Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:49][OH:50])=[C:7]([CH:48]=1)[C:8]([O:10][C@:11]([C:40]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=1[F:47])([CH2:34][N:35]1[CH:39]=[N:38][CH:37]=[N:36]1)[C@H:12]([S:14][C@@H:15]1[CH2:20][O:19][C@@H:18](/[CH:21]=[CH:22]/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:26]=2[F:33])[O:17][CH2:16]1)[CH3:13])=[O:9])#[N:2].[CH3:51][N:52]1[CH2:57][CH2:56][N:55]([C:58](=[O:64])[CH2:59][CH2:60][C:61](O)=[O:62])[CH2:54][CH2:53]1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:49][O:50][C:61](=[O:62])[CH2:60][CH2:59][C:58]([N:55]2[CH2:54][CH2:53][N:52]([CH3:51])[CH2:57][CH2:56]2)=[O:64])=[C:7]([CH:48]=1)[C:8]([O:10][C@:11]([C:40]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=1[F:47])([CH2:34][N:35]1[CH:39]=[N:38][CH:37]=[N:36]1)[C@H:12]([S:14][C@@H:15]1[CH2:16][O:17][C@@H:18](/[CH:21]=[CH:22]/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:26]=2[F:33])[O:19][CH2:20]1)[CH3:13])=[O:9])#[N:2]
Reactant: CN1CCN(C(=O)CCC(=O)O)CC1
Reactant: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@@](Cn1cncn1)(OC(=O)c1cc(C#N)ccc1CO)c1ccc(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@@](Cn1cncn1)(OC(=O)c1cc(C#N)ccc1COC(=O)CCC(=O)N1CCN(C)CC1)c1ccc(F)cc1F
Reaction time: 2 h

Procedure:
A solution of (1R,2R)-2-[[trans-2-[(1E,3E)-4-(4-cyano-2-fluorophenyl)-1,3-butadienyl]-1,3-dioxan-5-yl]thio]-1-(2,4-difluorophenyl)-1-[(1H-1,2,4-triazol-1-yl)methyl]propyl 5-cyano-2-(hydroxymethyl)benzoate (1.38 g, 1.97 mmol) obtained from Example 33 in dichloromethane (40 ml) was cooled to 0° C., and 4-(N,N-dimethylamino)pyridine (481.3 mg, 3.94 mmol), 4-(4-methyl-1-piperazinyl)-4-oxobutanoic acid (described in Bioorg. Med. Chem., 8, 2693 (2000); 708.0 mg, 3.54 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (830.8 mg, 4.33 mmol) were added thereto. The reaction mixture was stirred at the same temperature for 2 hours, and diluted with dichloromethane, then the organic layer was washed successively with water and a saturated aqueous solution of sodium chloride. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to chromatography on a silica gel (30 g) column (eluent; ethyl acetate:methanol=4:1) to afford a mixture of the title compound and 4-(N,N-dimethylamino)pyridine (component ratio; 6:1, 1.33 g). A part (790.8 mg) of the mixture was separated by recycle preparative HPLC [LC-908; Japan Analytical Industry Co., Ltd.; GPC column JAIGEL-1H (20 mm i.d. ×600 mm) and JAIGEL-2H (20 mm i.d. ×600 mm) connected in series for use; solvent, chloroform] to afford the title target compound (763.0 mg, 44% yield) as a colorless amorphous solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:29])[NH:23][CH:24]2[CH2:27][N:26]([CH3:28])[CH2:25]2)[CH:17]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:30])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:29])[NH:23][CH:24]2[CH2:25][N:26]([CH3:28])[CH2:27]2)[CH:17]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)NC3CN(C)C3)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1CC(NC(=O)c2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)C1

