Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].[CH:5]1([C:11]2[CH:21]=[CH:20][C:14]([O:15][CH2:16][CH:17]3[CH2:19][O:18]3)=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>CO>[CH:5]1([C:11]2[CH:12]=[CH:13][C:14]([O:15][CH2:16][C@H:17]3[O:18][C:2]([NH2:3])=[N:1][CH2:19]3)=[CH:20][CH:21]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: c1cc(C2CCCCC2)ccc1OCC1CO1
Reactant: N#CN
Agent: [Na]
Solvent: CO
Product: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a vigorously stirred solution of sodium hydrogen cyanamide (0.64 g, 10 mmol) in methanol (10 mL) was added dropwise 2-(4-cyclohexyl-phenoxymethyl)-oxirane (2.32 g, 10 mmol) after which the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to remove methanol. Anhydrous diethyl ether (50 mL) was added after which the resulting white precipitate was removed by filtration through celite and the filtrate concentrated. The residue was purified by flash chromatography (silica, 7N NH3 in methanol/methylene chloride) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[CH:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[NH:34]1[CH2:39][CH2:38][S:37][CH2:36][CH2:35]1>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:34]4[CH2:39][CH2:38][S:37][CH2:36][CH2:35]4)(=[O:22])=[O:21])[CH:15]=3)[CH:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)Cl)c3)c2)n1
Reactant: C1CSCCN1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)N4CCSCC4)c3)c2)n1
Temperature: 25 °C
Yield: 66 %

Procedure:
The title compound was prepared from the solution of 3-[6-methyl-4-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl-2′-yl]-benzenesulfonyl chloride (example 346 step 2) (ca. 0.2 g, 0.41 mmol) by treatment with excess thiomorpholine in THF (5 mL) at 50° C. for 16 h. Cooled to rt, diluted with EtOAc, washed with 1 N HCl, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with n-heptane/EtOAc followed by trituration with n-heptane/diethyl ether to give the title compound (0.150 g, 66%) as a white solid. MS (ISP) 555.8 [(M+H)+]; mp 156° C. (dec.).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=2)[C:9]2[C:4](=[CH:5][C:6]([O:21][CH3:22])=[C:7]([O:19][CH3:20])[CH:8]=2)[N:3]=1.O1CCCC1.C(O)(C)C.[CH3:32][NH2:33]>CO.C(OCC)(=O)C>[NH2:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:21][CH3:22])=[C:7]([O:19][CH3:20])[CH:8]=3)[N:3]=[C:2]([CH2:32][NH2:33])[N:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cc2nc(Cl)nc(-c3cccc(N)c3)c2cc1OC
Reactant: CN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COc1cc2nc(CN)nc(-c3cccc(N)c3)c2cc1OC
Temperature: 130 °C
Reaction time: 24 h

Procedure:
Fourteen grams of 3-(2-chloro-6,7-dimethoxyquinazolin-4-yl)phenylamine was suspended in 135 mL of a mixed solution consisting of tetrahydrofuran:isopropanol=2:1. To the reaction mixture was added 89 mL of a methylamine solution in methanol, and the reaction mixture was stirred in a pressure-resistant sealed tube reactor at 130° C. for 24 hours. After the reaction mixture was allowed to cool down to room temperature, it was diluted with 300 mL of ethyl acetate and then washed with 300 mL of water. A water layer was extracted with 100 mL of ethyl acetate, and the combined organic layer was washed with 100 mL of brine. The organic layer was separated and was then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, the organic layer was concentrated to dryness, and the resultant was triturated with a mixed solvent consisting of ethyl acetate:tetrahydrofuran=3:1. The obtained solid was filtrated, and the filtrate was then washed with ethyl acetate, and dried under aeration to yield 10 g of a target product. The filtrate was adsorbed on a 50 g silica gel column, and it was then eluted with a mixed solution consisting of ethyl acetate:methanol=9:1, and the eluent was concentrated to dryness. The residue was triturated with ethyl acetate, and the obtained solid was then filtrated. The solid was washed with diethyl ether, and dried under aeration to yield 1.4 g of a target product. Total yield: 82.9%
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH3:12])[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:17])([CH3:4])[CH3:3].ClC1C=C(C=CC=1)C(OO)=[O:23].O>ClCCl>[CH3:14][C:13]([C:7]1[CH:8]=[C:9]([S:11]([CH3:12])=[O:23])[CH:10]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:6]=1[OH:17])([CH3:16])[CH3:15]
Reactant: CSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: CS(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 2,6-bis(1,1-dimethylethyl)-4-(methylthio)phenol (2.0 g, 3.9 mmole) and meta-chloroperoxybenzoic acid (0.86 g, 4.1 mmole) in dichloromethane (25 ml) was stirred at room temperature for 20 hours. Water was added and the phases were separated. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to dryness. Chromatography on silica gel gave the title compound, m.p. 171°-173°.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:10](Br)[CH2:9][CH2:8][N:7]([C:12](=[O:25])[C@H:13]([CH:22]([CH3:24])[CH3:23])[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6]1)(=[O:3])[CH3:2].C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[C:1]([O:4][CH:5]1[CH:10]=[CH:9][CH2:8][N:7]([C:12](=[O:25])[C@@H:13]([CH:22]([CH3:23])[CH3:24])[NH:14][C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CN(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)CCC1Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC(=O)OC1C=CCN(C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)C1

