Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:21][CH3:22])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][S:26](Cl)(=[O:28])=[O:27]>N1C=CC=CC=1>[C:17]([C:16]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[CH:13][CH:14]=2)[N:9]([CH2:21][CH3:22])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:26]([CH:25]=[CH2:24])(=[O:28])=[O:27])=[CH:7][CH:6]=1)#[N:18]
Reactant: CCn1c(-c2ccc(N)cc2)c(C#N)c2ccc(OC)cc21
Reactant: O=S(=O)(Cl)CCCl
Solvent: c1ccncc1
Product: C=CS(=O)(=O)Nc1ccc(-c2c(C#N)c3ccc(OC)cc3n2CC)cc1
Reaction time: 4 h

Procedure:
A solution of 2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile, prepared by example 1Ga step B, (0.82 mg, 2.82 mmol), in pyridine (10 mL) was treated dropwise with chloroethyl sulfonylchloride (0.38 mL, 3.66 mmol) at room temperature. After stirring for 4 h, the reaction mixture was quenched with ice-water and enough 6N HCl was added until the pH was lowered to 2. The suspension was extracted with hot EtOAc (3×). The organic phases were then washed sequentially with 1N HCl, H2O and saturated NaCl and dried and concentrated to give ethenesulfonic acid [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl] amide as a pale orange solid which was used directly in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][N:6]=[C:5]2[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1.[H-].[Na+].[Cl-].[C:22]1([CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([C:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[N:6]=[C:5]2[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1
Reactant: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1cc(Br)cc2c(-c3cccc(F)c3)n[nH]c12
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc2c(-c3cccc(F)c3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c12
Reaction time: 0.25 h
Yield: 42.4 %

Procedure:
To a solution of 2.56 g of 5-bromo-3-(3-fluorophenyl)-7-methyl-1H-indazole in 30 ml of dimethylformamide was added 0.50 g of sodium hydride at room temperature, and the mixture was stirred at the same temperature for 15 minutes. At the same temperature, 2.34 g of triphenylmethane chloride was added and the mixture was stirred at the same temperature for one day. Water was added to the reaction mixture and the mixture was diluted with ethyl acetate. The organic layer was sequentially washed with saturated aqueous ammonium chloride solution and brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:10) and the resulting crystals were washed with diethyl ether, to give 1.94 g of the title compound as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]([O:13]CC)=O)[N:7]=1.Cl.[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH2:30][CH2:31][NH2:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CO.[OH-].[Na+].O.CN(C=O)C>[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH2:30][CH2:31][NH:32][C:11]([C:8]1[N:7]=[C:6]([CH2:5][C:4]2[CH:16]=[CH:17][CH:18]=[C:2]([F:1])[CH:3]=2)[O:10][N:9]=1)=[O:13]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: CCOC(=O)c1noc(Cc2cccc(F)c2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1noc(Cc2cccc(F)c2)n1
Yield: 40.3 %

Procedure:
This compound was prepared according to method F with ethyl 5-(3-fluorobenzyl)-1,2,4-oxadiazole-3-carboxylate (0.108 g; 0.432 mmol) in methanol (6 mL) and sodium hydroxide in water (2M, 6 mL); and 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.432 mmol), HATU (0.164 g; 0.432 mmol), N,N diisopropylethylamine (0.075 mL; 0.432 mmol) in DMF (6 mL). The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.0695 g (40%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(3-fluorobenzyl)-1,2,4-oxadiazole-3-carboxamide as a white solid.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[N:12]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1)[S:13]([C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1)(=[O:15])=[O:14].C([Sn](CCCC)(CCCC)[C:44]([O:46]CC)=[CH2:45])CCC.[F-].[K+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](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>[C:44]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[N:12]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1)[S:13]([C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1)(=[O:15])=[O:14])(=[O:46])[CH3:45]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC(F)(F)F)cc2)c2ncc3ccccc3c2Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC(F)(F)F)cc2)c2ncc3ccccc3c2C(C)=O)cc1
Reaction time: 6 h
Yield: 46.6 %

