Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:34]=[CH:33][C:14]3[CH2:15][CH2:16][C:17]4[C:18]([C:30]([NH2:32])=[O:31])=[N:19][N:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]#[CH:29])=[CH:24][CH:23]=5)[C:21]=4[C:13]=3[CH:12]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1>CN(C=O)C.CS(C)=O>[Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:34]=[CH:33][C:14]3[CH2:15][CH2:16][C:17]4[C:18]([C:30]([NH2:32])=[O:31])=[N:19][N:20]([C:22]5[CH:27]=[CH:26][C:25]([CH:28]=[CH2:29])=[CH:24][CH:23]=5)[C:21]=4[C:13]=3[CH:12]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C#Cc1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4cccnc4Cl)ccc2CC3)cc1
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: C=Cc1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4cccnc4Cl)ccc2CC3)cc1
Yield: 46.9 %

Procedure:
A solution of 8-{[(2-chloropyridin-3-yl)carbonyl]amino}-1-(4-ethynylphenyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide (557 mg, 1.19 mmol) in DMF-DMSO (20 mL-1 mL) was treated at RT with H2 (5 psi) and Pd—CaSO4 (5%, 100 mg) for 12 min. The mixture was filtered through celite pad, concentrated and added water. The solid product was collected via filtration, washed with water and ether, and dried to give product (262 mg, 47%). 1H NMR was consistent with its structure.
Reaction SMILES: [CH:1]1([O:4][C:5]2[N:10]=[C:9](S(C)(=O)=O)[C:8]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[C:7]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[N:6]=2)[CH2:3][CH2:2]1.C([Li])CCC.[OH:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1>>[CH:1]1([O:4][C:5]2[N:10]=[C:9]([O:35][C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)[C:8]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[C:7]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[N:6]=2)[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1nc(OC2CC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: Oc1cccnc1
Agent: [Li]CCCC
Product: Clc1ccc(-c2c(Oc3cccnc3)nc(OC3CC3)nc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2-Cyclopropyloxy-4-methylsulfonyl-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (Middle Rf product) (Example 55, Step A), (28 mg, 0.06 mmol) was reacted with 1 equivalent each of n-butyl lithium and 3-hydroxypyridine by the procedure described in Reference Examples 6 and 7. Workup and flash column chromatography on silica gel (eluted with 80/20 hexanes/ethyl acetate) afforded the title compound. HPLC/MS: m/e=498 (M+−1); Rt=4.30 min. 1H-NMR 500 MHz (CDCl3): δ 0.30 (m, 2H), 0.59 (m, 2H), 1.26 (m, J=5 Hz, 1H), 4.09 (s, 2H), 7.18-7.30 (m, 6H), 7.36 (d, J=2 Hz, 1H), 7.40 (dd, J=7 Hz, J=5 Hz, 1H), 7.57 (d, J=7 Hz, 1H), 8.53 (d, J=5 Hz, 2H).
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[C:13]([O:19]CC2C=CC=CC=2)[CH:12]=[CH:11][C:10]=1[C:27](=[O:29])[CH3:28])C1C=CC=CC=1>C(O)C.C1CCCCC=1.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[C:14]([C:15]([F:16])([F:17])[F:18])=[C:13]([OH:19])[CH:12]=[CH:11][C:10]=1[C:27](=[O:29])[CH3:28]
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(C(F)(F)F)c1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CC(=O)c1ccc(O)c(C(F)(F)F)c1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.8 %

Procedure:
Add 20% palladium hydroxide on carbon (11.0 g, 15 mmol) to a solution of 1-(2,4-bis-benzyloxy-3-trifluoromethyl-phenyl)-ethanone (6.00 g, 15 mmol) in ethanol (75 mL) and cyclohexene (75 mL) and stir. Purge the reaction vessel with argon. Heat to reflux. After 18 hours, cool to ambient temperature, filter and concentrate under reduced pressure to yield the title compound as a grey solid (3.00 g, 91%): 1H NMR (CD3CN) δ 2.55 (s, 3H), 6.51 (d, 1H), 7.88 (d, 1H), 13.91 (bs, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][CH3:11].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[CH3:15][N:16]([CH3:18])[CH:17]=[CH:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][CH3:11]
Reactant: CCC(=O)c1ccc(=O)[nH]c1C
Reactant: COC(OC)N(C)C
Product: CCC(=O)c1ccc(=O)[nH]c1C=CN(C)C

