Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH:14][C:15]3[N:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][N:16]=3)[CH:5]=[CH:4][C:3]1=2.[H-].[Na+].[CH3:29]I.O>CN(C=O)C>[CH3:29][N:14]([C:15]1[N:16]=[CH:17][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:20]=1)[C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:26])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=2[CH:7]=1
Reactant: CCOC(=O)c1cnc(Nc2ccc3c(c2)C(C)(C)CCC3(C)C)nc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(N(C)c2ccc3c(c2)C(C)(C)CCC3(C)C)nc1
Yield: 97 %

Procedure:
Ethyl 2-[N-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)amino]-pyrimidine-5-carboxylate (104 mg) was dissolved in dry DMF (3 ml), and the solution was added with a suspension of NaH (40 mg) in DMF (2 ml). The mixture was then added with methyl iodide (0.5 ml) and stirred. After the disappearance of the materials was observed with TLC, the reaction mixture was poured into water, and extracted with CH2Cl2. The organic layer was dried over Na2SO4, and the solvent was evaporated. The residue was purified by silica gel flash column chromatography (n-hexane: AcOEt=20:1) to obtain white crystals of ethyl 2-[N-methyl-N-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl)amino]pyrimidine-5-carboxylate (105 mg, 97%).
Reaction SMILES: [Li].[CH3:2][C:3]1([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=2[F:15])[CH2:6][NH:5][C:4]1=O>C1COCC1>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:3]2([CH3:2])[CH2:4][NH:5][CH2:6]2)=[C:9]([F:15])[CH:10]=1
Reactant: CC1(c2ccc(N)cc2F)CNC1=O
Agent: [Li]
Solvent: C1CCOC1
Product: CC1(c2ccc(N)cc2F)CNC1
Temperature: 0 °C
Reaction time: 20 h
Yield: 106.8 %

