Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.C([BH3-])#N.[Na+].[CH2:15]([O:17][C:18](=[O:28])[C:19]([CH:26]=O)([CH3:25])[CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH3:16]>C(O)C>[CH2:15]([O:17][C:18](=[O:28])[C:19]([CH2:25][NH:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([CH3:26])[CH2:20][CH2:21][CH:22]([CH3:23])[CH3:24])[CH3:16]
Reactant: NC1CCCC1
Reactant: CCOC(=O)C(C)(C=O)CCC(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(C)(CCC(C)C)CNC1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.3 %

Procedure:
Cyclopentylamine (1.49 mL, 15.1 mmol), glacial acetic acid (1.5 mL), and sodium cyanoborohydride (1.90 g, 30.2 mmol) were added sequentially to a solution of crude rac-2-formyl-2,5-dimethyl-hexanoic acid ethyl ester (prepared as described in Example 19c; 3.02 g, 15.1 mmol) in ethanol (45 mL) at 25° C. The mixture was stirred at 25° C. for 18 h, and then was concentrated in vacuo. The residue was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (self-packed glass column, gradient elution: 20-30% ethyl acetate in hexanes) to afford rac-2-cyclopentylaminomethyl-2,5-dimethyl-hexanoic acid ethyl ester (1.60 g, 5.94 mmol, 39%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ: 0.87 (6H, d, J=6.9 Hz), 1.01-1.06 (1H, m), 1.16 (3H, s), 1.27 (3H, t, J=6.9 Hz), 1.27-1.33 (4H, m), 1.43-1.64 (8H, m), 2.51 (1H, d, J=11.7 Hz), 2.79 (1H, d, J=11.7 Hz), 2.96-3.02 (1H, m), 4.12 (2H, q, J=7.2 Hz).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[N:22]1[N:23]([CH:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)[N:24]=[N:25][CH:26]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:29]4[CH2:30][CH2:31][CH:27]([N:23]5[N:24]=[N:25][CH:26]=[N:22]5)[CH2:28]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: c1nnn(C2CCNC2)n1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC(n4ncnn4)C3)c(F)cc2c1=O

Procedure:
A solution of 1-cyclopropyl-6,7,8-trifluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxylic acid (28.3 mg, 0.1 mmol), 3-(1,2,3,4-tetrazol-2-yl) pyrrolidine hydrochloride (35.1 mg, 0.2 mmol) and DBU (45.6 mg, 0.3 mmol) in acetonitrile (2 ml) was refluxed under nitrogen for 23 hrs. The solvent was then evaporated to dryness. The residue was diluted with water and extracted with chloroform. The organic extract was dried over Na2SO4, concentrated and the residue was crystallized from methanol-water. Yield: 12 mg, m.p. 192°-199° C. 1H NMR (CDCl3) δ: 8.7 (s, 1H), 8.5 (s, 1H), 7.8 (dd, 1H), 5.6-5.4 (m, 1H), 4.46-3.76 (m, 5H), 2.9-2.45 (m, 2H), 1.35-1.02 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[N:11](=[C:13]1[CH2:18][CH2:17][C@H:16]2[C@H:19]3[C@H:29]([CH2:30][CH2:31][C@:14]12[CH3:15])[C@:27]1([CH3:28])[C:22]([CH2:23][C@@H:24](O)[CH2:25][CH2:26]1)=[CH:21][CH2:20]3)[OH:12].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][C@H:24]2[CH2:25][CH2:26][C@@:27]3([CH3:28])[C:22](=[CH:21][CH2:20][C@@H:19]4[C@@H:29]3[CH2:30][CH2:31][C@@:14]3([CH3:15])[C@H:16]4[CH2:17][CH2:18][C:13]3=[N:11][OH:12])[CH2:23]2)=[O:7])=[CH:4][CH:3]=1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=NO)CC[C@@H]12
Reactant: Cc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Cc1ccc(C(=O)O[C@H]2CC[C@@]3(C)C(=CC[C@@H]4[C@@H]3CC[C@]3(C)C(=NO)CC[C@@H]43)C2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 43 %