Procedure:
1.684 g of 3-acetoxy-4-bromo-N—(N-BOC-valyl)-piperidine dissolved in 4 ml of toluene are treated with 4 ml of DBU in a sealed tube and heated to 90°. The mixture obtained is treated with EE, extracted with aqueous HCl, washed and from the organic phase obtained solvent is evaporated. 3-Acetoxy-N—(N-BOC-(R)-valyl)-1,2,3,6-tetrahydropyridine is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:16]([O:20][C:21](=[O:46])[CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][C:30]([NH:32][S:33]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)(=[O:35])=[O:34])=[CH:31][C:26]=2[N:25]=[C:24]1[CH2:43][CH2:44][CH3:45])([CH3:19])([CH3:18])[CH3:17]>CC#N.CCOC(C)=O.O>[C:16]([O:20][C:21](=[O:46])[CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][C:30]([N:32]([CH2:6][C:5]3[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=3)[S:33]([C:36]3[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=3)(=[O:34])=[O:35])=[CH:31][C:26]=2[N:25]=[C:24]1[CH2:43][CH2:44][CH3:45])([CH3:19])([CH3:18])[CH3:17]
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1nc2cc(N(Cc3ccc(Cl)cc3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-Chlorobenzyl chloride (0.27 mmol) and K2CO3 (63 mg, 0.45 mmol) were added to a solution of [5-(4-fluoro-benzenesulfonylamino)-2-propyl-benzoimidazol-1-yl]-acetic acid tert-butyl ester (40 mg, 0.09 mmol) in CH3CN (1 mL), and stirred overnight at 80° C. The reaction mixture was diluted with EtOAc and H2O, and then filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was carried onto the next reaction without any further purification or characterization.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O.[CH2:54]([O:56][C:57]([C:59]1[N:60]=[CH:61][N:62]2[C:68]=1[CH2:67][NH:66][CH2:65][C:64]1[CH:69]=[CH:70][CH:71]=[CH:72][C:63]2=1)=[O:58])[CH3:55]>C(Cl)Cl>[CH2:54]([O:56][C:57]([C:59]1[N:60]=[CH:61][N:62]2[C:68]=1[CH2:67][N:66]([C:11](=[O:13])[CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:65][C:64]1[CH:69]=[CH:70][CH:71]=[CH:72][C:63]2=1)=[O:58])[CH3:55]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Reactant: CCOC(=O)c1ncn2c1CNCc1ccccc1-2
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ncn2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a solution of (R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluoro-phenyl)butanoic acid (80 mg, 0.26 mmol) in dry DCM (15 mL), was added HOBT (42 mg, 0.31 mmol); EDC (60 mg, 0.31 mmol) and DIPEA (0.21 mL, 1.21 mmol) and the reaction mixture was stirred for 10 min. 5,6-Dihydro-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxylic acid ethyl ester trifluoroacetate (98 mg, 0.26 mmol) in DCM (5 mL) was added and the reaction was stirred at r.t. overnight under nitrogen atmosphere. After the completion of the reaction, as confirmed by TLC, the crude product was extracted with DCM (10 mL) and washed with 10% HCl solution (10 mL) and saturated sodium bicarbonate solution (10 mL) sequentially. The organic layer was separated, washed with water, dried over Na2SO4 and concentrated in vacuo to afford the crude compound, which was purified by column chromatography (silica gel, 3:7 EtOAc:Pet.Ether) to afford (R)-5-[3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-5,6-dihydro-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxylic acid ethyl ester (105 mg, 77%) as a viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][C:7]([CH:22]=[O:23])=[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[Cl:9].[O-:25]Cl=O.[Na+]>CC(O)(C)C.O>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][C:7]([C:22]([OH:25])=[O:23])=[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[Cl:9]
Reactant: COC(=O)CCCC(C=O)=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: [O-][Cl+][O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: COC(=O)CCCC(C(=O)O)=C(Cl)c1ccc(-c2ccccc2)cc1
Reaction time: 16 h

