Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:49])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:17](Br)=[C:16]([N:19](COCC[Si](C)(C)C)COCC[Si](C)(C)C)[N:15]3[N:36]=[CH:37][C:38]([C:39]4[CH:40]=[N:41][C:42]5[C:47]([CH:48]=4)=[CH:46][CH:45]=[CH:44][CH:43]=5)=[C:14]3[N:13]=2)[CH2:8][CH2:7]1)C.[Sn]([C:63]#[N:64])(CCCC)(CCCC)CCCC.Cl>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[NH2:19][C:16]1[N:15]2[N:36]=[CH:37][C:38]([C:39]3[CH:40]=[N:41][C:42]4[C:47]([CH:48]=3)=[CH:46][CH:45]=[CH:44][CH:43]=4)=[C:14]2[N:13]=[C:12]([CH:9]2[CH2:10][CH2:11][CH:6]([CH2:5][C:4]([OH:3])=[O:49])[CH2:7][CH2:8]2)[C:17]=1[C:63]#[N:64]
Reactant: CCCC[Sn](C#N)(CCCC)CCCC
Reactant: CCOC(=O)CC1CCC(c2nc3c(-c4cnc5ccccc5c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1c(C2CCC(CC(=O)O)CC2)nc2c(-c3cnc4ccccc4c3)cnn2c1N
Temperature: 100 °C
Reaction time: 18 h
Yield: 26.5 %

Procedure:
A degassed mixture of (4-{7-[bis-(2-trimethylsilanyl-ethoxymethyl)-amino]-6-bromo-3-quinolin-3-yl-pyrazolo[1,5-a]pyrimidin-5-yl}-cyclohexyl)-acetic acid ethyl ester (0.078 mmol, 60 mg), Bu3SnCN (50 mg, 0.156 mmoL), Pd[P(t-Bu)3]2 (8.3 mg, 0.016 mmoL) in Dioxane (1 mL) was heated at 100° C. for 18 h. The reaction mixture was concentrated in vacuo. The crude mixture was dissolved in 2:1 MeOH:H2O (1.5 mL) and was treated with 2N NaOH(aq) (0.5 mL). The resulting reaction mixture was stirred at room temperature for 18 hours. Aqueous hydrochloride solution (1.0 N, 2 ml) was added to the reaction mixture and the resulting solution was stirred at 65° C. for 2 h. The solution was concentrated and purified by prep-LC to afford the title compound (8.8 mg) as a mixture of cis and trans isomers: LC/MS RT=3.88 min. Mass calculated for, M+H 427.18, observed 427.18.
Reaction SMILES: [CH2:1]([C:8]1[CH:23]=[CH:22][C:11]([O:12][CH2:13][CH2:14][NH:15][C:16]([CH2:18][CH:19]2[CH2:21][CH2:20]2)=O)=[C:10]([Cl:24])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:8]1[CH:23]=[CH:22][C:11]([O:12][CH2:13][CH2:14][NH:15][C:16](=[S:34])[CH2:18][CH:19]2[CH2:21][CH2:20]2)=[C:10]([Cl:24])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CC1CC1)NCCOc1ccc(Cc2ccccc2)cc1Cl
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: S=C(CC1CC1)NCCOc1ccc(Cc2ccccc2)cc1Cl
Reaction time: 0.33 h
Yield: 89 %

Procedure:
A mixture of 500 mg (1.52 mmol) of N-[2-(4-benzyl-2-chlorophenoxy)ethyl]-cyclopropane carboxyamide, 614 mg (1.52 mmol) of a Lawesson's reagent and 20 ml of anhydrous toluene was refluxed by heating with stirring. After 20 minutes, the reaction mixture was cooled and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 487 mg of N-[2-(4-benzyl-2-chlorophenoxy)ethyl]-cyclopropane thiocarboxyamide as a colorless oily substance nD23.6 1.6041). After one week, the oily substance caked as a white solid (m.p. 90°-92° C.).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.[CH3:27][C:28]1([CH3:41])[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33](B(O)O)[CH:34]=2)[O:29]1.N1C=CC=CC=1.C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH3:27][C:28]1([CH3:41])[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([N:3]3[C:4](=[O:26])[C:5]([CH2:11][C:12]4[CH:17]=[CH:16][C:15]([C:18]5[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=5)=[CH:14][CH:13]=4)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=[C:2]3[CH3:1])[CH:34]=2)[O:29]1
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC1(C)C=Cc2cc(B(O)O)ccc2O1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc3c(c2)C=CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 96 h
Yield: 50.8 %