Procedure:
A mixture of ethyl 4-({(4-bromoisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}-sulfonyl)benzoate (122.0 mg, 0.20 mmol) prepared in Example 153, tributyl(1-ethoxyvinyl)tin (94.0 mg, 0.26 mmol) and dichlorobis(triphenylphosphine)palladium (II) (14.0 mg, 0.02 mmol) in 1,4-dioxane (1 mL) was heated to reflux under argon atmosphere for 16 hours. After cooling, the reaction solution was diluted with ethyl acetate, and poured into aqueous potassium fluoride solution. The mixture was stirred for 6 hours. The insoluble was filtered off, and then the filtrate was extracted with ethyl acetate. The organic layer was washed with water. Then, thereto was added 2 mol/L hydrochloric acid, and the mixture was stirred for 3 days. Then, the organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1→3:2) to give ethyl 4-({(4-acetylisoquinolin-3-yl) [4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoate (53.4 mg, 47%) as a white powder.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[C:12](/[CH:14]=[C:15](\[O-:17])/[CH3:16])#[N:13].[Na+].C(O)(=O)C.O>ClCCl.N1CCCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6](/[CH:10]=[C:14](/[C:15](=[O:17])[CH3:16])\[C:12]#[N:13])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: C/C([O-])=C/C#N
Reactant: O=Cc1ccc2[nH]ncc2c1
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)/C(C#N)=C/c1ccc2[nH]ncc2c1
Yield: 131.5 %

Procedure:
10 g (68.4 mmol) 1H-indazole-5-carbaldehyde [preparation described in US 2005/0227968-A1 (Intermediate 1)], 7.91 g (75.2 mmol) sodium (1Z)-1-cyanoprop-1-en-2-olate, 4.89 ml (85.5 mmol) acetic acid and 0.68 ml (6.84 mmol) piperidine in dry dichloromethane (500 ml) were stirred at reflux temperature for 7 h using an inverse water separator. Upon cooling, a precipitate was formed which was collected by filtration and washed with dichloromethane. The solid was dried in vacuo to afford the crude title compound (19 g, 75% purity by LC-MS, 96% of th.) which was used in subsequent steps without further purification.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH2:10][CH2:11][N:12]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[N:14]=[C:13]1[CH3:20])(=O)=O>CN(C)C=O>[N:1]([CH2:10][CH2:11][N:12]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[N:14]=[C:13]1[CH3:20])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1nc([N+](=O)[O-])cn1CCOS(C)(=O)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc([N+](=O)[O-])cn1CCN=[N+]=[N-]

Procedure:
To 2 parts of sodium azide is added a solution of 5 parts of 2-(2-methyl-4-nitro-1-imidazolyl)ethyl methanesulfonate (U.S. Pat. No. 3,882,136) in 60 parts of N,N-dimethylformamide. The resultant mixture is stirred at approximately 55° for 4 hours, then cooled and thereupon partitioned between water and toluene. The toluene phase is separated, washed with water, dried over anhydrous magnesium sulfate, and stripped of solvent by vacuum distillation. Crystallization of the residual oil from a mixture of ethyl acetate and hexane affords 1-(2-azidoethyl)-2-methyl-4-nitroimidazole as colorless crystals melting at 73°-75°. The product has the formula ##SPC7##
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([NH:10]C(=O)C)=[C:4]([CH3:14])[CH:3]=1.Cl.[OH-].[Na+]>CO>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([NH2:10])=[C:4]([CH3:14])[CH:3]=1
Reactant: COc1cc(NC(C)=O)c(C)cc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(N)c(C)cc1Br
Temperature: 95 °C

Procedure:
N-(4-bromo-5-methoxy-2-methylphenyl)acetamide was dissolved in methanol (15 mL) and concentrated HCl (30 mL). The mixture was refluxed at 95° C. overnight. After cooling to room temperature, the mixture was poured into ice water, and basified to pH=12 with conc. NaOH aqueous solution. The mixture was then extracted with ethyl acetate (3×50 mL). The combined organic layer was dried over Na2SO4 and concentrated. The crude product was purified by silica chromatography (15% ethyl acetate in hexanes) to give 4-bromo-5-methoxy-2-methylaniline as a beige solid; 1H NMR (400 mHz, CDCl3) 7.20 (s, 1H), 6.37 (s, 1H), 4.6 (br, 2H), 3.82 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][N:7]2[C:12](=[O:13])[N:11]([CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])[N:10]=[N:9][C:8]=12)(=[O:3])[NH2:2].Cl>>[C:1]([C:4]1[N:5]=[CH:6][N:7]2[C:12](=[O:13])[N:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[N:10]=[N:9][C:8]=12)(=[O:3])[NH2:2]
Reactant: CCOC(=O)CCn1nnc2c(C(N)=O)ncn2c1=O
Agent: Cl
Product: NC(=O)c1ncn2c(=O)n(CCC(=O)O)nnc12
Temperature: 45 °C
Reaction time: 16 h

