Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]P(=O)(OCC)OCC.O1CCCC1.C([Li])CCC.[CH:20](=[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:29](=[O:30])O1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCCCCC.O>[CH2:20]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:29](=[O:30])[CH:1]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOP(C)(=O)OCC
Reactant: O=C1OC(=Cc2ccccc2)c2ccccc21
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1C=C(Cc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Diethyl methylphosphonate (1.94 g.) suspended in 50 ml. of dry tetrahydrofuran is treated with 1.1 equivalents of butyl lithium in hexane under nitrogen at about -78°. After 10 minutes, one equivalent of benzalphthalide in 10 ml. of tetrahydrofuran is added while maintaining the temperature at about -78°. The reaction mixture is allowed to warm to room temperature and then left to stand at room temperature for 3 hours. The reaction mixture is diluted with water and then extracted with ether. The ether extracts are combined, washed with water, dried and the solvent removed under vacuum. The residue is chromatographed on silica eluting with methylene chloride:hexane (4:1) to afford 3-benzylind-2-en-1-one and a small amount of starting material.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]([O:14]C)=[O:13])[C:5]([C:8](OC)=O)=[N:6][CH:7]=1.[NH2:16][C@:17]([CH3:24])([CH:21]([CH3:23])[CH3:22])[C:18]([NH2:20])=[O:19].CC([O-])(C)C.[K+].O>C1(C)C=CC=CC=1>[CH:21]([C@:17]1([CH3:24])[C:18](=[O:19])[NH:20][C:8]([C:5]2[N:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=2[C:12]([OH:14])=[O:13])=[N:16]1)([CH3:23])[CH3:22]
Reactant: CC(C)[C@@](C)(N)C(N)=O
Reactant: COC(=O)c1cc(C)cnc1C(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cnc(C2=N[C@](C)(C(C)C)C(=O)N2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.6 %

Procedure:
A stirred mixture of dimethyl 5-methylpyridine-2,3-dicarboxylate (52.25 g, 0.25 mol) and (R)2-amino-2,3-dimethylbutyramide (33.43 g, 0.2563 mol, 96.2% R isomer) in dry toluene is treated with KOt-Bu (29.4 g, 0.2625 mol) at 35° C., stirred at ambient temperatures for 10 minutes, treated with a second portion of KOt-Bu (29.4 g, 0.2625 mol) at 40° C., heated at 80°-85° C. for 1.5-2.0 hr, cooled to room temperature, treated with water and stirred until dissolution of solids is complete. The phases are separated. The aqueous phase is acidified to pH 3 with concentrated HCl, stirred at pH 3 for 10-15 min., and filtered. The aqueous filtrate is extracted with methylene chloride. The filtercake is dispersed in methylene chloride and the dispersion is filtered. The methylene chloride extracts and the methylene chloride filtrate are combined, dried over MgSO4 and concentrated to dryness in vacuo to give the title product as a white solid, 47.3 g, 68.6% yield, 98.1% pure, 97% R isomer by quantitative NMR analysis.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]#[C:15][CH3:16])=[CH:8][CH:7]=1)(=[O:5])=[O:4].Br[CH:18]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:19]([O:21][CH3:22])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([S:3]([N:2]([CH3:1])[CH:18]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:19]([O:21][CH3:22])=[O:20])(=[O:5])=[O:4])=[CH:7][CH:8]=1)[C:14]#[C:15][CH3:16]
Reactant: COC(=O)C(Br)c1ccc(Cl)cc1
Reactant: CC#CCOc1ccc(S(=O)(=O)NC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)OC)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a similar manner as described in Example 211, a mixture of 2.39 g N-methyl-[4-(2-butynyloxy)phenyl]sulfonamide], methyl alpha-bromo(4-chlorophenyl)acetate, and powdered potassium carbonate in DMF was stirred at room temperature for 18 hours. The mixture was combined with water and the precipitate was collected and purified by chromatography on silica gel using hexane-ethyl acetate, 4:1 to give methyl 2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-(4-chlorophenyl)acetate as a yellow oil which was then used in the subsequent step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[N:24]=1.[C:25](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:25])[C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[N:24]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1Nc2cnc(Cl)nc2N(CCCc2ccccc2)CC1(F)F
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)C(F)(F)CN(CCCc2ccccc2)c2nc(Cl)ncc21
Reaction time: 4 h
Yield: 95.4 %

