Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[CH3:7][CH:8]1[CH:12]([CH3:13])[O:11][C:10]([C:14]2([C:20]3[CH:21]=[C:22]([S:26][C:27]4[CH:32]=[CH:31][C:30]([N:33]5[C:37](=O)[NH:36][C:35]([CH3:39])=[N:34]5)=[CH:29][CH:28]=4)[CH:23]=[CH:24][CH:25]=3)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[N:9]1.CI>CN(C)C=O>[CH3:7][CH:8]1[CH:12]([CH3:13])[O:11][C:10]([C:14]2([C:20]3[CH:21]=[C:22]([S:26][C:27]4[CH:28]=[CH:29][C:30]([N:33]5[C:1](=[O:4])[N:36]([CH3:37])[C:35]([CH3:39])=[N:34]5)=[CH:31][CH:32]=4)[CH:23]=[CH:24][CH:25]=3)[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[N:9]1
Reactant: O=C([O-])[O-]
Reactant: Cc1nn(-c2ccc(Sc3cccc(C4(C5=NC(C)C(C)O5)CCOCC4)c3)cc2)c(=O)[nH]1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1nn(-c2ccc(Sc3cccc(C4(C5=NC(C)C(C)O5)CCOCC4)c3)cc2)c(=O)n1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Solid potassium carbonate (4.5 mmol) is added to a solution of 2-[4-({3-[4-(4,5-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)tetrahydro-2H-pyran-4-yl]phenyl}thio)phenyl]-5-methyl-2,4-dihydro-3H-1,2,4-traizol-3-one (1.0 mmol) (example 21) in dry dimethylformamide. The reaction mixture is stirred a room temperature for about 15 minutes. Methyl iodide (3.0 mmol) is added and the reaction mixture is heated at about 100° C. for about 12 hours. The solvent is evaporated under vacuum, water is added and the reaction mixture is extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous sodium sulphate, filtered and the solvent is evaporated to afford the residue. Column chromatography of the residue over silica gel affords the title compound.
Reaction SMILES: [CH2:1]([N:8]([CH2:14][C:15]1([OH:28])[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)[C:9]([CH3:13])([CH3:12])[CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.CS(OS(C)(=O)=O)(=O)=O>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[C:9]([CH3:13])([CH3:10])[CH2:12][O:28][C:15]2([CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:19][CH2:20]2)[CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CN(Cc2ccccc2)C(C)(C)CO)CC1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(Cc1ccccc1)C(C)(C)CO2
Temperature: 65 °C
Yield: 28.3 %

Procedure:
To a solution of tert-butyl 4-[[benzyl-(2-hydroxy-1,1-dimethyl-ethyl)amino]methyl]-4-hydroxy-piperidine-1-carboxylate (330 mg, 0.841 mmol) in tetrahydrofuran was added N,N-diisopropylethylamine (439 μL, 2.52 mmol) and methanesulfonic anhydride (439 mg, 2.52 mmol) under a nitrogen atmosphere. The reaction mixture was heated at 65° C. for 18 h. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate (2×50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-80% of ethyl acetate/hexanes) to provide tert-butyl 8-benzyl-9,9-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (89 mg, 28%) as white solid. ESI-MS m/z calc. 374.5. found 375.3 (M+1)+; Retention time: 1.30 minutes (3 min run).
Reaction SMILES: [C:1]([C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].[Cl:12][C:13]1[CH:14]=[C:15]([NH:27][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31](I)[CH:30]=2)[CH:16]=[CH:17][C:18]=1[CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1>>[Cl:12][C:13]1[CH:14]=[C:15]([NH:27][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([C:2]#[C:1][C:3]3[N:7]4[N:8]=[CH:9][CH:10]=[CH:11][C:6]4=[N:5][CH:4]=3)[CH:30]=2)[CH:16]=[CH:17][C:18]=1[CH2:19][N:20]1[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]1
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(Cl)c2)cc1I
Reactant: C#Cc1cnc2cccnn12
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(Cl)c2)cc1C#Cc1cnc2cccnn12

