Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[N:6]=1)[CH2:3][NH2:4].[CH2:13]([O:15][C:16](=[O:28])[CH2:17][C:18]1[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[C:20](F)[C:19]=1[F:27])[CH3:14]>CS(C)=O>[CH2:13]([O:15][C:16](=[O:28])[CH2:17][C:18]1[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[C:20]([NH:4][CH2:3][C:2]([F:1])([F:12])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[N:6]=2)[C:19]=1[F:27])[CH3:14]
Reactant: CCOC(=O)Cc1c(C#N)ccc(F)c1F
Reactant: Cc1cccc(C(F)(F)CN)n1
Solvent: CS(C)=O
Product: CCOC(=O)Cc1c(C#N)ccc(NCC(F)(F)c2cccc(C)n2)c1F
Temperature: 150 °C
Yield: 42.5 %

Procedure:
A mixture of 2,2-Difluoro-2-(6-methyl-pyridin-2-yl)-ethylamine (223.6 mg, 1.3 mmol), as prepared in the preceding step, and (6-cyano-2,3-difluoro-phenyl)-acetic acid ethyl ester (225 mg, 1.0 mmol), as prepared in Example 2f, was dissolved in DMSO (1.0 mL) and heated at 150° C. under microwave irradiation for 1 hour. The reaction mixture was partitioned between ethyl acetate and water. The combined EtOAc extracts were dried over Na2SO4 and evaporated. The crude product was purified by flash column chromatography on silica gel (EtOAc/hexanes 2/1, v/v) to afford the product as a white solid (208 mg, 42.5% yield based on the initial amine). 1H NMR (CDCl3) δ 7.71 (t, J=8.02 Hz, 1H), 7.47 (d, J=8.15 Hz, 1H), 7.30 (dd, J=8.61 and 1.28 Hz, 1H), 7.25 (m, 1H), 6.79 (t, J=8.28 Hz, 1H), 4.18 (q, J=7.16 Hz, 2H), 4.12 (t, J=13.21 Hz, 2H), 3.81 (d, J=2.0 Hz, 2H), 2.60 (s, 3H), 1.27 (t, J=7.13 Hz, 3H); LC/MS (m/z) [M+1] 378.3 (calculated for C19H19F3N3O2, 378.1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:14])=[O:13])=[CH:8][C:4]=1[C:5](O)=[O:6].C(Cl)(=O)C([Cl:25])=O.CN(C=O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:14])=[O:13])=[CH:8][C:4]=1[C:5]([Cl:25])=[O:6]
Reactant: COc1ccc(S(=O)(=O)Oc2ccccc2)cc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(S(=O)(=O)Oc2ccccc2)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a suspension of 2-methoxy-5-phenoxysulfonylbenzoic acid (4.0 g, 13 mmol) in dry toluene (100 mL) was added oxalyl chloride (2.3 mL, 26 mmol) at room temperature. A drop of DMF was added and the mixture stirred at room temperature for 2 h. The mixture was evaporated in vacuo and the residue triturated with 1:1 toluene/hexane to give the title compound as a solid (4.04 g).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:16]([O:18][CH3:19])=[O:17]>[OH-].[Na+].O>[CH3:19][O:18][C:16]([NH:1][CH:2]([CH:3]([CH3:5])[CH3:4])[C:6]([OH:8])=[O:7])=[O:17]
Reactant: CC(C)[C@@H](N)C(=O)O
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)NC(C(=O)O)C(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of d-valine, (5.0 g) in 1N sodium hydroxide (42.7 mL) was added sodium carbonate (4.53 g). The solution was cooled to 0° C. and methyl chloroformate (0.289 mL) was added dropwise over 2 h and reaction mixture was stirred for 2 h at 0° C. White reaction mixture was diluted with enough H2O to form a colorless solution and washed with ethyl ether (3×30 mL). Aqueous layer was acidified to pH=2 with concentrated HCl to give a white precipitate that collected by filtration, washed with H2O and dried under high vacuum to give 2-Methoxycarbonylamino-3-methyl-butyric acid as a crystalline white solid (4.668 g). LCMS-ESI−: calc'd for C7H13NO4: 176.2 (M+H+). Found: 175.9 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:19][N:20](C=O)C>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:19]([C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8])#[N:20]