Procedure:
The process according to claim 9 which comprises reacting 6-methyl-5-(n-propanoyl)-2(1H)-pyridinone with dimethylformamide dimethyl acetal to produce 6-(2-dimethylaminoethenyl)-5-(n-propanoyl)-2(1H)-pyridinone.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[CH2:26]([O:28][C:29]([CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])[CH3:27].C(N(CC)CC)C>C(O)C>[CH2:26]([O:28][C:29]([CH:31]1[CH2:36][CH2:35][N:34]([C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[N:6]3[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Clc1ccc(-n2c(-c3ccc(Cl)cc3Cl)nc3c(Cl)ncnc32)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C1CCN(c2ncnc3c2nc(-c2ccc(Cl)cc2Cl)n3-c2ccc(Cl)cc2)CC1
Temperature: 70 °C

Procedure:
6-chloro-9-(4-chlorophenyl)-8-(2,4-dichlorophenyl)-9H-purine I-(1A-1)d (30 mg, 0.07 mmol), piperidine-4-carboxylic acid ethyl ester (34 mg, 0.22 mmol), and triethylamine (20 μl, 0.29 mmol) were combined in ethanol (1 ml) and heated at 70° C. for 2 hours. The reaction mixture was concentrated under a stream of N2 and then extracted into ethyl acetate from saturated NaHCO3 solution. The organic layers were combined, dried (Na2SO4), filtered, evaporated to dryness, and then purified by preparative TLC using 4% methanol in methylene chloride as eluant to obtain title compound 7A-1. A solution of the material in methylene chloride was treated with excess 1 N HCl in diethyl ether, stirred and evaporated to dryness to afford the hydrochloride salt of compound 7A-1 (24 mg, 65%) as a solid: +ESI MS (M+1) 530.1; 1H NMR (400 MHz, CD3OD) δ 8.35 (s, 2H), 7.60 (d, J=8.3 Hz, 1H), 7.56 (d, J=2.1 Hz, 1H), 7.50–7.45 (m, 3H), 7.34 (d, J=8.7 Hz, 2H), 4.15 (q, J=7.1 Hz, 2H), 3.68 (v br s, 2H), 2.85 (m, 1H), 2.16 (m, 2H), 1.89 (m, 2H), 1.25 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[CH:14][NH:15]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[C:18]([O:22][C:23]([N:25]1[C@@H:29]([CH3:30])[CH2:28]OS1(=O)=O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23](=[O:24])[NH:25][C@@H:29]([CH3:28])[CH2:30][N:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH:17]=2)[CH:13]=[CH:14]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: C[C@H]1COS(=O)(=O)N1C(=O)OC(C)(C)C
Reactant: COc1ccc(-c2ccc3cc[nH]c3c2)cc1
Product: COc1ccc(-c2ccc3ccn(C[C@H](C)NC(=O)OC(C)(C)C)c3c2)cc1

Procedure:
This compound was synthesized from 6-(4-methoxy-phenyl)-indole (synthesized from 6-bromo-indole according to Carrera, G. M. et al. Synlett 1994, 1, 93-94) and (S)-4-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester as described in example 4, step A1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:27])[C:5]2[N:6]=[C:7](OS(C(F)(F)F)(=O)=O)[C:8]3[CH:18]=[CH:17][CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[CH3:28][NH:29][CH3:30]>C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:27])[C:5]2[N:6]=[C:7]([N:29]([CH3:30])[CH3:28])[C:8]3[CH:18]=[CH:17][CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: CCN1c2ncccc2C(OS(=O)(=O)C(F)(F)F)=Nc2c(C)cc(C)nc21
Reactant: CNC
Solvent: CCOC(C)=O
Product: CCN1c2ncccc2C(N(C)C)=Nc2c(C)cc(C)nc21
Reaction time: 72 h

