Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[NH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)=[O:20]
Reactant: NCc1ccccn1
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(NCc1ccccn1)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (2.00 g, 5.50 mmol), 2-(aminomethyl)pyridine (0.710 g, 6.57 mmol), triethylamine (0.610 g, 6.03 mmol) and benzene (40 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(2-pyridyl)methyl-3,4,5,6-tetrahydrophthalamide as white crystals (1.410 g, 54.2% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].C(OC([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH2:40])=[CH:38][CH:39]=2)[CH2:30][C:29]1([CH3:42])[CH3:41])=O)(C)(C)C>>[CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10]([NH:40][C:37]3[CH:38]=[CH:39][C:34]([N:31]4[CH2:32][CH2:33][NH:28][C:29]([CH3:42])([CH3:41])[CH2:30]4)=[CH:35][N:36]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1(C)C
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNC(C)(C)C4)cn3)nc2n1C1CCCC1
Yield: 28.8 %

Procedure:
Following Buchwald Method B, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (50 mg, 0.17 mmol) and 4-(6-amino-pyridin-3-yl)-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (58 mg, 0.15 mmol) gave 7-cyclopentyl-2-[5-(3,3-dimethyl-piperazin-1-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (20 mg, 25%). MS (ESI) m/z 463.3 (M+H)+
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][CH:10]([CH:13]([OH:20])[CH:14]([OH:19])[CH:15]([OH:18])[CH2:16][OH:17])[CH2:11][NH-:12].[O:21]([C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[CH:33][CH:32]=1)[C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1>>[OH:9][CH:10]([CH:13]([OH:20])[CH:14]([OH:19])[CH:15]([OH:18])[CH2:16][OH:17])[CH2:11][NH-:12].[OH:9][CH:10]([C:11]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)[CH2:13][CH2:14][CH:15]1[CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH2:1][NH:8][C:35]([C:34]3[CH:33]=[CH:32][C:31]([O:21][C:22]4[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:29][CH:30]=4)=[CH:39][CH:38]=3)=[O:37])=[CH:3][CH:4]=2)[C:16]1=[O:17]
Reactant: NCc1ccccc1
Reactant: O=C(O)c1ccc(Oc2ccc(C(=O)O)cc2)cc1
Agent: [NH-]CC(O)C(O)C(O)C(O)CO
Product: O=C(O)c1ccc(Oc2ccc(C(=O)NCc3ccc(N4C(=O)C(CCC(O)c5ccccc5)C4c4ccccc4)cc3)cc2)cc1

Procedure:
The benzylamine from IIa was reacted with the 2,3,4,5,6-pentahydroxyhexylamide of 4,4′-oxybisbenzoic acid from If as described in Example I. This produced the 2,3,4,5,6-pentahydroxyhexylamide of 4-(4-{4-[3-(3-hydroxy-3-phenylpropyl)-2-oxo-4-phenylazetidin-1-yl]benzylcarbamoyl}phenoxy)benzoic acid (9) of molecular weight 789.89 (C45H47N3O10); MS (ESI): 790.26 (MH+).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][C:25]#[N:26].O>CN(C)C=O>[CH3:1][N:2]([CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([O:13][CH3:14])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:22][CH2:23][CH2:24][CH2:25][NH2:26]
Reactant: N#CCCCBr
Reactant: CNCCc1cc(OC)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(CCN(C)CCCCN)cc(OC)c1
Reaction time: 12 h
Yield: 80 %