Reactant: O=Cc1cc(Br)ccc1Oc1ccc(Cl)c(Cl)c1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(Oc2ccc(Cl)c(Cl)c2)c(C=O)c1
Temperature: 25 °C

Procedure:
Under N2 in a flame-dried 3-neck round bottomed flask fitted with a reflux condenser and magnetic stirrer, a mixture of 5-bromo-2-(3,4-dichlorophenoxy)-benzaldehyde (3.0 g, 8.7 mmol), zinc (II) cyanide (1.5 g, 13 mmol) and tetrakis(triphenylphosphine) palladium (0) (1.5 g, 1.3 mmol) in anhydrous DMF (145 ml) was stirred at room temperature while degassing with N2 for 5 min. After heating at approximately 80° C. for 90 min., the reaction was judged complete by thin layer chromatography (1:1 CH2Cl2:hexanes) and was allowed to cool to room temperature. The reaction mixture was then diluted with water and ethyl acetate and stirred another 10 min. The water layer was separated, extracted twice with EtOAc and combined with the original organic layer, and washed with an aqueous solution of Rochelle salt (potassium sodium tartrate tetrahydrate) followed by aqueous NaCl. The organic layer was dried with Na2SO4, filtered and concentrated in vacuo to an oil. The oil was flash chromatographed on a 5×15 cm column of silica gel (230-400 mesh), eluting with CH2Cl2:hexanes (1:1) to obtain the title product as a white solid, 1.5 g (60%), m.p. 122-126° C.
Reaction SMILES: [K].[Na].[Cl-:3].[Mg+2:4].[Cl-].[Cl:6][C:7]1[CH:12]=[C:11](Cl)[CH:10]=[C:9]([Cl:14])[CH:8]=1>O1CCCC1.Cl[Ni](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl-:6].[Mg+2:4].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:14])[CH:8]=1.[Cl-:3]
Reactant: Clc1cc(Cl)cc(Cl)c1
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [K]
Solvent: C1CCOC1
Product: Clc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5 g of potassium and sodium alloy (56:44) and 8.89 g of anhydrous magnesium chloride in 200 ml tetrahydrofuran (THF) was stirred at room temperature for one hour before refluxing for two hours. After cooling to room temperature, 13.64 g of 1,3,5-trichlorobenzene in 50 ml of THF was added over 1.5 hours during which time the reaction temperature was maintained below 35° C. The solution was then stirred for 10 hours at room temperature after which 105 mg of bis(triphenylphosphine)nickel dichloride was added, and the resulting reaction mixture refluxed for 24 hours. Most of the THF was removed under reduced pressure and the polymer product precipitated by methanol addition. After two precipitations 5.60 g of polymer was obtained: Tg=236° C.; Mn=7560; MW=17500; D=2.30.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:13]#[N:14])[NH:6][C:7](=O)[CH2:8][CH2:9][O:10][CH3:11])[CH3:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:25]2)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[N:6]=[C:7]([CH2:8][CH2:9][O:10][CH3:11])[S:25][C:13]=1[NH2:14])=[O:15])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C(C#N)NC(=O)CCOC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc(CCOC)sc1N
Temperature: 110 °C