Procedure:
The title compound was synthesized according to Example 14, from 3-ethynylimidazo[1,2-b]pyridazine and N-(3-chloro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-iodo-4-methylbenzamide. The product was obtained as a solid: 499 m/z (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH:14]=2)[CH2:9][CH2:8]1.[C:30](=S)=[S:31]>ClCCl.CO>[Cl:22][C:18]1[CH:17]=[C:16]2[C:21]([C:13]([CH:10]3[CH2:11][CH2:12][N:7]([CH2:6][CH2:5][N:4]4[CH2:3][CH2:2][NH:1][C:30]4=[S:31])[CH2:8][CH2:9]3)=[CH:14][N:15]2[C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)=[CH:20][CH:19]=1
Reactant: NCCNCCN1CCC(c2cn(-c3ccc(F)cc3)c3cc(Cl)ccc23)CC1
Reactant: S=C=S
Solvent: ClCCl
Solvent: CO
Product: Fc1ccc(-n2cc(C3CCN(CCN4CCNC4=S)CC3)c3ccc(Cl)cc32)cc1
Reaction time: 1 h

Procedure:
To a solution of compound 11a (4.5 g) in dichloromethane/methanol 1:1 (100 ml) was added 5 ml of carbondisulfide. The mixture was left at room temperature for one hour. Then the solvents were evaporated and finally the remaining viscous oil was heated at 130°-140° C. in solution in 1-pentanol. When the evolution of H2S had ceased the solvents were evaporated. The resulting oil was purified by column chromatography on silica gel (eluted with ethyl acetate/methanol 1:1) yielding 2 g of the title compound 12a as a crystalline base. Mp: 184°-186° C.
Reaction SMILES: Br[C:2]1[CH:19]=[C:18]([Cl:20])[C:5]([CH2:6][N:7]2[CH2:11][CH2:10][C:9]3([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:8]2=[O:17])=[C:4]([Cl:21])[CH:3]=1.[CH3:22][O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.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>[CH3:22][O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:19]=[C:18]([Cl:20])[C:5]([CH2:6][N:7]3[CH2:11][CH2:10][C:9]4([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]4)[C:8]3=[O:17])=[C:4]([Cl:21])[CH:3]=2)=[CH:28][CH:27]=1)=[O:25]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: O=C1N(Cc2c(Cl)cc(Br)cc2Cl)CCC12CCCCC2
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: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2cc(Cl)c(CN3CCC4(CCCCC4)C3=O)c(Cl)c2)cc1
Temperature: 90 °C
Yield: 63.5 %

Procedure:
Purge with N2 a mixture of 2-(4-bromo-2,6-dichloro-benzyl)-2-aza-spiro[4.5]decan-1-one (0.14 g, 0.36 mmol) and 4-methoxycarbonyl phenylboronic acid (0.19 g, 1.05 mmol) in toluene (10 mL) and 2M sodium carbonate (1.25 mL). Treat the reaction with Pd(PPh3)4 (0.041 g, 0.035 mmol) and heat to 90° C. for 4 hours under N2. Cool the reaction and dilute with ethyl acetate, and then wash with 1N HCl and water. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford crude product. Purify with a 0 to 100% ethyl acetate in hexanes gradient on silica gel to afford 0.102 g (64%) of the titled product. Rf=0.51 (1/1 hexanes/ethyl acetate). MS (m/z): 446
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:10]([CH2:20][OH:21])[CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:29])C(=O)C1.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>CC#N.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C@H:10]([CH2:20][OH:21])[CH2:9]2)=[CH:4][C:3]=1[Br:29]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1C[C@@H](c2ccc(N)nc2)C[C@H]1CO
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H](c2cnc(N)c(Br)c2)C[C@H]1CO
Reaction time: 0.17 h
Yield: 99.4 %

