Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([OH:33])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])=[CH:21][CH:22]=2)[CH:17]=[C:16]1[CH3:34].[CH3:35][N:36]([CH3:40])[C:37](Cl)=[O:38].CCOCC.Cl>N1C=CC=CC=1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:37](=[O:38])[N:36]([CH3:40])[CH3:35])=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:14][N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([OH:33])([C:25]([F:26])([F:27])[F:28])[C:29]([F:32])([F:31])[F:30])=[CH:21][CH:22]=2)[CH:17]=[C:16]1[CH3:34]
Reactant: CN(C)C(=O)Cl
Reactant: Cc1oc(-c2ccc(O)cc2)nc1Cn1c(C)cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1oc(-c2ccc(OC(=O)N(C)C)cc2)nc1Cn1c(C)cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 65.8 %

Procedure:
A solution of 25 mg (0.052 mmol) 4-{5-methyl-4-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-indol-1-ylmethyl]-oxazol-2-yl}-phenol (example 99) in 1 mL of pyridine was treated with 28 mg (0.26 mmol) of dimethyl carbamoylchloride and stirred at 60° C. for 2 hours. Et2O and aqueous HCl were added and the phases separated. The aqueous phase was extracted with Et2O and the combined organic phases dried over Na2SO4. Evaporation of the solvent and column chromatography on silica gel with n-heptane/EtOAc 1:1 yielded 19 mg (66%) of dimethyl-carbamic acid 4-{5-methyl-4-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-indol-1-ylmethyl]-oxazol-2-yl}-phenyl ester, light yellow solid, MS: 556 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[CH3:16][NH2:17]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:17][CH3:16])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CNS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 65.1 %

Procedure:
A solution of 4-chloro-3-nitrobenzenesulfonyl chloride (10 g, 39.1 mmol) in THF (100 mL) was cooled to −40° C. before being treated with a solution of methylamine hydrochloride (2.64 g, 39.1 mmol) in 10 ml of water followed by TEA (5.44 mL, 39.1 mmol). The reaction mixture was stirred and allowed to warm to room temperature over 1 hour before being partitioned between 350 mL EtOAc and 30 mL brine. The organic layer was washed twice with brine, dried over MgSO4 and subjected to flash chromatography (330 g silica gel, 0-40% EtOAc/hexane) to afford 4-chloro-N-methyl-3-nitrobenzenesulfonamide (6.38 g, 65%) as a light yellow solid. MS (m/z) 251.0 (M+H+).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:11](=[O:20])[NH:12][C:13]4[N:14]([N:16]=[C:17]([CH3:19])[CH:18]=4)[C:15]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2].[Na].Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:11](=[O:20])[N:12]([CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[C:13]4[N:14]([N:16]=[C:17]([CH3:19])[CH:18]=4)[C:15]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c1ncc1c(=O)[nH]c3cc(C)nn3c12
Reactant: ClCCN1CCOCC1
Agent: [Na]
Product: CCn1ncc2c1ncc1c(=O)n(CCN3CCOCC3)c3cc(C)nn3c12
Reaction time: 24 h

Procedure:
2.7 g. of 8-ethyl-2-methyl-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one (0.01 mol.) and 0.3 g. of sodium are refluxed for 1 hour in 30 ml. of diethylene glycoldimethylether with stirring. The temperature is lowered to 90° and 2 g. of 1-chloro-2-morpholinoethane are added and stirring is continued for 24 hours. The inorganic precipitate is filtered off, the solvent removed in vacuo and the crystalline product, 8-ethyl-2-methyl-4-(2-morpholino)ethyl-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido-[3,4-e]pyrimidin-5(8H)-one is recrystallized from ethyl acetate, yield 3.1 g. (81%); m.p. 140°-141°.
Reaction SMILES: [H-].[Na+].[SH:3][CH2:4][CH2:5][OH:6].CN(C)C=[N:10][S:11]([C:14]1[CH:19]=[CH:18][C:17](F)=[C:16]([F:21])[CH:15]=1)(=[O:13])=[O:12]>CN(C=O)C>[OH:6][CH2:5][CH2:4][S:3][C:17]1[CH:18]=[CH:19][C:14]([S:11]([NH2:10])(=[O:13])=[O:12])=[CH:15][C:16]=1[F:21]
Reactant: CN(C)C=NS(=O)(=O)c1ccc(F)c(F)c1
Reactant: OCCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(SCCO)c(F)c1
Temperature: 80 °C