Procedure:
A mixture of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (21 g), (2,2-dimethyl-2H-chromen-6-yl)boronic acid (12 g), copper(II) acetate (11 g), pyridine (24 mL), triethylamine (42 mL), molecular sieves 4 A (40 g) and dichloromethane (200 mL) was stirred for 4 days. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (15 g, 51%) as a colorless solid.
Reaction SMILES: COC(=O)CN[C:6](=[O:43])[CH2:7][NH:8][C:9](=[O:42])[C@H:10](C(C)C)[NH:11][C:12](=[O:38])[C@H:13]([CH:35]([CH3:37])[CH3:36])[NH:14][C:15](=[O:34])[C@H:16]([CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH:17]C(OC(C)(C)C)=O.[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46]>C(Cl)Cl>[F:48][C:47]([F:50])([F:49])[C:45]([OH:51])=[O:46].[CH3:45][O:46][C:6](=[O:43])[CH2:7][NH:8][C:9](=[O:42])[CH2:10][NH:11][C:12](=[O:38])[C@H:13]([CH:35]([CH3:36])[CH3:37])[NH:14][C:15](=[O:34])[C@H:16]([CH2:25][O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[NH2:17]
Reactant: COC(=O)CNC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C)C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CNC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](N)COCc1ccccc1)C(C)C
Yield: 92 %

Procedure:
N-tert-butoxycarbonyl O-benzyl L-seryl L-valyl L-valyl glycyl glycine methyl ester 24 (SEQ ID NO: 7) (0.525 g, 0.844 mmol) was dissolved in a 50% (v/v) solution of TFA in CH2Cl2 (12 mL) at room temperature. The reaction mixture was stirred for 1 h 30 min before the solvent and bulk of excess TFA were evaporated. Et2O (10 mL) was added to the liquid residue, which resulted in precipitation of a white solid. The Et2O was decanted off and the residue washed with additional portions of Et2O (2×10 mL) and dried under reduced pressure overnight affording the title compound as a white solid (0.494 g, 92%); δH (300 MHz; d6-DMSO) 8.47 (1H, d, J 9, NH(Valx)), 8.29-8.20 (5H, m, NH3+/NH(Glyx)/NH(Glyy)), 8.00 (1H, d, J 8, NH(Valy)) 7.38-7.27 (5H, m, Ph), 4.51 (2H, s, CH2Ph), 4.34 (1H, dd, J 7 and 9, CαH(Valx)), 4.17-4.12 (2H, m, CαH(Valy)/CαH(Ser(Bn))), 3.85 (2H, dd, J 4 and 6, CαH2(Glyx)), 3.76-3.64 (4H, m, CH2(Ser(Bn))/CαH2(Glyy)), 3.62 (3H, s, OCH3), 2.04-1.89 (2H, m, CH(CH3)2), 0.89-0.81 (12H, m, CH3); δC (75 MHz; d6-DMSO) 171.1, 170.6, 170.1, 169.2, 166.2, 158.3 (q, JCF 32) 137.5, 128.2, 127.6, 127.5, 116.9 (q, JCF 291), 72.5, 68.6, 58.1, 57.9, 52.2, 51.6, 41.6, 40.5, 30.6, 30.2, 19.1, 19.1, 18.2, 18.0; m/z (ESI) 522.2920 (M+; C25H40N5O7 requires 522.2927)
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][C:16]([OH:22])=[CH:17][CH:18]=3)[N:13]=[C:12]2[C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:7][CH:6]=1.C(O[CH2:34][CH3:35])(=O)C>N1CCCCC1>[OH:22][C:16]1[CH:15]=[C:14]2[C:19]([C:20](=[O:21])[N:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:11]4[CH2:35][CH2:34][CH2:6][CH2:7][CH2:8]4)=[CH:6][CH:7]=3)[C:12]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)=[N:13]2)=[CH:18][CH:17]=1
Reactant: CCOC(C)=O
Reactant: O=c1c2ccc(O)cc2nc(-c2ccc(O)cc2)n1-c1ccc(OCCCl)cc1
Solvent: C1CCNCC1
Product: O=c1c2ccc(O)cc2nc(-c2ccc(O)cc2)n1-c1ccc(OCCN2CCCCC2)cc1
Temperature: 25 °C