Procedure:
4-Methylbenzoic acid (p-toluic acid) (0.22 g, 1.6 mmol) (0.16 g, 1.6 mmol) was added to the stirred solution of 17-oximino-5-androsten-3β-ol (9) (0.5 g, 1.6 mmol) and dicyclohexylcarbodiimide (DCC) (0.34 g, 1.6 mmol) in anhydrous dichloromethane (30.0 ml). The reaction mixture was stirred for 48 hr at room temperature (20-25°) and completion of the reaction was monitored by TLC. The precipitated dicyclohexylurea (DCU) was filtered, solvent removed under vacuum and the residue was crystallized from ethyl acetate:petroleum ether (60:80) to obtain 12 (0.29 g, 58.0%) mp 135-139° C.
Reaction SMILES: [OH-].[K+].[OH:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[C:11]2[O:13][CH2:14][O:15][C:10]2=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17].[CH2:19](O)C>>[CH2:14]([O:13][C:11]1[CH:12]=[C:7]([NH:6][CH2:5][CH2:4][OH:3])[C:8]([N+:16]([O-:18])=[O:17])=[CH:9][C:10]=1[OH:15])[CH3:19]
Reactant: CCO
Reactant: O=[N+]([O-])c1cc2c(cc1NCCO)OCO2
Agent: [K+]
Agent: [OH-]
Product: CCOc1cc(NCCO)c([N+](=O)[O-])cc1O
Reaction time: 0.17 h

Procedure:
0.16 mol (10.5 g) of 85% pure potassium hydroxide pellets are dissolved in 80 ml of absolute ethanol on a boiling water bath. 0.08 mol (18.1 g) of 2-(β-hydroxyethyl)amino-4,5-methylenedioxy-1-nitrobenzene is added with stirring in the course of 10 minutes.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:10]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)=[N:11][NH:12][CH:13]=1.Cl[C:23]([O:25][CH3:26])=[O:24].O>CN(C)C1C=CN=CC=1.C1COCC1>[CH3:26][O:25][C:23]([N:12]1[CH:13]=[C:9]([Cl:8])[C:10]([C:14]2[CH:15]=[C:16]([Cl:21])[CH:17]=[C:18]([Cl:20])[CH:19]=2)=[N:11]1)=[O:24]
Reactant: Clc1cc(Cl)cc(-c2n[nH]cc2Cl)c1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)n1cc(Cl)c(-c2cc(Cl)cc(Cl)c2)n1
Reaction time: 20 h
Yield: 91.4 %

Procedure:
2.52 g (0.0204 mol) of 4-dimethylaminopyridine and 18.3 ml (0.132 mol) of triethylamine are added to 30.55 g (0.12 mol) of 4-chloro-3-(3,5-dichlorophenyl)pyrazole dissolved in 300 ml of THF. A solution of 12.5 g (0.132 mol) of methyl chloroformate in 100 ml of THF is run, dropwise and at 0° C., into this solution. Stirring is continued for 20 h at room temperature. The reaction mixture is poured into 500 ml of water and extracted with ethyl acetate. After drying the organic phase and concentration under vacuum, the residue is triturated with 150 ml of heptane, filtered and dried. We obtain 33.5 g of 1-methoxycarbonyl-4-chloro-3-(3,5-dichlorophenyl)pyrazole, melting at 144° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:19][C@@H:20]2[CH2:25][CH2:24][C@H:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]2)=[CH:4][C:5]([O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:6][CH:7]=1.[F:31][C:32]1[CH:33]=[C:34]([CH:40]=[CH:41][CH:42]=1)[C:35]([N:37]=[C:38]=S)=[O:36]>>[CH2:12]([O:11][CH2:10][CH2:9][O:8][C:5]1[N:6]=[CH:7][C:2]2[NH:1]/[C:38](=[N:37]\[C:35](=[O:36])[C:34]3[CH:40]=[CH:41][CH:42]=[C:32]([F:31])[CH:33]=3)/[N:19]([C@@H:20]3[CH2:25][CH2:24][C@H:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]3)[C:3]=2[CH:4]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:35](/[N:37]=[C:38]1/[N:19]([C@@H:20]2[CH2:21][CH2:22][C@H:23]([C:26]([O:28][CH3:29])=[O:27])[CH2:24][CH2:25]2)[C:3]2[CH:4]=[CH:5][N:6]=[CH:7][C:2]=2[NH:1]/1)(=[O:36])[C:34]1[CH:40]=[CH:41][CH:42]=[CH:32][CH:33]=1
Reactant: CCOC(=O)[C@H]1CC[C@@H](Nc2cc(OCCOCc3ccccc3)ncc2N)CC1
Reactant: O=C(N=C=S)c1cccc(F)c1
Product: CCOC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3cccc(F)c3)[nH]c3cnc(OCCOCc4ccccc4)cc32)CC1
Product: COC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccccc3)[nH]c3cnccc32)CC1
Yield: 82 %