Procedure:
A suspension of ethyl 3-(8-carbamoyl-oxoimidazo[5,1-d][1,2,3,5]tetrazin-3(4H)-yl)propanoate (0.5 g, 1.784 mmol) in 5 M hydrochloric acid (2.34 mL, 11.70 mmol) was heated at 45° C. After 16 hours, the reaction mixture was filtered and the residue was washed with water (5 mL) and acetone (5 mL). A portion (50 mg from a total of 332 mg) was recrystallized from hot acetonitrile/water to afford the title compound as an off white solid. Yield: 32 mg, 0.13 mmol, 47% pro rata. LCMS (ES+), m/z 281 (M+H)+ at the solvent front. 1H NMR (400 MHz, d6-DMSO) δ: 12.5 (1H, br s), 8.80 (1H, s), 7.75 (1H, br s), 7.65 (1H, br s), 4.45 (2H, t), 2.75 (2H, t).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][C:15]([CH:17]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]([OH:25])=O)[CH2:18]3)=[O:16])[CH:12]=2)[NH:7][N:6]=1)=[O:4].[C:26]1([C:32]#[C:33][CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C>>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][C:15]([CH:17]3[CH2:21][CH2:20][N:19]([CH2:22][C:23](=[O:25])[N:37]4[CH2:38][CH2:39][CH:34]([C:33]#[C:32][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH2:35][CH2:36]4)[CH2:18]3)=[O:16])[CH:12]=2)[NH:7][N:6]=1)=[O:4]
Reactant: CNC(=O)c1n[nH]c2ccc(NC(=O)C3CCN(CC(=O)O)C3)cc12
Reactant: C(#CC1CCNCC1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1n[nH]c2ccc(NC(=O)C3CCN(CC(=O)N4CCC(C#Cc5ccccc5)CC4)C3)cc12
Yield: 24 %