Procedure:
A flame-dried 3-neck 2-L round bottom flask equipped with mechanical stirrer, reflux condenser, and addition funnel was charged with 300 mL tetrahydrofuran and 350 mL 1M lithium aluminumhydride (0.35 mol) followed by cooling to 0° C. This solution was treated with a solution of 9.85 g 3-Methyl-3-(4-amino-2-fluorophenyl)-2-azetidinone (0.051 mol) in 210 mL THF with gas evolution and a yellow coloration. The cooling bath was removed and the reaction was heated to reflux with the rapid formation of a white precipitate. After 20 hours, the visually unchanged reaction mixture was cooled to room temperature and quenched by the successive addition of 13 mL water, 12 mL 5M sodium hydroxide, and 47 mL water. The resulting thick gelatinous suspension was diluted with one L ethyl acetate, filtered through a pad of CELITE, concentrated, and high vacuum dried to afford 9.82 g of the title compound as a light orange syrup. 1H NMR (300 MHz, CDCl3) δ 6.78 (t, 1H, J=8.5 Hz, aromatic), 6.37 (m, 2H, aromatic), 4.06 (d, 2H, J=8.2 Hz, N--CH2a s), 3.81 (bs, 3H, NHs), 3.58 (d, 2H, J=8.2 Hz, N--CH2b b), 1.65 (s, 3H, CH3).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([NH:13][C@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)=[N:10][C:9]([C:19]1[NH:23][C:22](=[O:24])[NH:21][N:20]=1)=[CH:8]2.CC1C=CC=C(C)N=1.[C:33](Cl)(=[O:36])[CH:34]=[CH2:35]>C(Cl)Cl>[C:33]([N:16]1[CH2:17][CH2:18][C@H:14]([NH:13][C:11]2[C:12]3[C:7](=[CH:6][CH:5]=[CH:4][C:3]=3[Cl:2])[CH:8]=[C:9]([C:19]3[NH:23][C:22](=[O:24])[NH:21][N:20]=3)[N:10]=2)[CH2:15]1)(=[O:36])[CH:34]=[CH2:35]
Reactant: O=c1[nH]nc(-c2cc3cccc(Cl)c3c(N[C@H]3CCNC3)n2)[nH]1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C=CC(=O)N1CC[C@H](Nc2nc(-c3n[nH]c(=O)[nH]3)cc3cccc(Cl)c23)C1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
To a mixture of (S)-3-(8-chloro-1-(pyrrolidin-3-ylamino)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one hydrochloride (100 mg, 0.3 mmol) in DCM (20 mL) was added 2,6-dimethylpyridine (97 mg, 0.91 mmol). The resulting mixture was cooled to −40° C. Acryloyl chloride (51 mg, 0.6 mmol, 10 mg/mL in dry DCM) was added dropwise and the mixture was stirred at −40° C. for 30 minutes. The reaction was subsequently quenched with MeOH (5 mL) and the mixture was concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (57 mg, 52%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.91 (s, 1H), 11.80 (s, 1H), 7.85-7.83 (m, 1H), 7.61-7.59 (m, 3H), 7.49-7.47 (m, 1H), 6.6-6.5 (m, 1H), 6.17-6.13 (m, 1H), 5.67-5.63 (m, 1H), 5.18-5.16 (m, 1H), 4.18-4.17 (m, 0.5H), 3.69-3.65 (m, 0.5H), 3.42 (m, 0.5H), 3.32-3.31 (m, 1.5H), 2.31-2.29 (m, 1H), 2.04-2.01 (m, 1H); ESI-MS m/z [M+H]+ 385.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]>C(Cl)(Cl)Cl>[CH2:13]([O:12][C:10](=[O:11])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(Br)cn1
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(Br)cn1)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of 2-amino-5-bromopyridine (6.92 g, 40 mmol) and 6.22 g (48 mmol) of diisoproplethylamine in 50 mL of chloroform was added dropwise to a solution of 8.19 g (48 mmol) of benzyl chloroformate in 20 mL of chloroform at about 0° C., with stirring. A voluminous white precipitate formed. After about 15 minutes, the mixture was filtered and the precipitate was washed three times with chloroform and dried to give 2.70 g of the title product, mp 184° C. (dec) (recrystallization solvent=2-propanol). 1H nmr (dimethylsulfoxide-d6): δ=10.48 (br s, 1 H), 8.37 (d, 1 H), 7.98 (d of d, 1 H), 7.81 (d, 1 H), 7.40 (m, 5 H), 5.17 (s, 2 H); ms (NH3Cl): m/z=307, 309 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH:45]=[O:46])=[C:19]([N:23]3[CH:27]=[C:26]([C:28]#[N:29])[C:25]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)=[O:38])=[CH:33][CH:32]=4)=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C[OH:50]>ClCCl.O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:45][OH:46])=[C:19]([N:23]3[CH:27]=[C:26]([C:28]([NH2:29])=[O:50])[C:25]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([N:39]5[CH2:40][CH2:41][O:42][CH2:43][CH2:44]5)=[O:38])=[CH:33][CH:32]=4)=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CO
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c(Nc5ccc(C(=O)N6CCOCC6)cc5)n4)c3C=O)ncc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c(Nc5ccc(C(=O)N6CCOCC6)cc5)n4)c3CO)ncc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-formyl-phenyl]-3-[4-(morpholine-4-carbonyl)-phenylamino]-1H-pyrazole-4-carbonitrile (52 mg, 0.0839 mmol) was dissolved in 6 mL of dichloromethane and 2 mL of methanol. Sodium borohydride solution (9.52 mg, 0.252 mmol) in water (0.5 mL) and methanol (1.0 mL) was added in drops. The mixture was stirred at room temperature for 1 hr. LC/MS showed a clean desired product. The mixture was evaporated to dryness and extracted with dichloromethane and water. The organic layer was dried over sodium sulfate and evaporated to give a pure desired 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-3-[4-(morpholine-4-carbonyl)-phenylamino]-1H-pyrazole-4-carbonitrile (51 mg, 98% yield). LC/MS clacd for C34H32FN7O4 (m/e) 621.25, obsd 622.1 (M+H, ES+); 1H NMR (400 MHz, CDCl3) δ ppm 1.45 (s, 9H), 3.59-3.77 (m, 8H), 4.37 (br. s., 2H), 6.59 (br. s., 1H), 7.43 (d, J=8.6 Hz, 2H), 7.48 (dd, J=7.8, 1.3 Hz, 1H), 7.54-7.61 (m, 4H), 7.66 (t, J=8.1 Hz, 1H), 7.81 (dd, J=8.1, 1.3 Hz, 1H), 8.32 (d, J=2.5 Hz, 1H), 8.74 (s, 1H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15][CH2:16][CH2:17]Cl)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][O:27][C:23]=2[CH:22]=1>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][N:31]3[CH2:30][CH2:29][CH:28]([C:25]4[C:24]5[CH:34]=[CH:35][C:21]([F:20])=[CH:22][C:23]=5[O:27][N:26]=4)[CH2:33][CH2:32]3)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)N1CCc2c(sc(C)c2CCCCCl)C1
Agent: Cl
Product: CC(=O)N1CCc2c(sc(C)c2CCCCN2CCC(c3noc4cc(F)ccc34)CC2)C1
Yield: 30.4 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 1.0 g of 6-acetyl-3-(4-chlorobutyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine and 0.9 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.5 g of 6-acetyl-3-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil, m.p. 158°-160° C. as 3/2oxalate thereof.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[NH:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.[NH4+].[Cl-].C(Cl)CCl.CC[N:30](CC)CC>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[O:7])[NH2:30])=[CH:4][C:3]=1[NH:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1
Reactant: COc1ccc(C(=O)Nc2cc(C(=O)O)ccc2N)cc1
Reactant: CCN(CC)CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccc(C(=O)Nc2cc(C(N)=O)ccc2N)cc1
Yield: 30 %