Procedure:
The title compound was prepared from cis-ethyl 4-(5-amino-2-(2-(benzyloxy)ethoxy)pyridin-4-ylamino)cyclohexanecarboxylate and 3-fluorobenzoyl isothiocyanate using a method analogous to the preparation of cis-methyl 4-((E)-2-(benzoylimino)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylate (2.5 g, 82% yield). MS m/z=561.2 [M+H]. Calc'd for C31H33FN4O5: 560.2.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:14][C:15]#[N:16]>>[Br:1][C:2]1[S:6][C:5](/[CH:7]=[C:14](/[C:13]2[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:11]([O:10][CH3:9])[CH:12]=2)\[C:15]#[N:16])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2ccc(Br)s2)cc1OC
Yield: 51.4 %

Procedure:
5-Bromothiophene-2-carboxaldehyde (381 mg) was condensed with 3,4-dimethoxybenzyl cyanide (355 mg) through Method A (production step 2), to thereby yield the target product (yield: 359 mg, 51%).
Reaction SMILES: [CH:1]1([OH:9])[CH2:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:17]1[C:22](=[O:23])[N:21]([O:24][C:25](ON2C(=O)CCC2=O)=[O:26])[C:19](=[O:20])[CH2:18]1>C(#N)C>[C:25](=[O:26])([O:24][N:21]1[C:22](=[O:23])[CH2:17][CH2:18][C:19]1=[O:20])[O:9][CH:1]1[CH2:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: OC1CCC=CCCC1
Agent: O=C(OC1CC/C=C/CCC1)ON1C(=O)CCC1=O
Agent: OC1CC/C=C/CCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(OC1CCC=CCCC1)ON1C(=O)CCC1=O
Temperature: 25 °C

Procedure:
50 mg of (E)-cyclooct-4-enol (major isomer) and 0.2 mL triethylamine were added to 3 mL anhydrous acetonitrile. To this solution was slowly added 250 mg of N,N-disuccinimidyl carbonate. The reaction mixture was stirred at room temperature until thin layer chromatography revealed that the reaction was complete (approximately 48 hours). The acetonitrile was removed by rotary evaporation and the remaining residue was suspended in ether, washed with 0.1M HCl followed by brine, and dried with magnesium sulfate. The ether was evaporated and the resulting oil was purified by column chromatography (1:1 Ethyl Acetate:Hexane) yielding 80 mg (75% yield) of the title compound. 1H NMR (400 MHz CDCl3): δ 5.65-5.54 (m, 1H), 5.5-5.4 (m, 1H), 4.5-4.4 (m, 1H), 2.88-2.78 (s, 4H), 2.45-2.3 (m, 2H), 2.2-1.5 (m, 8H).
Reaction SMILES: ClC1N=C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)C(Cl)=CN=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])[C:24]([Cl:38])=[CH:23][N:22]=1.COC1C(N)=CC2CCC(N3CCOCC3)CCC=2C=1.[F:59][CH:60]([F:77])[CH2:61][NH:62][CH:63]1[CH2:69][CH2:68][C:67]2=[C:70]([NH2:76])[C:71]([O:74][CH3:75])=[CH:72][CH:73]=[C:66]2[CH2:65][CH2:64]1>>[Cl:38][C:24]1[C:25]([NH:27][C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])=[N:26][C:21]([NH:76][C:70]2[C:67]3[CH2:68][CH2:69][CH:63]([NH:62][CH2:61][CH:60]([F:77])[F:59])[CH2:64][CH2:65][C:66]=3[CH:73]=[CH:72][C:71]=2[O:74][CH3:75])=[N:22][CH:23]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1ccc2c(c1N)CCC(NCC(F)F)CC2
Agent: COc1cc2c(cc1N)CCC(N1CCOCC1)CC2
Agent: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: CNC(=O)c1ccccc1Nc1nc(Nc2c(OC)ccc3c2CCC(NCC(F)F)CC3)ncc1Cl