Yield: 82.2 %

Procedure:
A suspension of cyano-(3-methoxy-propionylamino)-acetic acid ethyl ester (0.95 g, 4.44 mmol) in toluene (11.00 ml) was flushed with argon. 2,4-bis(4-Methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (Lawesson's reagent) (0.90 g, 2.22 mmol) was added at once and the mixture was warmed at 110° C. for 2 h. Toluene was evaporated and the residue purified by flash chromatography (heptane/ethyl acetate) to yield 5-amino-2-(2-methoxy-ethyl)-thiazole-4-carboxylic acid ethyl ester (0.42 g, 40%), MS (ISP): m/e=231.1 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:20]=[CH:19][C:14]4[O:15][CH2:16][CH2:17][O:18][C:13]=4[CH:12]=3)[O:10][C:3]=12.[CH3:21][C:22]1[C:30]([NH2:31])=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>>[O:15]1[C:14]2[CH:19]=[CH:20][C:11]([C:9]3[O:10][C:3]4[C:4](=[N:5][CH:6]=[CH:7][C:2]=4[NH:31][C:30]4[C:22]([CH3:21])=[C:23]5[C:27](=[CH:28][CH:29]=4)[NH:26][CH:25]=[CH:24]5)[CH:8]=3)=[CH:12][C:13]=2[O:18][CH2:17][CH2:16]1
Reactant: Clc1ccnc2cc(-c3ccc4c(c3)OCCO4)oc12
Reactant: Cc1c(N)ccc2[nH]ccc12
Product: Cc1c(Nc2ccnc3cc(-c4ccc5c(c4)OCCO5)oc23)ccc2[nH]ccc12

Procedure:
The title compound was prepared by procedure E using 7-chloro-2-(2,3-dihydro-1,4-benzodioxin-6-yl)furo[3,2-b]pyridine (28.50 mg; 0.10 mmol; 1.00 eq.) instead of 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine, and 4-methyl-1H-indol-5-ylamine (15.21 mg; 0.10 mmol; 1.05 eq.) instead of 6-amino-2,2-difluoro-4H-benzo[1,4]oxazin-3-one, and was obtained as a beige solid (22 mg, 55%). (HPLC (method F): 96%, RT: 3.96 min); 1H NMR (500 MHz, DMSO-d6) δ [ppm] 11.15 (s, 1H), 8.52 (s, 1H), 7.92 (d, J=5.5, 1H), 7.54 (d, J=1.8, 1H), 7.46 (d, J=8.5, 1H), 7.41-7.34 (m, 1H), 7.34-7.26 (m, 2H), 6.98 (dd, J=14.6, 8.5, 2H), 6.51 (s, 1H), 6.05 (d, J=5.4, 1H), 4.31 (s, 4H), 2.36 (s, 3H); MS (m/z) 398 [M+H]+, RT: 3.9 min.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([CH3:11])[C:7](OC)=[O:8].[NH3:12]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([CH3:11])[C:7]([NH2:12])=[O:8]
Reactant: COC(=O)C(C)c1cccs1
Reactant: N
Product: CC(C(N)=O)c1cccs1
Temperature: 70 °C
Yield: 71.3 %

Procedure:
Methanolic ammonia (10 ml) was added to methyl 2-(thiophen-2-yl)propanoate (200 mg, 1.17 mmol) in sealed tube, the reaction mixture was heated to 70° C. for 18 h. The volatiles were evaporated and the residue was washed with n-pentane to afford 130 mg (71.3%) of 2-(thiophen-2-yl)propanamide as brown color solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[CH:12]1([CH2:15][CH2:16][NH:17][C:18]([C:20]2[N:21]=[N:22][C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)=[O:19])[CH2:14][CH2:13]1>>[CH:12]1([CH2:15][CH2:16][NH:17][C:18]([C:20]2[N:21]=[N:22][C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:4](=[O:5])[C:3]4[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=4[F:11])[CH2:28][CH2:27]3)=[CH:24][CH:25]=2)=[O:19])[CH2:14][CH2:13]1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)c3c(F)cccc3F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 2,6-difluorobenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder (44% yield). 1H NMR (400 MHz, CDCl3) δ 8.07, 8.07-7.99, 7.44-7.38, 7.02-6.96, 4.0-3.99, 3.86-3.83, 3.58-3.50, 3.39-3.38, 1.52, 1.15-1.10, 0.77-0.74, 0.49-0.45, 0.11-0.08.