Procedure:
A mixture of methyl 3,3-dimethyl-2-(3-(1-methylazetidin-3-ylcarbamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (100 mg, 0.25 mmol) in methanol (3.75 mL) and 1M sodium hydroxide aqueous solution (2.94 mL, 2.94 mmol) was heated to reflux for 1.5 h, LC-MS showed the reaction was complete and only the desired product formed. The solvent was concentrate in vacuo and the residue was dissolved in water and acidified with 1 M hydrochloric acid solution. The white precipitated solid was collected by filtration to afford 59 mg of 3,3-dimethyl-2-(3-(1-methylazetidin-3-ylcarbamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid was a white solid. Yield: 61.4%. MS (ESI+APCI) M+1=394.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([C:16]2[N:17]=[N:18][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([F:31])([F:30])[F:29])[CH:20]=2)[OH:15])=[CH:4][CH:3]=1.[CH2:32]([O:34][C:35]([C:37]1([C:40]2[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][CH:41]=2)[CH2:39][CH2:38]1)=[O:36])[CH3:33]>>[CH2:32]([O:34][C:35]([C:37]1([C:40]2[CH:45]=[CH:44][C:43]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:15])[C:16]4[N:17]=[N:18][N:19]([CH2:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[C:28]([F:30])([F:31])[F:29])[CH:20]=4)=[CH:6][CH:7]=3)=[CH:42][CH:41]=2)[CH2:38][CH2:39]1)=[O:36])[CH3:33]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cn(Cc2ccccc2C(F)(F)F)nn1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cn(Cc5ccccc5C(F)(F)F)nn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(2-trifluoromethyl-benzyl)-1H-[1,2,3]triazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:5][C:4]([CH3:15])([CH3:14])[NH:3]1.[CH2:17](Br)[CH:18]=[CH2:19]>C(Cl)(Cl)Cl>[CH2:19]([CH:7]1[C:2]([CH3:16])([CH3:1])[NH:3][C:4]([CH3:15])([CH3:14])[CH:5]=[C:6]1[N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH:18]=[CH2:17]
Reactant: CC1(C)C=C(N2CCCCC2)CC(C)(C)N1
Reactant: C=CCBr
Solvent: ClC(Cl)Cl
Product: C=CCC1C(N2CCCCC2)=CC(C)(C)NC1(C)C
Reaction time: 24 h

Procedure:
2.2 of the 1,2,5,6-tetrahydro-2,2,6,6-tetramethyl-4-piperidinopyridine thus obtained and 1.2 g of allyl bromide were dissolved in 3 ml of chloroform and the solution was allowed to stand for 24 hours at room temperature. The crystals which precipitated were filtered off, washed with hexane and dissolved in 4 ml of concentrated aqueous ammonia; the solution was then extracted with hexane. The extract was dried over potassium carbonate and, after removing the hexane, 1.3 g of 5-allyl-1,2,5,6-tetrahydro-2,2,6,6-tetramethyl-4-piperidinopyridine were obtained. The compound showed a single spot on thin layer chromatography using a 0.25 mm thick layer of alumina (available from Merck & Co. under the trade name "60F 254") and using a mixture of benzene/hexane/ethyl acetate/triethylamine (2 : 2 1 : 0.5 by volume) s developing solvent; the Rf value was 0.80.
Reaction SMILES: [CH2:1]([CH:3]([CH2:20][CH3:21])[CH:4]([C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:9]=[CH:8][CH:7]=1)O)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:67]=[N+:68]=[N-:69])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[N:67]([CH:4]([C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:9]=[CH:8][CH:7]=1)[CH:3]([CH2:20][CH3:21])[CH2:1][CH3:2])=[N+:68]=[N-:69]
Reactant: CCC(CC)C(O)c1ccnn1Cc1ccc(OC)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(CC)C(N=[N+]=[N-])c1ccnn1Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 65.5 %