Procedure:
A mixture of 2,4-dimethyl-11-ethyl-6-trifluoromethanesulfonyloxy-11H-dipyrido[3,2-b:2',3'-e][1,4]diazepine (0.3 g, 0.75 mmole) and dimethylamine (excess, used as solvent) were placed in a sealed pressure tube and left at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate, washed with water, dried, filtered and concentrated. The 260 mg of product thus obtained was recrystallized from ethyl acetate/hexane to give the title compound, m.p. 150°-152° C.
Reaction SMILES: [BH4-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]1([C:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[O:27][C:26]=2[C:34](=[O:36])[CH3:35])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[C:19]1([C:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[O:27][C:26]=2[CH:34]([OH:36])[CH3:35])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)c1oc2ccccc2c1-c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [BH4-]
Solvent: C1CCOC1
Product: CC(O)c1oc2ccccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
Tetrabutylammonium borohydride (nBu4NBH4) (750 mg, 2.91 mmol) was added to a solution of 1-(3-phenylbenzofuran-2-yl)ethanone (459 mg, 1.94 mmol) in THF (9 mL) and IMS (1 mL) and the mixture was stirred at RT for 1 h. The reaction mixture was then quenched by addition of MeOH and volatiles were removed under reduced pressure. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-40% EtOAc in cyclohexane) affording 1-(3-phenylbenzofuran-2-yl)ethanol as an oil (452 mg, 98%). LCMS: RT 3.57 min [M−OH]+ 221.1
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH2:10][NH:9][C:8]=2[CH:13]=1)([O-])=O>CO.[Pd]>[O:12]1[C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:13][C:8]=2[NH:9][CH2:10][CH2:11]1
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCO2
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)NCCO2

Procedure:
A solution of 6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine (1.8 g, 10.0 mmol) in methanol (150 mL) was hydrogenated on a Parr hydrogenator for 6 hours with 10% palladium on carbon (1.06 g) as a catalyst. The reaction mixture was filtered through Celite to remove the catalyst and the Celite rinsed with methanol. The filtrate was evaporated under vacuum to yield 3,4-dihydro-2H-benzo[1,4]oxazin-6-yl amine as a solid product.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4](Cl)[N:3]=1.[NH2:25][C@@H:26]1[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]1[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:25][C@@H:26]2[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]2[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[N:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N
Reactant: COc1ccc(CN2Cc3c(F)c(Cl)nc(Cl)c3C2=O)c(OC)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCOC[C@@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)c1
Temperature: 85 °C
Reaction time: 8 h
Yield: 10.7 %