Reaction SMILES: [Li+].[OH-].[CH3:3][N:4]([CH3:40])[C:5]([C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]3[C:15]=2[CH2:16][CH2:17][C@H:18]3[O:24][C:25]2[CH:38]=[CH:37][C:28]3[C@H:29]([CH2:32][C:33]([O:35]C)=[O:34])[CH2:30][O:31][C:27]=3[CH:26]=2)=[C:9]([CH3:39])[CH:8]=1)=[O:6]>C(O)C.O>[CH3:40][N:4]([CH3:3])[C:5]([C:7]1[CH:8]=[C:9]([CH3:39])[C:10]([C:14]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]3[C:15]=2[CH2:16][CH2:17][C@H:18]3[O:24][C:25]2[CH:38]=[CH:37][C:28]3[C@H:29]([CH2:32][C:33]([OH:35])=[O:34])[CH2:30][O:31][C:27]=3[CH:26]=2)=[C:11]([CH3:13])[CH:12]=1)=[O:6]
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(C(=O)N(C)C)cc5C)ccc(F)c43)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(C(=O)N(C)C)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
LiOH×H2O (11 mg) is added to a solution of methyl 2-((S)-6-((R)-4-(4-(dimethylcarbamoyl)-2,6-dimethylphenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (70 mg) in ethanol (2.6 mL) and water (0.5 mL) and the mixture is stirred for 24 hours at room temperature. After concentration the mixture is diluted with water, acidified with aqueous citric acid solution and extracted with dichloromethane. After concentration the mixture is partitioned between dichloromethane and citric acid. The organic phase is dried (MgSO4) and concentrated to give the title compound. Yield 21 mg, LC (method 20): tR=5.87 min; Mass spectrum (ESI+): m/z=504 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][C:17]([S:20][C:21]2[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]([OH:31])=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:22]=2)([CH3:19])[CH3:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[C:36]([O:40][CH2:41][CH2:42][CH2:43][CH2:44]O)(=[O:39])[CH:37]=[CH2:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:36]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][O:11][C:10]1[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:8][C:7]([S:16][C:17]([S:20][C:21]2[CH:22]=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:24]([OH:31])=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:26]=2)([CH3:18])[CH3:19])=[CH:6][C:5]=1[C:2]([CH3:1])([CH3:3])[CH3:4])(=[O:39])[CH:37]=[CH2:38]
Reactant: C=CC(=O)OCCCCO
Reactant: CC(C)(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CC(=O)OCCCCOc1c(C(C)(C)C)cc(SC(C)(C)Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1C(C)(C)C
Yield: 28.6 %

Procedure:
To a solution of probucol (2.58 g, 5 mmol) in THF (50 ML) were added 4-hydroxybutyl acrylate (1.0 ml, 10 mmol), triphenylphosphine (2.62 g, 10 mmol) and diethyl azodicarboxylate (1.57 ml, 10 mmol). The resultant mixture was stirred under nitrogen at reflux over weekend. It was evaporated. Silica gel chromatography (hexanes/dichloromethane 4:1) gave the title compound as a brown oil (0.92 g). 1H-NMR (400 MHz, CDCl3): 7.54 (s, 2 H), 7.46 (s, 2 H), 6.42 (dd, 1 H), 6.14 (dd, 1 H), 5.84 (dd, 1 H), 5.38 (s, 1 H), 4.23 (t, 2 H), 3.75 (t, 2 H), 1.97 (m, 2 H), 1.82 (m, 2 H), 1.46 (s, 6 H), 1.45 (s, 18 H), 1.42 (s, 18 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH:11]=O)[N:10]=2)[CH:7]=1.C(C1NC(C=O)=C(C)N=1)C.[Cl:23][C:24]1[CH:29]=[C:28]([CH2:30][CH2:31][C:32]2([CH:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[CH2:37][C:36](=[O:38])[CH2:35][C:34](=[O:39])[O:33]2)[CH:27]=[CH:26][C:25]=1[C:45]([CH3:49])([CH3:48])[C:46]#[N:47].C1(C2(CCC3C=CC(C(C)(C)C#N)=C(F)C=3)CC(O)=CC(=O)O2)CCCC1>>[Cl:23][C:24]1[CH:29]=[C:28]([CH2:30][CH2:31][C:32]2([CH:40]3[CH2:41][CH2:42][CH2:43][CH2:44]3)[CH2:37][C:36]([OH:38])=[C:35]([CH2:11][C:9]3[N:10]=[C:5]4[N:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]4[N:8]=3)[C:34](=[O:39])[O:33]2)[CH:27]=[CH:26][C:25]=1[C:45]([CH3:49])([CH3:48])[C:46]#[N:47]
Reactant: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: O=Cc1nc2ncc(Cl)cn2n1
Agent: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(O)=CC(=O)O2)cc1F
Agent: CCc1nc(C)c(C=O)[nH]1
Product: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4ncc(Cl)cn4n3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared analogously to Example A(97) where 6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substituted in place of 2-ethyl-4-methyl-1H-imidazole-5-carbaldehyde and 2-{2-Chloro-4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-2-methyl-propionitrile from Example A(147) (was substituted in place of 2-{4-[2-(2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl}-2-methylpropanenitrile. 1H NMR (400 MHz, CDCl3) δ: 1.17-1.59 (m, 8H), 1.56-1.6 (m, 2H)), 1.82 (s, 6H), 1.88-2.01 (m, 2H), 2.31-2.79 (m, 3H), 3.79 (d, J=16 Hz, 1H), 3.89 (d, J=16 Hz, 1H), 7.34-7.52 (m. 3H), 8.91 (d, J=2.5 Hz, 1H), 9.63 (d, J=2.5 Hz, 1H), 10.9 (s, 1H). C28H29Cl2N5O3: C, 60.65; H, 5.27; N, 12.63. Found: C, 60.45; H, 5.19; N, 12.40. MS (ESI): 555.2(M+H+).