Procedure:
To 2-ethyl-1-[1-(4-methoxybenzyl)-1H-pyrazol-5-yl]butan-1-ol (1.21 g, 4.20 mmol) in THF (40 mL) at 0° C. was added triphenylphosphine (1.65 g, 6.29 mmol), diethyl azodicarboxylate (1.0 mL, 6.3 mmol), and diphenylphosphoryl azide (1.4 mL, 6.3 mmol). The reaction mixture was warmed to room temperature and stirred for 15.5 h. The solvent was removed in vacuo and the resulting residue was purified by column chromatography (EtOAc/hexanes, 1:9, then 1:4) to give 0.862 g (66%) of 5-(1-azido-2-ethylbutyl)-1-(4-methoxybenzyl)-1H-pyrazole.
Reaction SMILES: Br[C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C(=O)([O-])[O-].[Na+].[Na+].[CH3:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1B(O)O.COCCOC>C(Cl)Cl.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.O.CCO>[F:10][C:3]1[C:2]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][C:18]=2[CH3:17])=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: N#Cc1cccc(Br)c1F
Reactant: Cc1ccncc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: Cc1ccncc1-c1cccc(C#N)c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.3 %

Procedure:
A reaction flask was charged with tetrakis(triphenylphosphine)palladium(0) (1.040 g, 0.900 mmol), 3-bromo-2-fluorobenzonitrile (3.6 g, 18.00 mmol), sodium carbonate (7.63 g, 72.0 mmol), and 4-methylpyridin-3-ylboronic acid (2.59 g, 18.90 mmol). The mixture was stirred at room temperature for 10 min under N2, then DME (67.2 mL), EtOH (33.6 mL), and water (33.6 mL) were added sequentially. The resultant mixture was heated at 90° C. overnight. After 17 hr, the reaction mixture was allowed to cool to room temperature. The reaction was quenched with water. The reaction mixture was diluted with EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (3×). The organic phases were combined, dried over Na2SO4, filtered, and concentrated to afford a brown residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (120 g column, 85 mL/min, 0-70% EtOAc in hexanes over 25 min, tr=15 min) gave the title compound (2.80 g, 13.19 mmol, 73.3% yield) as a purple residue. ESI MS (M+H)+=213.1. HPLC Peak tr=1.01 minutes. Purity >99%. HPLC Conditions: C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH2:4][OH:5].F[C:8]1[CH:13]=[C:12]([C:14]2[C:15]([C:26]3[O:27][CH:28]=[CH:29][CH:30]=3)=[N:16][C:17]([NH2:25])=[N:18][C:19]=2[C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[CH:11]=[CH:10][N:9]=1>CN(C)C=O>[NH2:25][C:17]1[N:16]=[C:15]([C:26]2[O:27][CH:28]=[CH:29][CH:30]=2)[C:14]([C:12]2[CH:11]=[CH:10][N:9]=[C:8]([O:5][CH2:4][CH2:3][OH:6])[CH:13]=2)=[C:19]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[N:18]=1
Reactant: Nc1nc(-c2ccco2)c(-c2ccnc(F)c2)c(-c2ccco2)n1
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc(-c2ccco2)c(-c2ccnc(OCCO)c2)c(-c2ccco2)n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 36.3 %

Procedure:
In a reaction vessel, sodium hydride (15 mg, 0.372 mmol) was suspended in N,N-dimethylformamide (4 ml) and ethylene glycol (23 mg, 0.372 mmol) was added thereto, followed by stirring at 80° C. for 30 minutes under an atmosphere of nitrogen gas. Subsequently, 5-(2-fluoro-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine (100 mg, 0.310 mmol) was added thereto, followed by stirring for 14 hours under the same conditions. Then, the reaction was terminated by adding water thereto. The reaction mixture was extracted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and then the filtrate was concentrated. The resulting crude product was purified by silica gel column chromatography, to give the title compound (41 mg, 36%) as a pale yellow solid.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Br:19])C(=O)C1.O>CN(C=O)C>[Br:19][C:11]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][NH:9][CH:10]=1
Reactant: c1ccc(-c2cc[nH]n2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Brc1c[nH]nc1-c1ccccc1
Yield: 92.5 %