Procedure:
Sodium hydride (1.11 g, 50% oil dispersion, 0.023 mol) was washed with petroleum ether then suspended in freshly degassed DMF (50 ml). 2-Mercaptoethanol (1.8 g, 0.023 mol) was added dropwise under nitrogen. When gas evolution ceased, N,N-Dimethyl-N'-(3,4-difluorobenzenesulfonyl)formamidine (5 g, 0.02 mol) was added and the mixture was heated in an oil bath about 2 hours (80° C.). DMF was removed in vacuo and the residue was treated with 100 ml of 10% NaOH. After an additional hour of stirring the solution was acidified with concentrated HCl and extracted with ethylacetate (2×100 ml), and dried over anhydrous magnesium sulfate. Removal of solvent left 3 g of a white solid which when recrystallized from butyl chloride had m.p.=109°-111° C.
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:23])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CN2CCN(C(=O)OCc3ccccc3)CC2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(CN2CCN(C(=O)OCc3ccccc3)CC2)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.4 %

Procedure:
To a solution of benzyl 4-((6-(tert-butoxycarbonylamino)pyridin-3-yl)methyl)piperazine-1-carboxylate (104; 2.20 g, 5.20 mmol) in dichloromethane (10 mL) was added TFA (3.4 g, 31.2 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 12 h and then concentrated under reduced pressure. Enough saturated aqueous Na2CO3 was added to adjust the pH=9. The resulting mixture was then extracted with dichloromethane (3×25 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to afford benzyl 4-((6-aminopyridin-3-yl)methyl)piperazine-1-carboxylate 105 (1.50 g, 89%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[C:33]1([N:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)N)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:33]3[C:34]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(F)c3)CC2)c1
Reactant: NN(c1ccccc1)c1ccccc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc(F)c4)n(-c4ccccc4)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1,1-diphenylhydrazine hydrochloride: ESMS m/e: 574.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]([Cl:15])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([OH:13])=[C:8]([Cl:14])[CH:7]=1.O[CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:14][C:8]1[CH:7]=[C:6]([O:5][CH2:4][CH:3]=[C:2]([Cl:1])[Cl:15])[CH:11]=[C:10]([Cl:12])[C:9]=1[O:13][CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1
Reactant: OCc1ccncc1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClC(Cl)=CCOc1cc(Cl)c(OCc2ccncc2)c(Cl)c1
Temperature: 25 °C
Yield: 52.2 %

Procedure:
To a solution of 0.43 g of 4-(3,3-dichloro-2-propenyloxy)-2,6-dichlorophenol, 0.16 g of 4-(hydroxymethyl)pyridine and 0.39 g of triphenylphosphine dissolved in 10 ml of tetrahydrofuran was added dropwise a solution of 0.30 g of diisopropyl azodicarboxylate dissolved in 5 ml of tetrahydrofuran, while stirring at room temperature. After stirring at room temperature for 12 hours, the reaction mixture was concentrated, to which 20 ml of diethyl ether was added, and the precipitate was filtered. The filtrate was concentrated, and the residue was subjected to silica gel chromatography, which afforded 0.29 g of 3,5-dichloro-4-(4-pyridylmethyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene (51% yield), m.p. 74.0° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1>CN(C)C1C=CN=CC=1.C1(C)C(C)=CC=CC=1>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][CH:21]=[C:20]2[O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc([N+](=O)[O-])cc1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1C
Product: COc1cc2nccc(Oc3ccc(C(=O)c4ccc([N+](=O)[O-])cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.4 %