Procedure:
A solution of [3-(3-methylcarbamoyl-1H-indazol-5-ylcarbamoyl)-pyrrolidin-1-yl]-acetic acid (0.13 mmols), 4-phenylethynyl-piperidine (0.13 mmols), 1-hydroxybenztriazole (18 mg, 0.13 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (27 mg, 0.14 mmol) and DIEA (45 μl, 0.26 mmols) was stirred overnight and directly subjected to purification by reversed phase HPLC to obtain 16 mg of the title product.
Reaction SMILES: BrBr.O1C=CC2C=CC=CC1=2.Br[CH:13]1[O:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[CH:14]1[Br:22]>C(Cl)(Cl)Cl.C(O)C>[Br:22][C:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[O:17][CH:13]=1
Reactant: BrC1Oc2ccccc2C1Br
Agent: BrBr
Agent: c1ccc2occc2c1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: Brc1coc2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
Bromine (13.1 mL, 250 mmol) dissolved in chloroform (50 mL) is added dropwise to a solution of benzo[b]furan (25 g, 210 mmol) in chloroform (200 mL) at −10° C. over 20 minutes. The mixture is then stirred at 0° C. for 1 hour and the volatiles are evaporated. The residue is stirred with ethanol (50 mL) and then filtered. The solid material is washed with diethyl ether (100 mL) on the filter. This furnishes 23.0 g (39%) of 2,3-dibromo-2,3-dihydro-benzo[b]furan as white crystalline material. Potassium hydroxide pellets (9.3 g, 165 mmol) are dissolved in ethanol (40 mL) and cooled to 0° C. 2,3-Dibromo-2,3-dihydro-benzo[b]furan (23.0 g, 82.7 mmol) dissolved in ethanol (90 mL) is added dropwise hereto at a constant temperature of 0° C. After complete addition the mixture is heated to reflux for 2 hours. The mixture is concentrated in vacuo and water (100 mL) is added. The aqueous layer is extracted with ethyl acetate (3×100 mL). The combined organic fractions are washed with brine (100 mL), dried (MgSO4) and concentrated to furnish 14.7g (90%) of the wanted product as an oil.
Reaction SMILES: ClC1C=C(Cl)C(Cl)=CC=1[O:10][C:11](=O)[C@H:12]([CH3:21])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[CH2:23]([O:30][C:31](=[O:34])[CH2:32][NH2:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[CH2:23]([O:30][C:31](=[O:34])[CH2:32][NH:33][C:11](=[O:10])[C@H:12]([CH3:21])[NH:13][C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Oc1cc(Cl)c(Cl)cc1Cl
Reactant: NCC(=O)OCc1ccccc1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
19.3 Parts N-t-butoxycarbonyl-L-alanine 2,4,5-trichlorophenyl ester and 9.7 parts glycine benzyl ester are dissolved in 200 parts methylene chloride and the resulting solution is stirred overnight at room temperature. Removal of the solvents under reduced pressure affords crude N-t-butoxycarbonyl-L-alanylglycine benzyl ester which is purified by low pressure column chromatography. The purified blocked dipeptide is then dissolved in 50 parts dioxane and stirred with a 10 fold excess of 2 N HCl in dioxane for 15 minutes. The solvent is removed by evaporation under reduced pressure to give, after trituration with ethyl ether, L-alanylglycine benzyl ester hydrochloride. This compound is represented by the following formula
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[C:10](Cl)(Cl)=[S:11].C(N(C(C)C)CC)(C)C>ClCCl>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[N:4]=[C:10]=[S:11]
Reactant: Nc1c(F)cccc1F
Reactant: S=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Fc1cccc(F)c1N=C=S
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
1,3-Difluoro-2-isothiocyanato-benzene was synthesized as follows, according to scheme 1. A solution of 2,6-difluoro aniline (0.13 g, 1.01 mmol) in dichloromethane (10.00 ml) was treated with thiophosgene (0.12 g, 1.06 mmol) and diisopropylethylamine (0.26 g, 2.01 mmol). The mixture was stirred for 1 h at room temperature. The solvent was then evaporated, leaving 1,3-difluoro-2-isothiocyanato-benzene (0.17 g, 99%) as a light brown gum, which was used crude.
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][CH2:2]1.[Li].[Li+].CC([N-]C(C)C)C.[CH:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1>O1CCCC1.C1CCCCC1.O.C(OCC)(=O)C>[OH:25][CH:16]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)[CH:2]1[CH2:3][CH2:4][O:5][C:1]1=[O:6]
Reactant: COc1cccc(C=O)c1
Reactant: O=C1CCCO1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C(O)C2CCOC2=O)c1
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a solution of γ-butyrolactone (3.0 g) in tetrahydrofuran (THF) (30 ml) was added lithium diisopronylamide (LDA) (28 ml, 1.5 M solution in cyclohexane) at -78° C. under N2, and then after 30 minutes, a solution of m-anisaldehyde (4.7 g) in THF (10 ml) was added in the solution. After being stirred for 2 hours at the same temperature, the solution was poured into the mixture of ethyl acetate and water. The organic layer was washed with 1N-HCl solution, sat. NaHCO3 and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 3-[hydroxy(3-methoxyphenyl)methyl)-2-oxotetrahydrofuran (7.4 g) MS (m/z): 205 (M+ +17) IR (Neat): 3400, 1725 cm-1NMR (CDCl3, δ): 2.2-2.8 (4H, m), 3.81 (3H, s), 4.1-4.4 (2H, m), 4.80 (1H, d, J=8.0 Hz), 6.8-7.1 (3H, m), 7.27 (1H, t, J=8.0 Hz)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)[CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][N:32]=[C:31]([C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=5)[CH:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Fc1cccc(-c2cc(Br)ccn2)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4ccnc(-c5cccc(F)c5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 4-bromo-2-(3-fluoro-phenyl)-pyridine.
Reaction SMILES: Cl.[CH3:2][CH:3]([C@@H:5]1[CH2:10][O:9][CH2:8][CH2:7][NH:6]1)[CH3:4].[Cl:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH2:19])[N:13]=1.CCN(C(C)C)C(C)C>C(#N)CC>[Cl:11][C:12]1[CH:17]=[C:16]([N:6]2[CH2:7][CH2:8][O:9][CH2:10][C@H:5]2[CH:3]([CH3:4])[CH3:2])[N:15]=[C:14]([NH2:19])[N:13]=1
Reactant: CC(C)[C@@H]1COCCN1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H]1COCCN1c1cc(Cl)nc(N)n1
Temperature: 110 °C
Yield: 80.5 %

Procedure:
(3R)-3-(1-Methylethyl)morpholine HCl salt (3.50 g, 21.1 mmol) and 4,6-dichloro-2-pyrimidinamine (3.81 g, 23.2 mmol, 1.1 equiv) were charged into a 60 mL sealable tube, followed with addition of 20 mL of propionitrile and Hunig's base (11.1 mL, 63.4 mmol, 3 equiv). The vessel was sealed and heated at 110° C. in an oil bath for 68 hours. The mixture was concentrated in vacuo, and the residue was partitioned between water (50 mL) and EtOAc (150 mL). The aqueous was extracted with another 100 mL of EtOAc. The combined organic was dried over Na2SO4, filtered, and concentrated in vacuo. The foamy residue was taken up in CHCl3 with some EtOAc to give a suspension, which was filtered. The solids collected were mostly starting 4,6-dichloro-2-pyrimidinamine. The filtrate underwent silica gel column chromatography using gradient elution of 1% EtOAc in CHCl3 to 80% EtOAc in CHCl3 to afford the title compound (4.36 g) as a glassy foam. LC-MS (ES) m/z=257 [M+H]+.
Reaction SMILES: [O-]CC.[Na+].C1(C)C=CC=CC=1.C([O:14][C:15](=[O:31])[CH2:16][C:17](=[N:24][N:25]1[CH2:29][CH2:28][CH2:27][C:26]1=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)C.Cl>O>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]1[C:16]([C:15]([OH:14])=[O:31])=[C:29]2[CH2:28][CH2:27][CH2:26][N:25]2[N:24]=1
Reactant: CCOC(=O)CC(=NN1CCCC1=O)c1ccccn1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)c1c(-c2ccccn2)nn2c1CCC2
Temperature: 100 °C
Yield: 93.2 %

