Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:45]=[CH:44][C:6]([CH2:7][C@@:8]2([CH3:43])[N:12]3[C:13]([C:16]([NH:18][C:19]4([C:22]([NH:24][C@@H:25]5[CH2:29][CH2:28][C@H:27]([C:30](OC)=[O:31])[CH2:26]5)=[O:23])[CH2:21][CH2:20]4)=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:34]3[CH:39]=[C:38]([Cl:40])[CH:37]=[C:36]([Cl:41])[CH:35]=3)[C:9]2=[O:42])=[CH:5][CH:4]=1)#[N:2].[NH3:46]>>[C:30]([C@H:27]1[CH2:28][CH2:29][C@@H:25]([NH:24][C:22]([C:19]2([NH:18][C:16]([C:13]3[N:12]4[C@@:8]([CH2:7][C:6]5[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:45][CH:44]=5)([CH3:43])[C:9](=[O:42])[N:10]([C:34]5[CH:39]=[C:38]([Cl:40])[CH:37]=[C:36]([Cl:41])[CH:35]=5)[C:11]4=[N:15][CH:14]=3)=[O:17])[CH2:21][CH2:20]2)=[O:23])[CH2:26]1)(=[O:31])[NH2:46]
Reactant: COC(=O)[C@H]1CC[C@@H](NC(=O)C2(NC(=O)c3cnc4n3[C@](C)(Cc3ccc(C#N)cc3)C(=O)N4c3cc(Cl)cc(Cl)c3)CC2)C1
Reactant: N
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)N[C@@H]4CC[C@H](C(N)=O)C4)CC3)n21
Temperature: 80 °C
Reaction time: 65 h
Yield: 55 %

Procedure:
To methyl (1S,3R)-3-({[1-({[(3R)-3-(4-cyanobenzyl)-1-(3,5-dichlorophenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[1,2-a]imidazol-5-yl]carbonyl}amino)cyclopropyl]-carbonyl}amino)cyclopentanecarboxylate (109.2 mg, 0.168 mmol) was added ammonia (7N in methanol, 4 mL, 28 mmol) and the reaction tube was sealed. The reaction solution was stirred at 80° C. for 65 h. The reaction solution was then cooled to room temperature and concentrated in vacuo. The resultant residue was purified via reverse phase HPLC to afford 58.6 mg of the title compound as a white solid, m/z 634.2 [M+1]+.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5].Cl[CH2:17][CH:18]([OH:41])[CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH:26]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1>CS(C)=O>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH:26]([C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)[N:23]2[CH2:22][CH2:21][N:20]([CH2:19][CH:18]([OH:41])[CH2:17][N:3]3[C:14](=[O:15])[C:13]4[N:11]([CH3:12])[CH:10]=[N:9][C:8]=4[N:6]([CH3:7])[C:4]3=[O:5])[CH2:25][CH2:24]2)=[CH:28][CH:29]=1
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: OC(CCl)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cn1cnc2c1c(=O)n(CC(O)CN1CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC1)c(=O)n2C
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.9 %