Procedure:
6-(4'-Biphenylyl)-6-chloro-5-formyl-hex-5-enoic acid methyl ester (1 g) was dissolved in t-BuOH (75 mL). A solution of NaClO2 (2.42 g) and NaH2PO4 (2.42 g) in 25 mL H2O was added dropwise. The solution was stirred for 16 hours. The methanol was removed in vacuo. The solution was acidified (3N HCl) and the product ester 12 extracted with EtOAc. 1 g, 95%. NMR and IR spectra of 12 were obtained.
Reaction SMILES: [OH2:1].NN.[C:4]1(=O)[N:8]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH2:10]2)[C:7](=O)C2=CC=CC=C12>C(O)C>[CH3:4][N:8]([CH3:7])[C:9]1([O:1][CH2:11][CH2:10][CH2:9][NH2:8])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: O=C1c2ccccc2C(=O)N1C1CCCc2ccccc21
Reactant: O
Agent: NN
Solvent: CCO
Product: CN(C)C1(OCCCN)CCCc2ccccc21

Procedure:
80% hydrazine hydrate (10.0 ml) is added to a stirred solution of the phthalimido tetrahydronaphthalene obtained in the previous step (52 g) dissolved in absolute ethanol (500 ml). The reaction mixture is refluxed for 3 hours, allowed to cool, and the resultant solid filtered and the filtrate evaporated in vacuo. The yellow solid residue is triturated with aqueous 5% HCl, filtered, washed with aqueous HCl, and the filtrate extracted with ether. The acidic aqueous portion is made basic with 50% sodium hydroxide. The resultant diphasic mixture is extracted with ether, the ether extracts dried, filtered, and evaporated, yielding a yellow viscous liquid (30.1 g). The liquid is dried under high vacuum, yielding 27.7 g of the crude product, which is used as is in the next step.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C([O-])([O-])=O.[Cs+].[Cs+].[C@@H]1(N)CCCC[C@H]1N.CCCCCCCCCCCC.Br[C:33]1[CH:34]=[C:35]([CH2:39][C:40]([OH:42])=[O:41])[CH:36]=[CH:37][CH:38]=1.[OH-].[Na+]>O1CCOCC1.[Cu]I>[N:1]1([C:33]2[CH:34]=[C:35]([CH2:39][C:40]([OH:42])=[O:41])[CH:36]=[CH:37][CH:38]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: c1cn[nH]c1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: CCCCCCCCCCCC
Solvent: C1COCCO1
Product: O=C(O)Cc1cccc(-n2cccn2)c1
Yield: 65 %