Procedure:
A solution of 3-phenyl-1H-pyrazole (4.08 g, 28.3 mmol) and NBS (5.04 g, 28.3 mmol) in DMF (40 mL) was stirred for 1 h at room temperature. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from hexane/AcOEt to give the title compound (5.84 g, 93% yield) as a white solid: mp 114-116° C.; NMR (300 MHz, CDCl3): δ ppm 7.39-7.50 (31-1, m), 7.64 (1H, s), 7.77 (2H, d, J=6.8 Hz), 10.73 (1H, brs).
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:3][CH2:4][N:5](S(C2C=CC(C)=CC=2)(=O)=O)[C:6]2[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=2/[C:8]/1=[CH:9]/[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)=[O:11].[OH-].[Na+]>S(=O)(=O)(O)O>[F:33][C:2]1([F:1])[CH2:3][CH2:4][NH:5][C:6]2[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=2/[C:8]/1=[CH:9]/[C:10]([N:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]1)=[O:11]
Reactant: Cc1ccc(S(=O)(=O)N2CCC(F)(F)/C(=C\C(=O)N3CCN(C)CC3)c3ccccc32)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CN1CCN(C(=O)/C=C2/c3ccccc3NCCC2(F)F)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.4 %

Procedure:
(Z)-4,4-Difluoro-5-[2-(4-methylpiperazin-1-yl)-2-oxoethylidene]-1-tosyl-2,3,4,5-tetrahydro-1H-1-benzoazepine (11.7 g) was dissolved in 20 ml of concentrated sulfuric acid, followed by stirring for 24 hours at room temperature. The reaction solution was poured over 700 ml of a 1N aqueous solution of sodium hydroxide and extracted with chloroform. The organic layer was washed with a saturated aqueous solution of NaCl, and after drying over magnesium sulfate, the solvent was evaporated off. The resulting residue was crystallized from diethyl ether to give 7.62 g of (Z)-4,4-difluoro-5-[2-(4-methylpiperazin-1-yl)-2-oxoethylidene]-2,3,4,5-tetrahydro-1H-1-benzoazepine as a colorless powder.
Reaction SMILES: [O:1]([CH:8]([CH3:12])[C:9](=O)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C(OCC)=O.C(OC(=O)C(=O)CC(=O)COC1C=CC=CC=1)C.C(OC(C1NN=C(COC2C=CC=CC=2)C=1)=O)C.C(OC([C:64]1[N:65]([CH2:77][CH:78]([NH:80][C:81](OC(C)(C)C)=O)C)[N:66]=C(COC2C=CC=CC=2)C=1)=O)C.CC1CN2N=C(COC3C=CC=CC=3)C=C2C(=O)N1.CC1CN2N=C(COC3C=CC=CC=3)C=C2CN1>>[O:1]([CH:8]([C:9]1[CH:10]=[C:64]2[CH2:81][NH:80][CH2:78][CH2:77][N:65]2[N:66]=1)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(COc2ccccc2)nn1CC(C)NC(=O)OC(C)(C)C
Reactant: CC(=O)C(C)Oc1ccccc1
Agent: CC1Cn2nc(COc3ccccc3)cc2C(=O)N1
Agent: CC1Cn2nc(COc3ccccc3)cc2CN1
Agent: CCOC(=O)C(=O)CC(=O)COc1ccccc1
Solvent: CCOC(=O)C(=O)OCC
Product: CC(Oc1ccccc1)c1cc2n(n1)CCNC2

Procedure:
The compound was prepared from 3-phenoxy-butan-2-one and diethyl oxalate using the methods described in the preceding examples 9 (2,4-dioxo-5-phenoxy-pentanoic acid ethyl ester), 10 (5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester), 11 (rac-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester), 12 (rac-6-methyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one), and 13 (rac-6-methyl-2-phenoxymethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([C@@H:15]3[CH2:17][C@H:16]3[C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]4[C:26]=3I)[CH:9]=2)[N:3]=1.[F-].[Cs+].[CH2:30]([Sn](CCCC)(CCCC)C=C)[CH2:31]CC>CCOC(C)=O>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([C@@H:15]3[CH2:17][C@H:16]3[C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]4[C:26]=3[CH:30]=[CH2:31])[CH:9]=2)[N:3]=1
Reactant: Cc1nc([C@@H]2C[C@H]2c2nc3ccccn3c2I)cc(-n2nc(C)nc2C)n1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Product: C=Cc1c([C@@H]2C[C@H]2c2cc(-n3nc(C)nc3C)nc(C)n2)nc2ccccn12
Temperature: 80 °C