Procedure:
A solution of (2S,4R)-tert-butyl 4-(6-aminopyridin-3-yl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (230 mg, 0.784 mmol) in MeCN (10 mL) was treated with NBS (147 mg, 0.823 mmol). After 10 min, the reaction was complete. The reaction was treated with 10 mL 1:1 sat. aq. NaHCO3:sat.aq. Na2S2O3 and the mixture was stirred vigorously for 10 min. The mixture was diluted with ethyl acetate (30 mL) and the layers were separated. The organics were washed with brine, dried over magnesium sulfate and concentrated to provide (2S,4R)-tert-butyl 4-(6-amino-5-bromopyridin-3-yl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (290 mg, 100% yield). LCMS (m/z): 372.1/374.0 (MH+), 0.55 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:32])[C@H:13]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:14]C(OCC1C=CC=CC=1)=O)([CH3:4])([CH3:3])[CH3:2].[ClH:34]>O1CCCC1.[Pd]>[ClH:34].[C:1]([O:5][C:6](=[O:33])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:32])[C@@H:13]([CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[NH2:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)[C@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 106.3 %

Procedure:
To a well-stirred, nitrogen-blanketed mixture of benzyloxycarbonyl-L-phenylalanyl-L-proline tert-butyl ester (23.00 g, 50.82 mmol) and 1[hydrochloric acid (51 mL, 51 mmol) in tetrahydrofuran (500 mL) was added 10% palladium on carbon (2.3 g). The suspension was stirred at ambient temperature for about 5 minutes before the nitrogen blanket was removed and replaced with hydrogen at one atmosphere. After about 5 hours, the suspension was suction-filtered through Celite and the filtrate was concentrated down to dryness to afford 19.17 g (100%) of the title compound as a dense, white solid, m.p. 168°-170° C.; 1H NMR (D2O) δ 7.41-7.38 (m, 3H), 7.28-7.26 (m, 2H), 4.56-4.51 (m, 1H), 4.20-4.16 (m, 1H), 3.53-3.46 (m, 1H), 3.27-3.21 (m, 1H), 3.14-3.07 (m, 1H), 2.72-2.64 (m, 1H), 2.05-1.65 (m, 4H), 1.58-1.49 (m, 1H), 1.45 (s, 9H); 13C NMR (D2O) ppm 174.85, 169.57, 135.40, 131.49, 131.10, 130.16, 86.09, 62.33, 54.82, 51.95, 49.51, 38.59, 30.63, 29.11, 25.88; IR (KBr, cm-1) 3242, 2980 , 2930, 2874, 1750, 1730, 1658, 1524, 1488, 1452, 1366, 1150; MS m/z (MH+ -HCl) calcd 319.2022, obsd 319.2013.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[CH:10]1[CH2:18][C:17]2[NH:16][N:15]=[C:14]([CH3:19])[C:13]=2[C:12](=O)[CH2:11]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl.O>C(O)C>[ClH:2].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[CH:10]1[CH2:18][C:17]2[NH:16][N:15]=[C:14]([CH3:19])[C:13]=2[C:12](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:11]1
Reactant: N=C(N)NN
Reactant: Cc1n[nH]c2c1C(=O)CC(c1cc(Cl)ccc1Cl)C2
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1n[nH]c2c1C(=NNC(=N)N)CC(c1cc(Cl)ccc1Cl)C2
Yield: 186.6 %

Procedure:
To a solution of 6-(2,5-dichlorophenyl)-3-methyl-4,5,6,7-tetrahydroindazol-4-one hydrochloride (1.1 g), aminoguanidine hydrochloride (0.49 g) in ethanol (30 ml) were added concentrated hydrochloric acid (0.9 ml) and water (0.9 ml), and the mixture was refluxed for 5 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate, and the aqueous layer was concentrated under reduced pressure. Precipitated crystals were recrystallized from ethanol-water to give 6-(2,5-dichlorophenyl)-4-guanidinoimino-3-methyl-4,5,6,7-tetrahydroindazole hydrochloride (Compound 176) (1.2 g) as colorless crystals.
Reaction SMILES: C([O:5][C:6](=[O:51])[CH2:7][CH:8]([C:34](=[O:50])[NH:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:40][CH:39]=1)[CH2:9][CH2:10][C:11](=[O:33])[NH:12][O:13]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C.ONC(CC(C(=O)NCCC1C2C(=CC=CC=2)NC=1)CC(O)=O)=O>>[C:41]1([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:42]=[CH:43][C:38]([CH2:37][CH2:36][NH:35][C:34]([CH:8]([CH2:9][CH2:10][C:11](=[O:33])[NH:12][OH:13])[CH2:7][C:6]([OH:51])=[O:5])=[O:50])=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)CC(CCC(=O)NOC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCCc1ccc(-c2ccccc2)cc1
Agent: O=C(O)CC(CC(=O)NO)C(=O)NCCc1c[nH]c2ccccc12
Product: O=C(O)CC(CCC(=O)NO)C(=O)NCCc1ccc(-c2ccccc2)cc1