Procedure:
A solution containing 0.25 g (0.000612 mol) of 3-[4-(2-chloro-ethoxy)-phenyl]-7-hydroxy-2-(4-hydroxy-phenyl)-3H-quinazolin-4-one in 7 mL of piperidine was stirred and heated to reflux for 2 hours. After cooling to room temperature, ethyl acetate was added to the reaction mixture and the solvents were co-evaporated to near dryness in a rotary evaporator. The dark residue was extracted with ethyl acetate and water. The aqueous layer was removed and chilled on ice. The precipitate which then formed was collected by vacuum filtration (0.052 g, mp 185-190° C.) and was shown to be the hydrochloride salt monohydrate.
Reaction SMILES: [CH:1]1([NH:6][CH2:7][C:8]2[S:12][C:11](B(O)O)=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:29]1[CH2:34][CH2:33][N:32]([S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[CH2:31][CH2:30]1.C([O-])([O-])=O.[K+].[K+]>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>[CH:1]1([NH:6][CH2:7][C:8]2[S:12][C:11]([C:17]3[CH:18]=[C:19]4[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=3)[NH:22][CH:21]=[C:20]4[CH:29]3[CH2:30][CH2:31][N:32]([S:35]([CH2:38][CH3:39])(=[O:36])=[O:37])[CH2:33][CH2:34]3)=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: OB(O)c1ccc(CNC2CCCC2)s1
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: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNC5CCCC5)s4)cc23)CC1
Yield: 85 %

Procedure:
Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), cyclopentylamine (28 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 48 mg of crude {5-[(cyclopentylamino)methyl]-2-thienyl}boronic acid. The crude {5-[(cyclopentylamino)methyl]-2-thienyl}boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give 93.5 mg of the title compound (85%).
Reaction SMILES: CN(C)C=[N:4][S:5]([C:8]1[N:9]([CH3:21])[N:10]=[C:11]2[C:16]=1[C:15]([O:17][CH2:18][CH2:19][F:20])=[CH:14][CH:13]=[CH:12]2)(=[O:7])=[O:6].Cl>C(O)C>[F:20][CH2:19][CH2:18][O:17][C:15]1[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=1)=[N:10][N:9]([CH3:21])[C:8]=2[S:5]([NH2:4])(=[O:6])=[O:7]
Reactant: CN(C)C=NS(=O)(=O)c1c2c(OCCF)cccc2nn1C
Agent: Cl
Solvent: CCO
Product: Cn1nc2cccc(OCCF)c2c1S(N)(=O)=O
Yield: 85 %

Procedure:
A mixture comprising 3 4 g of N1,N1 -dimethyl-N2 -([4-(2-fluoroethoxy)-2-methyl-2H-indazol-3-yl]sulfonyl}formamidine, 5 ml of concentrated hydrochloric acid and 50 ml of ethanol, was refluxed for 12 hours. Disappearance of the starting material was confirmed by TLC, and then ethanol was distilled off. Water was added to the residue, whereupon the formed crystals were collected by filtration and washed with water and IPE to obtain 2.4 g (yield: 85%) of the desired product. Melting point: 178°-180° C.
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[C:13]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1)(=[O:28])=[O:27].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:2]2[N:24]=[C:5]3[C:6]([NH:10][CH2:11][C:12]4[C:13]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[N:14][CH:15]=[CH:16][CH:17]=4)=[CH:7][CH:8]=[CH:9][N:4]3[N:3]=2)=[CH:31][CH:30]=1)(=[O:27])=[O:28]
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: CN(c1ncccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN(c1ncccc1CNc1cccn2nc(Nc3ccc(S(C)(=O)=O)cc3)nc12)S(C)(=O)=O