Procedure:
To Example 8 (0.11 g, 0.23 mmol), cesium fluoride (0.14 g, 0.93 mmol) and bis(tri-t-butylphosphine)palladium(O) (18 mg, 0.04 mmol) under nitrogen was added degassed dioxane (2.3 mL) followed by tributyl(vinyl)stannane (0.30 mg, 0.93 mmol). The reaction was heated at 80° C. for 2 h and, after cooling to room temperature, was diluted with EtOAc (10 mL). The organic layer was washed with saturated aqueous sodium carbonate (2×10 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-100% EtOAc/hexanes) to give Example 10. 1H NMR (500 MHz, CDCl3) δ 8.17 (d, J=7.0 Hz, 1H), 7.60 (s, 1H), 7.55 (d, J=9.2 Hz, 1H), 7.21-7.17 (m, 1H), 6.93-6.82 (m, 2H), 5.63 (d, J=18.1 Hz, 1H), 5.43 (d, J=12.1 Hz, 1H), 2.93-2.87 (m, 1H), 2.89 (s, 3H), 2.74-2.70 (m, 1H), 2.67 (s, 3H), 2.39 (s, 3H), 2.00-1.92 (m, 2H) ppm; MS: m/z=372.3 (M+H).
Reaction SMILES: [PH4+].[Li]CCCC.[O:7]1[CH2:12][CH2:11][CH2:10][C:9](=O)[CH2:8]1.[CH2:14]1C[O:17][CH2:16][CH2:15]1>>[O:7]1[CH2:12][CH2:11][CH2:10][C:9](=[CH:14][CH2:15][CH2:16][OH:17])[CH2:8]1
Reactant: O=C1CCCOC1
Reactant: C1CCOC1
Agent: [Li]CCCC
Agent: [PH4+]
Product: OCCC=C1CCCOC1
Reaction time: 1 h
Yield: 69 %

Procedure:
To a suspension of the phosphonium salt (69 g, 1.5 eg) in dry THF (1100 mL) at 0° C. under nitrogen atmosphere was added n-BuLi (2.5 M, 111 mL, 0.413 mol). The solution was stirred for 1 hr, followed by addition of dihydro-2H-pyran-3(4H)-one (11.5 g, 0.115 mol). Stirring was continued at rt overnight. The mixture was quenched by sat. aq. NH4Cl, and then filtered. The filtrate was dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified through column chromatography to give 3-(dihydro-2H-pyran-3(4H)-ylidene)propan-1-ol (11.2 g, 69%). 1H NMR (CD3OD) δ 4.2-3.9 (d, 2H), 3.8-3.5 (m, 4H), 2.4-2.2 (m, 4H), 5.3-5.2 (d, 1H), 2.1-1.8 (s, 1H), 1.8-1.6 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[C:6]([F:8])[CH:7]=1.C([Li])CCC.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[N:25]2[CH2:28][C:27](=O)[CH2:26]2)=[CH:20][CH:19]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O>C1COCC1.CN(C)C1C=CN=CC=1.CCOCC>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([CH:24]([C:21]2[CH:20]=[CH:19][C:18]([Cl:17])=[CH:23][CH:22]=2)[N:25]2[CH2:28][C:27](=[C:9]([C:4]3[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=3)[C:10]#[N:11])[CH2:26]2)=[CH:31][CH:32]=1
Reactant: N#CCc1cc(F)cc(F)c1
Reactant: O=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: [Li]CCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#CC(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 540 mg (3.53 mmol) of 3,5-difluorophenylacetonitrile in 8 mL of THF a solution of 1.41 mL (3.53 mmol) of butyllithium (2.5M solution in hexanes) was added and it was stirred for 30 minutes at −78° C. Then a solution of 985 mg (3.21 mmol) of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one (1) in THF was added and it was stirred for 3 h at −78° C. Then 510 mg (4.17 mmol) of 4-dimethylaminopyridine, 840 uL (4.82 mmol) of N,N-diisopropylethylamine and 558 uL (7.06 mmol) of methanesulfonyl chloride was added and it was stirred at −78° C. to rt overnight. The solution was poured into 80 mL of ether and washed with 10 mL of aq NaHCO3. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate=9:1 to afford the title compound; 1NMR (CDCl3) δ 3.84 (m, 2H), 4.25 (m, 2H), 4.54 (s, 1H), 6.76 (m, 1H), 6.78 (m, 2H), 7.33 (m, 3H), 7.38 (m, 2H); Mass Spectrum: m/e=430 (M+1 35Cl, 35Cl) and 432 (M+1 35Cl, 37Cl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][N:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:12]([C:14]23[CH2:23][CH:18]4[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]4)[CH2:15]2)[CH2:21]3)=O)[CH:6]=[CH:7][CH:8]=1>CCOC(C)=O>[C:14]12([CH:12]3[C:6]4[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[CH2:9][CH2:10][N:11]3[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:15][CH:16]3[CH2:17][CH:18]([CH2:19][CH:20]([CH2:22]3)[CH2:21]1)[CH2:23]2
Reactant: COc1cccc(CCN(C(=O)C23CC4CC(CC(C4)C2)C3)c2ccccc2)c1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)CCN(c1ccccc1)C2C12CC3CC(CC(C3)C1)C2