Procedure:
This compound was prepared by deprotection of the compound of Example 151, as previously described for the compound of Example 128.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:10]([CH3:24])[CH2:9]1)=O)(C)(C)C.[ClH:25]>O1CCOCC1.CCOCC>[ClH:25].[CH3:24][CH:10]1[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC1CNCCN1c1ccc(C(F)(F)F)cc1
Temperature: 90 °C

Procedure:
To 0.58 mmol rac-3-methyl-4-(4-trifluoromethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester in 3 ml dioxane was added 8.7 mmol HCl (as a 4 M solution in dioxane), and the mixture was heated at 90° C. for 3 h. The mixture was then cooled 0° C. and diluted with 10 ml ether. The ensuing white crystals were collected by filtration, washing with ether, and dried in vacuo to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][NH:13][C:14]2=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([NH:27][C:28]([C:30]1[S:34][C:33](Br)=[N:32][C:31]=1[CH3:36])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([NH:27][C:28]([C:30]1[S:34][C:33]([N:13]2[CH:12]=[CH:11][C:10]3[C:15](=[CH:16][CH:17]=[CH:18][C:9]=3[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:14]2=[O:19])=[N:32][C:31]=1[CH3:36])=[O:29])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=c1[nH]ccc2c(OCc3ccccc3)cccc12
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Product: Cc1nc(-n2ccc3c(OCc4ccccc4)cccc3c2=O)sc1C(=O)NCc1ccccc1
Yield: 2 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 5-(benzyloxy)isoquinolin-1(2H)-one in place of 4-aminopyridin-2(1H)-one to react with N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 2% yield: mp 225-226° C.; 1H NMR (300 MHz, CD3OD) δ 7.77 (d, J=6.0 Hz, 1H), 7.41-7.25 (m, 11H), 7.10-7.08 (m, 2H), 6.99 (d, J=9.0 Hz, 1H), 4.55 (s, 2H), 4.50 (s, 2H), 2.57 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.0, 159.6, 153.5, 151.3, 136.7, 135.0, 128.3, 127.2, 126.8, 126.7, 126.6, 126.4, 125.6, 125.4, 125.3, 125.2, 124.2, 115.5, 114.3, 99.9, 41.7, 31.1, 14.1; MS (ES+) m/z 482.3 (M+1).
Reaction SMILES: [C:1]([C:3](=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]([O:6][CH2:7][CH2:8][OH:9])=[O:5])#[N:2].[H-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27]>>[CH2:27]([O:9][CH2:8][CH2:7][O:6][C:4](=[O:5])[C:3]([C:1]#[N:2])=[C:10]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: N#CC(C(=O)OCCO)=C(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: C=CCOCCOC(=O)C(C#N)=C(c1ccccc1)c1ccccc1
Temperature: 66 °C

Procedure:
Into a round bottom flask equipped with magnetic stirrer, reflux condenser and drying tube was charged 20 ml. of dry tetrahydrofuran and 3.2 g. (0.011 moles) of 2-hydroxyethyl 2-cyano-3,3-diphenylacrylate and the solution is rapidly stirred. Then sodium hydride 0.79 g. (0.016 moles) as a 50% oil dispersion was added portionwise. To the resulting suspension was added 5.3 g. (0.044 moles) of allyl bromide and the mixture was heated at reflux (66° C.) for 5.5 hours. Upon cooling, a white insoluble solid (NaBr) was removed by filtration. The organic filtrate was evaporated, leaving as the desired product a pale yellow oil.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[CH:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH:23]1([CH:22]=[C:21]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=2)[C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:30][CH:29]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(C(F)(F)F)cc1)n2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cnc2[nH]c(C(=CC3CCCC3)c3ccc(C(F)(F)F)cc3)cc2c1
Yield: 100.9 %