Procedure:
A solution of 108 (200 mg, 0.70 mmol), NH4Cl (74 mg, 1.40 mmol), HOBT-hydrate (104 mg, 0.77 mmol), EDC (119 mg, 0.77 mmol) and Et3N (0.29 ml, 2.1 mmol) in DMF (3 ml) was stirred for 16 h at room temperature. The solvent was evaporated, ethyl acetate was added and the organic layer was washed successively with saturated solutions of NH4Cl, NaHCO3 and NaCl, dried over MgSO4, filtered and concentrated. The crude product was triturated in ethyl acetate and filtered to give the title compound 109 (60 mg, 30%). 1H NMR: (DMSO) δ (ppm): 9.57 (s, 1H), 7.96 (d, J=8.8 Hz, 2H), 7.67 (d, J=2.2 Hz, 1H), 7.59 (sb, 1H), 7.52 (dd, J=8.2, 2.0 Hz, 1H), 7.02 (d, J=8.8 Hz, 2H), 6.90 (sb, 1H), 6.72 (d, J=8.4 Hz, 1H), 5.41 (s, 2H), 3.83 (s, 3H). MS: (calc.) 285.1; (obt.) 286.1 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](OCC)=[C:8]2[CH:14]=[N:13][NH:12][C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21]>O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:22][CH2:18][CH2:19][CH2:20][CH3:21])=[C:8]2[CH:14]=[N:13][NH:12][C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2[nH]ncc2c1OCC
Reactant: CCCCN
Solvent: O
Product: CCCCNc1c(C(=O)OCC)cnc2[nH]ncc12

Procedure:
4-Ethoxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester is treated with butylamine at 90° for 1 hour. After this period the mixture is cooled, diluted with water and the white crystalline precipitate is filtered off. Recrystallization from diethyl ether yields 4-butylamino-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester.
Reaction SMILES: C1([O:7][C:8]([N:10]2[C:16]([CH3:17])=[CH:15][C:14]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:13]=3[C:12]([C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25]([CH3:32])[CH:24]=3)=[N:11]2)=O)C=CC=CC=1.[CH:33]1([NH2:36])[CH2:35][CH2:34]1>>[CH:33]1([NH:36][C:8]([N:10]2[C:16]([CH3:17])=[CH:15][C:14]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:13]=3[C:12]([C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25]([CH3:32])[CH:24]=3)=[N:11]2)=[O:7])[CH2:35][CH2:34]1
Reactant: CC1=Cc2ccc(Cl)cc2C(c2ccc([N+](=O)[O-])c(C)c2)=NN1C(=O)Oc1ccccc1
Reactant: NC1CC1
Product: CC1=Cc2ccc(Cl)cc2C(c2ccc([N+](=O)[O-])c(C)c2)=NN1C(=O)NC1CC1
Yield: 59 %

