Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1Cl)[CH3:2].[N:13]1[S:14][N:15]=[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:17]=12.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[O:22][C:20]1[CH:19]=[CH:18][C:17]2=[N:13][S:14][N:15]=[C:16]2[CH:21]=1)[CH3:2]
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: Oc1ccc2nsnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccnc1Oc1ccc2nsnc2c1
Yield: 81.9 %

Procedure:
A mixture of 2-chloro-nicotinic acid ethyl ester (0.516 g, 3 mmol), benzo-[2,1,3]-thiadiazol-5-ol (0.46 g, 3 mmol) and cesium carbonate (2.07 g, 6.3 mmol) was stirred in 40 mL N,N-dimethylformamide at 80° C. for 48 hours. The dark orange mixture was cooled and poured into water (600 mL) and extracted with ethyl acetate. The combined organic layers were washed with water and brine, and dried (Na2SO4). The mixture was concentrated in vacuo to give 0.74 g yellow solid (82% yield).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@@H:11]1[C:15]2[N:16](S(C3C=CC(C)=CC=3)(=O)=O)[CH:17]=[CH:18][C:14]=2[C:13](=[O:29])[NH:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+]>CO>[CH2:1]([O:8][CH2:9][CH2:10][C@@H:11]1[C:15]2[NH:16][CH:17]=[CH:18][C:14]=2[C:13](=[O:29])[NH:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2[C@@H](CCOCc2ccccc2)NC3=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C1N[C@H](CCOCc2ccccc2)c2[nH]ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To a solution of (R)-6-(2-(benzyloxy)ethyl)-1-tosyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (724e, 3.51 g, 8.55 mmol) in MeOH (50 mL) in an ice bath was added K2CO3 (2.36 g, 17.10 mmol) in one portion. The resulting white suspension was stirred in an ice bath for 1 h and at RT for 1 h. The resulting suspension was filtered through a pad of Celite washing with MeOH. 10 g silica gel was added to the filtrate and concentrated in vacuo. The resulting solid was purified using an ISCO Combiflash RF (40 g Grace Reverlis column, using a gradient of 0-10% 2 M NH3/MeOH in DCM) affording (R)-6-(2-(benzyloxy)ethyl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (724f; 1.84 g, 7.17 mmol, 84% yield) as an orange-brown viscous oil. m/z (ESI, +ve) 257.1 (M+1)+. The material (724f) was further purified by chiral SFC (mobile phase CO2/30% MeOH (20 mM NH3), chiral column AS (250×30 mm), wave length 245 nm, flow rate 120 mL/min) The first eluting peak was collected and concentrated in vacuo to give (S)-6-(2-(benzyloxy)ethyl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (724g) (537 mg, 3.04 mmol, 24% yield, >99% ee) as an orange tar. The second eluting peak was collected and concentrated in vacuo to give (R)-6-(2-(benzyloxy)ethyl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (724) (780 mg, 3.04 mmol, 35% yield, >99% ee) as an orange tar. 1H NMR (400 MHz, CDCl3) δ ppm 8.46 (1H, br. s.), 7.33-7.44 (5H, m), 6.58 (1H, t, J=2.3 Hz), 6.32 (1H, dd, J=2.8, 1.9 Hz), 5.70 (1H, br. s.), 4.56 (2H, s), 4.52 (1H, dd, J=8.4, 4.7 Hz), 3.77 (2H, dd, J=6.7, 4.3 Hz), 1.90-2.07 (2H, m). m/z (ESI, +ve) 257.1 (M+1)+.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([OH:21])=O)[N:13]2[CH3:18])C1C=CC=CC=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[OH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21])[N:13]2[CH3:18]
Reactant: Cn1c(C(=O)O)cc2c(OCc3ccccc3)cccc21
Reactant: C1CCNC1
Product: Cn1c(C(=O)N2CCCC2)cc2c(O)cccc21