Procedure:
A solution of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-trifluoromethyl-phenyl)-vinyl]-5-methoxy-1H-pyrrolo[2,3-b]pyridine (260 mg, 0.49 mmol) in tetrahydrofuran (0.5 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 2 mL, 2 mmol) were stirred at room temperature for 12 h. The mixture was diluted with ethyl acetate (150 mL), and washed with a saturated aqueous ammonium chloride solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-[2-cyclopentyl-1-(4-trifluoromethyl-phenyl)-vinyl]-5-methoxy-1H-pyrrolo[2,3-b]pyridine (191 mg, quant.) as a white solid: LC/MS m/e calcd for C22H21F3N2O [M+H]+ 387.42, observed 387.2.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH3:17][N:18]([CH2:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1)[C:19]1[S:20][CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:23]=1.O>O1CCCC1>[CH3:17][N:18]([CH2:30][C:31]1[CH:32]=[CH:33][C:34](/[CH:35]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:37][CH:38]=1)[C:19]1[S:20][CH:21]=[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:23]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CN(Cc1ccc(C=O)cc1)c1nc(-c2ccccc2)cs1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc(CN(C)c2nc(-c3ccccc3)cs2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
To an ice-cooled solution of ethyl diethylphosphonoacetate (0.81 g, 3.6 mmol) in tetrahydrofuran (10 mL) was added 60% sodium hydride (0.14 g, 3.4 mmol), and the mixture was stirred for 30 min. A solution of 4-[[methyl(4-phenyl-2-thiazolyl)amino]methyl]benzaldehyde (0.80 g, 2.6 mmol) in tetrahydrofuran (10 mL) was added dropwise. The mixture was stirred at room temperature for 3 hrs, water was added, and the mixture was extracted with ethyl acetate. The extract was dried and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=18:1) to give the title compound (0.96 g, yield 98%) as a powder.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26].[C:28]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:33]=[CH:32][C:31]([C:34]([NH:36][C:37]2[CH:45]=[CH:44][C:40]([C:41]([O-])=[O:42])=[CH:39][CH:38]=2)=[O:35])=[CH:30][CH:29]=1>C1COCC1.C(#N)C.C(OCC)(=O)C.O.C(N(CC)CC)C>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH:26][C:41]([C:40]1[CH:39]=[CH:38][C:37]([NH:36][C:34]([C:31]2[CH:32]=[CH:33][C:28]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[CH:29][CH:30]=2)=[O:35])=[CH:45][CH:44]=1)=[O:42]
Reactant: CN(C)CCN
Reactant: O=C([O-])c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)CCNC(=O)c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.3 %

Procedure:
WSC (0.248 g), HOBt (0.156 g), N,N-dimethyl ethylenediamine (0.097 g) and triethylamine (0.21 ml) were added to a mixed solution of 4-(4-biphenylylcarbonylamino)benzoate (0.323 g) in THF (15 ml) and acetonitrile (15 ml). After stirring at room temperature for 18 hours, water was added to the reaction mixture, and extraction was conducted using ethyl acetate. The organic layer was washed with 10% aqueous potassium carbonate and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was recrystallized using methanol/diethyl ether to give the titled compound (0.100 g).
Reaction SMILES: CS(O)(=O)=O.[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:16])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].[CH3:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1O>>[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:16])=[C:11]([CH:15]=1)[C:12]([O:14][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH:18]1[CH3:17])=[O:13]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: CC1CCCCC1O
Agent: CS(=O)(=O)O
Product: CC1CCCCC1OC(=O)c1cc(N)ccc1Cl
Reaction time: 6 h
Yield: 81.4 %