Procedure:
To sodium hydride (0.3 g, 6.25 mmol of 50% with oil, prewashed with pentane) was added dry dimethyl sulfoxide (12 mL) and theobromine (0.9 g, 5 mmol). A fine suspension was formed to which was added 1-(1-chloro-2-hydroxy-3-propanyl)-4-(4, 4'-difluorobenzhydryl)piperazine (1.9 g, 5 mmol) dissolved in dry DMSO (10 mL) over 5 minutes. The mixture was stirred at room temperature under nitrogen for 24 hours and then heated to 70° C. for 20 hours. The DMSO was evaporated in vacuo (1 mmHg) at 75° C. and the residue was triturated in methylene chloride and filtered through Celite®. The filtrate was evaporated in vacuo to give a tacky solid (2.62 g) which was purified by flash chromatography over silica gel using 10% methanol/methylene chloride to give the desired product which was further purified with ether. The ether insoluble material was pure product (0.6 g, 25%), mp 138° -140° C.; DCI/MS: 525; 100 MHz 1H NMR (CDCl3)δ: 7.85 (s, 1H), 7.32 (m, 4H), 6.95 (m, 4H), 4.2 (s, IH), 4.1-4.22 (m, 3H), 3.97 (s, 3H), 3.57 (s, 3H), 2.3-2.5 (m, 10H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:22][CH:21]=3)[C:17]([C:18]#[N:19])=[C:13]2[N:12]=[CH:11][CH:10]=1.[BH4-].[Na+]>CCO>[CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:22][CH:21]=3)[C:17]([C:18]#[N:19])=[C:13]2[NH:12][CH2:11][CH2:10]1
Reactant: CNc1ccccc1-c1ccnc2c(C#N)c(-c3ccc(Oc4ccccc4)cc3)nn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CNc1ccccc1C1CCNc2c(C#N)c(-c3ccc(Oc4ccccc4)cc3)nn21
Reaction time: 15 h
Yield: 56.9 %

Procedure:
To a solution of 7-(2-(methylamino)phenyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (250 mg, 0.6 mmol) in 10 mL EtOH was added NaBH4 (100 mg). The reaction mixture was stirred at it for 15 hr, and then concentrated to remove EtOH. The residue was partitioned between 30 mL of water and 30 mL of EA. The organic layer was concentrated. The residue was dissolved in 10 mL of MeOH, followed by 10% w/w Pd/C (50 mg). The reaction mixture was stirred at it under 1 atm. of H2 for 15 hr. Then, the mixture was filtered. The filtrate was concentrated and purified by the flash chromatography (PE/EA=1/1) to give the product as a white solid (144 mg, yield: 56.5%). MS (ESI) m/e [M+1]+ 421.9.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH3:20][N:21]([CH3:34])[CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[CH2:30][CH2:31][NH:32][CH3:33]>>[CH3:34][N:21]([CH3:20])[CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[CH2:30][CH2:31][N:32]([CH3:33])[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3]
Reactant: CNCCN1CCCCC1CCN(C)C
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Product: CN(C)CCC1CCCCN1CCN(C)C(=O)N1c2ccccc2C(=O)Nc2cccnc21
Yield: 52 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[2-[2-(dimethylamino)ethyl]-piperidin-1-yl]-N-methyl-ethanamine in a yield of 52% of theory. Colourless crystals, m.p. 114°-116° C. (after recrystallisation from diisopropylether and acetonitrile and decoction with water).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:28][C:21]3=[N:22][CH:23]=[C:24]([CH2:26][OH:27])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][N:30]([CH2:32][C:33](O)=[O:34])[CH3:31].CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:28][C:21]3=[N:22][CH:23]=[C:24]([CH2:26][O:27][C:33](=[O:34])[CH2:32][N:30]([CH3:31])[CH3:29])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(CO)cnc3[nH]2)cc1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CN(C)CC(=O)OCc1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 55.1 %