Procedure:
From 4-benzyloxy-1-methyl-1H-indole-2-carboxylic acid and pyrrolidine the title compound was prepared by a method analogous to that described in Example 11. MS ES (M++H)=245.
Reaction SMILES: CS[C:3]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19](=O)[C:18]3=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]3[C:16]2=[O:25])=[CH:11][CH:10]=1)([CH3:8])[C:4]([O:6][CH3:7])=[O:5].C(Cl)Cl>C(O)(=O)C.[Zn].S([O-])([O-])(=O)=O.[Cu+2]>[O:25]=[C:16]1[C:17]2[C:18](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][N:15]1[C:12]1[CH:13]=[CH:14][C:9]([CH:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5])=[CH:10][CH:11]=1
Reactant: COC(=O)C(C)(SC)c1ccc(N2C(=O)c3ccccc3C2=O)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)C(C)c1ccc(N2Cc3ccccc3C2=O)cc1
Yield: 83.1 %

Procedure:
Methyl α-methylthio-α-(p-phthalimidophenyl)propionate (355 mg), 600 mg of zinc powder and 32 mg of anhydrous copper sulfate were heated under reflux for 5 hours in 3 ml of acetic acid. Methylene chloride (30 ml) was added, and the insoluble matter was separated by filtration and washed with 20 ml of methylene chloride. The filtrate and the washing were combined, washed twice with 10 ml of water, and dried over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure. The residue was chromatographed on a silica gel column using methylene chloride as an eluent to afford 245 mg of methyl α-[p-(1-oxo-2-isoindolinyl)phenyl]propionate as colorless crystals in a yield of 83%.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH:11]([F:13])[F:12])[CH:3]=1.[Li+].[Cl-].[CH2:16]([Sn](CCCC)(CCCC)CCCC)[CH:17]=[CH2:18]>C1(C)C=CC=CC=1.CCOC(C)=O.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>[CH2:18]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH:11]([F:13])[F:12])[CH:3]=1)[CH:17]=[CH2:16]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1ccc(Br)cc1OC(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCc1ccc(C#N)c(OC(F)F)c1

Procedure:
To a solution of 4-bromo-2-(difluoromethoxy)benzonitrile (620 mg, 2.5 mmol) in 30 ml of toluene was added LiCl (322 mg, 7.5 mmol), Pd(PPh3)4 (60 mg), Allyl tributyltin (990 mg, 3.0 mmol), and then the mixture was heated to reflux overnight. After the reaction was completed, the reaction solution was diluted with EtOAc and filtered. The filtrate was concentrated and purified with silica gel column chromatograph to give crude 4-allyl-2-(difluoromethoxy)benzonitrile.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:31]C(=O)OC(C)(C)C)[C:17](=[O:30])[NH:18][C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH:20]=2)=[CH:11][CH:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:3][C:2]([C:4]([F:7])([F:6])[F:5])=[O:1].[NH2:31][C@@H:16]([CH2:15][C:12]1[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=1)[C:17]([NH:18][C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)[CH:20]=1)=[O:30]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Cl)cc1)C(=O)Nc1cc(-c2ccncc2)no1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1ccc(Cl)cc1)C(=O)Nc1cc(-c2ccncc2)no1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.3 %

Procedure:
To a 100 ml flask was (S)-tert-butyl 3-(4-chlorophenyl)-1-oxo-1-(3-(pyridin-4-yl)isoxazol-5-ylamino)propan-2-ylcarbamate TFA salt 3.1.B (200 mg, 0.54 mmole), 10 ml of CH2Cl2, and 10 ml of TFA. The reaction was stirred at room temperature for 4 hours at which time the solvent was removed to give (S)-2-amino-3-(4-chlorophenyl)-N-(3-(pyridin-4-yl)isoxazol-5-yl)propanamide TFA salt 3.1.C as a light yellow solid (250 mg, 100% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)/[C:5](/[F:22])=[C:6](\[F:21])/[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=1.[S-:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[Na+]>C(O)C>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([CH:4]([CH2:3][CH2:2][S:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)/[C:5](/[F:22])=[C:6](\[F:21])/[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=2)=[CH:24][CH:25]=1
Reactant: [S-]c1ccccc1
Reactant: F/C(Cc1cccc(Oc2ccccc2)c1)=C(/F)C(CCBr)c1ccc(Cl)cc1
Agent: [Na+]
Solvent: CCO
Product: F/C(Cc1cccc(Oc2ccccc2)c1)=C(/F)C(CCSc1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.2 %