Procedure:
Add sodium ethoxide (145 g, 2.03 mol), followed by toluene (7 L) and 3-(2-oxo-pyrrolidin-1-ylimino)-3-pyridin-2-yl-propionic acid ethyl ester (Preparation 3-B; 280 g, 1.02 mol) to a 22 L flask equipped with mechanical stirrer, nitrogen inlet and a reflux condenser. Heat the mixture to 100° C. for 21 h. Cool to room temperature, add water (6 L), and adjust to pH 5 with concentrated hydrochloric acid. Separate the organic layer and extract the aqueous layer with 10% isopropyl alcohol in chloroform (2×9 L). Combine the organic layers, dry (sodium sulfate), filter, and concentrate in vacuo to yield 218 g (93%) of the title compound as a yellow solid MS ES+ m/e 230 (M+1).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)[N:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:43]1([C:49]2[N:50]=[C:51]([C:54]3([CH2:60][NH2:61])[CH2:59][CH2:58][O:57][CH2:56][CH2:55]3)[S:52][CH:53]=2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[C:43]1([C:49]2[N:50]=[C:51]([C:54]3([CH2:60][NH:61][C:13](=[O:15])[C:12]4[CH:16]=[C:8]([C:5]5[N:4]=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=5)[CH:9]=[N:10][CH:11]=4)[CH2:55][CH2:56][O:57][CH2:58][CH2:59]3)[S:52][CH:53]=2)[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCC1(c2nc(-c3ccccc3)cs2)CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: O=C(NCC1(c2nc(-c3ccccc3)cs2)CCOCC1)c1cncc(-c2noc(C(F)(F)F)n2)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 33.9 %

Procedure:
To a stirred solution of compound 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid (100 mg, 0.4 mmol) in dry DMF (5 mL) were added HATU (180 mg, 0.46 mmol) followed by hydrochloride salt of (4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine (120 mg, 0.4 mmol) and NMM (0.12 mL, 1.1 mmol) at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for further 10 h. The reaction mixture was diluted with EtOAc. The organic layer was washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluent 50-60% EtOAc in petroleum ether) to get pure product N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide (70 mg, yield 37%): 1H NMR (400 MHz, CDCl3) δ 9.43 (d, J=2 Hz, 1H), 9.21 (br s, 1H), 8.76 (br s, 1H), 7.87 (d, J=7 Hz, 2H), 7.75 (br s, 1H), 7.53 (s, 1H), 7.41-7.32 (m, 3H), 3.99-3.95 (m, 2H), 3.79-3.74 (m, 2H), 2.35-2.32 (m, 2H), 2.07-2.03 (m, 2H). MS (ESI) m/z: Calculated for C24H20F3N5O3S: 515.12. found: 516.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=2)=[N:3]1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].O>C(Cl)Cl>[CH3:1][C:2]1([CH3:21])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:14]=[CH:15][C:16]([CH2:19][O:20][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:17][CH:18]=2)=[N:3]1
Reactant: CC1(C)COC(c2ccccc2-c2ccc(CO)cc2)=N1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)COC(c2ccccc2-c2ccc(COS(C)(=O)=O)cc2)=N1
Reaction time: 3 h
Yield: 99.1 %

Procedure:
2.0 g (7.1 mmol) of 4,4-dimethyl-2-(4'-hydroxymethylbiphenyl-2-yl)oxazoline and 1.43 g (14.1 mmol) of triethylamine were dissolved in methylene chloride (20 ml). A solution of 0.98 g (8.6 mmol) of methanesulfonyl chloride in methylene chloride (10 ml) was dropwise added thereto under cooling with salt-ice. After stirring for 3 hours as such, the reaction liquid was poured into water, followed by the extraction with methylene chloride. After washing with water and drying, vacuum concentration was conducted. 2.53 g of the title compound was obtained as an oil (yield 99%).