Procedure:
Prepared in an analogous fashion to Example 1047 replacing (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide with 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide and 3-Methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine was replaced with N*7*-(2,2-Difluoro-ethyl)-2-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-1,7-diamine to afford 2-{5-Chloro-2-[7-(2,2-difluoro-ethylamino)-2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide. LC/MS (ESI): 531.23. 1H NMR (400 MHz, DMSO, d6) δ 9.07 (m, 2H), 8.87 (m, 1H), 8.74 (m, 1H), 8.16 (m, 1H), 8.01 (m, 1H), 7.71 (m, 1H), 7.01 (m, 2H), 6.89 (m, 1H), 6.38 (td, 1H), 3.78 (s, 3H), 3.55 (m, 2H), 3.38 (m, 1H), 3.07 (m, 1H), 2.79 (s, 3H), 2.68-2.86 (m, 2H), 2.32 (m, 3H), 1.33 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH2:12])=[S:11])=[CH:5][CH:4]=1)#[N:2].[CH3:13][I:14]>CC(=O)CC>[IH:14].[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[NH:12])[S:11][CH3:13])=[CH:7][CH:8]=1)#[N:2]
Reactant: CI
Reactant: N#Cc1ccc(NC(N)=S)cc1
Solvent: CCC(C)=O
Product: CSC(=N)Nc1ccc(C#N)cc1
Product: I
Reaction time: 24 h
Yield: 77.9 %

Procedure:
To a solution of 6.7 g (0.037 mol) of 4-cyanophenylthiourea in 150 cm3 of 2-butanone, 13.1 g (0.092 mol) of methyl iodide are added. After 24 hours of contact at room temperature, the solid formed is filtered, washed with 2-butanone (2×20 cm3) then with ethyl ether (2×50 cm3), which makes it possible to obtain 9.2 g (yield 76%; melting point 212° C.) of N-(4-cyanophenyl)-S-methylisothiourea hydroiodide: ##STR16##
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[CH3:12]OC(OC)(C)C.Cl>CO>[C:1]([O:11][CH3:12])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: COC(C)(C)OC
Reactant: O=C(O)[C@H](O)c1ccccc1
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](O)c1ccccc1
Reaction time: 20 h