Procedure:
N-(3-{[2-(4-Methanesulfonyl-phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino]-methyl}-pyridin-2-yl)-N-methyl-methanesulfonamide was prepared from N-{3-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-pyridin-2-yl}-N-methyl-methanesulfonamide (75.0 mg, 0.204 mmol) and 4-methanesulfonyl-phenylamine (39.0 mg, 0.228 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.009 g, 9%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.43 (dd, J=4.6, 1.4 Hz, 1H), 7.92-7.83 (m, 4H), 7.76 (d, J=8.8 Hz, 2H), 7.29 (dd, J=7.7, 4.7 Hz, 1H), 7.12 (s, 1H), 6.74 (t, J=7.5 Hz, 1H), 6.38 (d, J=7.7 Hz, 1H), 5.37 (t, J=6.4 Hz, 1H), 4.78 (d, J=6.3 Hz, 2H), 3.33 (s, 3H), 3.10 (s, 3H), 3.05 (s, 3H). MS=502 (MH)+.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:9](=[O:10])[CH2:8][S:7][C:6]1=[S:11])([OH:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH3:18][C:19]([CH3:23])([CH3:22])[CH:20]=O.Cl>O.CN(C=O)C>[C:1]([CH2:4][N:5]1[C:9](=[O:10])[C:8](=[CH:18][C:19]([CH3:23])([CH3:22])[CH3:20])[S:7][C:6]1=[S:11])([OH:3])=[O:2]
Reactant: CC(C)(C)C=O
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C=C1SC(=S)N(CC(=O)O)C1=O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
Into 20 ml of dry DMF was dissolved 1.5 g (0.008 mole) of 3-carboxymethylrhodanine. To the solution was added 2.2 g (0.016 mole) of K2CO3 at a room temperature, and further 1 g (0.012 mole) of 2,2-dimethylpropanal was added dropwise at 60° C. After agitating at 60° C. for 30 minutes, the reaction mixture was poured into water. The resultant was adjusted to pH 4 with a dilute hydrochloric acid and then extracted with ethyl acetate. The extract was purified through a silica gel column and recrystallized from a mixed solvent of ethyl acetate and ethanol to give 1.3 g of 3-carboxymethyl-5-(2,2-dimethylpropylidene)rhodanine in the form of light yellow needle (yield: 63%).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:4](=[O:20])[NH:3]1.[Br:22][C:23]1[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[C:24]=1[CH2:25]Br>>[Br:22][C:23]1[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[C:24]=1[CH2:25][N:3]1[C:2]([CH3:21])([CH3:1])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:17])[F:18])[CH:9]=2)[C:4]1=[O:20]
Reactant: CC1(C)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reactant: Clc1cc(Cl)c(CBr)c(Br)c1
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1Cc1c(Cl)cc(Cl)cc1Br
Yield: 83 %

Procedure:
Compound 35.2 was prepared as described for example 6.2, by reacting compound 1.1 with 2-bromo-4,6-dichlorobenzyl bromide 35.3. 4-[3-(2-Bromo-4,6-dichlorobenzyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile was obtained in a yield of 83%. 1H NMR: 8.35, d, 1H, 8.2, s, 1H, 8.05, d, 1H, 7.9, s, 1H, 7.8, s, 1H; 4.9, s, 2H, 1.35, s, 6H.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[C:7]([CH2:17][C:18](Cl)=[O:19])([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH:21]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[C:7]([CH2:17][C:18]([N:32]3[CH2:31][CH2:30][N:29]([C:26]4[CH:25]=[CH:24][C:23]([F:22])=[CH:28][CH:27]=4)[CH2:34][CH2:33]3)=[O:19])([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH:21]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc2c(c1)C(CC(=O)Cl)(c1ccccc1)C(=O)O2
Product: Cc1ccc2c(c1)C(CC(=O)N1CCN(c3ccc(F)cc3)CC1)(c1ccccc1)C(=O)O2

Procedure:
This compound was prepared by condensing 2-(2,3-dihydro-5-methyl-2-oxo-3-phenyl-3-benzofuranyl)acetyl chloride with 4-(4-fluorophenyl)piperazine according to the process described in Example 9, Stage B.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH3:18][N:19]([CH3:30])[CH2:20][CH2:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][N:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:29][C:26]1[CH:25]=[N:24][C:23]([NH:22][CH2:21][CH2:20][N:19]([CH3:30])[CH3:18])=[CH:28][CH:27]=1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CN(C)CCNc1ccc(N)cn1
Product: CN(C)CCNc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cn1
Yield: 66 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1 mmol) was reacted with N2-(2-(dimethylamino)ethyl)pyridine-2,5-diamine (270 mg, 1.5 mmol) to afford the desired product (300 mg, 66%) as a yellow solid: ESI MS m/z 454 [C22H24BrN5O+H]+.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH2:9][CH2:10][O:11][C:12]1[N:13]=[C:14]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][CH:33]([N:36]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]4)[CH2:32][CH2:31]3)=[CH:26][CH:25]=2)[C:15]([C:20]([NH2:22])=[O:21])=[N:16][C:17]=1[CH2:18][CH3:19])C1C=CC=CC=1>[Pd].C(O)(=O)C>[NH2:8][CH2:9][CH2:10][O:11][C:12]1[N:13]=[C:14]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([N:30]3[CH2:31][CH2:32][CH:33]([N:36]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]4)[CH2:34][CH2:35]3)=[CH:28][CH:29]=2)[C:15]([C:20]([NH2:22])=[O:21])=[N:16][C:17]=1[CH2:18][CH3:19]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1OCCN(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1OCCN
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.2 %