Procedure:
10.0 g of N-methyl-(2-(3,5-dimethoxyphenyl)ethyl)amine was dissolved in 130 ml of N,N-dimethylformamide, followed by the addition of 10.63 g of anhydrous potassium carbonate and 6.12 ml of 4-bromobutyronitrile. The reaction was carried out at a room temperature for 12 hours. Water was added to the reaction mixture. The obtained mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with water and a saturated aqueous solution of common salt successively, dried over anhydrous potassium carbonate and distilled to remove the solvent. 150 ml of ethanol, 11 ml of concentrated hydrochloric acid and 1 g of platinum oxide were added to the obtained residue to carry out hydrogenation at a room temperature under 3 kg/cm2 for 12 hours. The catalyst was filtered out and the filtrate was concentrated under a reduced pressure, followed by the addition of concentrated aqueous ammonia. The obtained mixture was extracted with chloroform. The chloroform phase was dried over anhydrous potassium carbonate. After the solvent had been distilled off, the residue was distilled under a reduced pressure to obtain 10.85 g of the title compound as a colorless oil (yield: 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][CH:12]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:9])=[CH:4][N:3]=1.FC(F)(F)C(O)=[O:30].OO.C(Cl)(Cl)Cl>ClCCl.CC(OCC)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][CH:12]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:9])=[CH:4][N+:3]=1[O-:30]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCCCCCC(CCCCCC)COC(=O)c1ccc(Cl)nc1
Agent: OO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCCCCCCCC(CCCCCC)COC(=O)c1ccc(Cl)[n+]([O-])c1
Reaction time: 5 h

Procedure:
The product from Stage (a) (45.8 g, 0.12 mol) was dissolved in dichloromethane (350 ml) and trifluoroacetic acid (60 ml) was added dropwise during 30 minutes. H2O2 (100 vol, 31 ml, 0.24 mol) was then added during 15 minutes and the solution was boiled under reflux for 4 hours. A further addition of H2O2 (5 ml) was made and boiling was continued for a further 5 hours when it was shown by TLC (SiO2, CHCl3 :CH3CO2C2H5 =1:1) that only a trace of starting material remained. The mixture was poured onto ice and the organic solution was extracted with aqueous sodium carbonate and water, dried (MgSO4) and concentrated at 0.2 mm pressure to 46 g of oil. Microanalysis for C22H36NO3Cl, % theory (found): C: 66.39 (66.2); H: 9.12 (9.5); N: 3.52 (3.2); Cl: 8.91 (8.7). M.S. m/z=397. NMR(CDCl3)=7.65 (m, 2, ArH), 8.90 (2, 1, ArH), otherwise as starting material.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]1[C:12]2[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[O:22])[C:13]=2[N:14]=[CH:15][N:16]=1)[CH3:2].[C:30](Cl)(=[O:33])[CH2:31][CH3:32]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]1[C:12]2[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH:24]3[CH2:25][CH2:26][N:27]([C:30](=[O:33])[CH2:31][CH3:32])[CH2:28][CH2:29]3)=[O:22])[C:13]=2[N:14]=[CH:15][N:16]=1)[CH3:2]
Reactant: CCOc1ccc(F)cc1-c1ncnc2c(C(=O)NC3CCNCC3)c(C)[nH]c12
Reactant: CCC(=O)Cl
Product: CCOc1ccc(F)cc1-c1ncnc2c(C(=O)NC3CCN(C(=O)CC)CC3)c(C)[nH]c12

Procedure:
Starting from 4-(2-ethoxy-5-fluorophenyl)-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide (example D.f17) and commercially propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[O:12][CH:13]=[C:14]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]4[CH:32]=[CH:31][N:30]=[C:29]4[CH2:33][CH2:34][C:35]([OH:37])=O)=[CH:20][CH:19]=3)[N:15]=2)=[CH:5][CH:4]=1.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.P(C#N)(OCC)(OCC)=O>C(N(CC)CC)C>[F:38][C:2]([F:1])([F:39])[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[C:11]2[O:12][CH:13]=[C:14]([CH2:16][O:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]4[CH:32]=[CH:31][N:30]=[C:29]4[CH2:33][CH2:34][C:35]([N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)=[O:37])=[CH:22][CH:23]=3)[N:15]=2)=[CH:7][CH:8]=1
Reactant: C1COCCN1
Reactant: O=C(O)CCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Product: O=C(CCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1)N1CCOCC1