Procedure:
To a solution of 1.0 g (0.0028 mole) of 2-chloro-7,7-difluoro-9-(3-phenyl-propyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-281) in 20 mL of dimethylformamide was added 1.4 g (0.0042 mole) of cesium carbonate, followed by 0.53 mL (0.0084 mole) of iodomethane. After stirring four hours, the mixture filtered and then concentrated under reduced pressure. Ice water and dichloromethane were added. The mixture was extracted with dichloromethane twice. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 0.98 g of 2-chloro-7,7-difluoro-5-methyl-9-(3-phenyl-propyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-281) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][CH:18]([OH:34])[C:19]2[S:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7].[H-].[Na+].Br[CH:38]([CH3:40])[CH3:39]>>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][CH:18]([O:34][CH:38]([CH3:40])[CH3:39])[C:19]2[S:20][C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:9])([CH3:10])[C:6]([OH:8])=[O:7]
Reactant: CC(C)Br
Reactant: CC(C)(Oc1ccc(CCC(O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl)C(=O)O
Agent: [H-]
Agent: [Na+]
Product: CC(C)OC(CCc1ccc(OC(C)(C)C(=O)O)c(Cl)c1Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)s1

Procedure:
2-(2,3-Dichloro-4-(3-isopropoxy-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoic acid is prepared from 2-(2,3-dichloro-4-(3-hydroxy-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoic acid using 5 equivalents of sodium hydride and 4 equivalents of 2-bromopropane according to general procedure H.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:3]=12.[CH3:18][NH:19][CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(N(C(C)C)CC)(C)C>CC#N>[CH2:16]([N:13]1[C:4]2=[N:5][CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]([N:19]([CH3:18])[CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[C:3]2[CH:15]=[N:14]1)[CH3:17]
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Reactant: CNC1CCOCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc2c(cnn2CC)c1N(C)C1CCOCC1
Yield: 76.5 %

Procedure:
Intermediate 1 (1.2 g, 4.76 mmol), Intermediate 50 (0.79 g, 5.2 mmol) and diisopropylethylamine (4 ml, 24 mmol) in MeCN (8 ml) was heated at 70° C. for 24 hours. The solvent was removed in vacuo and the residue partitioned between DCM and water. The organic phase was concentrated in vacuo and the residue chromatographed on silica (50 g) eluting with cyclohexane:ethyl acetate (2:1 followed by 1:1 then 1:2). Appropriate fractions were combined and evaporated to give Intermediate 51 as a brown oil (1.21 g). LCMS showed MH+=334; TRET=2.61 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:23])OCC)[CH:5]=[C:6]([Cl:17])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1.Cl>O>[CH3:19][N:18]1[CH:4]=[CH:3][N:18]([C:4]2[CH:5]=[C:6]([Cl:17])[C:7]([O:8][C:9]3[CH:10]=[C:11]([Cl:16])[CH:12]=[C:13]([Cl:15])[CH:14]=3)=[C:2]([Cl:1])[CH:3]=2)[C:19]1=[O:23]
Reactant: CCOC(=O)Nc1cc(Cl)c(Oc2cc(Cl)cc(Cl)c2)c(Cl)c1
Agent: Cl
Solvent: O
Product: Cn1ccn(-c2cc(Cl)c(Oc3cc(Cl)cc(Cl)c3)c(Cl)c2)c1=O