Procedure:
(R)-Mandelic acid (2.568 g, 16.87 mmol) and 2,2-dimethoxypropane (5.1 mL, 41.48 mmol) were dissolved in MeOH (100 mL) and 12M HCl (100 mL) was added. The resulting solution was stirred for 20 hr under a CaCl2 tube and evaporated to dryness under reduced pressure. EtOAc (100 mL) and saturated aqueous NaHCO3 (100 mL) were added, and the aqueous phase was extracted with EtOAc (3×100 mL). The organic fractions were dried with MgSO4, and evaporated under reduced pressure to give (R)-methyl mandelate, (R)-4, quantitatively (2.78 g) as a white solid which was of sufficient purity for the next step.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN1CC[O:27][CH2:26][CH2:25]1.[CH:30]1([S:33]([C:36]2[CH:41]=[CH:40][C:39]([CH:42]([C:50]3[NH:54][C:53]([C:55]4[N:60]=[CH:59][C:58]([CH2:61][N:62]5[CH2:67][CH2:66][NH:65][C@@H:64]([CH3:68])[CH2:63]5)=[CH:57][CH:56]=4)=[CH:52][CH:51]=3)[CH2:43][CH:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:32][CH2:31]1>O1CCCC1.C(OCC)(=O)C.C(O)(=O)C>[C:26]([N:65]1[CH2:66][CH2:67][N:62]([CH2:61][C:58]2[CH:59]=[N:60][C:55]([C:53]3[NH:54][C:50]([CH:42]([C:39]4[CH:38]=[CH:37][C:36]([S:33]([CH:30]5[CH2:32][CH2:31]5)(=[O:34])=[O:35])=[CH:41][CH:40]=4)[CH2:43][CH:44]4[CH2:45][CH2:46][O:47][CH2:48][CH2:49]4)=[CH:51][CH:52]=3)=[CH:56][CH:57]=2)[CH2:63][C@@H:64]1[CH3:68])(=[O:27])[CH3:25]
Reactant: C[C@H]1CN(Cc2ccc(-c3ccc(C(CC4CCOCC4)c4ccc(S(=O)(=O)C5CC5)cc4)[nH]3)nc2)CCN1
Reactant: CN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N1CCN(Cc2ccc(-c3ccc(C(CC4CCOCC4)c4ccc(S(=O)(=O)C5CC5)cc4)[nH]3)nc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of acetic acid (5.6 μL) in tetrahydrofuran (2 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (25.0 mg), 1-hydroxybenzotriazole (18.0 mg) and N-methylmorpholine (30 μL), and the mixture was stirred at room temperature for 30 min. To to the reaction mixture was added a solution of (3S)-1-{[6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridin-3-yl]methyl}-3-methylpiperazine (45.0 mg) in tetrahydrofuran (1 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to basic silica gel column chromatography, and the title compound (43.0 mg, yield 90%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate. MS: 591 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[S:12][C:11]([C:13]#[N:14])=[N:10][N:9]=2)[CH2:3][CH2:2]1.[F:15][C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:19]N1CCC(N)CC1.C(N(C(C)C)CC)(C)C>C(#N)C.ClCCl>[F:15][C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:19][N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]2[S:12][C:11]([C:13]#[N:14])=[N:10][N:9]=2)[CH2:5][CH2:6]1
Reactant: NC1CCN(Cc2ccc(F)c(F)c2)CC1
Reactant: N#Cc1nnc(NC2CCNCC2)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: ClCCl
Product: N#Cc1nnc(NC2CCN(Cc3ccc(F)c(F)c3)CC2)s1
Yield: 24.6 %

Procedure:
A mixture of 5-chloro-[1,3,4]thiadiazole-2-carbonitrile (0.3 g, 2.06 mmol) (D6) (prepared by a procedure similar to that described in U.S. Pat. No. 5,736,545), 1-(3,4-difluoro-benzyl)-piperidin-4-ylamine (D7) (0.47 g, 2.06 mmol) and diisopropylethylamine (0.54 ml, 3.09 mmol) in acetonitrile (5 ml) in a sealed tube, was stirred at 80° C. for 1 h., under microwave irradiation. After this period, the reaction mixture was diluted with dichloromethane and extracted with a saturated solution of sodium carbonate (25 ml). The organic layer was separated, dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by short open column chromatography (silica gel; 0-2.5% ammonia in methanol (7M)/dichloromethane). The desired fractions were collected and evaporated in vacuo. The crude product was precipitated from acetonitrile to yield E19 (0.17 g, 25%) as a solid. C15H15F2N5S requires 335. Found 336 (MH+).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]=[C:12]1[CH2:18][CH:17]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:16]2[CH:28]=[C:29]([C:32]([O:34][CH3:35])=[O:33])[CH:30]=[CH:31][C:15]=2[O:14][CH2:13]1.[CH2:36](Br)[CH:37]=[CH2:38].Cl>O1CCCC1.ClCCl.O>[CH2:38]([C:17]1([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:16]2[CH:28]=[C:29]([C:32]([O:34][CH3:35])=[O:33])[CH:30]=[CH:31][C:15]=2[O:14][CH2:13][C:12](=[CH2:11])[CH2:18]1)[CH:37]=[CH2:36]
Reactant: C=C1COc2ccc(C(=O)OC)cc2C(S(=O)(=O)c2ccccc2)C1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: C=CCC1(S(=O)(=O)c2ccccc2)CC(=C)COc2ccc(C(=O)OC)cc21
Reaction time: 0.25 h
Yield: 67 %