Procedure:
Under argon, 4-hydroxyphenyl 4-nitrophenyl ketone (370 mg) obtained in Example 134 and 4-dimethylaminopyridine (204 mg) were added to xylene (5 ml), and the admixture was stirred at room temperature for 1 hour. 4-Chloro-6,7-dimethoxyquinoline (340 mg) was added, and the mixture was then refluxed with heat for 23 hours. The reaction mixture was treated in the same manner as described in Example 130 to obtain 238 mg of the title compound (yield: 36%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.[F:14][C:15]([F:26])([F:25])[S:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])/[C:6](=[CH:21]/[C:20]1[CH:23]=[CH:24][C:17]([S:16][C:15]([F:26])([F:14])[F:25])=[CH:18][CH:19]=1)/[CH2:5]2
Reactant: O=Cc1ccc(SC(F)(F)F)cc1
Reactant: COc1cc2c(cc1Br)CCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1Br)C/C(=C\c1ccc(SC(F)(F)F)cc1)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 11 (250 mg, 1.04 mol) in toluene 15 mL was added 4-((trifluoromethyl)thio)benzaldehyde 72 (235 mg, 1.144 mol). PTSA (357 mg, 2.08 mol) was added, the reaction mixture stirred at 120° C. for 6 h, diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound 104 and was purified through flash chromatography by using 100-200 mesh silica gel. The resulting compound (E)-5-bromo-6-methoxy-2-(4-((trifluoromethyl) thio)benzylidene)-2,3-dihydro-1H-inden-1-one 104 was eluted at 10% ethyl acetate in hexane to afford yellow coloured solid.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]1[N:25]=[C:24]2[C:20]([NH:21][C:22](=[O:34])[N:23]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])=[C:19]([C:35]([O:37]CC)=O)[N:18]=1)(C(C)(C)C)(C)C.[NH2:40]C1C(C(OCC)=O)=NC(NC2C=CC=C(CO[Si](C(C)(C)C)(C)C)C=2)=NC=1NC1C=CC=CC=1OC>ClCCl>[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]1[N:25]=[C:24]2[C:20]([NH:21][C:22](=[O:34])[N:23]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])=[C:19]([C:35]([NH2:40])=[O:37])[N:18]=1
Reactant: CCOC(=O)c1nc(Nc2cccc(CO[Si](C)(C)C(C)(C)C)c2)nc(Nc2ccccc2OC)c1N
Reactant: CCOC(=O)c1nc(Nc2ccccc2CO[Si](C)(C)C(C)(C)C)nc2c1[nH]c(=O)n2-c1ccccc1OC
Solvent: ClCCl
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(Nc3ccccc3CO)nc21
Yield: 91 %