Procedure:
Ethyl [3,5-dichloro-4-(3,5-dichlorophenoxy)phenyl]carbamate (0.02 mole), water (30 ml) and concentrated hydrochloric acid (3 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer and condenser. The mixture is refluxed for a period of about 30 minutes and then cooled and extracted with ethyl acetate. The extract is washed with dilute aqueous sodium bicarbonate, with two portions of water and is then dried. The ethyl acetate is removed by mild warming under reduced pressure to yield the desired product 1-methyl-3-[3,5-dichloro-4-(3,5-dichlorophenoxy) phenyl]-4-imidazolin-2-one.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:25])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH:18][CH3:19])=[CH:13][C:12]=2[O:20][CH2:21][CH:22]([F:24])[F:23])[CH2:5][CH2:4]1.[C:28]([O:32][C:33](=[O:47])[NH:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([N:43]=[C:44]=S)[C:37]=1[Cl:46])([CH3:31])([CH3:30])[CH3:29].CC(C)N=C=NC(C)C>>[F:1][C:2]([F:26])([F:27])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:11]2[C:12]([O:20][CH2:21][CH:22]([F:23])[F:24])=[CH:13][C:14]3[N:18]([CH3:19])[C:44]([NH:43][C:38]4[C:39]([Cl:42])=[CH:40][CH:41]=[C:36]([CH2:35][NH:34][C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:47])[C:37]=4[Cl:46])=[N:17][C:15]=3[CH:16]=2)=[O:25])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Reactant: CNc1cc(OCC(F)F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N
Agent: CC(C)N=C=NC(C)C
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)OC(C)(C)C)c2Cl)nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(OCC(F)F)cc21

Procedure:
The title compound is prepared from N-(trans-4-trifluoromethyl-cyclohex-1-yl)-2-(2,2-difluoro-ethoxy)-4-methylamino-5-amino-benzoic acid amide and (2,4-dichloro-3-isothiocyanato-benzyl)-carbamic acid tert-butyl ester with DIC in analogy to examples 7b/7c.
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:5]=1[NH:6][CH2:7][CH:8]=[O:9])[CH2:2][CH3:3].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[Cl:27][CH2:28][C:29](Cl)=[O:30]>O>[Cl:27][CH2:28][C:29]([N:6]([CH2:7][CH:8]=[O:9])[C:5]1[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:4]=1[CH2:1][CH2:2][CH3:3])=[O:30]
Reactant: CCCc1ccc(F)cc1NCC=O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCCc1ccc(F)cc1N(CC=O)C(=O)CCl
Temperature: 25 °C

Procedure:
The dimethyl acetal of 2-(2-propyl-5-fluoroanilino)-acetaldehyde (0.1 mole), sodium carbonate (0.06 mole) dissolved in water (50 ml) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and cooling means. The mixture is cooled to a temperature of about 0° C. and α-chloroacetyl chloride (0.11 mole) is incrementally added with stirring. After the addition is completed stirring is continued and the reaction mixture is permitted to warm to room temperature. After this time the mixture is filtered, washed with dilute hydrochloric acid and stripped of solvent to yield the desired product the dimethyl acetal of 2-(N-α-chloroacetyl-2-propyl-5-fluoroanilino)acetaldehyde.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][C:12]1([CH3:23])[C:16](C)(C)OB(C=C(C)C)O1.C(=O)(O)[O-].[Na+].ClCCl>O1CCOCC1.O.CC(=O)OCC>[C:12]([C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[CH:11]=[C:12]([CH3:23])[CH3:16])([CH3:23])([CH3:16])[CH3:11]
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: CC(C)=CB1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CC(C)=Cc1ccc([N+](=O)[O-])cc1C(C)(C)C
Temperature: 90 °C
Reaction time: 20 h
Yield: 162.9 %