Procedure:
A mixture of 4,6-dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (320 mg, 0.862 mmol), tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (280 mg, 1.293 mmol) and DIPEA (0.226 mL, 1.293 mmol) in ACN (5 mL) was stirred at 85° C. overnight. UPLC indicated the presence of starting material, so the mixture was stirred at 85° C. overnight. UPLC showed about 50% conversion. Additional stirring at 85° C. for 3 d and at 100° C. overnight did not appreciably increase the conversion, so the reaction was stopped and the solvent was removed. The resulting crude material was reconstituted in MeOH/DMF (10 mL) and purified via preparative HPLC eluting with water (0.05% TFA) and ACN (50%, 0.035% TFA). The collected fractions were combined and the ACN was removed via rotary evaporation. The resulting aqueous solution was neutralized with saturated aqueous NaHCO3, washed with EtOAc (2×200 mL), dried over Na2SO4, and filtered. The organic phase was stripped to dryness via rotary evaporation to give the title compound (51 mg, 11%). [M+H] calc'd for C26H32ClFN4O6, 552; found, 552.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:6]2[CH:16]=[C:17]([CH2:19][CH3:20])[S:18][C:5]=2[N:4]2[C:21]([CH2:24][CH2:25][CH3:26])=[N:22][N:23]=[C:3]12.C(N(CC)CC)C.[CH:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][C:35]=1[C:44](Cl)=[O:45]>C(Cl)(Cl)Cl>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:16]=[C:17]([CH2:19][CH3:20])[S:18][C:5]=2[N:4]2[C:21]([CH2:24][CH2:25][CH3:26])=[N:22][N:23]=[C:3]2[CH:2]([NH:1][C:44]([C:35]2[CH:36]=[CH:37][C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:34]=2)=[O:45])[N:8]=1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CCCc1nnc2n1-c1sc(CC)cc1C(c1ccccc1Cl)=NC2N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCc1nnc2n1-c1sc(CC)cc1C(c1ccccc1Cl)=NC2NC(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
In 20 ml of chloroform was dissolved 1.5 g of 6-amino-4-(2-chlorophenyl)-2-ethyl-9-propyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepine, and 0.47 g of triethylamine was added to the solution. A solution of 0.89 g of naphthalene-2-carbonyl chloride in 10 ml of chloroform was added dropwise to the mixture at not more than 10° C. The mixture was further stirred for 1 hour at room temperature and washed with 0.1N hydrochloric acid, 0.1N sodium hydroxide and a saturated solution of sodium chloride in order. Thereafter, the solvent was distilled off under reduced pressure, and the residue was washed with diisopropyl ether. Ethanol was added to yield crystals, which were collected by filtration. The crystals were recrystallized from chloroform-ethanol to give 1.4 g of 4-(2-chlorophenyl)-2-ethyl-6-(2-naphthalenecarboxamido)-9-propyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine, m.p. 226°-227° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[CH2:12]([CH2:14][NH2:15])[OH:13]>C(O)C>[CH3:8][C:6]1[N:7]=[C:2]([NH:15][CH2:14][CH2:12][OH:13])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: NCCO
Reactant: Cc1nc(Br)ccc1[N+](=O)[O-]
Solvent: CCO
Product: Cc1nc(NCCO)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
6-bromo-2-methyl-3-nitropyridine (2 g, 9.22 mmol) was dissolved in ethanol (20 mL) and to this solution was added ethanolamine (1.115 mL, 18.43 mmol). The reaction was left to stir overnight under nitrogen, at room temperature. The reaction was concentrated in vacuo, then diluted with ethyl acetate and saturated sodium bicarbonate solution. The organic phase was separated and washed with saturated sodium bicarbonate and brine, then dried using a hydrophobic frit and concentrated in vacuo to give the title compound as a yellow solid (1.68 g). Crude material used directly in next step, without further purification. LCMS (2 min, formic) Rt 0.60 min, m/z (ES+) 198 (M+H).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH:18]=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[NH:20]3)=[CH:16][CH:15]=2)=[O:13])=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9].Br[CH2:30][CH2:31][CH2:32][CH2:33][N:34]1[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]2[C:35]1=[O:44]>CC#N>[Br:1][C:2]1[S:3][C:4]([C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH:18]=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:20]3[CH2:30][CH2:31][CH2:32][CH2:33][N:34]3[C:38](=[O:39])[C:37]4[C:36](=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:35]3=[O:44])=[CH:16][CH:15]=2)=[O:13])=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccccc4)[nH]c3c2)sc1Br
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Solvent: CC#N
Product: COC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccccc4)n(CCCCN4C(=O)c5ccccc5C4=O)c3c2)sc1Br
Temperature: 25 °C
Yield: 42.7 %