Procedure:
0.023 ml (1.1 equivalents) of 1,3-dimethylpropyleneurea and then 0.189 ml (1.1 equivalents) of 1.06M lithium bis(trimethylsilyl)amide in tetrahydrofuran are added at ambient temperature to 61 mg (0.17 mmol) of methyl 3-methylene-5-(phenylsulfonyl)-2,3,4,5-tetrahydro-1-benzoxepin-7-carboxylate, prepared according to example 1, in solution in 1.8 ml of tetrahydrofuran. The reaction medium then assumes a dark yellow color. After stirring for 15 minutes, 0.0165 ml (1.1 equivalents) of allyl bromide is added. After stirring for 5 minutes, water, 1N hydrochloric acid and dichloromethane are added. After separating the organic and aqueous phases, the aqueous phase is extracted three times with dichloromethane. The combined organic phases are washed with brine, are dried and are finally concentrated under vacuum. The crude reaction product is then purified by chromatography on silica gel (ethyl acetate/heptane 25/55) to give 51 mg (67%) of methyl 5-allyl-3-methylene-5-(phenylsulfonyl)-2,3,4,5-tetrahydro-1-benzoxepin-7-carboxylate in the form of an oil; 1H NMR (300 MHz, CDCl3): 3.25 (m, 4H), 3.9 (s, 3H), 4.25 (d, J=14.3 Hz, 1H), 4.6 (d, J=14.3 Hz, 1H), 4.93 (s, 1H), 5.10 (s, 1H), 5.21 (m, 2H), 5.83 (m, 1H), 6.86 (d, J=8.5 Hz, 1H), 7.4 (m, 4H), 7.57 (m, 1H), 7.95 (dd, J=8.46 and 2 Hz, 1H), 8.21 (d, J=2.07 Hz, 1H).
Reaction SMILES: [N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][OH:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:33][C:34]1([Cl:50])[CH:36]([C:37]2[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=2)[CH:35]1[CH2:44][C:45]([O:47]CC)=[O:46].N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(O)(C(F)(F)F)=O>C1COCC1>[Cl:33][C:34]1([Cl:50])[CH:36]([C:37]2[CH:42]=[CH:41][C:40]([O:13][CH2:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[CH2:6][CH2:7][CH2:8][NH:9][C:10]=4[N:1]=3)=[CH:39][CH:38]=2)[CH:35]1[CH2:44][C:45]([OH:47])=[O:46]
Reactant: CCOC(=O)CC1C(c2ccc(O)cc2)C1(Cl)Cl
Reactant: OCCc1ccc2c(n1)NCCC2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC1C(c2ccc(OCCc3ccc4c(n3)NCCC4)cc2)C1(Cl)Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.5 %