Procedure:
A mixture of 1-iodo-4-nitrobenzene (2.49 g, 10.0 mmol), 4,4,5,5-tetramethyl-2-(2-methylprop-1-enyl)-1,3,2-dioxaborolane (1.82 g, 10.0 mmol), sodium bicarbonate (2.52 g, 30.0 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (816 mg, 1.0 mmol) in dioxane/water (5:1, 60 mL) was stirred at 90° C. for 20 h under N2. LCMS and TLC monitored the reaction was completed. The reaction mixture was cooled to RT and concentrated. The residue was dissolved in 100 mL of EtOAc, washed with water (150 mL×3) and brine, dried over Na2SO4, filtered and concentrated under vacuo. The crude product was purified by silica gel column, eluting with PE:EA (6:1), to obtain the desired product (1.9 g, 100% yield) as a yellow oil, 1H-NMR (400 MHz, CDCl3) δ ppm 8.17 (d, 2H, J=8.8 Hz), 7.35 (d, 2H, J=8.8 Hz), 6.36 (s, 1H), 1.96 (d, 3H, J=0.4 Hz), 1.90 (d, 3H, J=0.4 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@@H:14]([CH3:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)OCC(C)C.[NH2:25][C:26]1[CH:30]=[C:29]([Br:31])[S:28][C:27]=1[C:32]([NH2:34])=[O:33].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[Br:31][C:29]1[S:28][C:27]([C:32](=[O:33])[NH2:34])=[C:26]([NH:25][C:10]([C@@H:9]2[CH2:13][C@H:14]([CH3:16])[CH2:15][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:12])[CH:30]=1
Reactant: C[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NC(=O)c1sc(Br)cc1N
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H]1C[C@@H](C(=O)Nc2cc(Br)sc2C(N)=O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
To a solution of (4S)-1-(tert-butoxycarbonyl)-4-methyl-L-proline (491 mg) and triethylamine (0.353 mL) in tetrahydrofuran (5 mL) was added 2-methylpropyl chlorocarbonate (0.292 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. Thereafter, to the reaction system was added 3-amino-5-bromothiophene-2-carboxamide (225 mg) produced in Example 1, step D, and the mixture was stirred at 60° C. for 24 hr. Ethyl acetate (20 mL) and aqueous sodium hydrogen carbonate (10 mL) were added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate (5 mL). The combined organic layers were washed with brine (5 mL) and dried over anhydrous sodium sulfate. Insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was crystallized from ethanol (5 mL). The obtained colorless solid was fractionated by high performance liquid chromatography (column: CHIRALPAK AD (50 mm i.d.×500 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (850/150), flow rate: 80 mL/min, column temperature: 30° C.) to give the title compound (302 mg) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:33][C:34]1[CH:35]=[CH:36][C:37]([N:43]2[N:47]=[CH:46][CH:45]=[N:44]2)=[C:38]([CH:42]=1)[C:39](O)=[O:40].S1C=CC=C1C1C=CC=CC=1C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[C:3]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][N:14]([C:39]([C:38]4[CH:42]=[C:34]([F:33])[CH:35]=[CH:36][C:37]=4[N:43]4[N:47]=[CH:46][CH:45]=[N:44]4)=[O:40])[CH2:15]3)[CH2:10]2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Reactant: Cc1cnc(C)c(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Solvent: ClCCl
Product: Cc1cnc(C)c(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4-n4nccn4)C[C@@H]32)n1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-8-(3,6-Dimethyl-pyrazin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane (Intermediate 10) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 5-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 13) for 2-thiophen-2-yl-benzoic acid. DCM was used in place of DMF. MS (ESI) mass calcd. For C21H22FN7O, 407.45; m/z found 408.2 [M+H]+. 1H NMR (CD3OD): 8.05-7.84 (m, 2H), 7.66-7.24 (m, 4H), 4.59-3.44 (m, 7H), 3.04-2.31 (m, 6H), 2.09-2.96 (m, 3H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:35][O:36][CH2:37][CH2:38]Br.[OH-].[Na+]>CN(C=O)C>[CH3:35][O:36][CH2:37][CH2:38][N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:6][CH2:7]1
Reactant: COCCBr
Reactant: Clc1ccc(-c2n[nH]c(C3CCNCC3)c2-c2ccncc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCN1CCC(c2[nH]nc(-c3ccc(Cl)cc3)c2-c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a stirred suspension of 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole hydrochloride (Example C-74) (500 mg, 1.2 mmol) in 12 mL of DMF was added Hunig's base (790 mg, 6.1 mmol) and 2-bromoethyl methyl ether (850 mg, 6.1 mmol). The solution was stirred at room temperature for 5 days. The solution was poured onto 2.5 N NaOH and was extracted with ethyl acetate (3×100 mL). The combined extracts were washed with water (3×100 mL) and brine (1×100 mL). The organic phase was dried over Na2SO4 and was filtered. The solvent was removed under reduced pressure to leave a solid. The solid was triturated and filtered to leave the title compound: 1HNMR (CDCl3) δ 8.63 (d, J=4.23 Hz, 2H), 7.28 (m, 4H), 7.14 (d, J=4.43 Hz, 2H), 3.57 (t, J=5.24 Hz, 2H), 3.38 (s, 3H), 3.14 (bd, J=10.1 Hz, 2H), 2.79 (m, 1H), 2.68 (t, J=5.04, 2H), 2.08 (m, 4H, 1.92 (m, 2H). MS (M+H): 397 (base peak).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[CH:8]=[C:7]([N+:9]([O-])=O)[N:6]=[N:5]1.[Cl-].[NH4+].CO>[Zn].O1CCCC1>[CH3:1][O:2][CH2:3][N:4]1[CH:8]=[C:7]([NH2:9])[N:6]=[N:5]1
Reactant: COCn1cc([N+](=O)[O-])nn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: COCn1cc(N)nn1
Reaction time: 18 h
Yield: 79.6 %