Procedure:
Methanesulfonic acid (99%, 100 g, 1.0 mole) was added slowly to a stirred mixture of 5-amino-2-chlorobenzoic acid (85%, 100 g, 0.5 mole) in 2-methylcyclohexanol (200 g, 1.85 mole). The mixture was heated under reflux with stirring for 6 hours, then the excess 2-methylcyclohexanol was evaporated under reduced pressure. The residue was then dissolved in methylene chloride (800 ml), washed with water (300 ml), 5% sodium bicarbonate solution (300 ml), water (300 ml), dried (magnesium sulfate), and filtered. The solvent was then evaporated to give 109 g of 2-methylcyclohexyl 5-amino-2-chlorobenzoate as a light brown oil.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([NH:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1)[CH3:16].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3]2[C:9]3[C:10]([CH:15]([CH3:16])[N:17]([C:18]([C:19]4[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=4)=[O:27])[C:2]=2[CH:7]=1)=[CH:11][CH:12]=[CH:13][CH:14]=3
Reactant: COc1ccc(C(=O)NC(C)c2ccccc2-c2ccc(F)cc2F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1c2ccccc2-c2ccc(F)cc2N1C(=O)c1ccc(O)cc1
Yield: 94.3 %

Procedure:
3-fluoro-5-(4-methoxybenzoyl)-6-methyl-5,6-dihydrophenanthridine—_The title compound was prepared from N-[1-(2′,4′-difluoro-1,1′-biphenyl-2-yl)ethyl]-4-methoxybenzamide (1.29 g, 3.5 mmol), anhydrous THF (10 mL), and lithium bis(trimethylsilyl)amide (4.0 mL, 1M in THF) according to the procedure and in the same manner as described in Example 33, step d. The residue was purified by flash column chromatography (Biotage® 40 Mi, 30-50% methyl tert-butylether in hexane) affording 1.1 g (90%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 (d, J=6.76 Hz, 3 H) 3.77 (s, 3 H) 5.68 (q, J=6.67 Hz, 1 H) 6.60 (dd, J=10.39, 2.60 Hz, 1 H) 6.90 (d, J=8.84 Hz, 2 H) 7.07 (td, J=8.64, 2.73 Hz, 1 H) 7.27 (d, J=8.58 Hz, 2 H) 7.40 (m, 3 H) 7.97 (m, 1 H) 8.00 (dd, J=8.84, 6.24 Hz, 1 H); MS (ESI) m/z 348 ([M+H]+); HRMS: calcd for C22H18FNO2, 347.1322 (M), 348.13944 ([M+H]+); found (ESI_FT), 348.13914.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:24]2[S:28][C:27]([C:29]3([O:33]COC)[CH2:32][CH2:31][CH2:30]3)=[N:26][CH:25]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]4[CH2:23][CH2:22][CH2:21][O:20]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.ClC1C(C2SC(C3(OCOC)CCC3)=NC=2)=C2C=C(C3N=C(C4CCCN(C(OC(C)(C)C)=O)C4)ON=3)NC2=NC=1>>[Cl:1][C:2]1[C:3]([C:24]2[S:28][C:27]([C:29]3([OH:33])[CH2:32][CH2:31][CH2:30]3)=[N:26][CH:25]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]4[CH2:23][CH2:22][CH2:21][O:20]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5ccc(OCC6CCCO6)cc5)cc34)s2)CCC1
Agent: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5noc(C6CCCN(C(=O)OC(C)(C)C)C6)n5)cc34)s2)CCC1
Product: OC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5ccc(OCC6CCCO6)cc5)cc34)s2)CCC1

Procedure:
The title compound was prepared as described in Example 22E, substituting 5-(5-chloro-2-(4-((tetrahydrofuran-2-yl)methoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(1-(methoxymethoxy)cyclobutyl)thiazole (Example 70B) for 1 tert-butyl 3-(3-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (Example 22D). 1H NMR (500 MHz, DMSO-d6) ppm 12.45 (s, 1H) 8.29 (s, 1H) 8.25 (s, 1H) 7.94 (d, 2H) 7.04 (d, 2H) 6.94 (d, 1H) 6.66 (s, 1H) 4.17 (m, 1H) 4.00 (m, 2H) 3.79 (m, 1H) 3.69 (m, 1H) 2.63 (m, 2H) 2.41 (m, 2H) 1.80-2.06 (m, 5H) 1.69 (m, 1H); MS ESI(+) m/z 482.0 [M+H]+.