Procedure:
To a solution of {2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-methanol (prepared as in Example 8, 30 mg, 0.075 mmol), dimethylamino-acetic acid (21 mg, 0.11 mmol) in N,N-dimethylformamide (1.0 mL) and N-methylmorpholine (33 uL, 0.23 mmol) was added 1-hydroxybenzotriazole hydrate (20 mg, 0.113 mmol) followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (29 mg, 0.11 mmol) in one portion. The mixture was stirred at 25° C. for 6 h, diluted with ethyl acetate (100 mL), washed with a 1 N sodium bicarbonate solution, 1 N aqueous hydrochloric acid solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded dimethylamino-acetic acid 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-ylmethyl-ester (20 mg, 54.9%) as a light yellow solid: LC/MS m/e calcd for C26H33N3O4S1 [M+H]+ 484.63, observed 484.3; 1H NMR (400 MHz, CDCl3) δ ppm 1.19 (m, 2H), 1.48 (m, 2H), 1.56-1.86 (m, 5H, H), 2.12 (m, 1H), 2.27 (m, 1H), 2.43 (s, 6H, 2×NCH3), 3.02 (s, 3H), 3.29 (s, 2H, NCH2), 4.28 (t, J=7.8 Hz, 1H), 5.28 (s, 2H), 6.38 (s, 1H), 7.50 (d, J=8.0 Hz, 2H), 7.87 (d, J=8.0 Hz, 2H), 7.39 (s, 1H), 8.16 (s, 1H), 10.87 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=3)=[CH:13][CH:14]=2)[C:5]2[N:6]([CH:7]=1)[CH2:26][CH2:27][S:28](=[O:30])(=[O:29])[N:8]=2
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncc(Cl)cc1-c1ccc(Oc2ccc(Cl)cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=C(Cl)C=C(c3ccc(Oc4ccc(Cl)cn4)cc3)C2=N1
Temperature: 80 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
A mixture of 5-chloro-3-{4-[(5-chloropyridin-2-yl)oxy]phenyl}pyridin-2-amine (440 mg) in THF (dry) (10 mL) was added to a mixture of NaH (60%, 265 mg) and 2-chloroethanesulfonyl chloride (648 mg) in THF (dry) (10 mL) at room temperature. The mixture was stirred at room temperature overnight and 80° C. for 3 hr. Water was added and the mixture was concentrated in vacuo. The residue was washed with water and Et2O to give an off-white solid. The solid was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (520 mg) as an off-white solid. The solid was crystallized from CH3CN-IPE to give a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:11]#[C:12][Si](C)(C)C)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[CH:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cccc(C#C[Si](C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#Cc1cccc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.7 %

Procedure:
A solution 3-tert-butyl-trimethylsilanylethynyl benzene (Intermediate 102, 0.47 g, 2.04 mmol) in methanol (20 mL) was treated with potassium carbonate (2.8 g, 20.2 mmol) and the resulting reaction mixture was stirred at ambient temperature for 3 days. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil. Flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent afforded the title compound as a light yellow oil (0.125 g, 39%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:5]([S:18]([C:21]2[CH:26]=[CH:25][C:24](OS(C(F)(F)F)(=O)=O)=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:4][N:3]=1.C([O-])(O)=O.[Na+].[CH3:40][N:41](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:5]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([C:40]#[N:41])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:4][N:3]=1
Reactant: Cc1cc(C)c(Nc2nc(C)ncc2S(=O)(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc2)c(C)c1
Reactant: CN(C)C=O
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: [C-]#N
Product: Cc1cc(C)c(Nc2nc(C)ncc2S(=O)(=O)c2ccc(C#N)cc2)c(C)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
A mixture of trifluoromethanesulfonic acid 4-[2-methyl-4-(2,4,6-trimethylphenylamino)-pyrimidine-5-sulfonyl]-phenyl ester (146 mg, 0.283 mmol), zinc cyanide (66 mg, 0.57 mmol), and DMF (2 mL) was degassed with N2 for 10 min, and then Pd(PPh3)4 (16 mg, 0.014 mmol) was added. The mixture was stirred at 80° C. under N2 for 2 h and then cooled to room temperature. The reaction mixture was treated with saturated aqueous NaHCO3, and extracted (3×) with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (67:33 hexanes/EtOAc) to provide the target compound (108 mg, 97%) as a white solid: mp 258–260° C.; 1H NMR (500 MHz, CDCl3) δ 8.76 (s, 1H), 8.21 (br s, 1H), 8.08 (d, J=8.6 Hz, 2H), 7.84 (d, J=8.6 Hz, 2H), 6.92 (s, 2H), 2.40 (s, 3H), 2.31 (s, 3H), 2.00 (s, 6H); ESI MS m/z 393 [(M+H)+, calcd for C21H21N4O2S, 393.1].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1.[F:29][C:30]([F:42])([F:41])[O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(Cl)(Cl)Cl.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]>[CH3:28][N:25]1[CH2:24][CH2:23][N:22]([C:19]2[CH:20]=[CH:21][C:16]([NH:15]/[CH:14]=[C:5]3\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]4[C:4]\3=[CH:3][C:2]([C:35]3[CH:34]=[CH:33][C:32]([O:31][C:30]([F:29])([F:41])[F:42])=[CH:37][CH:36]=3)=[CH:11][CH:10]=4)=[CH:17][CH:18]=2)[CH2:27][CH2:26]1
Reactant: CN1CCN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(-c5ccc(OC(F)(F)F)cc5)cc43)cc2)CC1
Reaction time: 0.25 h
Yield: 71.8 %