Procedure:
Pyrazole (1.2 eq), Cs2CO3 (2.5 eq), CuI (0.5 eq), trans-1,2-cyclohexanediamine (0.6 eq) and dodecane (1 eq), were added to a stirred solution of 3-bromophenylacetic acid (1 eq) in dioxane at room temperature under an inert atmosphere. The mixture was irradiated in a microwave reactor (PersonalChemistry Emrys™ Optimiser, 300 W, 160° C., 20 min), then added to a 1N aqueous solution of NaOH, and extracted with Et2O. The aqueous phase was acidified to pH=3 with HCl 2N, then extracted with ethyl acetate; this phase was washed with brine, dried over Na2SO4 and the solvent was removed under reduced pressure. The crude material was purified on SPE cartridge (Silica) eluting with a gradient from Cyclohexane/ethyl acetate 8:2, to Cyclohexane/ethyl acetate 1:1, affording the title compound in 65% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][C:14]=1[F:23].[OH-].[Na+].Cl>C1COCC1.CO>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][C:14]=1[F:23]
Reactant: COC(=O)c1ccc(F)c(-c2c(F)cc(S(C)(=O)=O)cc2F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)c1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Methyl 6-[2,6-difluoro-4-(methylsulfonyl)phenyl]-5-fluoropyridine-2-carboxylate (78.0 mg, 0.226 mmol) was dissolved in THF (0.2 mL) and MeOH (0.2 mL), and 1.0 M aq. NaOH (0.90 mL, 0.90 mmol) was then added. The reaction mixture was stirred at room temperature for 40 min. The solution was then neutralized with HCl (12 M) to pH=7 and concentrated under reduced pressure to remove all the solvents. The residue was dissolved in THF and MeOH, dried, filtered and concentrated under reduced pressure to give the sub-title compound as a white powder. LCMS calc. for C13H9F3NO4S (M+H)+: m/z=332.0. Found: 332.2.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH3:21][C:22]1[N:23]=[C:24]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][N:34]=2)[CH:30]=O)[S:25][CH:26]=1>>[CH2:19]([O:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][N:34]=[C:27]([C:24]3[S:25][CH:26]=[C:22]([CH3:21])[N:23]=3)[CH:28]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1)[CH3:20]
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OCC
Reactant: Cc1csc(-c2cc(C=O)ccn2)n1
Product: CCOc1cccc(F)c1C1CC(C)C(=O)N1Cc1ccnc(-c2nc(C)cs2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate with 2-(4-methylthiazol-2-yl)isonicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.86 min.; [M+H]+: 426.01 g/mol.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C@@H:8]([CH2:20][CH2:21][CH2:22][C:23]([CH3:25])=[CH2:24])[C:9](N1[C@@H](C(C)C)COC1=O)=[O:10]>CCOCC>[CH3:7][C@@H:8]([CH2:20][CH2:21][CH2:22][C:23]([CH3:25])=[CH2:24])[CH2:9][OH:10]
Reactant: C=C(C)CCC[C@H](C)C(=O)N1C(=O)OC[C@@H]1C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C=C(C)CCC[C@H](C)CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
As reported by Schinzer et al.104, a solution of lithium aluminum hydride (8.4 ml of 1.0M solution in THF, 8.4 mmol, 1.5 equiv) was added dropwise to a solution of compound 74 (1.5 g, 5.62 mmol, 1 equiv) in ether (40 ml) at 0° C. The reaction mixture was stirred at 0° C. for 30 min before it was warmed to room temperature and stirred for an additional 10 h. The reaction mixture was cooled again to 0° C. and excess hydride was quenched by dropwise addition of water (0.32 ml), 15% aqueous sodium hydroxide (0.32 ml), and water (1 ml). Anhydrous sodium sulfate was added, and the resulting suspension was stirred at room temperature for 4 h. The white precipitate formed was filtered through a plug of celite and washed with ether. The filtrate and washings were concentrated in vacuo to give a crude oil that was purified by flash column chromatography (15% EtOAc/hexanes) to give alcohol 75 (0.772 g, 97%) as a colorless oil. The column was eluted with ethyl acetate to recover the chiral auxiliary: [α]22D=−10.3 (c=0.8, CHCl3); TLC Rf=0.39 (silica gel, 25% EtOAc/hexanes); 1H NMR (600 MHz, CDCl3) δ 4.670 (s, 1H), 4.64 (s, 1H), 3.50-3.46 (m, 1H), 3.41-3.37 (m, 1H), 2.02-1.92 (ni, 2H), 1.685 (s, 3H), 1.65-1.34 (m, 4H), 1.12-1.04 (m, 1H), 0.909-0.89 (d, 3J=6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 146.224, 110.011, 68.538, 38.237, 35.898, 32.948, 25.146, 22.576, 16.787.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]2[S:13][C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:11][C:10]=2[C:20]2[C:21]([F:38])=[C:22]([NH:26][S:27]([C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[F:37])(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][N:4]=1.N1C=CC=CC=1.[CH3:45][S:46](Cl)(=[O:48])=[O:47].CCOC(C)=O>ClCCl>[F:37][C:31]1[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:30]=1[S:27]([NH:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:10]2[N:11]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[S:13][C:9]=2[C:7]2[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][NH:1][S:46]([CH3:45])(=[O:48])=[O:47])[N:8]=2)[C:21]=1[F:38])(=[O:28])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: NCc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)NCc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Yield: 33.3 %

Procedure:
To a suspension of N-{3-[5-[2-(aminomethyl)-4-pyrimidinyl]-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.1 g, 0.178 mmol) in dichloromethane (0.500 ml) was added pyridine (0.036 ml, 0.444 mmol) and a solution of methane sulphonyl chloride (0.025 g, 0.222 mmol) in dichloromethane (0.2 ml) and stirred overnight. The reaction was concentrated. The crude product was added to a silica gel column and eluted with DCM with MeOH (0% to 10%) and collected fractions to obtain crude product. The crude product was treated with EtOAc and hexanes and sonicated to form a white solid. The solid was filtered to obtain 2,5-difluoro-N-{2-fluoro-3-[5-(2-{[(methylsulfonyl)amino]methyl}-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide (38 mg, 33%) as white solid. MS (ESI): 641 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([C@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:24][CH2:23]2)[CH2:11]1)C(OC(C)(C)C)=O.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>>[CH3:1][N:2]([C@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:24][CH2:23]2)[CH2:11]1)[S:39]([CH3:38])(=[O:41])=[O:40]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1C[C@H](CN2CCC(CCCc3ccc(F)cc3)CC2)[C@@H](c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Product: CN([C@@H]1C[C@H](CN2CCC(CCCc3ccc(F)cc3)CC2)[C@@H](c2ccccc2)C1)S(C)(=O)=O