Procedure:
The title compound was prepared by analogy to Preparation 65 except that adamantane-1-carboxylic acid [2-(3-methoxy-phenyl)-ethyl]-phenyl-amide was used instead of 4-methoxy-N-[2-(3-methoxy-phenyl)-ethyl]-N-phenyl-benzamide, and the final residue was subjected to flash chromatography using hexanes:EtOAc from 20:1 to 10:1.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][CH2:14][C@H:15]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH:17]([CH3:19])[CH3:18].C(=O)([O-])O.[Na+]>C1COCC1>[CH3:8][S:9]([O:13][CH2:14][C@H:15]([NH:20][C:21]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:27])[CH2:16][CH:17]([CH3:19])[CH3:18])(=[O:11])=[O:10]
Reactant: CC(C)C[C@H](CO)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)C[C@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
Triethylamine (59 ml) and methanesulfonylchloride (25 ml) were added to a THF solution (200 ml) containing (R)-tert-butyl (1-hydroxy-4-methylpentan-2-yl)carbamate (46.2 g) in an ice bath, followed by stirring for 0.5 hours. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate and the solvent was distilled away under reduced pressure. A white solid of (R)-2-((tert-butoxycarbonyl)amino)-4-methylpentyl methanesulfonate (60 g) was thus obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][N:3]=1.[O:7]1[C:11]2([CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1>CCOCC>[CH3:1][C:2]1[CH:6]=[C:5]([C:14]2([OH:17])[CH2:15][CH2:16][C:11]3([O:10][CH2:9][CH2:8][O:7]3)[CH2:12][CH2:13]2)[S:4][N:3]=1
Reactant: Cc1ccsn1
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: CCOCC
Product: Cc1cc(C2(O)CCC3(CC2)OCCO3)sn1

Procedure:
The title compound was prepared as a white solid from 3-methyl-isothiazole (Focus Synthesis) and 1,4-dioxa-spiro[4.5]decan-8-one in ether using the procedure described in Step A of Example 33.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12](=O)[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[C:7]([CH:11]=1)[C:8](O)=[O:9].O.[NH2:25][NH2:26]>>[CH3:1][O:2][C:3]1[CH:11]=[C:7]2[C:6]([C:12]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)=[N:25][NH:26][C:8]2=[O:9])=[CH:5][CH:4]=1
Reactant: NN
Reactant: COc1ccc(C(=O)c2ccc(C(F)(F)F)cc2)c(C(=O)O)c1
Solvent: O
Product: COc1ccc2c(-c3ccc(C(F)(F)F)cc3)n[nH]c(=O)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting 5-methoxy-2-(4-trifluoromethylbenzoyl)benzoic acid unpurified with hydrazine hydrate.