Procedure:
2.07 g (4.6 mmoles) 8-chloro-4-methyl-1-(3-methyl-4-nitrophenyl)-3H-2,3-benzodiazepine-3-carboxylic acid phenyl ester are boiled in 10 ml of cyclopropylamine for 10 hours. The separated crystals are filtered off, and the crude product is re-crystallized from ethanol. Thus 1.12 g (59%) of the desired compound melting at 221-223° C. is obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:4][N:3]=1.[C:20]([CH:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)([CH3:23])([CH3:22])[CH3:21]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[C:20]([C@H:24]1[CH2:25][CH2:26][C@H:27]([NH:30][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:4][N:3]=2)[CH2:28][CH2:29]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: Clc1ncc(CCc2cccnc2)c2ccccc12
Reactant: CC(C)(C)C1CCC(N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)[C@H]1CC[C@H](Nc2ncc(CCc3cccnc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Under a N2 atmosphere, 300 mg (1.11 mmol) of 1-chloro-4-[2-(pyridin-3-yl)-ethyl]-isoquinoline (step 1.6) and 520 mg (3.3 mmol) 4-tert-butyl-cyclohexylamine (cis/trans mixture) are stirred at 120° C. After 2 days, a further 520 mg of 4-tert-butyl-cyclohexylamine are added, followed by 1 g after a total of 4 days. Stirring continues for 3 days at 150° C., then the reaction mixture is cooled to RT and diluted with EtOAc and NaHCO3 solution. The water phase is separated off and extracted twice with EtOAc. The organic phases are washed 3 times with water and brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2; toluene/EtOAc 3:1) and elution (toluene/EtOAc 3:1+1% Et3N) yields trans 1-(4-tert-butyl-cyclohexylamino)-4-[2-(pyridin-3-yl)-ethyl]-isoquinoline (crystallised from DIPE), followed by cis 1-(4-tert-butyl-cyclohexylamino)-4-[2-(pyridin-3-yl)-ethyl]-isoquinoline. trans derivative: m.p. 124-125° C.; 1H NMR (CDCl3) δ8.47 (m, 2H), 7.83 (d, 1H), 7.77 (m, 2H), 7.64 (t, 1H), 7.47 (m, 2H), 7.19 (m, 1H), 4.98 (d, HN), 4.05 (m, 1H), 3.14 (t, 2H), 2.98 (t, 2H), 2.27 (m, 2H), 1.86 (m, 2H), 1.25 (m, 4H), 1.07 (m, 1H), 0.90 (s, 9H). cis derivative: 1H NMR (CDCl3) δ8.47 (m, 2H), 7.85 (d, 1H), 7.77 (m, 2H), 7.66 (t, 1H), 7.50 (m, 2H), 7.20 (m, 1H), 5.40 (d, HN), 4.45 (m, 1H), 3.14 (t, 2H), 2.98 (t, 2H), 2.13 (m, 2H), 1.7 (m, 4H), 1.28 (m, 2H), 1.13 (m, 1H), 0.92 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1.[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[CH2:12][Br:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(Oc2cccc(F)c2)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cccc(Oc2cccc(CBr)c2)c1
Temperature: 10 °C
Yield: 58.3 %

Procedure:
90 g (0.445 mol) of 3-(3-fluorophenoxy)-toluene were dissolved in 300 ml of anhydrous carbon tetrachloride and heated under reflux together with 79.3 g of N-bromosuccinimide. After reaching 70° C., 5 g of azodiisobutyronitrile were added. After about 10-20 minutes the reaction commenced, with evolution of heat, and after the exothermic reaction had subsided the mixture was heated for a further 4 hours under reflux. The reaction batch was then cooled to 10° C., the succinimide was filtered off and the carbon tetrachloride was distilled of in vacuo. The oil which remained was distilled at 143°-150° C./1 mm Hg. 72.9 g (58.2% of theory) of 3-(3-fluorophenoxy)-benzyl bromide were obtained.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][NH:27][CH3:28])=[CH:24][CH:23]=1.O>CS(C)=O>[F:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][N:27]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=2)[CH3:28])=[CH:24][CH:23]=1
Reactant: CNCc1ccc(F)cc1
Reactant: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)Oc1cc(N(C)Cc2ccc(F)cc2)ccc1[N+](=O)[O-]
Temperature: 90 °C

