Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:31]=1[CH2:32]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:31]=1[CH2:32][O:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: Cc1cccc(C)c1CO
Reactant: CCOC(=O)c1ccc(OC)c(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OC)c(OCc2c(C)cccc2C)c1
Temperature: 25 °C

Procedure:
A solution of Ethyl 3-hydroxy-4-methoxybenzoate (Step A, 9.10 g, 46.4 mmol) and diisopropyl azodicarboxylate (DIAD, 10.23 g, 50 mmol) in dry THF (20 ml) was added drop wise to a solution of 2,6-Dimethylbenzyl alcohol (6.94 g, 51 mmol) and triphenylphosphine (TPP, 13.27 g, 50 mmol) in dry THF (60 ml) at 0° C. under argon. The reaction mixture was warmed to room temperature for 4 hours or until all the starting material is consumed, diluted with ether and washed with water (2×). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex: ethyl acetate 2:1) to give the title compound.
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.[C:25]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=[CH:29][CH:28]=[C:27]([C:31](O)=[O:32])[CH:26]=1>C(O)(C)C>[C:25]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([N:15]=[N+:16]=[N-:17])=[O:32])[CH:26]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)c1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 119.5 %

Procedure:
To a vial (8 mL) diphenylphosphoryl azide (0.39 mL, 1.8 mmol) and triethylamine (0.25 mL, 1.8 mmol) were added to a stirred solution of biphenyl-3-carboxylic acid (0.30 g, 1.5 mmol) in isopropanol (3 mL). The vial was closed with a lid, and the reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated, and water (50 mL) was added. The mixture was extracted with ethyl acetate (3×50 mL). The combined extracts were dried over sodium sulfate, filtered, and concentrated to provide the title compound (0.40 g, 100%) was used in the next reaction without characterization or purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:27]([NH:26][C:23]4[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=4)=[O:28])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: COc1ccc(N=C=O)cc1
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)N2CCN(c3ccnc4cc(Cl)ccc34)CC2)cc1

Procedure:
7-Chloro-4-(piperazin-1-yl)quinoline (316 mg, 1.28 mmol) and 4-methoxyphenyl isocyanate (194 μL, 1.50 mmol) in THF (10 mL) are reacted according to method C yielding the title product as a colorless needles after column chromatography with hexane-EtOAc and recrystallization from ether.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:13]2[CH2:14][CH2:15][C:16](=[O:19])[NH:17][N:18]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][NH2:12].[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:13]2[CH2:14][CH2:15][C:16](=[O:19])[NH:17][N:18]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:20]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[O:27]
Reactant: Cc1cc(C2=NNC(=O)CC2)ccc1CCCCN
Reactant: O=C(O)c1cccnc1
Product: Cc1cc(C2=NNC(=O)CC2)ccc1CCCCNC(=O)c1cccnc1

Procedure:
By treating 6-[3-methyl-4-(4-aminobutyl)phenyl]-4,5-dihydropyridazin-3(2H)-one and nicotinic acid in the same manner as in Example 87, 6-[3-methyl-4-[4-(pyridin-3-ylcarbonylamino)butyl]phenyl]-4,5-dihydropyridazin-3(2H)-one was obtained.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][O:5][C:3]1=[O:4].[H][H]>C1COCC1>[OH:1][CH:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][O:5][C:3]1=[O:4]
Reactant: [H][H]
Reactant: CC1(C)COC(=O)C1=O
Solvent: C1CCOC1
Product: CC1(C)COC(=O)C1O