Procedure:
1-(methoxymethyl)-4-nitro-1H-1,2,3-triazole (5.517 g, 34.891 mmol), zinc powder (22.697 g, 349.185 mmol) and ammonium chloride (18.678 g, 349.187 mmol) were added successively into a mixed solvent of methanol (100 mL) and tetrahydrofuran (100 mL), and stirred for 18 hours. The insoluble was removed by suction filtration. After concentration, 1-(methoxymethyl)-4-amino-1H-1,2,3-triazole was obtained as 3.56 g of a brown-yellow oil, at a yield of 79.6%.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:13][OH:14].[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:13][O:14][C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1
Reactant: OCc1cc(Cl)cc(Cl)c1
Reactant: CSc1nsc(Cl)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nsc(OCc2cc(Cl)cc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
Into 4 ml of N,N-dimethylformamide were dissolved 334 mg of 5-chloro-3-methylthio-1,2,4-thiadiazole and 389 mg of 3,5-dichlorobenzyl alcohol, 96 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 0.5 hour under ice-cooling and for 4 hours at room temperature. The reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with t-butyl methyl ether. The organic layer was concentrated, and the residue obtained was subjected to silica gel column chromatography to give 380 mg of 5-(3,5-dichlorobenzyloxy)-3-methylthio-1,2,4-thiadiazole (hereinafter, referred to as the present compound (28)).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].C1(S(O[C@H:26]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH3:27])(=O)=O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].CC(CC)=O>O>[N+:13]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[O:1][C@@H:26]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH3:27])[C:6]([O:8][CH2:9][CH3:10])=[O:7])([O-:15])=[O:14]
Reactant: CCOC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: CCCCCC[C@H](C)OS(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCCCCC[C@@H](C)Oc1ccc(C(=O)OCC)cc1[N+](=O)[O-]
Yield: 91.4 %