Procedure:
To a stirred solution of 4 (45 mg, 0.10 mmol) in anhydrous CH3CN (5 mL) was added CsF-Celite (125 mg) under N2, followed by addition of N-(4-bromobutyl)-phthalimide (28 mg, 0.10 mmol). The resulting mixture was refluxed for five hours, cooled to room temperature, and filtered. The filtrate was evaporated in vacuo. MPLC purification (Hex:EtOAc/4:1) of the residue gave 5 as a yellow solid (28 mg, 43%). 1H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.74 (m, 6H), 7.59 (s, 1H), 7.47 (m, 5H), 6.60 (s, 1H), 4.32 (t, J=7.2 Hz, 2H), 3.73 (s, 3H), 3.71 (s, 2H), 3.52 (t, J=6.8 Hz, 2H), 1.72 (m, 2H), and 1.51 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 187.3, 170.4, 168.5, 145.2, 144.3, 136.8, 135.6, 134.9, 134.2, 134.1, 132.5, 132.1, 130.7, 129.5, 129.0, 128.8, 123.5, 123.4, 121.5, 120.6, 112.5, 103.1, 52.5, 43.7, 37.3, 35.1, 27.4, and 25.8.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6](F)[N:5]=[CH:4][N:3]=1.[CH2:10]([OH:15])[C:11]#[C:12][CH2:13][CH3:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:15][CH2:10][C:11]#[C:12][CH2:13][CH3:14])[N:5]=[CH:4][N:3]=1
Reactant: Fc1ncnc(F)c1F
Reactant: CCC#CCO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCC#CCOc1ncnc(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
0.5 g of 4,5,6-trifluoropyrimidine, 0.38 g of 2-pentyn-1-ol and 0.62 ml of triethylamine were added to 1 ml of toluene, then the mixture was stirred at room temperature for 1 hour. Then the reaction mixture was subjected to silica gel column chromatography to obtain 0.53 g of 4,5-difluoro-6-(2-pentynyloxy)pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.CCN=C=NCCCN(C)C.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:34]1[CH2:35][CH2:36][N:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=3)[CH2:32][CH2:33]1)=[O:13])=[CH:5]2
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: O=C(c1cc2cc(F)ccc2[nH]1)N1CCN(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-Fluoro-1H-indole-2-carboxylic acid (4.0 g) and EDCI (4.29 g) were combined in dichloromethane (90 mL) and treated with 1-(2-pyridinyl)piperazine (3.64 g). After stirring at 25° C. for 24 hours, the mixture was washed with 150 mL of water and filtered. The filter cake was washed in succession with 300 mL of water, 250 mL of dichloromethane and 20 mL of ethyl acetate to provide the title compound. 1H NMR (d6-DMSO, 300 MHz) δ 3.61 (m, 4H), 3.85 (m, 4H), 6.67 (dd, 1H, J=7.5,4.8 Hz), 6.85 (m, 2H), 7.06 (m, 1H), 7.40 (m, 2H), 7.65 (m, 1H), 8.04 (dd, 1H, J=4.5,1.8 Hz), 11.72 (bs, 1H). MS (DCI/NH3) m/z 325 (M+H)+.
Reaction SMILES: [CH2:1]1[C:13]2[N:4]([C:5](=O)[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH:12]=2)[CH2:3][CH2:2]1.[BH4-].[Na+]>P(Cl)(Cl)(Cl)=O.CO>[CH2:1]1[CH:13]2[N:4]([CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH2:12]2)[CH2:3][CH2:2]1
Reactant: O=c1c2ccccc2cc2n1CCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CO
Product: c1ccc2c(c1)CC1CCCN1C2
Temperature: 0 °C
Yield: 41.6 %

Procedure:
A suspension of 2,3-dihydropyrrolo[1,2-b]isoquinolin-5(1H)-one (10.8 g, 58.3 mmol) [G. M. Coppola, J. Heterocycl. Chem., 181, 18, 767] in phosphorus oxychloride (100 ml) was heated at reflux for 1.5 h. Upon cooling, the solvent was removed in vacuo to give an oil. This oil was immediately taken up in cold methanol (275 ml) and sodium borohydride (4.0 g) was added portionwise to this solution while maintaining the reaction mixture at 0° C. The solvent was concentrated and the residue was dissolved in water and washed twice with ethyl acetate. The aqueous solution was made basic with potassium carbonate solution and extracted with ethyl acetate. The organic phase was dried (magnesium sulfate) and concentrated to give an oil. Column chromatography on silica gel gave unreacted starting material (3.57 g, 36%) and the title compound (4.2 g, 63% based on recovered starting material) as a light oil; MS 174 (M+H)+ ; NMR (CDCl3) 7.0-7.2 (broad m, 4H), 4.13 (d, 1H, J=15), 3.40 (d, 1H, J=15), 3.27 (dt, 1H), 2.9-3.1 (M, 1H), 2.71 (t, 1H), 1.4-2.4 (m, 6H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[O:13])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[ClH:14].Cl.[Cl:16][C:17]1[CH:33]=[CH:32][C:20]([CH2:21][N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30][SH:31])[CH2:24][CH2:23]2)=[CH:19][CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:16].[ClH:14].[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[SH:31][CH2:30][CH2:29][CH2:28][N:25]2[CH2:26][CH2:27][N:22]([CH2:21][C:20]3[CH:19]=[CH:18][C:17]([Cl:16])=[CH:33][CH:32]=3)[CH2:23][CH2:24]2)[OH:13])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: SCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CCCCc1ccc(N=C=O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1ccc(NC(O)=[SH]CCCN2CCN(Cc3ccc(Cl)cc3)CC2)cc1
Yield: 56.8 %