Procedure:
An amount of 6-bromo-4-{[4-(4-methyl-piperazin-1-yl)-phenylamino]-methylene}-4H-isoquinoline-1,3-dione (0.1 g, 0.2267 mmol) in 1 mL of N,N′-dimethylformamide is added to 4-(trifluoromethoxy)phenylboronic acid (0.07 g, 0.34 mmol), 0.032 g (0.034 mmol) of tris(dibenzylideneacetone)dipalladium(0), tri(t-butyl)phosphine (0.014 g, 0.068 mmol) and cesium carbonate (0.148 g, 0.4534 mmol). The reaction mixture is stirred at 130 oC under N2 for 15 min. Mass spectroscopy suggested the completion of the reaction. The mixture is diluted with chloroform and filtered through Celite. The filtrate is evaporated to dryness and purified by column chromatography using 5% methanol/methylene chloride as eluent to yield 85 mg (72% yield) of the title compound as orange solid. MS (ESI) m/z 523.2 (M+H)+1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12](Cl)=[N:13][C:14]([S:17][CH3:18])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[C:20]1([NH:26][C:27]2[C:28]([NH2:33])=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CN1CCOCC1.CO>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12]([NH:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[NH:26][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:13][C:14]([S:17][CH3:18])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CSc1ncc(C(=O)Nc2ccc(F)cc2)c(Cl)n1
Reactant: Nc1ccccc1Nc1ccccc1
Solvent: CN1CCOCC1
Solvent: CO
Solvent: ClCCl
Product: CSc1ncc(C(=O)Nc2ccc(F)cc2)c(Nc2ccccc2Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.1 %

Procedure:
To a mixture of 4-chloro-2-methylsulfanylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide (100 mg, 0.34 mmol) in dichloromethane (10 mL) was added N-phenyl-benzene-1,2-diamine (148 mg, 0.4 mmol) followed by N-methylmorpholine-bound resin (300 mg). The mixture was stirred at an ambient temperature for 16 h and was then heated at reflux for an additional 2 h. Methanol (5 mL) was added and the mixture was stirred at an ambient temperature for 40 h. The mixture was filtered through a plug of celite and the filter plug was washed with hot ethyl acetate (25 mL). The resulting solution was treated with hexanes to precipitate 70 mg (0.16 mmol, 47% yield) of the titled compound as a purple-red solid. 1H NMR (300 MHz, DMSO-d6) δ 10.64 (s, 1H), 10.29 (s, 1H), 8.74 (s, 1H), 8.10 (m, 1H), 7.58 (m, 3H), 7.25–7.05 (m, 7H), 6.79–6.679(m, 3H), 2.5(s, 3H); MS (EI) m/z 444.05 (M−H)−.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][N:9]2[C:13]([CH2:14][CH:15]=[CH:16][OH:17])=[C:12]([Cl:18])[N:11]=[C:10]2[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:6][CH:5]=1)([O-])=O.C(O)(=O)C>C(O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:13]([CH2:14][CH:15]=[CH:16][OH:17])=[C:12]([Cl:18])[N:11]=[C:10]2[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:23][CH:24]=1
Reactant: CCCCc1nc(Cl)c(CC=CO)n1Cc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCc1nc(Cl)c(CC=CO)n1Cc1ccc(N)cc1