Procedure:
Ethyl 2-(2-((tert-butyldimethylsilyloxy)methyl)phenylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate. Ethyl 5-amino-2-(3-((tert-butyldimethylsilyloxy)methyl)phenylamino)-6-(2-methoxyphenylamino)pyrimidine-4-carboxylate (0.200 g, 0.382 mmol) and 1,1′-1,1′-carbonyldiimidazole (0.433 g, 2.67 mmol) in dichloromethane (20 mL) were reacted according to General Procedure F and purified using biotage chromatography (10 to 90% EtOAc in hexanes) to afford the title compound (0.190 g, 91%). MS (ESI) m/z 550.5 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH:27]1([S:32][CH2:33][C:34]2[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:39][CH2:38][C:37]1[CH:40]=[CH:41][C:34]([CH2:33][S:32][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:35][CH:36]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: NCc1ccc(CSC2CCCC2)cc1
Solvent: Cc1ccccc1
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc(CSC4CCCC4)cc3)c2CC1)C(F)(F)F
Yield: 40.7 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.4 g, 0.94 mmol) with 4-(cyclopentylthiomethyl)-benzylamine (229 mg, 1.03 mmol) in toluene (10 mL). Purify the crude mixture by chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 4:1 gradient) to obtain 7-chloro-6-[4-(cyclopentylthiomethyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (190 mg, 41%). MS (ES+) m/z: 498 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH:12]1([CH2:15][CH2:16][NH:17][C:18]([C:20]2[N:21]=[N:22][C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)=[O:19])[CH2:14][CH2:13]1>>[CH:12]1([CH2:15][CH2:16][NH:17][C:18]([C:20]2[N:21]=[N:22][C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:4](=[O:5])[C:3]4[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:2]=4[Cl:1])[CH2:28][CH2:27]3)=[CH:24][CH:25]=2)=[O:19])[CH2:14][CH2:13]1
Reactant: O=C(Cl)c1cc(F)ccc1Cl
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)c3cc(F)ccc3Cl)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 2-chloro-5-fluorobenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (94% yield). m.p. 194-196° C. 1H NMR (300 MHz, CDCl3) δ 8.05, 7.96, 7.41-7.37, 7.11-7.03, 7.00, 4.07-3.34, 1.55-1.46, 0.79-0.68, 0.48-0.42, 0.11-0.06. 13C NMR (75 MHz, CDCl3) δ 165.7, 163.0, 160.0, 159.7, 145.5, 136.7, 131.5, 127.1, 125.3, 117.8, 115.2, 112.5, 46.0, 44.8, 44.6, 41.2, 39.6, 34.5, 8.6, 4.2. MS (ES+) m/z 432.2 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][CH:4]=1.[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K]>CN(C)C=O>[C:11]1(=[O:21])[N:15]([CH2:2][C:3]2[N:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][CH:4]=2)[C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12
Reactant: N#Cc1cccc(CCl)n1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: N#Cc1cccc(CN2C(=O)c3ccccc3C2=O)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.1 %

Procedure:
A mixture of 6-chloromethyl-2-pyridinecarbonitrile (2.75 g) and potassium phthalimide (3.35 g) in N,N-dimethylformamide (27.5 ml) was stirred at ambient temperature for 4 hours. After the solvent was evaporated in vacuo, water (50 ml) was added to the residue and the resulting precipitate was collected by filtration to give 6-phthalimidomethyl-2-pyridinecarbonitrile (4.60 g).
Reaction SMILES: Cl.[NH2:2][C:3]1([CH2:8]Cl)[CH2:7][CH2:6][CH2:5][CH2:4]1.[N+:10]([C:13]1[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[C:16]([N:23]=[C:24]=[S:25])=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[N+:10]([C:13]1[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[C:16]([N:23]=[C:24]2[S:25][CH2:8][C:3]3([CH2:7][CH2:6][CH2:5][CH2:4]3)[NH:2]2)=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(N=C=S)c2c1CCCC2
Reactant: NC1(CCl)CCCC1
Agent: Cl
Product: O=[N+]([O-])c1ccc(N=C2NC3(CCCC3)CS2)c2c1CCCC2