Procedure:
The procedure described in Example 2 was followed, using 1.0 g of 4-n-butylphenyl isocyanate, 2.0 g of 3-[4-(4-chlorobenzyl)piperazin-1-yl]propanethiol dihydrochloride, 0.7 g of triethylamine and 50 ml of methylene chloride, to give 0.85 g (28% of theory) of N-(4-n-butylphenyl)-S-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 243°-246° C.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.C(Cl)Cl>[Cl:8][C:7]1[C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: C1CNCCN1
Reactant: Clc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: Clc1nccnc1N1CCNCC1
Temperature: 110 °C
Reaction time: 1.25 h
Yield: 40.7 %

Procedure:
A mixture of 2,3-dichloropyrazine (1.35 g, 15.32 mmol), piperazine (2.34 g, 27.2 mmol) and K2CO3 (1.25 g, 9.04 mmol) in acetonitrile (5.5 mL) was stirred at 110° C. for 1.25 h in a sealed tube. The reaction mixture was diluted with CH2Cl2, filtered, and concentrated to give a yellowish semisolid residue which was purified by chromatography on silica gel using CHCl3/MeOH (9:1) as eluent. The obtained solid was redissolved in CHCl3 and applied to a short (3 cm) plug of alumina. Elution with ether/CHCl3 (9:1) afforded 1.24 g (69%) of the title product as a white solid: mp 47-53° C. HRMS m/z calcd for C8H11CIN4 (M)+ 198.0672, found 198.0673.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:13])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=O)([O-:3])=[O:2].[NH2:14][CH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>CN(C)C=O>[NH2:13][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][C:7]=1[C:8]([NH:21][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([C:15]#[N:14])=[CH:17][CH:18]=1)=[O:10]
Reactant: N#Cc1ccc(CN)cc1
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Solvent: CN(C)C=O
Product: N#Cc1ccc(CNC(=O)c2ccc([N+](=O)[O-])cc2N)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
31.7 g (0.17 mol) of 4-nitro-anthranilic acid are dissolved in 350 ml dimethylformamide and after the addition of 45.4 g (0.28 mol) of N,N′-carbonyldiimidazole stirred for 30 minutes at 50° C. Then a solution of 23 g (0.17 mol) of 4-aminomethyl-benzonitrile in 100 ml dimethylformamide is added dropwise and stirred for 2 hours at 50° C. The solution is evaporated down, dissolved in ethyl acetate and extracted with sodium hydrogen carbonate solution. The combined organic extracts are dried and evaporated down. The residue is chromatographed on silica gel and eluted with methylene chloride/ethanol (97:3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH2:14][CH2:13][NH:12][C:11](=[O:15])[CH:10]=2)=[CH:4][CH:3]=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[CH2:14][CH2:13][NH:12][C:11](=[O:15])[C:10]=3[C:4]=2[CH:3]=1
Reactant: O=C1C=C(Nc2ccc(F)cc2)CCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C1NCCc2[nH]c3ccc(F)cc3c21
Yield: 56.6 %

Procedure:
Cupric acetate (2.9 g) was added to a stirred solution of 4-[(4-fluorophenyl)amino]-5,6-dihydro-2(1H)-pyridinone (1.5 g) and palladium (II) acetate (200 mg) in dry DMF (40 ml). The mixture was heated at 130° for 1 h, evaporated in vacuo and the residue was extracted with methanol (250 ml). This solution was concentrated in vacuo and the residue was purified by FCC eluting with System A (100:8:1) to give the title compound (840 mg), m.p. 242°-245°.