Procedure:
To a solution of 2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-1-ethanol (0.16 g, 0.9 mmol) and Polymer bound PPh3(0.3 g, 0.9 mmol) in dry THF (6 mL) was added ethyl [2,2-dichloro-3-(4-hydroxyphenyl)cyclopropyl]acetate (0.18 g, 0.6 mmol) followed by diisopropyl azodicarboxylate (0.2 mL, 1 mmol). The reaction mixture was stirred at room temperature. After 18 hours, the reaction mixture was filtered through Celite to remove the polymer and washed with excess THF. Filtrate was concentrated. The concentrated residue in 50% acetonitrile in water (4 mL) was added LiOH (01 g). The reaction mixture was stirred 3 hours at room temperature. Reaction mixture was acidified by adding TFA and purified by reverse phase HPLC to afford 0.12 g (36%) of desired product. 1H NMR (CD3OD) δ 7.64 (d, 1H, J=8 Hz), 7.26 (d, 2H, J=8.4 Hz), 6.93 (d, 2H, J=8.8 Hz), 6.77 (d, 1H, J=7.6 Hz), 4.32 (t, 2H, J=6 Hz), 3.53 (t, 2H, J=5.6 Hz), 3.19 (t, 2H, J=6 Hz), 2.87-2.59 (m, 5 H), 2.32-2.26 (m, 1H), 2.01-1.95 (m, 2 H). HRMS calcd for C21H22N2O3 (M+H): 421.1080. found 421.1069.
Reaction SMILES: O.[OH-].[Li+].[C:4]([C:6]1[CH:7]=[C:8](/[C:12](/[CH3:19])=[CH:13]/[C:14]([O:16]CC)=[O:15])[CH:9]=[CH:10][CH:11]=1)#[N:5].CO>O1CCCC1.O>[C:4]([C:6]1[CH:7]=[C:8](/[C:12](/[CH3:19])=[CH:13]/[C:14]([OH:16])=[O:15])[CH:9]=[CH:10][CH:11]=1)#[N:5]
Reactant: CCOC(=O)/C=C(\C)c1cccc(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C/C(=C\C(=O)O)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of lithium hydroxide monohydrate (10.8 g, 0.26 mol) in tetrahydrofuran (100 ml) and water (100 ml) was added crude ethyl (E)-3-(3-cyanophenyl)-2-butenoate (Preparation 31) in tetrahydrofuran (150 ml). The resultant mixture was made homogeneous by the addition of methanol (approx. 50 ml), and then stirred at room temperature for 16 h. The mixture was concentrated in vacuo and acidified with 2N hydrochloric acid, following which a solid precipitated. The solid was collected by suction filtration, washing with cold water. The solid was then dried and recrystallised from acetonitrile. From the first crop, 15.8 g (49% over 2 steps) of the pure E-isomer was isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([NH2:24])[CH2:19]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.C(OC([N:43]1[CH2:48][CH2:47][O:46][CH:45]([C:49](O)=[O:50])[CH2:44]1)=O)(C)(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[OH-].[Li+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:49]([CH:45]5[O:46][CH2:47][CH2:48][NH:43][CH2:44]5)=[O:50])[CH2:19]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](N)C4)n3)c3cc(Cl)cnc32)cc1
Agent: On1nnc2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(N[C@@H]1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1)C1CNCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1S,3R)—N1-[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]cyclohexane-1,3-diamine (0.06 g, 0.12 mmol) in CH2Cl2 (3 mL) was added 4-tert-butoxycarbonylmorpholine-2-carboxylic acid (40.4 mg, 0.17 mmol), EDC (0.03 g, 0.14 mmol), HOBt (0.02 g, 0.12 mmol) and iPr2NEt (0.06 g, 0.47 mmol), and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in CH2Cl2 (2 mL) and TFA (2 mL) and allowed to stir at room temperature for 2 hours. The resulting solution was concentrated in vacuo, dissolved in THF (4 mL) and treated with 1N aqueous lithium hydroxide (3.0 mL, 3.0 mmol). The reaction mixture was heated in the microwave to 130° C. for 20 min. The solvent was evaporated under reduced pressure, and the residue was purified by HPLC, using 5-70% MeOH/H2O with 6 mM HCl over 15 minutes. The purified fractions were concentrated to provide the bis-hydrochloride of N-[(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]morpholine-2-carboxamide.