](C)(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 2-L, 3-neck jacketed round bottomed flask equipped with an overhead mechanical stirrer, N2-inlet and temperature probe was charged with octylmagnesium chloride (2.1 M, 248.3 g, 0.560 mol) and tetrahydrofuran (1 vol, 102 g) and the solution was chilled to 0° C. (internal temperature). Trimethylsilyl acetylene (57.5 g, 0.585 mol) was added subsurface by syringe over about 25 min (Tmax=13° C.). The solution was stirred at 0° C. for 1 hour and was then cooled to −10° C. (internal temperature). A solution of (S)-1-tert-butyl 2-methyl 5-oxopyrrolidine-1,2-dicarboxylate (125 g, 0.509 mmol) in tetrahydrofuran (250 g) was added subsurface by rotary pump over a 2-hour period. The flask and pump were rinsed with about 25 g of tetrahydrofuran, which was added to the reaction flask. The reaction was monitored by HPLC until completion. A 2-L flask was charged with water (870 g) and NH4Cl (174 g) and the contents were mixed until all of the solid dissolved. About ½ of the 20% NH4Cl solution (504 g) was removed Isopropyl acetate (380 g) was added to the flask and the mixture was cooled to <5° C. The reaction solution was added to the isopropyl acetate/NH4Cl solution over about 20 minutes (Tmax=5° C.). The bath was removed and the mixture was allowed to warm to above 10° C. The mixture was transferred to a separatory funnel and the layers were separated. The gray semi-solid that was present was kept with the organic layer. The aqueous layer was extracted with isopropyl acetate (328 g) and the organic layers were combined. The organic layer was washed with the remainder of the 20% NH4Cl solution and with 20% NaCl solution (435 mL). The organic layer was concentrated and diluted with isopropyl acetate a total of two times. The mixture was filtered to remove precipitated salts. The isopropyl acetate solution of the title compound was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[CH3:7][N:8]([CH3:13])[S:9](Cl)(=[O:11])=[O:10].C(N(CC)CC)C>C(Cl)Cl>[CH3:7][N:8]([CH3:13])[S:9]([N:4]1[CH:3]=[C:2]([CH3:1])[CH:6]=[N:5]1)(=[O:11])=[O:10]
Reactant: Cc1cn[nH]c1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cnn(S(=O)(=O)N(C)C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-methyl-1H-pyrazole (10.4 g, 127.2 mmol) in CH2Cl2 (200 mL). N,N-dimethylsulfamoyl chloride (17.14 mL, 167.1 mmol) and triethylamine (35 mL, 251.1 mmol) were added to the reaction. The reaction mixture was stirred for 30 min at 0° C. in a water/ice bath and then stirred overnight at room temperature. The reaction was quenched with NaHCO3 (sat.) (40 mL) and the aqueous phase was extracted with 3×200 mL of EtOAc. The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/hexanes (1:6) as the eluent to afford the title compound (22.2 g, 92%) as a light yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][N:19]=[C:18]([Cl:27])[N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.O>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([C:22]([OH:24])=[O:23])=[CH:20][N:19]=[C:18]([Cl:27])[N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc(Cl)nc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CNc2nc(Cl)ncc2C(=O)O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.1 %

Procedure:
To a solution of ethyl 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methylamino)-2-chloropyrimidine-5-carboxylate (797 mg, 2.00 mmol) in THF (10 mL), aq. 1N NaOH (10 mL, 10.0 mmol) was added. The mixture was stirred at room temperature for 18 h. It was acidified to pH 1-2 with 6N HCl. Water and EtOAc were added. The organic phase was separated, washed with brine, dried over Na2SO4, concentrated in vacuo to give 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methylamino)-2-chloropyrimidine-5-carboxylic acid (720 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[NH:7][C:6]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=1[F:20])=[O:4].COC(=O)C1C=CC(OC)=NC=1NC1C=CC(Br)=CC=1F.C(O)(=O)C.Br>CCOC(C)=O>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:6]2[NH:7][C:8](=[O:11])[CH:9]=[CH:10][C:5]=2[C:3]([OH:4])=[O:2])=[C:14]([F:20])[CH:15]=1
Reactant: COC(=O)c1ccc(=O)[nH]c1Nc1ccc(Br)cc1F
Agent: Br
Agent: COC(=O)c1ccc(OC)nc1Nc1ccc(Br)cc1F
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(=O)[nH]c1Nc1ccc(Br)cc1F
Temperature: 92.5 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
Preparation of 2-(4-bromo-2-fluorophenylamino)-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester: To 2-(4-bromo-2-fluorophenylamino)-6-methoxy-nicotinic acid methyl ester (1.00 g, 2.82 mmol) in a sealed flask was added glacial acetic acid (10 mL) and HBr (10 mL, 48 wt % in H2O). The reaction mixture was stirred at 90-95° C. for 2 hours and then cooled to room temperature. The reaction mixture was diluted with EtOAc and washed with H2O, saturated NaHCO3, and saturated NaCl, dried over Na2SO4 and concentrated under reduced pressure. The crude product was triturated twice with dichloromethane/methanol and the resulting solid was collected and dried under vacuum to yield 0.756 g (79%) pure desired product as a white solid.