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[H-].[Na+].[OH:11][CH:12]1[CH2:29][CH2:28][C:15]2([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH2:14][CH2:13]1.[I-].[Na+].C([O-])(O)=O.[Na+]>CS(C)=O.CO>[N:6]1[CH:7]=[CH:8][C:3]([O:11][CH:12]2[CH2:13][CH2:14][C:15]3([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:17][CH2:16]3)[CH2:28][CH2:29]2)=[CH:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(O)CC2)CC1
Reactant: Clc1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CO
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CCC(Oc3ccncc3)CC2)CC1
Reaction time: 8 h

Procedure:
4-Chloropyridine hydrochloride (1.3 g) was added to sodium hydride (0.89 g) in DMSO (20 ml) and the mixture was stirred for 10 min. tert-Butyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate (2.0 g) in DMSO (20 ml) was then added slowly and the mixture was stirred overnight (TLC control: conversion approx. 30-35%). A catalytic amount of sodium iodide was added and the reaction mixture was stirred at 80° C. for 8 h (TLC control). Methanol and NaHCO3 solution was added to the reaction mixture and the mixture was stirred for 20 min. It was then extracted with ethyl acetate and the extract was washed again with NaHCO3 solution and cold water. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude product obtained in this way was purified by column chromatography (silica gel, 70% ethyl acetate/hexane). Yield: 1.0 g (40%)
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17](O)=[O:18].[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([N:29]2[CH2:34][CH2:33][N:32]([CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH2:31][CH2:30]2)=[C:25]([CH:28]=1)[C:26]#[N:27]>>[C:26]([C:25]1[CH:28]=[C:21]([NH:20][C:17]([C:3]2[CH:4]=[N:5][N:6]([C:7]3[CH:8]=[CH:9][C:10]([C:13]([F:15])([F:16])[F:14])=[CH:11][CH:12]=3)[C:2]=2[CH3:1])=[O:18])[CH:22]=[CH:23][C:24]=1[N:29]1[CH2:34][CH2:33][N:32]([CH:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH2:31][CH2:30]1)#[N:27]
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(C(F)(F)F)cc1
Reactant: N#Cc1cc(N)ccc1N1CCN(C2CCOCC2)CC1
Product: Cc1c(C(=O)Nc2ccc(N3CCN(C4CCOCC4)CC3)c(C#N)c2)cnn1-c1ccc(C(F)(F)F)cc1
Yield: 48.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 5-methyl-1-(4-trifluoromethylphenyl)pyrazole-4-carboxylic acid (1.1 g) and 5-amino-2-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]benzonitrile (1.1 g), the title compound (1.0 g) was obtained, melting point: 274° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31](OCC)=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:37][CH2:38][C@H:39]([OH:41])[CH3:40]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31]([NH:37][CH2:38][C@H:39]([OH:41])[CH3:40])=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: C[C@@H](O)CN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O
Product: C[C@@H](O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxohexahydro-1H-azepin-1-yl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (2R)-1-amino-2-propanol using methods similar to Example 563 to provide an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.06-1.12 (m, 4 H), 1.54 (d, J=5.05 Hz, 4 H), 1.60-1.75 (m, 4 H), 2.36-2.45 (m, 2 H), 3.15-3.25 (m, 1 H), 3.32-3.47 (m, 4 H), 3.82 (ddd, J=10.84, 6.63, 4.42 Hz, 1 H), 4.15-4.24 (m, 4 H), 4.96 (d, J=4.84 Hz, 1 H) 7.10-7.18 (m, 2 H), 7.38-7.44 (m, 2 H), 8.00 (d, J=1.26 Hz, 1 H), 8.56 (d, J=1.47 Hz, 1 H), 10.44 (t, J=5.58 Hz, 1 H), 17.21 (s, 1 H); ES+ MS: 525 (M+H+).