Procedure:
2-Oxo-3,3-dimethyl-γ-butyrolactone (18) was hydrogenated according to General Procedure B in THF at 20.7 barg (300 psig) hydrogen at ambient temperature using bis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5 μmol; 0.01 equiv) and ligand (S,R)-2g (3.7 mg; 6 μmol; 0.012 equiv) for 6 hours to afford 99.6% conversion to 2-hydroxy-3,3-dimethyl-γ-butyrolactone (19) with 97.2% ee as determined by chiral GC analysis.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]=[C:20]=[O:21]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:20]([NH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[F:12])=[O:21]
Reactant: O=C=Nc1ccccc1F
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1ccccc1F
Yield: 62.5 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N′-(2-fluorophenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-fluoro phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (0.59 g, 31%). EI-MS m/z 292 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11](=[O:22])[NH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.Cl.[N:24]1[CH:29]=[CH:28][C:27]([CH2:30]Cl)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11](=[O:22])[N:10]([CH2:30][C:27]3[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: ClCc1ccncc1
Reactant: COc1cc2c(-c3ccnc(Br)c3)n[nH]c(=O)c2cc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(-c3ccnc(Br)c3)nn(Cc3ccncc3)c(=O)c2cc1OC
Temperature: 80 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
2-Bromo-4-(6,7-dimethoxyphthalazin-1(2H)-on-4-yl)pyridine (362 mg), 4-picolyl chloride hydrochloride (180 mg), and potassium carbonate (359 mg) are added to dimethylformamide (10 ml), and the mixture is heated with stirring at 80° C. for three hours under nitrogen atmosphere. Water is added to the reaction mixture, and the mixture is extracted with methylene chloride. The extract is washed, dried, and concentrated to give 2-bromo-4-[6,7-dimethoxy-2-(4-pyridyl)methylphthalazin-1(2H)-on-4-yl]pyridine (355 mg).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:9]2[CH:10]=[C:11](B3OC(C)(C)C(C)(C)O3)[C:12]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:8]=2[O:7][C:6]=1[C:29]1[C:33]([CH3:34])=[CH:32][O:31][N:30]=1)=[O:4].Cl[C:36]1[CH:45]=[CH:44][C:43]2[CH2:42][CH2:41][N:40]3[C:46]4[CH:47]=[CH:48][CH:49]=[C:50]([F:53])[C:51]=4[CH:52]=[C:39]3[C:38]=2[N:37]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:53][C:50]1[C:51]2[CH:52]=[C:39]3[C:38]4[N:37]=[C:36]([C:11]5[C:12]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:16])=[O:17])=[CH:13][C:8]6[O:7][C:6]([C:29]7[C:33]([CH3:34])=[CH:32][O:31][N:30]=7)=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[C:9]=6[CH:10]=5)[CH:45]=[CH:44][C:43]=4[CH2:42][CH2:41][N:40]3[C:46]=2[CH:47]=[CH:48][CH:49]=1
Reactant: CNC(=O)c1c(-c2nocc2C)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Fc1cccc2c1cc1n2CCc2ccc(Cl)nc2-1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2nocc2C)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CC4)cc12
Temperature: 85 °C
Reaction time: 3 h
Yield: 48.6 %

Procedure:
To a mixture of N-methyl-2-(4-methylisoxazol-3-yl)-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (60 mg, 0.12 mmol), 2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridine (50 mg, 0.18 mmol) and K3PO4.3H2O (98 mg, 0.37 mmol) in dioxane/H2O (1.5 mL/0.5 mL) was added Pd2(dba)3 (8 mg, 0.008 mmol) and X-Phos (8 mg, 0.016 mmol) under N2. The mixture was stirred at 85° C. for 3 h. It was concentrated, diluted with water, extracted with EtOAc, and dried over Na2SO4. The residue was purified by prep-TLC (DCM:MeOH=60:1) to get the product (35 mg, yield: 48%). 1H-NMR (CDCl3, 400 MHz) δ 9.12 (d, J=3.6 Hz, 1H), 8.68 (s, 1H), 8.40 (s, 1H), 7.76 (s, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.28˜7.26 (m, 1H), 7.21˜7.12 (m, 2H), 6.85˜6.75 (m, 1H), 4.36 (t, J=6.4 Hz, 2H), 3.46 (s, 3H), 3.33 (t, J=6.4 Hz, 2H), 3.03 (d, J=4.8 Hz, 3H), 2.60 (s, 3H), 2.40 (s, 3H). MS (M+H)+: 600.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([OH:10])[CH2:8][OH:9].[C:11]1([CH:21]2[CH2:23][O:22]2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1>C(OCC)(=O)C>[OH:9][CH2:8][CH2:7][O:10][CH2:23][CH:21]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[OH:22]
Reactant: OCCO
Reactant: c1ccc2c(C3CO3)cccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: OCCOCC(O)c1cccc2ccccc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 4.5 g of potassium tert-butoxide and 45 ml of ethylene glycol was heated to 80° C. Thereto was dropwise added 13.7 g of 2-(1-naphthyl)oxirane in 1 hour. The resulting mixture was stirred for 1 hour at the same temperature. The reaction mixture was cooled and added to a mixture of 50 ml of ethyl acetate and 50 ml of ice water. The organic layer was separated. The aqueous layer was extracted twice each with 20 ml of ethyl acetate. The extracts were combined with the previously separated organic layer. The combined organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: toluene/ethyl acetate=1/3) to obtain 8.3 g of 2(2-hydroxyethoxy)-1-(1-naphthyl)ethanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.[S:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=S.CCN(C(C)C)C(C)C>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:9][CH3:10])[C:12]2[S:11][CH2:17][C:15](=[O:16])[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCNc1cccc(F)c1
Reactant: O=C1CSC(=S)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCN(C1=NC(=O)CS1)c1cccc(F)c1
Temperature: 0 °C
Reaction time: 72 h
Yield: 76.6 %