Procedure:
A mixture of 0.2 g of 3-[1-(4-nitrobenzyl)-2-butyl-4-chloroimidazol-5-yl]propen-1-ol, 0.15 g of iron and 0.3 mL of glacial acetic acid in 10 mL of absolute ethanol was refluxed for 1 hour. The reaction mixture was concentrated to dryness and the residue was dissolved in 20 mL of water and the solution was made basic to pH 8 by adding K2CO3. The mixture was then extracted with ethyl acetate and the ethyl acetate layer was washed with water. The organic layer was concentrated to give a crude product which was purified by flash silica gel column chromatography (ethyl acetate elution). A pure product was obtained as an amorphous solid; NMR (200 MHz, CDCl3): δ 6.76 and 6.62 (dd, 4H, J=8.5 Hz); 6.42-6.22 (m, 2H); 2.57 (t, 2H, J=7.3 Hz); 1.65 (m, 2H); 1.33 (m, 2 H); 0.87 (t, 2H, J=7.3 Hz).
Reaction SMILES: Cl.C[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14]C)[CH:10]=[N:9][CH:8]=[CH:7]2.[BrH:16]>>[BrH:16].[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[OH:14])[CH:10]=[N:9][CH:8]=[CH:7]2
Reactant: COc1cc2ccncc2cc1OC
Agent: Br
Agent: Cl
Product: Oc1cc2ccncc2cc1O
Yield: 97.6 %

Procedure:
63.4 g (0.28 mol) of 6,7-dimethoxyisoquinoline hydrochloride was dissolved in 630 ml of 47% hydrobromic acid, and the mixture was refluxed for 24 hours under stirring in nitrogen atmosphere. The reaction mixture was allowed to stand still under cooling with ice. The crystals formed were collected by filtration and washed with cold water and acetone. They were dried in air overnight and then dried at a temperature of from 90° to 95° C. for 6 hours to obtain 66.4 g (yield: 97.6%) of the above identified compound.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@@H:7]([CH3:16])[CH:6]=1)=O.C(N)(=S)C1C=CN=CC=1.[C:26](=[S:29])([S-:28])[NH2:27].[NH4+]>CO>[CH3:16][C@H:7]1[CH:6]=[C:5]([C:3]2[N:27]=[C:26]([SH:29])[S:28][CH:2]=2)[CH2:9][N:8]1[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11]
Reactant: C=CCOC(=O)N1CC(C(=O)CCl)=C[C@@H]1C
Reactant: NC(=S)[S-]
Agent: NC(=S)c1ccncc1
Agent: [NH4+]
Solvent: CO
Product: C=CCOC(=O)N1CC(c2csc(S)n2)=C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.3 %

Procedure:
To a solution of allyl (2S)-4-(chloroacetyl)-2-methyl-2,5-dihydro-1H-pyrrole-1-carboxylate(0.15 g, 0.62 mmol) in methanol (2 ml) were added at 0–5° C. thioisonicotinamide (5 mg) and ammonium dithiocarbamate (82 mg, 0.74 mmol). The temperature was raised to room temperature and the mixture was stirred for 15 minute, followed with stirring at 55–60° C. for 1 hour. The solvent was removed under reduced pressure and the residue was washed with ethanol to give allyl (2S)-2-methyl-4-(2-mercapto-1,3-thiazol-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate(60 mg, 34%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:22](O)=[O:23])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(P(=O)(OCC)OCC)#N.[CH2:35]([NH:37][CH2:38][CH3:39])[CH3:36]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:22](=[O:23])[N:37]([CH2:38][CH3:39])[CH2:35][CH3:36])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCNCC
Reactant: Cc1ccccc1C(C(=O)O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)C(c1ccccc1C)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 79 %