Procedure:
4-Fluoro-2-isopropoxy-1-nitrobenzene (1.0 g) was dissolved in dry dimethylsulfoxide (25 mL). Potassium carbonate (1.4 g) and (4-fluorobenzyl)-(methyl)-amine (0.84 g) were added. The resulting mixture was heated to 90° C. over night. After cooling to room temperature, water (75 mL) was added, and the resulting mixture was extracted with ethyl acetate (3×75 mL). The organic phase was dried over sodium sulfate, filtered, and evaporated in vacuo to yield the title compound as slightly yellow solid (1.6 g, 100%).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][C:7]=1[CH:14]=[CH2:15])(=[O:4])=[O:3].Cl.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29](O)=[O:30])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[C:28]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:29]([NH:11][CH2:10][C:9]2[CH:12]=[CH:13][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[C:7]([CH:14]=[CH2:15])[CH:8]=2)=[O:30])=[CH:23][CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccc(C=C(C(=O)O)c2ccccc2)cc1
Reactant: C=Cc1cc(CN)ccc1NS(C)(=O)=O
Agent: Cl
Product: C=Cc1cc(CNC(=O)C(=Cc2ccc(C(C)(C)C)cc2)c2ccccc2)ccc1NS(C)(=O)=O
Yield: 46 %

Procedure:
4-Methanesulfonylamino-3-vinyl-benzylamine and HCl salt (153 mg, 0.582 mmol) were reacted with 3-(4-tert-butyl-phenyl)-2-phenyl-acrylic acid (160.4 mg) to give 3-(4-tert-butyl-phenyl)-N-(4-methanesulfonylamino-3-vinyl-benzyl)-2-phenyl-acrylamide (130.8 mg, 46%).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](=[N:18][CH2:19][C@H:20]([OH:37])[CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:25][CH:24]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.O1CCCC1>O1CCCC1>[CH:1]([N:14]1[CH2:15][CH:16]([NH:18][CH2:19][C@H:20]([OH:37])[CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:27][CH:28]=2)[CH2:17]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O[C@@H](CN=C1CN(C(c2ccccc2)c2ccccc2)C1)COc1ccc(OCc2ccccc2)cc1
Agent: B
Solvent: C1CCOC1
Product: O[C@@H](CNC1CN(C(c2ccccc2)c2ccccc2)C1)COc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 93 %

Procedure:
To a solution of (2S)-1-(1-Benzhydryl-azetidin-3-ylideneamino)-3-(4-benzyloxy-phenoxy)-propan-2-ol (0.49 g, 1 mmol) in tetrahydrofuran (4 ml) was added 1.2 ml of borane-tetrahydrofuran (1.0 M in THF), and the mixture was stirred at room temperature for 20 h. It was then quenched with 1.5 ml of 2 N NaOH, and the volatiles were evaporated. The aqueous solution was removed, and the residue was washed with water, and treated with 3 ml of 2 N HCL and 3 ml of methanol for 20 h. The mixture was then made alkaline with 1 N NaOH, and the methanol was evaporated. The resulting suspension was filtered, and the precipitate washed with water, and dried in vacuo to give 0.46 g of a white solid; m.p. 109-110°C.; MS (ES) m/z 495.7 (MH+); HRMS (El) Calcd. for C32H34N2O3 (M+): 494.2570, Found: 494.2561.
Reaction SMILES: C([O:8][C:9]1[C:15]([F:16])=[C:14]([O:17][C:18]2[CH:19]=[N:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=2)[CH:13]=[CH:12][C:10]=1[NH2:11])C1C=CC=CC=1.O1CCCC1>[Pd].CO>[NH2:11][C:10]1[C:9]([OH:8])=[C:15]([F:16])[C:14]([O:17][C:18]2[CH:19]=[N:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=2)=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)c1ccc(Oc2ccc(N)c(OCc3ccccc3)c2F)cn1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2ccc(N)c(O)c2F)cn1
Reaction time: 20 h
Yield: 99.4 %