Procedure:
To a solution of (3-fluorophenyl)-ethylamine (3.06 g, 22 mmol) and rhodanine (2.66 g, 20 mmol) in acetonitrile (70 mL) was added DIEA (7.66 mL, 44 mmol) at room temperature. Then, this solution was cooled to 0° C. and mercuric chloride (5.97 g, 22 mmol) was added in two portions. After addition, the suspension was allowed to warm to room temperature and stirred for 3 days. The resulting black solids were filtered through a plug of celite and washed with dichloromethane (500 mL) and methanol (250 mL). The combined solvents were removed under the vacuum and the crude residue was dissolved in ethyl acetate (25 mL) at hot condition and stored in the refrigerator overnight. Then, the solids were collected by filtration and washed with ethyl acetate. After drying in air, 3.65 g (76.6% yield) of 2-[(3-fluorophenyl)-ethylamino]-thiazol-4-one was isolated as a white amorphous solid: HRES(+) m/e calcd for C11H11FN2OS (M+H)+239.0649, found 239.0647.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([OH:10])=O.C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([Cl:14])=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1CCCCC1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1CCCCC1C(=O)Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.3 %

Procedure:
To a solution of 2-methylcyclohexanecarboxylic acid (6.00 mL, 42.6 mmol, mixture of cis and trans) in DCM (60 mL) was added oxalyl chloride (4.80 mL, 55.3 mmol) followed by DMF (0.03 mL, 0.4 mmol). The reaction mixture was stirred at ambient temperature for about 4 h before it was concentrated under reduced pressure to constant weight to afford 2-methylcyclohexanecarbonyl chloride (mixture of diastereomers) as a yellow oil (7.0 g, 97%): 1H NMR (400 MHz, CDCl3) δ 2.98-2.94 (m, 1H), 2.39-2.35 (m, 1H), 1.91-1.82 (m, 1H), 1.79-1.72 (m, 1H), 1.69-1.60 (m, 2H), 1.57-1.47 (m, 2H), 1.42-1.36 (m, 1H), 1.34-1.26 (m, 1H), 1.04-0.96 (m, 3H).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([C:21]([O:23][CH3:24])=[O:22])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:25][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>C1COCC1>[Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[C:11]([CH3:25])([C:21]([O:23][CH3:24])=[O:22])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
To a solution of 1-tert-butyl 2-methyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}pyrrolidine-1,2-dicarboxylate (5.11 g, 14.2 mmol) in dry THF (60 mL) at −78° C. was dropwise added lithium bistrimethylsilylamide (17.0 mL, 17.0 mmol, 1.0 M in THF). After being stirred for 30 minutes, iodomethane (1.77 mL, 28.4 mmol) was then added. The mixture was stirred at −78° C. for one hour, warmed to 0° C. for one hour and finally quenched with NaHCO3/H2O. The resulting mixture was extracted twice with ethyl acetate. The combined extracts were dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with hexane to 5% ethyl acetate/hexane to provide 2.66 g (50%) of a mixture of product isomers as a colorless oil. LC/MS (M-Boc+H)+ m/z=274.1. 1H NMR (CDCl3) δ 4.38 (m, 1H), 3.71 (m, 4H), 3.36 (m, 1H), 1.84-2.35 (m, 2H), 1.61 (m, 3H), 1.44 (m, 9H), 0.88 (m, 9H), 0.07 (m, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[C:10]([CH2:12][C:13]([NH:15][CH:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:14])[CH:9]=[CH:8][C:5]=1[CH2:6]Cl)[CH3:2].[C-:35]#[N:36].[Na+].O>CS(C)=O>[CH2:1]([O:3][C:4]1[CH:11]=[C:10]([CH2:12][C:13]([NH:15][CH:16]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)=[O:14])[CH:9]=[CH:8][C:5]=1[CH2:6][C:35]#[N:36])[CH3:2]
Reactant: [C-]#N
Reactant: CCOc1cc(CC(=O)NC(c2ccccc2)c2ccccc2N2CCCCC2)ccc1CCl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOc1cc(CC(=O)NC(c2ccccc2)c2ccccc2N2CCCCC2)ccc1CC#N
Temperature: 60 °C
Reaction time: 5 h

Procedure:
A solution of 2-ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzyl chloride (2.6 g, 5.45 mmol) in dimethylsulphoxide (10 ml) is added dropwise at 50°-60° C. to sodium cyanide (0.32 g, 6.5 mmol) in dimethylsulphoxide (40 ml). The mixture is then stirred for 5 hours at 60° C., added to water and extracted with chloroform. The extract is concentrated by evaporation in vacuo. The residue is purified by column chromatography on silica gel (toluene/ethyl acetate=5/1).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C1COCC1>[C:32]([NH:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1)(=[O:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CN)C1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Yield: 97.1 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-(aminomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (150 mg) in THF (2 ml) were added triethylamine (0.084 mL) and acetyl chloride (47 mg), and the mixture was stirred at under ice-cooling for 2 hr. The solvent was evaporated under reduced pressure, distilled water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (162 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][C:5](O)=[N:6][C:7]=1[CH:8]([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH3:36][NH:37][S:38]([CH3:41])(=[O:40])=[O:39]>O.C(OCCCC)(=O)C>[Br:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][C:5]([N:37]([CH3:36])[S:38]([CH3:41])(=[O:40])=[O:39])=[N:6][C:7]=1[CH:8]([CH3:10])[CH3:9]
Reactant: CNS(C)(=O)=O
Reactant: CC(C)c1nc(O)nc(-c2ccc(F)cc2)c1Br
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCOC(C)=O
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1Br
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 38.1 %

Procedure:
5-Bromo-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-ol (62.2 g, 199 mmol), potassium carbonate (35.83 g, 259 mmol) and butyl acetate (435.4 mL) were charged to a 2 L multi-neck flask and stirred/heated to 42° C. p-Toluenesulfonyl chloride (41.83 g, 219 mmol) was then added in portions over 50 minutes, maintaining the temperature at ≦45° C. The reaction was stirred at this temp for 2.5 hours, at which point LCMS showed only the desired intermediate (MH+=467) present. Potassium carbonate (41.25 g, 299 mmol) and butyl acetate (186.6 mL) were then added and reaction heated to 120° C. Once at this temperature N-methylmethanesulfonamide (28.21 g, 259 mmol) was added over 30 mins. The reaction was held at this temperature for 18 hours, then butyl acetate (330 mL) and water (412 mL) were added, reducing the reaction temperature to 75° C. Stirring was continued at this temperature for 20 minutes, then the reaction mixture was transferred to a separating funnel, and allowed to stand for 10 mins to separate. The aqueous layer was separated off and re-extracted with butyl acetate (250 mL) by stirring at 60° C. for 15 mins. The organic layers were combined and 1 M aqueous NaOH (330 mL) added. This mixture was stirred at 60° C. for 20 minutes, then the lower aqueous phase separated off. The organic layer was concentrated in vacuo to 20% original volume, then allowed to cool and crystallize. The crude solid was isolated by filtration (50.5 g slightly damp), and this material recrystallized from methanol (500 mL), filtered and dried at 50° C. to constant weight to give the title compound (30.54 g, 38% yield) as a white crystalline solid.
Reaction SMILES: [OH-:1].[Na+].O.[C:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[N:26]3[C:21]([CH:22]=[N:23][C:24](S(C)(=O)=O)=[N:25]3)=[CH:20][CH:19]=2)[CH:13]=1)(=[O:11])=[O:10])([CH3:7])([CH3:6])[CH3:5]>C(O)(=O)C>[C:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[N:26]3[C:21]([CH:22]=[N:23][C:24]([OH:1])=[N:25]3)=[CH:20][CH:19]=2)[CH:13]=1)(=[O:11])=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(S(C)(=O)=O)nn23)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
10 M sodium hydroxide in water (2.74 mL, 52.4 mmol) was heated at 100° C. N-tert-butyl-3-(2-methanesulfonyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (780 mg, 1.91 mmol) was added portion wise over 10 minutes. The reaction mixture was heated at 120° C. for 60 minutes and then cooled to room temperature. Glacial acetic acid was added to adjust the pH to 4 and the mixture was stirred at room temperature for 30 minutes. The solid was filtered and washed sequentially with water (75 mL) and Et2O (50 mL) to obtain N-tert-butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide as a red-orange solid (460 mg, 70%). LCMS (m/e) 347 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.00 (s, 1H), 8.68 (s, 1H), 8.47 (d, 1H, J=8.0 Hz), 7.78 (d, 1H, J=7.7 Hz), 7.71-7.64 (m, 1H), 7.59 (s, 1H), 7.30 (d, 1H, J=4.8 Hz), 7.01 (d, 1H, J=4.8 Hz), 1.91 (s, 1H), 1.13 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11].C(NC(C)C)(C)C>C(OC(C)C)(=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:8][C:5]1[N:4]=[CH:3][C:2]([C:14]#[C:13][Si:10]([CH3:12])([CH3:11])[CH3:9])=[CH:7][N:6]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ncc(Br)cn1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CC(=O)OC(C)C
Product: Cc1ncc(C#C[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Isopropyl acetate (30 mL) was added to a mixture of 5-bromo-2-methylpyrimidine (3 g, 17.3 mmol), copper(I) iodide (0.066 g, 0.35 mmol) and bis(triphenylphosphine)palladium (II) dichloride (0.243 g, 0.35 mmol) in a 100 mL 3-neck flask equipped with a condenser. The resulting solution was sparged with a stream of nitrogen for 15 minutes and kept under nitrogen during further manipulations. Trimethylsilylacetylene (3.12 mL, 22.5 mmol) and diisopropylamine (4.90 mL, 34.7 mmol) were added successively to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The dark mixture was heated at 60° C. for 15 hours, then cooled to room temperature, diluted with isopropyl acetate (15 mL) and filtered through diatomaceous earth. The filtrate was washed successively with saturated aqueous NaHCO3 (2×25 mL), 10% aqueous Na2S2O3 (20 mL) and brine, then dried (MgSO4) and concentrated under vacuum. The dark residue was purified by flash chromatography on silca gel (hexanes-ethyl acetate, gradient from 100:0-70:30) to provide the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 0.27 (s, 9H), 2.74 (s, 3H), 8.68 (s, 2H).
Reaction SMILES: [Cl:1][C:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O)=[CH:3][Cl:4].[H][H].[O-][Si]([O-])=O.[Mg+2]>C(OCC)(=O)C.C(OCC)(=O)C.CCCCCC.[Pd]>[NH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[O:5][C:2]([Cl:1])=[CH:3][Cl:4]
Reactant: O=[N+]([O-])c1ccccc1OC(Cl)=CCl
Reactant: [H][H]
Agent: [Pd]
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Nc1ccccc1OC(Cl)=CCl
Yield: 89.2 %

Procedure:
Two hundred and eighteen grams of 1,2-dichloro-1-(2-nitrophenoxy)ethene in ethyl acetate with 2.2 g of 10% palladium-on-charcoal was treated with 60 pounds per square inch gauge of hydrogen at 60° until there was no further uptake of hydrogen. The reaction mixture was filtered through Celite® and concentrated in vacuo to yield a brown oil. This oil was taken up in 20% ethyl acetate/hexane and passed through a column of Florisil® two times to yield 169.5 g of oil after evaporation of the solvent.