Procedure:
Using 3-[1-[4-[4-[(2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl)methoxy]phenyl]butyl]-1H-imidazol-2-yl]propionic acid (200 mg), morpholine (97.1 μl), diethyl cyanophosphate (84.5 μl) and triethylamine (77.6 μl), the same reaction as Example 5-(ii) was carried out to yield the titled compound (217 mg).
Reaction SMILES: Br[CH2:2][C:3](=[CH2:7])[C:4]([OH:6])=[O:5].[CH3:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][SH:16].CN(C)C=O>C(OCC)(=O)C>[CH2:15]([S:16][CH2:2][C:3](=[CH2:7])[C:4]([OH:6])=[O:5])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8]
Reactant: C=C(CBr)C(=O)O
Reactant: CCCCCCCCS
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(CSCCCCCCCC)C(=O)O

Procedure:
A mixture of 2-bromomethylacrylic acid (1.0 g, 6.0 mmol), n-octylthiol (1.2 mL, 6.6 mmol), and dimethylformamide (10 mL) is refluxed overnight. The mixture is then transferred to ethyl acetate and extracted with aqueous 10% hydrochloric acid and distilled water. The organic phase is concentrated in vacuo to afford the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]3[CH2:18][CH2:19][N:20](C(OCC4C=CC=CC=4)=O)[CH2:21][C:5]=3[C:4]=2[CH:3]=1>C(OCC)(=O)C.CO.[Pd]>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[C:6]3[CH2:18][CH2:19][NH:20][CH2:21][C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCc2c(c3cc(F)ccc3n2-c2ccc(F)cc2)C1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Fc1ccc(-n2c3c(c4cc(F)ccc42)CNCC3)cc1
Reaction time: 4 h

Procedure:
In a Parr bottle were combined 5% Pd/C (10 g of 50% water-wet) and 60 g of 8-fluoro-5-(p-fluorophenyl)-2-carbobenzoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (60 g, 0.143 mole) in 400 ml ethyl acetate and 100 ml methanol and the mixture hydrogenated at 44-80 psig for 4 hours. Catalyst was recovered by filtration and the filtrate evaporated to solids in vacuo. The residue taken into CH2Cl2, carbon treated, dried (Na2SO4) and CH2Cl2 displaced with hexane by distillation to a final pot temperature of 70° C. The white, crystalline product was recovered by filtration, 35.6 g, m.p. 126°-129° C.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]([OH:8])=O)(=[O:4])=[O:3].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[C:46]1([C:52]2[CH:57]=[C:56]([CH:58]3[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]3)[CH:55]=[CH:54][C:53]=2[NH:64][C:65]([C:67]2[NH:68][CH:69]=[C:70]([C:72]#[N:73])[N:71]=2)=[O:66])[CH2:51][CH2:50][CH2:49][CH2:48][CH:47]=1.CCN(CC)CC>C(Cl)Cl>[C:46]1([C:52]2[CH:57]=[C:56]([CH:58]3[CH2:59][CH2:60][N:61]([C:6](=[O:8])[CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:62][CH2:63]3)[CH:55]=[CH:54][C:53]=2[NH:64][C:65]([C:67]2[NH:68][CH:69]=[C:70]([C:72]#[N:73])[N:71]=2)=[O:66])[CH2:51][CH2:50][CH2:49][CH2:48][CH:47]=1
Reactant: CS(=O)(=O)CC(=O)O
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)CC(=O)N1CCC(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 25.2 %