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 28 in Step A and methylsulfonyl chloride in Step B, the title compound can be prepared.
Reaction SMILES: C(C1C=CC=CC=1C1C=CC=CC=1C#N)#N.[Br-].[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Zn+:26])#[N:19].ClC1C=CC=CC=1C#N.[Br:36]C1C=CC=CC=1C#N>[Ni]>[Zn:26].[Br-:36].[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Zn+:26])#[N:19]
Reactant: N#Cc1ccccc1Br
Agent: [Ni]
Agent: N#Cc1ccccc1-c1ccccc1C#N
Agent: N#Cc1ccccc1Cl
Product: [Zn]

Procedure:
Preparation of 2,2′-dicyanobiphenyl by nickel catalyzed reaction of 2-cyanophenylzinc bromide with 2-chlorobenzonitrile: Activated zinc was prepared and reacted with 2-bromobenzonitrile to provide 2-cyanophenylzinc bromide, as follows: A mixture of 0.208 g (30.0 mmol) lithium wire and 3.91 g (30.5 mmol) naphthalene in 15 mL of THF was stirred at room temperature for 4 h. To the resultant dark green solution was then added a solution of 2.04 g (15.0 mmol) zinc chloride in 15 mL of THF. After stirring the mixture for 10 minutes, 0.91 g (5.0 mmol) 2-bromobenzonitrile was added and the reaction mixture refluxed for 8 h. The resultant mixture was then filtered through a small pad of celite under nitrogen to provide a clear, dark solution of 2-cyanophenylzinc bromide.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:5]=[CH:6][N:7]=1.CCOC(C)=O.[CH3:22][N:23]1CCCC1=O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].[C-]#N.[C-]#N.[Zn+2]>[F:14][C:11]1[CH:12]=[CH:13][C:8]([N:4]2[CH:5]=[CH:6][N:7]=[C:2]([C:22]#[N:23])[C:3]2=[O:15])=[CH:9][CH:10]=1
Reactant: O=c1c(Cl)nccn1-c1ccc(F)cc1
Reactant: CN1CCCC1=O
Agent: [Fe+2]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1nccn(-c2ccc(F)cc2)c1=O
Temperature: 120 °C
Yield: 80 %

Procedure:
A mixture of 3-chloro-1-(4-fluorophenyl)pyrazin-2(1H)-one (1.0 g, 4.5 mmol), dppf (0.25 g, 0.45 mmol), Pd2(dba3) (0.20 g, 0.22 mmol) and Zn(CN)2 (0.31 g, 2.7 mmol) in N-methylpyrrolidone (20 mL) was heated at 120° C. for 15 hours in a sealed vial. The residue was cooled to room temperature, treated with EtOAc (300 mL), washed with a solution of saturated aq. NH4Cl, conc. NOH, water (72 mL, a ratio of 4:1:4) and brine, dried over MgSO4, and concentrated. The crude was purified by silica gel flash column chromatography (100% CH2Cl2) to afford 0.77 g (80%) of the desired product. LRMS (ESI pos) m/e 216.0 (M+1). 1H-NMR (400 MHz, CDCl3) δ 7.58 (d, 1H), 7.46 (d, 1H), 7.42 (m, 2H), 7.26 (m, 2H); 19F-NMR (376 MHz, CDCl3) δ −109.6.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].[Cl:9][C:10]([Cl:18])=[CH:11][CH:12](Br)[C:13](Br)([CH3:15])[CH3:14].C(=O)([O-])[O-].[Ca+2]>C(O)C.[Cl-].[Ca+2].[Cl-].[Cu]>[C:6]([C:5]1([C:4]([O:3][CH2:1][CH3:2])=[O:8])[CH:12]([CH:11]=[C:10]([Cl:18])[Cl:9])[C:13]1([CH3:15])[CH3:14])#[N:7]
Reactant: CC(C)(Br)C(Br)C=C(Cl)Cl
Reactant: CCOC(=O)CC#N
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Product: CCOC(=O)C1(C#N)C(C=C(Cl)Cl)C1(C)C

Procedure:
A mixture of ethylcyanoacetate, 1,1-dichloro-3,4-dibromo-4-methylpent-1-ene and calcium carbonate is heated in ethanol (100 parts by volume) at reflux in the presence of calcium chloride (22.2 parts) and copper salt as catalyst. The crude ethyl 1-cyano-3-(2',2'-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylate is isolated as described in Example 77. Details are given in the following table: