Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([OH:23])=[O:22])[CH2:9]2)=[CH:4][CH:3]=1.CO.[CH3:26]C1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:26][O:22][C:21]([C:10]1[CH2:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[N:11]=1)=[O:23]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C1=NN(c2ccc(Cl)cc2Cl)C(c2ccc(Cl)cc2)C1
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C1=NN(c2ccc(Cl)cc2Cl)C(c2ccc(Cl)cc2)C1
Temperature: 80 °C
Reaction time: 24 h
Yield: 498.2 %

Procedure:
A mixture of 5-(4-chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid (78.0 g, 0.21 mol), methanol 150 mL, p-TsOH.H2O (0.042 mol) in toluene (350 mL) was stirred for 24 hours at 80° C. The reaction mixture was cooled to room temperature and the solvent was concentrated in vacuo. The residue was taken up in EtOAc (300 mL) and subsequently washed with sat. aq. NH4Cl and water and dried. The solvent was removed in vacuo to yield the title compound (80.27 g, 99%) white solid.
Reaction SMILES: Br[CH:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[CH2:3]1.[CH2:16]([NH:23][CH2:24][CH2:25][NH2:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])(O)=O.[Na+]>CN(C)C=O>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:15])([CH3:14])[CH2:3][CH:2]([NH:26][CH2:25][CH2:24][NH:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:7]=2[CH:8]=1)#[N:13]
Reactant: NCCNCc1ccccc1
Reactant: CC1(C)CC(Br)c2cc(C#N)ccc2O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CC(NCCNCc2ccccc2)c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 48 h
Yield: 216.7 %

Procedure:
A solution of 4-bromo-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (1.50 g, 5.64 mmole, from Example 8,part B) and N-benzylethylenediamine (8.48 g, 10 eq.) containing NaHCO3 (4.80 g, 5 eq.) in N,N-dimethylformamide (30 ml) was stirred for 48 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and distilled H2O. The organic phase was washed with distilled H2O, saturated NaCl solution, dried over Na2SO4 and evaporated in vacuo to obtain 4.10 g of an orange oil. The crude product was chromatographed on silica eluting with 9:1 methylene chloride/methanol (trace of NH4OH) to obtain 0.91 g (48%) of the title compound as a colorless gum. 1H NMR (CDCl3) δ8.00 (s, 1H), 7.49-7.34 (m, 6H), 6.88 (d, J=8.80 Hz, 1H), 3.93-3.82 (m, 3H), 3.03-2.80 (m, 5H), 2.25 (dd, J= 5.57 and 13.20 Hz, 1H), 1.67 (m, 1H), 1.53 (s, 3H), 1.35 (s, 3H); 13C NMR (CDCl3) δ157.66, 139.89, 132.52, 132.03,128.43, 128.14, 127.05, 125.55, 119.65, 118.06, 102.89, 76.86, 53.73, 49.38, 49.01, 45.32, 39.25, 36.40, 29.72, 25.02; MS: (M+H)+ @334.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][C@@H:25]([CH2:30][OH:31])[CH2:26][CH:27]([CH3:29])[CH3:28]>>[OH:31][CH2:30][C@@H:25]([NH:24][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1)[CH2:26][CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)C[C@@H](N)CO
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N[C@H](CO)CC(C)C)cn1
Yield: 49 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using (R)-(−)-leucinol instead of 2-aminoethyl isopropylether, to the title compound (130 mg, 49%) which was obtained as a white solid. MS: m/e=408.4 [M−H]−.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:10][C:11]([CH3:13])=[O:12]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:16]([O:15][C:9](=[O:14])[C:10](=[CH:3][N:4]([CH3:5])[CH3:6])[C:11]([CH3:13])=[O:12])[CH3:17]
Reactant: CCOC(=O)CC(C)=O
Reactant: COC(OC)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)C(=CN(C)C)C(C)=O
Reaction time: 3 h
Yield: 71.6 %

Procedure:
A mixture of 200 g (1.68 moles) of N,N-dimethylformamide dimethyl acetal, 145.68 g (1.12 moles) of ethyl acetoacetate, and 0.5 g (0.003 mole) of p-toluenesulfonic acid monohydrate was heated in a water bath with stirring for three hours. The color of the reaction mixture changed progressively from orange to red and finally to brown. Heating was discontinued, and the reaction mixture was allowed to sit at room temperature for approximately 18 hours. At the conclusion of this period, the mixture was distilled under vacuum, and six fractions having a boiling point in the range 145°-150° C. were analyzed by NMR spectroscopy. The NMR spectrum of each fraction was consistent with the proposed structure. These fractions were combined, yielding a total of 148.51 g of ethyl-2-dimethylaminomethyleneacetoacetate.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:9][N:10]2[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[N:11]2)[S:7][CH:8]=1)(=O)[NH2:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:29]2)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:1]([C:4]1[N:5]=[C:6]([CH2:9][N:10]2[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[N:11]2)[S:7][CH:8]=1)(=[S:29])[NH2:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)c1cnn(Cc2nc(C(N)=O)cs2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnn(Cc2nc(C(N)=S)cs2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.1 %

Procedure:
To a solution (10 mL) of the compound (524 mg, 1.87 mmol) obtained in Example 33b in toluene was added 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson reagent, 756 mg, 1.87 mmol), and the mixture was heated under reflux overnight. The reaction mixture was allowed to cool to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was stirred for 30 min, and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained crude product was purified by column chromatography (hexane-hexane/ethyl acetate=1/1) and recrystallization (ethyl acetate-hexane) to give the title compound (200 mg, 36%) as pale-yellow crystals.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[CH:11]=[CH:10][C:9]([CH:13]([CH3:15])[CH3:14])=[CH:8][C:7]=2[C:6](=[O:16])[C:5]2[C:17](=O)[C:18]3[C:23]([C:4]1=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:2].Cl.[NH2:26][OH:27]>C(N(CC)CC)C.C(O)C>[CH2:1]([N:3]1[C:12]2[CH:11]=[CH:10][C:9]([CH:13]([CH3:15])[CH3:14])=[CH:8][C:7]=2[C:6](=[O:16])[C:5]2[C:17](=[N:26][OH:27])[C:18]3[C:23]([C:4]1=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:2]
Reactant: NO
Reactant: CCn1c2c(c(=O)c3cc(C(C)C)ccc31)C(=O)c1ccccc1-2
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCn1c2c(c(=O)c3cc(C(C)C)ccc31)C(=NO)c1ccccc1-2

Procedure:
5-Ethyl-8-isopropyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10,11-dione (300 mg, 0.95 mmol) was dissolved in a solution of hydroxylamine hydrochloride (525 mg, 7.6 mmol) and triethylamine (0.5 mL) in 20 mL of ethanol. The solution was refluxed overnight and then concentrated dryness. The residue was diluted with water and extracted with chloroform twice. The combined organic layers were washed with saturated sodium chloride solution, dried with sodium sulfate followed by evaporation to remove the solvent. The title compound was obtained by subjecting the resulting residue to silica gel-chromatography (chloroform:actone=20:1) and then to crystallization from diethyl ether. 1H-NMR (CDCl3) δ 1.32 (6H, d, CH(CH3)2, 1.73 (3H, t, NCH2CH3), 3.03 (1H, septet, CH), 4.79 (2H, q, NCH2), 7.41-8.00 (6H, m, Ar—H), 8.25 (1H, s, H-9), 15.31 (1H, s, N═OH)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]2[N:10]=[CH:11][N:12]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[C:4]=2[CH:3]=1.[OH:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][C:25]=1[C:33]([F:36])([F:35])[F:34].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CCOC(C)=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].O.O1CCOCC1>[OH:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[N:7]=[C:6]([C:8]#[N:9])[C:5]3[N:10]=[CH:11][N:12]([CH:13]4[CH2:18][CH2:17][CH2:16][CH2:15][O:14]4)[C:4]=3[CH:3]=2)=[CH:26][C:25]=1[C:33]([F:34])([F:35])[F:36]
Reactant: OCCCOc1ccc(B(O)O)cc1C(F)(F)F
Reactant: N#Cc1nc(Cl)cc2c1ncn2C1CCCCO1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: N#Cc1nc(-c2ccc(OCCCO)c(C(F)(F)F)c2)cc2c1ncn2C1CCCCO1
Yield: 63 %

Procedure:
6-Chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (1.4 g), 4-(3-hydroxypropoxy)-3-(trifluoromethyl)phenylboronic acid (2.2 g), tris(dibenzylideneacetone)dipalladium (0.25 g), tricyclohexylphosphine (0.18 g) and potassium phosphate (2 g) were added to dioxane (20 ml) and water (6 ml) and the mixture was heated to reflux under nitrogen for two hours. The reaction mixture was diluted with EtOAc (200 mL), filtered through celite, and washed with water (150 mL). Organic layer was dried over sodium sulphate and solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography using EtOAc:Heptane as eluant to yield 6-[4-(3-hydroxypropoxy)-3-(trifluoromethyl)-phenyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (1.5 g).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]2[C:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][C:12]([CH3:14])([CH3:13])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>C(O)C>[CH3:2][CH:1]([C:4]1[S:8][C:7]2[C:9]([CH3:15])([CH3:16])[CH2:10][CH2:11][C:12]([CH3:14])([CH3:13])[C:6]=2[CH:5]=1)[OH:3]
Reactant: CC(=O)c1cc2c(s1)C(C)(C)CCC2(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1cc2c(s1)C(C)(C)CCC2(C)C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
21.7 g of 2-acetyl-4,5,6,7-tetrahydro-4,4,7,7-tetramethylbenzo[b]thiophene are dissolved in 250 ml of ethanol and the solution is treated gradually with 5.5 g of sodium borohydride. The mixture is left to come to room temperature and is stirred for a further 2 hours. The mixture is poured on to ice, extracted with ether, the organic phase is washed once with saturated sodium chloride solution, dried and evaporated. The crude product is filtered over silica gel (eluting agent hexane/ether 3:1) and recrystallized from hexane. There are obtained 20.2 g of 4,5,6,7-tetrahydro-α,4,4,7,7-pentamethylbenzo[b]thiophene-methanol in the form of colorless crystals, m.p. 53°-55° C.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:15]([NH2:17])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1.N1C=CC=CC=1>O1CCOCC1>[CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:15](=[S:27])[NH2:17]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1ccc2c(c1)Nc1ccccc1S2
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: NC(=S)c1ccc2c(c1)Nc1ccccc1S2
Temperature: 110 °C

Procedure:
A reaction mixture comprising 3.4 g (14 mmoles) of 10H-phenothiazine-2-carboxamide (J. Org. Chem. 1961, 26, 1138-1143) and 3.4 g (8.4 mmoles) of Lawesson reagent in solution in 40 ml of 1,4-dioxane to which 20 ml of pyridine has been added is heated at 110° C. for 1 h 30. The brown solution is then concentrated under vacuum and the residue is diluted in 200 ml of AcOEt and 100 ml of H2O. After stirring and decantation, the organic phase is washed successively with 100 ml of a 1N aqueous solution of HCl and 100 ml of salt water. After drying over sodium sulphate, filtration and evaporation of the solvent under vacuum, an orange powder is obtained. This powder is washed with Et2O, the filtrate is eliminated, and extracted with acetone. The acetone filtrate is then concentrated under vacuum and the evaporation residue is then purified using a silica column (eluent: Heptane/AcOEt:1/1 to 416). Orange powder. Melting point: 208-209° C.
Reaction SMILES: [CH3:1][C@H:2]([CH2:5][Br:6])[CH2:3][OH:4].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH3:1][C@H:2]([CH2:5][Br:6])[CH2:3][O:4][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: C[C@@H](CO)CBr
Product: C[C@H](CBr)COCc1ccccc1

Procedure:
The starting material, 3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy))-(R)-2-fluoropropyloxy)-(R)-2-methylpropane-1-methanesulfonate, was prepared as follows: (S)-2-methyl-3-bromopropanol was alkylated with benzyl bromide to produce (S)-2-methyl-3-bromo-1-benzyloxypropane, which was then combined with 3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy))-(R)-2-fluoropropanol, followed by hydrogenation with 10% Pd/C to remove the benzyl protecting group. The title compound was prepared by combining 5-hexyloxy-2-(4-hydroxyphenyl)pyrimidine (0.7 g, 2.58 mmol) and 3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy))-(R)-2-fluoropropyloxy)-(R)-2-methylpropane-1-methanesulfonate (1.7 g, 2.58 mmol) essentially as described in Example 8 of International Patent Publication No. WO 96/33251. The resulting crude product was further purified by chromatography eluting with 10:1 hexanes/ethyl acetate, and was recrystallized from heptane, followed by Kugelrohr distillation (b.p. 180-190° C. at 0.02 torr; yield 1.28 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH:11][CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:5]=1.[CH2:20](OC(OCC)OCC)C>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]=[CH:20][N:11]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[CH:5]=1)=[O:19]
Reactant: CCOC(OCC)OCC
Reactant: COC(=O)c1ccc(N)c(NCCN2CCCC2)c1
Product: COC(=O)c1ccc2ncn(CCN3CCCC3)c2c1

Procedure:
4-Amino-3-(2-pyrrolidin-1-yl-ethylamino)-benzoic acid methyl ester (xii) (1.14 g, 4.33 mmol) and triethylorthoformate (20 mL, 120 mmol) were heated at 120° C. for 18 h before being evaporated to dryness. The residue was taken in EtOAc and aqueous saturated NaHCO3. The aqueous layer was extracted 2 times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to dryness to afford the title compound as a brown oil (tR 1.83 min (conditions 8), MH+=274).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]2[C:13]([O:18][CH3:19])=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.[Br-].[CH2:21]([Zn+])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>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.Cl[Pd]Cl.[Fe+2]>[CH2:21]([C:2]1[CH:3]=[C:4]([C:12]2[C:13]([O:18][CH3:19])=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: [Zn+]Cc1ccccc1
Reactant: COc1ncccc1-c1cc(Br)cc(C(C)(C)C)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Product: COc1ncccc1-c1cc(Cc2ccccc2)cc(C(C)(C)C)c1
Temperature: 70 °C
Yield: 81.9 %

Procedure:
step 1—A mixture of 3-(3-bromo-5-tert-butyl-phenyl)-2-methoxy-pyridine (184 mg, 0.575 mmol) and PdCl2(dppf)2 (40 mg, 0.049 mmol) in a Schlenk flask was purged with argon 3 times before THF (5 mL) was added followed by benzylzinc bromide (0.5M in THF, 2.3 mL, 1.150 mmol). The reaction was then heated at 70° C. overnight then cooled to RT, filtered through a pad of CELITE and the filtrate was concentrated. The crude residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (0 to 4% EtOAc) to afford 156 mg (82%) of 3-(3-benzyl-5-tert-butyl-phenyl)-2-methoxy-pyridine (126) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([C:14]#[N:15])=[CH:4][N:3]=1.[OH-].[NH4+]>C1COCC1.[Ni]>[NH2:15][CH2:14][C:5]1[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: N#Cc1cnc(N)nc1-c1ccccc1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NCc1cnc(N)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a solution of 2-amino-4-phenylpyrimidine-5-carbonitrile (1.0 equiv.) in THF (0.15 M) was added ammonium hydroxide and Raney nickel. The mixture was stirred at room temperature under hydrogen atmosphere overnight and then the reaction mixture was filtered through celite. The filtrate was concentrated in vacuo to give the crude title compound (56% yield) as a yellow solid. The product was used without further purification. 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 8.34 (s, 1H), 7.69-7.65 (m, 2H), 7.46-7.44 (m, 3H), 6.50 (br, 2H), 3.54 (s, 2H), 1.70 (br, 2H); MS (ESI) m/z=201.2 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:12](=[C:14]([C:18](O)=[O:19])[CH:15]=[CH:16][CH:17]=3)[N:13]=2)=[C:5]([CH3:21])[CH:4]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:46][C@H:47]1[CH:52]2[CH2:53][CH2:54][N:49]([CH2:50][CH2:51]2)[CH2:48]1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:49]12[CH2:54][CH2:53][CH:52]([CH2:51][CH2:50]1)[C@H:47]([NH:46][C:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:11]3[O:10][C:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[CH3:21])=[N:13][C:12]=13)=[O:19])[CH2:48]2
Reactant: COc1ccc(-c2nc3c(C(=O)O)cccc3o2)c(C)c1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc3c(C(=O)N[C@@H]4CN5CCC4CC5)cccc3o2)c(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29.9 %

Procedure:
A mixture of 2-(4-methoxy-2-methylphenyl)benzoxazole-4-carboxylic acid (100 mg, 0.35 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (134 mg, 0.70 mmol), 1-hydroxybenzotriazole (95 mg, 0.70 mmol) and (S)-(−)-3-aminoquinuclidine dihydrochloride (87 mg, 0.44 mmol) in DMF (3 mL) was stirred at room temperature for 10 min, then triethylamine (0.20 mL, 1.4 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine (2×50 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford (S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-methoxy-2-methylphenyl)benzoxazole-4-carboxamide (41 mg, 30%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 9.46 (d, J=7.0 Hz, 1H), 8.20-8.15 (m, 2H), 7.72 (dd, J=7.1, 1.0 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 6.95-6.90 (m, 2H), 4.51-4.42 (m, 1H), 3.91 (s, 3H), 3.70-3.63 (m, 1H), 3.22-3.00 (m, 4H), 2.98-2.90 (m, 1H), 2.86 (s, 3H), 2.35-2.30 (m, 1H), 2.20-2.10 (m, 1H), 2.00-1.95 (m, 2H), 1.75-1.70 (m, 1H); MS (ESI+) m/z 392 (M+H); HPLC 96.6% (AUC), tR=13.19 min.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]([CH3:50])[CH2:43][CH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:39][CH2:40][N:42]([CH3:50])[CH2:43][CH:44]2[CH2:45][CH2:46][O:47][CH2:48][CH2:49]2)=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN(CC1CCOCC1)C(=O)CCl
Product: CCN(Cc1ccc(OCCN(C)CC2CCOCC2)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 59.3 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-N-methyl-N-(tetrahydropyran-4-ylmethyl)acetamide (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (9.9 mg) was obtained.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][N:7]([CH2:18][CH2:19][CH2:20][OH:21])[C:8](=[O:17])[C:9]1[C:14]([I:15])=[CH:13][CH:12]=[N:11][C:10]=1Cl.[H-].[Na+].O>O1CCCC1>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][N:7]1[CH2:18][CH2:19][CH2:20][O:21][C:10]2[N:11]=[CH:12][CH:13]=[C:14]([I:15])[C:9]=2[C:8]1=[O:17]
Reactant: O=C(c1c(I)ccnc1Cl)N(CCCO)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1c2c(I)ccnc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
N-[3,5-Bis(trifluoromethyl)benzyl]-2-chloro-N-(3-hydroxypropyl)-4-iodonicotinamide (compound of Reference Example 2; 6.86 g) was dissolved in tetrahydrofuran (60 mL). While the resulting solution was chilled on an ice bath, sodium hydride (581 mg, 60% oil suspension) was added, and the mixture was stirred for 30 minutes. The temperature of the mixture was then allowed to rise to room temperature, and the mixture was further stirred for 1 hour. While the reaction mixture was chilled on an ice bath, water was added, and then the resulting mixture was subjected to extraction with ethyl acetate. The resulting extract was washed with a saturated aqueous solution of sodium chloride, and was then dried on anhydrous sodium sulfate. The solvent was removed by distillation to obtain a residue, and then the residue was purified on a silica gel column chromatography (ethyl acetate:n-hexane=2:1) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-iodo6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (2.69 g, 42%).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[I:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([CH3:24])[CH:17]=1>>[I:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([CH3:24])[CH:17]=1
Reactant: Cc1cc(I)ccc1CO
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: Cc1cc(I)ccc1COc1ccnn1-c1cc(C#N)ccn1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-iodo-2-methylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.33 (3H, s), 5.15 (2H, s), 5.76 (1H, d, J=1.6 Hz), 7.14 (1H, d, J=8.0 Hz), 7.39 (1H, dd, J=1.6 Hz, 5.2 Hz), 7.55-7.59 (3H, m), 8.00 (1H, s), 8.66 (1H, d, J=5.2 Hz). [M+H] Calc'd for C17H13IN4O, 417. Found, 417.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OCC)(=O)C>[C:11]1([CH:10]=[N:3][NH:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NN=Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 89.1 %

Procedure:
To a solution of t-butyl carbazate (5.62 g, 42.5 mmol) in ethyl acetate (15 mL) was added with stirring benzaldehyde (4.51 g, 42.5 mmol). Crystallization occurred and the resulting slurry was stirred at rt for 45 min. Hexanes (70 mL) was added and the slurry was cooled to 0° C. The slurry was stirred at 0° C. for 60 min, then filtered and rinsed with cold hexanes (20 mL) and dried in vacuo at 40° C. to afford the title compound as a solid (8.34 g, 89.0%): mp 184.1-184.9° C.; 1H NMR (DMSO-d6) δ 10.91 (s, 1H), 7.99 (s, 1H), 7.58 (d, 2H, J=3 Hz), 7.39 (m, 3H), 1.45 (s, 9H); 13C NMR (DMSO-d6) δ 153.0, 143.8, 135.3, 130.0, 129.4, 127.2, 80.1, 28.8; IR (KBr mull) 2983, 1735, 1511, 1157 cm−1; A portion was recrystallized (ethyl acetate) for analysis. Anal. Calcd. For C12H16N2O2: C, 65.43; H, 7.32; N, 12.72. Found: C, 65.16; H, 7.43; N, 12.62.