Procedure:
To a mixture of 5-[2-(dibenzylamino)ethoxy]-6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (172 mg) and acetic acid (2.84 mL) was added 10% palladium-supported carbon (53% wet product) (55 mg), followed by stirring at room temperature for 6 hours under a hydrogen gas atmosphere (4 atm). The mixture was filtered through celite, and then 20% palladium hydroxide-supported carbon (36 mg) was added thereto, followed by stirring overnight under a hydrogen gas atmosphere (4 atm). The mixture was filtered through celite and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH2 type: eluent; chloroform:methanol=99:1) to obtain 5-(2-aminoethoxy)-6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (123 mg) as a yellow solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:10][CH:9]2[CH:5]([CH2:6][CH2:7][CH2:8]2)[CH:4]1[CH2:11][NH:12][C:13](=[O:27])[C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([NH:21]C(=O)C)=[CH:16][C:15]=1[O:25][CH3:26])[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([N:3]1[CH2:10][CH:9]2[CH:5]([CH2:6][CH2:7][CH2:8]2)[CH:4]1[CH2:11][NH:12][C:13](=[O:27])[C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([NH2:21])=[CH:16][C:15]=1[O:25][CH3:26])[CH3:2]
Reactant: CCN1CC2CCCC2C1CNC(=O)c1cc(Cl)c(NC(C)=O)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN1CC2CCCC2C1CNC(=O)c1cc(Cl)c(N)cc1OC

Procedure:
7 parts of N-ethyl-2-(2-methoxy-4-acetylamino-5-chloro benzamido methyl)-3-azabicyclo (3,3,0) octane were heated for 30 minutes in the presence of 17.7 parts of a 2N solution of sodium hydroxide and 15 parts of ethanol. After cooling, the precipitate was filtered and recrystallized in 40 parts of acetonitrile. There were obtained 5 parts of N-ethyl-2-(2-methoxy-4-amino-5-chloro benzamido methyl)-3-azabicyclo(3,3,0) octane, M.P. 128°-129° C.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][CH2:10][C@@H:11]1[CH:26]=[C:25]2[C@@H:15]([CH2:16][C:17]3[C:27]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]2=4)[NH:19][CH:18]=3)[N:13]([CH3:14])[CH2:12]1.C(N(CC)CC)C.O>CN(C)C=O>[O:9]([CH2:10][C@@H:11]1[CH:26]=[C:25]2[C@@H:15]([CH2:16][C:17]3[C:27]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]2=4)[NH:19][CH:18]=3)[N:13]([CH3:14])[CH2:12]1)[Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN1C[C@H](CO)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN1C[C@H](CO[Si](C)(C)C(C)(C)C)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96.6 %

Procedure:
Tert-butyldimethylsilyl chloride (TBS-Cl, 19.6 g) is added into a mixture of Lysergol (30 g) and triethylamine (16.7 g) in N,N-dimethylformamide (150 mL) and the mixture is stirred at room temperature for 2-3 h. The mixture is cooled and water (240 mL) is added. The resulting suspension is stirred for an additional 2 h and then filtered and washed with water. The product is dried under vacuum to give 42 g of 8β-(tert-butyldimethylsiloxymethyl)-9,10-didehydro-6-methyl-ergoline in 96.5% yield.
Reaction SMILES: [C:1]([C:3]([C:9]#[N:10])=[C:4]([C:7]#[N:8])[C:5]#[N:6])#[N:2].[BrH:11]>CC(C)=O.C(OCC)(=O)C.C(O)(=O)C>[NH2:2][C:1]1[NH:6][C:5]([Br:11])=[C:4]([C:7]#[N:8])[C:3]=1[C:9]#[N:10]
Reactant: Br
Reactant: N#CC(C#N)=C(C#N)C#N
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: N#Cc1c(N)[nH]c(Br)c1C#N
Reaction time: 1 h
Yield: 66.8 %