Procedure:
1-Amino-5,6,7,8-tetrahydronaphthaline was converted to 1-acetamino-5,6,7,8-tetrahydronaphthaline according to Method A2a, Step 1. The acetanilide was converted to 1-acetamino-4-nitro-5,6,7,8-tetrahydronaphthaline according according to Method A2a, Step 2. The acetanilide was deprotected according to Method A2a, Step 3 to give 1-amino-4-nitro-5,6,7,8-tetrahydronaphthaline. The aniline was converted to 4-nitro-5,6,7,8-tetrahydro-1-naphthyl isothiocyanate according to Method A2a, Step 3. 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 4-nitro-5,6,7,8-tetrahydro-1-naphthyl isothiocyanate according to Method C1a to give 2-(4-nitro-5,6,7,8-tetrahydro-1-naphthylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(4-nitro-5,6,7,8-tetrahydro-1-naphthylimino)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]([CH3:31])[C:16]([NH:18][C:19]2[C:24]([Cl:25])=[C:23]([O:26][CH3:27])[CH:22]=[C:21]([O:28][CH3:29])[C:20]=2[Cl:30])=[O:17])[CH:10]=1.C(N(CC)CC)C.[Cl:39]/[CH:40]=[CH:41]\[C:42](O)=[O:43].C(Cl)Cl.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>>[Cl:39]/[CH:40]=[CH:41]\[C:42]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:10]=[C:11]([N:15]([CH3:31])[C:16]([NH:18][C:19]2[C:20]([Cl:30])=[C:21]([O:28][CH3:29])[CH:22]=[C:23]([O:26][CH3:27])[C:24]=2[Cl:25])=[O:17])[N:12]=[CH:13][N:14]=1)=[O:43]
Reactant: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2cc(Nc3ccccc3N)ncn2)c1Cl
Reactant: O=C(O)/C=C\Cl
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2cc(Nc3ccccc3NC(=O)/C=C\Cl)ncn2)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
The title compound was synthesized following the approach outlined in Procedure 2A (Example 100), modifying step (i) to the following procedure: To a solution of 1-(6-((2-aminophenyl)amino)pyrimidin-4-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylurea (20 mg, 0.043 mmol), triethylamine (21.8 g, 0.22 mmol), and (Z)-3-chloroacrylic acid (5.5 g, 0.052 mmol) in DCM (0.86 ml, 13.3 mmol), cooled to 0° C. was added 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (49 g, 0.78 mmol, 50% solution of EtOAc). The resulting mixture was stirred at room temperature for 2 h and concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (15 mg, yield: 63%). 1H NMR (400 MHz, CDCl3) δ X; MS (ESI): 551.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.[CH3:20][C:21]1[N:22]=[C:23]([CH:26]=O)[S:24][CH:25]=1>>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH3:13])[CH2:26][C:23]3[S:24][CH:25]=[C:21]([CH3:20])[N:22]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: Cc1csc(C=O)n1
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: Cc1csc(CN(C)Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)n1
Yield: 62 %

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)methylamine was reacted with 4-methyl-2-thiazole-carboxaldehyde using standard reductive amination conditions. The resulting crude solid was triturated with diethyl ether to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-(4-methyl-thiazol-2-ylmethyl)-amine as a solid (62% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was triturated with diethyl ether and methanol to give 429 as a solid (95% yield). NMR (CDCl3, 400 MHz), 2.46 (3H, s), 2.47 (3H, s), 3.91 (4H, t, J=4.4), 3.97 (2H, s), 3.99 (2H, s), 4.07 (4H, t, J=5.2), 5.24 (2H, s), 6.90 (1H, d, J=0.8), 7.34 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=469
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](OCC)=[O:14])=[N:10][C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:4][CH:3]=1.[NH2:26][N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13]([NH:26][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:14])=[N:10][C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:6][CH:7]=1
Reactant: NN1CCCCC1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Br)cc2)s1
Solvent: ClCCl
Product: O=C(NN1CCCCC1)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Br)cc2)s1
Temperature: 50 °C
Yield: 78 %

Procedure:
Part E: A stirred mixture containing ethyl 5-(4-bromophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxylate (1.00 gram, 2.2 mmol) and 1-aminopiperidine (10 mL) is heated overnight at 50° C. The resulting mixture is allowed to attain room temperature, dichloromethane is added and the resulting solution is twice washed with water, dried over MgSO4, filtered and concentrated in vacuo to give an oil. Flash chromatographic purification of this oil (ethyl acetate/petroleum ether=1/3 (v/v)) gives 5-(4-bromophenyl)-4-(2,4-dichlorophenyl)-N-(1-piperidinyl)thiazole-2-carboxamide (870 mg, 78% yield). Melting point: 171-173° C.
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[C:30]1([C:36]2[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][CH:37]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:30]1([C:36]2[CH:37]=[CH:38][C:39]([C:40]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:3])=[O:29])[CH2:19][C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22][CH:21]=3)=[O:18])[CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[O:41])=[CH:43][CH:44]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Agent: Cl
Product: CN(C(=O)c1ccc(-c2ccccc2)cc1)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with 4-phenylbenzoic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(4-phenylbenzoyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 546 (M+H)+.