Procedure:
A flask was charged with methanesulfonyl-acetic acid (14 mg, 0.10 mmol), EDCI (30 mg, 0.15 mmol), HOBt (14 mg, 0.10 mmol), DIEA (36 μL, 0.20 mmol) and 0.5 mL DCM and stirred at 25° C. After 10 min, a solution containing 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (40 mg, 0.08 mmol) (as prepared in Example 20, step (b)) and NEt3 (14 μL, 0.09 mmol) in 0.5 mL DCM was added and the reaction allowed to proceed for 10 h at 25° C. The reaction mixture was loaded on a 5-g SPE cartridge (silica) and the title compound was eluted with 10% EtOH/EtOAc to give 10 mg (25%) of a white solid. 1H-NMR (400 MHz, CDCl3): δ 11.60 (br s, 1H), 9.52 (s, 1H), 8.30 (d, 1H), 7.74 (s, 1H), 7.60 (dd, 1H), 7.03 (d, 1H), 5.86 (m, 1H), 4.84 (m, 1H), 4.18 (s, 2H), 4.12 (m, 1H), 3.32 (m, 1H), 3.20 (s, 3H), 2.82 (m, 2H), 2.30 (m, 4H), 1.98 (m, 2H), 1.84 (m, 5H), 1.72 (m, 1H). Mass spectrum (ESI, m/z): Calcd. for C25H29N5O4S, 496.2 (M+H). found 496.2.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].C(N(CC)CC)C.Cl[C:22]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([CH:39]3[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]3)=[CH:35][CH:34]=2)[N:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:13][O:12][C:10](=[O:11])[CH2:9][C:8]1[C:3]([C:1]#[C:2][C:26]2[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:22][N:23]=[C:24]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([CH:39]4[CH2:40][CH2:41][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:43][CH2:44]4)=[CH:35][CH:34]=3)[N:25]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Reactant: C#Cc1ncccc1CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cccnc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 120 °C
Yield: 71.6 %

Procedure:
A solution of methyl 2-(2-ethynylpyridin-3-yl)acetate (I120) (43.6 mg, 0.249 mmol) in dimethylformamide (2 mL) and triethylamine (107 μL, 0.765 mmol) were added to a mixture of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I45) (87.4 mg, 0.191 mmol), Pd(PPh3)2Cl2 (13 mg, 0.019 mmol), Cu(I)I (5.5 mg, 0.029 mmol) and triphenylphosphine (7.5 mg, 0.017 mmol) in dimethylformamide (2 mL). The reaction mixture was heated under microwave irradiation at 120° C. for 10 minutes. The cooled mixture was diluted with EtOAc and passed through a plug of celite, washing with ethyl acetate (100 mL). The solvent was removed under reduced pressure and the residue partitioned between EtOAc (70 mL) and water (50 mL). The layers separated and the aqueous layer extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (70 mL) and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give a dark brown residue. The residue was purified by column chromatography on silica gel (0-40% EtOAc in petroleum benzine 40-60° C.) to yield the title compound (I121) (81.5 mg, 72%) as a brown viscous oil which was used without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][C:5]([C@H:9]2[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10]2)=[CH:4][N:3]=1.[CH3:16][C@H:17]1[CH2:22][NH:21][CH2:20][CH2:19][N:18]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O.O>[C:26]([O:25][C:23]([N:18]1[CH2:19][CH2:20][N:21]([C:2]2[C:7]([F:8])=[CH:6][C:5]([C@H:9]3[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10]3)=[CH:4][N:3]=2)[CH2:22][C@@H:17]1[CH3:16])=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC1(C)OC[C@H](c2cnc(Cl)c(F)c2)O1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H]1CN(c2ncc([C@H]3COC(C)(C)O3)cc2F)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62.6 %