Procedure:
A mixture of 2-(benzyloxy)-3-fluoro-4-{[6-(methylsulfonyl)pyridin-3-yl]oxy}aniline (5.5 g), 10% palladium on carbon (containing 50% water, 1.6 g), tetrahydrofuran (100 mL) and methanol (80 mL) was hydrogenated at room temperature for 20 h under balloon pressure. The catalyst was removed by filtration and washed with tetrahydrofuran-methanol. The combined filtrate and washings were concentrated in vacuo and the residue was dissolved in ethyl acetate. The solution was concentrated in vacuo to give the title compound (4.2 g, 100%) as a light brown amorphous solid. MS 299 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[CH2:36]([NH2:40])[CH:37]([CH3:39])[CH3:38]>>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:40][CH2:36][CH:37]([CH3:39])[CH3:38])[N:7]=2)=[C:9]([C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: CC(C)CN
Product: CC(C)CNc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (100 mg, 0.186 mmol) and isobutylamine (2 mL) the title compound was obtained as a white powder (52 mg, 48.7% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.76 (s, 1H), 8.04 (d, J=5.2 Hz, 1H), 7.35-7.57 (m, 6H), 7.28 (t, J=7.8 Hz, 1H), 5.84 (bs, 1H), 2.95 (bs, 2H), 1.80 (bs, 1H), 1.40 (s, 9H), 0.86 (d, J=5.5 Hz, 6H). MS (ESI): 574 [M−H]−.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:11]([C@@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][Br:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl[CH2:33][O:34][CH3:35]>C1COCC1>[CH2:11]([C@@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:31])[C@H:25]([CH2:33][O:34][CH3:35])[CH2:26][CH2:27][CH2:28][CH2:29][Br:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(CCCCCBr)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: COCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC[C@H](CCCCBr)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a round-bottom flask containing THF (80 ml) cooled to −78° C. and purged with a continuous stream of N2 gas was added KHMDS (1 M in THF, 22.6 ml, 4 eq.). In a separate flask purged with a continuous stream of N2 gas was added (R)-4-benzyl-3-(6-bromohexanoyl)oxazolidin-2-one (2.00 g, 1 eq.) dissolved in THF (10 ml) and cooled to −78° C. The solution containing (R)-4-benzyl-3-(6-bromohexanoyl)oxazolidin-2-one was transferred to the KHMDS solution, and chloro(methoxy)methane (7.2 g, 15.8 eq.) was added dropwise. The reaction mixture was allowed to stir for an additional 2 h, quenched with saturated aqueous NH4Cl and concentrated. Water was added. The mixture was extracted with EtOAc. The organic layers were dried over MgSO4 and concentrated. Silica gel chromatography using 30-100% DCM-heptane yields the title compound.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C([Li])(C)(C)C.[CH2:12]([Sn:16](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15]>C1COCC1>[CH2:21]([Sn:16]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:17][CH2:18][CH2:19][CH3:20])[C:2]1[CH:3]=[N:4][NH:5][CH:6]=1)[CH2:22][CH2:23][CH3:24]
Reactant: Ic1cn[nH]c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn[nH]c1
Temperature: 25 °C

Procedure:
To a solution of 4-iodopyrazole (0.964 g) in THF (20 mL) under nitrogen and cooled to -60° C. is added t-butyllithium (1.7M in pentane, 9 mL) at such a rate that the temperature remained below -55° C. Tributyltin chloride (1.2 mL) was then added and the mixture was allowed to warm to room temperature. The reaction was quenched with water, diluted with ethyl acetate, washed with water, dried (anhyd Na2SO4), filtered, and evaporated. Chromatography of the residue over silica gel (ethyl acetate/hexane) gave 4-(tributylstannyl)pyrazole (0.288 g) as an oil.