Procedure:
To 4-(Carboxy-o-tolyl-methyl)-piperazine-1-carboxylic acid tert-butyl ester (352) (0.654 g, 1.95 mmol) in DMF (5 mL) was added diethyl cyanophosphonate (0.29 mL, 1.95 mmol), diethylamine (0.24 mL, 2.35 mmol) and TEA (0.32 mL, 2.35 mmol). The mixture was stirred at room temperature for 12 h and then diluted with EtOAc (50 mL). The reaction mixture was washed with sat. NaHCO3 (50 mL), H2O (50 mL) and brine (50 mL). The organic phase was concentrated to dryness. The crude material was purified by chromatography (silica gel 60 mesh, eluting with 50% hexanes/50% EtOAc) yielding 0.60 g (79%) pure product.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14]([CH2:18][OH:19])=[N:13][C:12]([NH:20][C:21]1[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=1)=[CH:11]2.CCN(CC)CC>C(Cl)Cl>[CH3:1][S:2]([N:23]1[C:24]([CH3:26])=[CH:25][C:21]([NH:20][C:12]2[N:13]=[C:14]([CH2:18][O:19][S:2]([CH3:1])(=[O:4])=[O:3])[C:15]3[C:10]([CH:11]=2)=[CH:9][C:8]([O:7][CH3:6])=[CH:17][CH:16]=3)=[N:22]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2c(CO)nc(Nc3cc(C)[nH]n3)cc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(COS(C)(=O)=O)nc(Nc3cc(C)n(S(C)(=O)=O)n3)cc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
MsCl (1.0 g) in 20 mL CH2Cl2 was added slowly to a mixture of [6-Methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-yl]-methanol (11.0 g) and Et3N (1.42 g) in 50 mL CH2Cl2 at 0° C. The reaction mixture was stirred at r.t. for 3 h, and then washed with saturated NaHCO3 (aq) and NaCl(aq). The organic layer was dried over Na2SO4, and concentrated to give the crude product.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: C1CCNCC1
Reactant: O=Cc1cccc(Br)n1
Product: Brc1cccc(CN2CCCCC2)n1
Yield: 82.7 %

Procedure:
The title compound was prepared in a manner similar to that described in Example 18, Step C, using 6-bromo-pyridine-2-carbaldehyde (0.406 g, 2.18 mmol) and piperidine (0.186 g, 2.18 mmol). The crude product was purified (SiO2: 0-4% 2 M NH3 in MeOH/DCM) to provide the title compound (0.46 g, 83%).
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[F:17])[C:10](O)([C:18]3[C:27]([OH:28])=[CH:26][C:21]4[O:22][CH2:23][CH2:24][O:25][C:20]=4[CH:19]=3)[C:9]2=[O:30])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[C:31]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[F:17])[CH:10]([C:18]3[C:27]([OH:28])=[CH:26][C:21]4[O:22][CH2:23][CH2:24][O:25][C:20]=4[CH:19]=3)[C:9]2=[O:30])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2c(F)cccc2C1(O)c1cc2c(cc1O)OCCO2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C1C(c2cc3c(cc2O)OCCO3)c2cccc(F)c2N1C(c1ccccc1)c1ccccc1
Yield: 60.8 %

Procedure:
To a solution of 1-(diphenylmethyl)-7-fluoro-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one (4.27 g, 8.8 mmol) in trifluoroacetic acid (100 mL) at 0° C. was added triethylsilane (2.8 mL, 18 mmol) and the reaction mixture was concentrated in vacuo. The crude product was purified by column chromatography and eluted with a 0% to 66% gradient of ethyl acetate in hexanes to afford 1-(diphenylmethyl)-7-fluoro-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one (2.5 g, 61%) as a colorless solid: MS (ES+) m/z 465.9 (M+1).