Procedure:
To a solution of 114 (1.60 g, 6.91 mmol) in toluene (21.1 mL) under an argon atmosphere was added (S)-tert-butyl 2-methylpiperazine-1-carboxylate (115, 1.38 g, 6.91 mmol, AK Scientific, Inc., Union City, Calif.), sodium tert-butoxide (0.73 g, 7.60 mmol, Sigma-Aldrich), and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (i.e., “X-Phos,” 0.49 g, 1.04 mmol, Sigma-Aldrich). The mixture was degassed under argon and then tris(dibenzylideneacetone)dipalladium (Pd2(DBA)3, 0.63 g, 0.69 mmol, Sigma-Aldrich) was added to form a reaction mixture. The reaction mixture, heated in an oil bath maintained at temperature within the range of from 80° C. to 85° C., was stirred for 1.5 hours. Thereafter, the mixture was cooled to a temperature of about 25° C., poured onto cold water, and extracted with EtOAc. The organic layer was separated, washed with brine, and concentrated to an oil which was chromatographed on a silica gel column eluted with 10:90 EtOAc:hexanes and 20:80 EtOAc:hexanes to provide 1.71 g of 116 as a solid (63% yield). 1H NMR (CDCl3) δ: 1.25 (3H, d, J=6.80 Hz), 1.46 (3H, s), 1.48 (9H, s), 1.53 (3H, s), 2.89 (1H, dt, J=3.29, 13.59 Hz), 3.09 (1H, dd, J=3.73, 12.06 Hz), 3.23 (1H, dt, J=2.85, 13.59 Hz), 3.69 (1H, t, J=7.89 Hz), 3.83 (1H, d, J=12.72 Hz), 3.92 (1H, d, J=13.81 Hz), 4.01 (1H, d, J=12.90 Hz), 4.27 (1H, t, J=6.14 Hz), 4.31 (1H, brs), 5.01 (1H, t, J=7.24 Hz), 7.30 (1H, d, J=1.97 Hz), 7.95 (1H, s). LC/MS (M+1): m/z=396.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([OH:16])(=O)/[CH:10]=[CH:11]\[C:12]([NH2:14])=[O:13].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:12]1(=[O:13])[NH:14][C:9](=[O:16])[CH:10]=[CH:11]1
Reactant: NC(=O)/C=C\C(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: C=Cc1ccccc1
Product: O=C1C=CC(=O)N1

Procedure:
5.0 g of Styrene/maleamic acid and 0.5 g of anhydrous sodium acetate were added to 50 mL of acetic anhydride in a round bottom flask equipped with an inert gas inlet tube, magnetic stirrer and a heating bath. The resulting solution was heated and maintained at 80°-85° C. under nitrogen for 3 hr. The cooled solution was poured in a slow stream into a well stirred beaker of 400 ml cold (5°-10° C.) water. The resulting solid was collected by suction filtration, washed with four portions of acidic (1 mL acetic acid per 200 mL of water) ice water and vacuum dried. Nearly quantitative yields of product were obtained.
Reaction SMILES: Cl.Cl[C:3]1[CH:4]=[CH:5][C:6]2[CH2:15][C@H:14]3[C@@H:9]([CH2:10][CH2:11][CH2:12][N:13]3[CH2:16][CH2:17][CH3:18])[CH2:8][C:7]=2[N:19]=1.Br.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH-].[Na+]>O>[CH2:21]([NH:28][C:3]1[CH:4]=[CH:5][C:6]2[CH2:15][C@H:14]3[C@@H:9]([CH2:10][CH2:11][CH2:12][N:13]3[CH2:16][CH2:17][CH3:18])[CH2:8][C:7]=2[N:19]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCCN1CCC[C@H]2Cc3nc(Cl)ccc3C[C@@H]21
Reactant: NCc1ccccc1
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCN1CCC[C@H]2Cc3nc(NCc4ccccc4)ccc3C[C@@H]21
Temperature: 240 °C
Reaction time: 0.25 h
Yield: 22.3 %

Procedure:
A mixture of (±)-trans-2-chloro-6-propyl-5,5a,6,7,8,9,9a,10-octahydropyrido[2,3-g]quinoline hydrochloride (2.27 g, 7.50 mmol) and benzylamine hydrobromide (15.0 g) was heated to 240° C. to form a brown, molten semi-solid. After 15 minutes, the molten semi-solid was poured into water, made basic with dilute NaOH solution, and extracted with methylene chloride. The extract was dried (Na2SO4) and concentrated to give a brown oil. Purification by flash chromatography (6% methanol in methylene chloride, NH4OH) provided (±)-trans-2-benzylamino-6-propyl-5,5a,6,7,8,9,9a,10-octahydropyrido[2,3-g]quinoline (Rf =0.35, 561 mg, 22% yield) as a brown oil.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C(N(CC)C(C)C)(C)C.[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][S:31][C:32]1[C:37]([N+:38]([O-:40])=[O:39])=[CH:36][CH:35]=[CH:34][N:33]=1)[C:23]([OH:25])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15]>C(#N)C>[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][S:31][C:32]1[C:37]([N+:38]([O-:40])=[O:39])=[CH:36][CH:35]=[CH:34][N:33]=1)[C:23]([O:25][CH2:2][C:3]#[N:4])=[O:24])=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNSc1ncccc1[N+](=O)[O-])C(=O)O
Reactant: N#CCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNSc1ncccc1[N+](=O)[O-])C(=O)OCC#N
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.2 %