Procedure:
Tetracyanoethylene (10.02 g, 78.23 mmol) was dissolved in the mixed solvent of acetone (60 mL) and ethyl acetate (120 mL), to which hydrogen bromide (33 wt %, 60 mL) dissolved in acetic acid was added at 0˜5° C. The yellow solid compound observed after one hour-stirring was isolated by filtering. After washing the compound with cold distilled water (100 mL), the mixture was dried in the air to give the target compound (11.02 g, 52.22 mmol, 66.8%).
Reaction SMILES: C[O-].[Na+].Cl[C:5]1[O:9][N:8]=[C:7]([C:10]2[N:14]3[N:15]=[C:16]([OH:23])[C:17]4[C:22]([C:13]3=[N:12][N:11]=2)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:6]=1.FC1C=CC(F)=C2C=1C(OCC1C=CC=CN=1)=NN1C(C3C=[C:42](C)[O:41]N=3)=NN=C12.O>CN(C)C=O>[OH:23][C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]2=[N:12][N:11]=[C:10]([C:7]3[CH:6]=[C:5]([O:41][CH3:42])[O:9][N:8]=3)[N:14]2[N:15]=1
Reactant: Oc1nn2c(-c3cc(Cl)on3)nnc2c2ccccc12
Reactant: Cc1cc(-c2nnc3c4c(F)ccc(F)c4c(OCc4ccccn4)nn23)no1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(-c2nnc3c4ccccc4c(O)nn23)no1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Sodium methoxide (165 mg, 0.3 mmol) was added to a stirred suspension of 3-(5-chloroisoxazol-3-yl)-6-hydroxy-1,2,4-triazolo[3,4-a]phthalazine (400 mg, 0.14 mmol) (prepared from Intermediate 7 using the procedure described in Example 15 part b) in N,N-dimethylformamide (20 ml) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 3 h then water was added (6 ml) and the solvents evaporated in vacuo. The residue was taken up in water and acidified to pH 2 using 2M hydrochloric acid. The resulting precipitate was filtered off, washed with hexane and azeotroped with ethanol to give crude 6-hydroxy-3(5-methoxyisoxazol-3-yl)-1,2,4-triazolo[3,4-a]phthalazine, MS (ES+) 284 [MH]+. The title-compound was prepared from this material using the procedure described in Example 103 part a, 1H NMR (250 MHz, CDCl3) δ 2.49 (3H, s, CH3), 4.15 (3H, s, CH3), 6.10 (1H, s, Ar—H), 7.45 (2H, d, J=8.5 Hz, Ar—H), 7.92 (1H, m, Ar—H), 8.06 (1H, m, Ar—H), 8.26-8.32 (3H, m, 3 of Ar—H), 8.64 (1H, d, Ar—H); MS (ES+) 438 [MH]+.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:15](=[O:18])[NH:16][N:17]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:7]=1.[S:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[NH:28][CH2:29][CH2:30][NH2:31].C(N(CC)CC)C>C1COCC1>[S:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[NH:28][CH2:29][CH2:30][NH:31][C:2]1[C:3]2[N:4]([C:15](=[O:18])[NH:16][N:17]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:7]=1
Reactant: O=c1[nH]nc2c(Br)nc(-c3ccc(Cl)cc3)cn12
Reactant: NCCNc1nc2ccccc2s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=c1[nH]nc2c(NCCNc3nc4ccccc4s3)nc(-c3ccc(Cl)cc3)cn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 50 mg of the product of Step A, 43 mg of N1-benzothiazol-2-yl-ethane-1,2-diamine, and 124 mg of triethylamine in THF (1.0 mL) was heated to reflux. After 16 h, the reaction mixture was cooled to ambient temperature and then partitioned between EtOAc and water. The organic layer was dried over sodium sulfate, filtered, and concentrated to a residue that was purified by silica gel chromatography to afford the title compound as a white solid. MS (M+H+)=438.3.