Procedure:
A mixture of 4 g of ethyl 4-hydroxy-3-nitrobenzoate, 5.4 g of (S)-2-octyl benzenesulphonate 6.9 g of potassium carbonate and 110 ml of ethyl methyl ketone was heated to reflux overnight. Subsequently, the cooled reaction mixture was poured into water and extracted three times with 50 ml of diethyl ether each time. The combined organic phases were washed with 500 ml of water, dried over magnesium sulphate, filtered and concentrated. Chromatography of the residue on silica gel with dichloromethane gave 5.6 g of ethyl 3-nitro-4-[(R)-2-octyloxy)benzoate as of a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:14]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=3)[N:19]=[C:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[C:17]=2[CH3:33])[OH:15])[CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.C([Sn]([C:47]#[N:48])(CCCC)CCCC)CCC>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].CN1C(=O)CCC1>[F:26][C:22]1[CH:21]=[C:20]2[C:25]([C:16]([CH:14]([OH:15])[C:4]3[CH:3]=[C:2]([CH:7]=[C:6]([N:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)[CH:5]=3)[C:47]#[N:48])=[C:17]([CH3:33])[C:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[N:19]2)=[CH:24][CH:23]=1
Reactant: CCCC[Sn](C#N)(CCCC)CCCC
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1C(O)c1cc(Cl)cc(N2CCOCC2)c1
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: NCCc1[c-]cccc1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1C(O)c1cc(C#N)cc(N2CCOCC2)c1

Procedure:
A solution of (3-chloro-5-morpholinophenyl)(7-fluoro-3-methyl-2-(pyridin-2-yl)-quinolin-4-yl)methanol (0.050 g, 0.108 mmol), tributyltin cyanide (0.034 g, 0.108 mmol), XPhos precatalyst (CAS 1028206-56-5; 0.014 g, 0.022 mmol), and NMP (1.0 mL) was heated in a microwave at 150° C. for 2 h. Upon completion, the reaction mixture was partitioned between EtOAc and water, and the organic phase was dried over magnesium sulfate and concd. This afforded a crude material that was purified by column chromatography (silica; 0-100% EtOAc in hexanes) to yield 3-((7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yl)(hydroxy)methyl)-5-morpholinobenzonitrile as an amorphous beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.70 (1H, d), 8.31 (1H, m), 8.01 (1H, d, J=1.8 Hz), 7.83 (1H, d, J=7.8 Hz), 7.72 (1H, d), 7.51 (1H, m), 7.41 (1H, m), 7.33 (1H, s), 7.24 (1H, s), 6.85 (1H, s), 6.75 (1H, d, J=4.3 Hz), 6.59 (1H, d), 3.71 (4H, t, J=4.8 Hz), 3.14 (4H, q, J=4.4 Hz), 2.46 (3H, s). Mass Spectrum (ESI) m/e=455.0 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3]/[CH:4]=[CH:5]/[CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:8].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].O>C(Cl)Cl>[CH3:31][S:32]([O:1][CH2:2][CH2:3]/[CH:4]=[CH:5]/[CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:23])=[O:8])(=[O:34])=[O:33]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)C/C=C/CCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)C/C=C/CCOS(C)(=O)=O
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
To a solution of (E)-tert-butyl 2-(6-hydroxyhex-3-enamido)phenylcarbamate (10) (398 mg, 1 mmol) and triethylamine (151.5 mg, 1.5 mmol) in DCM (10 mL) was added methanesulfonyl chloride (127.6 mg, 1.1 mmol) at 0° C. and stirred for 0.5 hour, then the reaction was stirred at room temperature for 1 hr, then water (10 mL) was added, the mixture was extracted with DCM (3×20 mL), the combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give the desired compound of (E)-6-(2-(tert-butoxycarbonylamino)phenylamino)-6-oxohex-3-enyl methanesulfonate (358 mg, yield 90%) as oil after purification by column chromatography (eluent: PE:EA=10:1). LC-MS found 399 (M+H)+.