Procedure:
Bromoacetonitrile (76 μl, 1.124 mmol) and N,N-diisopropylethylamine (196 μl, 1.124 mmol) were added to a solution of ((S)-2-((tert-butoxycarbonyl)amino)-6-(((3-nitropyridin-2-yl)thio)amino)hexanoic acid (Compound tk87) (150 mg, 0.375 mmol) in acetonitrile (6 ml), and the reaction solution was stirred at room temperature for 5 hours. Bromoacetonitrile (49 μl, 0.413 mmol) was further added and the mixture was stirred at room temperature for 1 hour to complete the reaction. The reaction mixture was concentrated under reduced pressure using an evaporator, and the residue was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-cyanomethyl 2-((tert-butoxycarbonyl)amino)-6-(((3-nitropyridin-2-yl)thio)amino)hexanoate (Compound tk88) (152 mg, 92%).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[C:19]#[N:20])[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=[O:26].[K+].[K+].OO>CS(C)=O>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[C:19]([NH2:20])=[O:26])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccccc1C=C1c2ccccc2CCc2ccccc21
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccccc1C=C1c2ccccc2CCc2ccccc21

Procedure:
Dissolve 2-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-benzonitrile (100 mg, 0.32 mmol) in DMSO (3 mL) and add solid K2CO3 (50 mg) followed by 30% H2O2 (100□1). Stir the reaction for 3 h. and quench by pouring into water. Collect the white solid and dry in a vacuum oven to yield 84 mg (81%). 1H NMR (DMSO-d6) δ2.95 (br s, 2H), 3.38 (br s, 2H), 6.67-7.56 (m, 12H), 7.90 (s, 1H); MS (ES) 326 (M+1) (M−1). HPLC shows 95% purity.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].CO[C:7]1[CH:12]([C:13](OCC)=[O:14])[CH2:11][CH:10]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:9][N:8]=1>O>[NH2:3][C:2]1[N:4]=[C:13]([OH:14])[C:12]2[CH2:11][CH:10]([CH2:18][O:19][Si:20]([C:23]([CH3:25])([CH3:24])[CH3:26])([CH3:22])[CH3:21])[CH2:9][NH:8][C:7]=2[N:1]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)C1CC(CO[Si](C)(C)C(C)(C)C)CN=C1OC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC1CNc2nc(N)nc(O)c2C1
Temperature: 90 °C
Yield: 73.1 %

Procedure:
A mixture of 9.8 g of guanidine free base and 13.8 g of 2-methoxy-3-carboethoxy-5-[t-butyl(dimethyl)silyloxymethyl]-3,4,5,6-tetrahydropyridine was heated at 90° C. under nitrogen for 18 hours. The mixture was cooled to room temperature, and water was added to give a white precipitate. This was filtered to give 9.5 g of the title compound: MS m/z 311 (M+ +1), 310 (M+); 300-MHz 1H NMR (DMSO-d6) δ0.03 (s, 6 H), 0.85 (S, 9 H), 1.70-1.88 (m, 2 H), 2.27-2.38 (m, 1 H), 2.78-2.88 (m, 1 H), 3.16-3.27 (m, 1 H), 3.37-3.45 (m, 1 H), 3.49-3.58 (m, 1 H), 5.92 (b s, 2 H), 6.21 (b s, 1 H), 9.67 (b s, 1 H).