Reaction SMILES: C([Li])CCC.[O:6]1CCCC1.Cl[C:12]1[N:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:15]=[CH:14][N:13]=1>C(OCC)(=O)C.O>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][O:18][C:16]2[CH:15]=[CH:14][NH:13][C:12](=[O:6])[N:17]=2)=[CH:21][CH:22]=1
Reactant: Fc1ccc(COc2ccnc(Cl)n2)cc1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1nc(OCc2ccc(F)cc2)cc[nH]1
Reaction time: 0.5 h
Yield: 24 %

Procedure:
n-Butyl lithium (2.6 M n-hexane solution, 7.2 mL) was added to tetrahydrofuran solution (10 mL) of 2-popenyl alcohol (1.8 mL) at −78° C., and stirred at the same temperature for 30 minutes. This reaction liquid was gradually added to tetrahydrofuran solution (20 mL) of 2-chloro-4-(4-fluorobenzyloxy)pyrimidine (4.36 g) and stirred at 60° C. for 4 hours, followed by 24 hours' reflux. Cooling the reaction liquid to room temperature, ethyl acetate was added thereto, followed by washing with water and saturated brine and drying over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, the residue was dissolved in tetrahydrofiaan (20 mL). To the solution piperidine (2 mL) and tetrakis(triphenylphosphine)palladium (780 mg) were added and stirred at room temperature for 4 hours. The reaction liquid was added to water (100 mL)-ethyl acetate (50 mL) mixture, and the insoluble matter was recovered by filtration to provide the title compound (0.96 g, 24%).
Reaction SMILES: C([C@@H]1COC(=O)N1C([C@H:16]1[C@H:20]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH2:19][N:18]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:17]1)=O)C1C=CC=CC=1.[OH-].[Li+].[C:37]([O:40]CC)(=[O:39])C.Cl>C1COCC1.O>[C:31]([O:30][C:28]([N:18]1[CH2:19][C@@H:20]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C@H:16]([C:37]([OH:40])=[O:39])[CH2:17]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)[C@H](c2ccc(Cl)cc2)C1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](C(=O)O)[C@H](c2ccc(Cl)cc2)C1

Procedure:
To a mixed solution of the compound (17.0 g) obtained in step 4 in THF (60 mL) and water (15 mL) was added at 0° C. 4N lithium hydroxide (35.1 mL), and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added ethyl acetate, and the mixture was acidified with 2N hydrochloric acid. The organic layer was dried, and the solvent was evaporated under reduced pressure to give (3S,4R)-1-(tert-butoxycarbonyl)-4-(4-chlorophenyl)pyrrolidine-3-carboxylic acid (7.35 g) as a white powder.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[CH3:11][N:12]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:11]([C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2)#[N:12]
Reactant: CN1CCCC1=O
Reactant: Brc1cccc2[nH]ncc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cccc2[nH]ncc12
Temperature: 85 °C

Procedure:
4-Bromoindazole (1.0 g, Judkins et al., WO 9641803) and zinc cyanide (0.6 g) were added to N-methylpyrrolidinone (12.5 ml) and placed under an argon atmosphere. To this mixture was added tetrakis(triphenylphosphine)palladium(0) (0.88 g) and the reaction was heated to 85° C. overnight. The reaction mixture was cooled and partitioned between ethyl acetate and water, the organic layer was washed with brine, dried (MgSO4), and evaporated to dryness. The product was purified by chromatography on silica gel using ethyl acetate-dichloromethane (5:95) as the eluting solvent to afford 0.581 g pure 4-cyanoindazole.