Procedure:
To a stirred solution of 1-[(2E)-6-bromo-4-(4-chlorophenyl)-2,3-difluoro-2-hexenyl]-3-phenoxybenzene (0.308 g, 0.64 mmol) in ethanol (9.6 ml) under nitrogen was added sodium thiophenoxide (0.253 g, 1.91 mmol) and the resulting mixture was stirred at room temperature for two hours. The reaction mixture was concentrated in vacuo, diluted with water (25 ml) and extracted with methylene chloride (3×25 ml). The combined organic extracts were washed with water (2×25 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to a colorless oil (0.187 g). Chromatography on a preparative thin layer silica gel plate eluting with ethyl acetate:hexane (5:95) afforded the title compound as a colorless oil (0.176 g) which was characterized by IR, 1HNMR and mass spectral analysis.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([O:24][CH:25]([CH3:27])[CH3:26])[CH:18]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:12]2[C:7]3[C:6]([CH3:15])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[S:14][C:8]=3[N:9]=[CH:10][N:11]=2)=[C:19]([O:24][CH:25]([CH3:27])[CH3:26])[CH:18]=1
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Reactant: CC(C)Oc1cc(F)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC(C)C)c2c1C
Temperature: 110 °C

Procedure:
4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (112 mg), 4-fluoro-2-isopropoxyaniline (77.9 mg) and p-toluenesulfonic acid monohydrate (15 mg) were dissolved in dioxane (3.0 ml). The reaction was heated at 110° C. under microwave irradiation. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in dichloromethane and extracted with water. The organic phase was dried and concentrated in vacuo. The residue was triturated with diisopropyl ether and filtered.
Reaction SMILES: [N:1]1([CH:6]([CH2:12][CH2:13][CH2:14][CH3:15])[C:7](OCC)=[O:8])[CH:5]=[N:4][CH:3]=[N:2]1.[NH3:16]>>[N:1]1([CH:6]([CH2:12][CH2:13][CH2:14][CH3:15])[C:7]([NH2:16])=[O:8])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CCCCC(C(=O)OCC)n1cncn1
Reactant: N
Product: CCCCC(C(N)=O)n1cncn1
Reaction time: 8 h

Procedure:
Ethyl α-1,2,4-triazol-1-ylcaproate (3.0 g) was added to liquid ammonia (0.880, 15 ml) and the mixture was shaken well for a few minutes and then left overnight at room temperature. The white solid was filtered and washed with water to give, after recrystallisation from water, the title compound.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[N:9]1([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:25]4[CH2:26][C:27]5[S:28][CH:29]=[CH:30][C:31]=5[C:24]=4[N:23]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[N:22]=3)=[CH:17][CH:16]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>C(Cl)Cl>[Br:8][C:29]1[S:28][C:27]2[CH2:26][C:25]3[C:21]([C:18]4[CH:17]=[CH:16][C:15]([N:9]5[CH2:14][CH2:13][O:12][CH2:11][CH2:10]5)=[CH:20][CH:19]=4)=[N:22][N:23]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:24]=3[C:31]=2[CH:30]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(N3CCOCC3)cc2)c2c1-c1ccsc1C2
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(N3CCOCC3)cc2)c2c1-c1cc(Br)sc1C2
Reaction time: 2 h
Yield: 80 %

Procedure:
NBS (0.18 g, 1.0 mmol) was added to a solution of 6-(4-Morpholin-4-yl-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.23 g, 0.5 mmol) in CH2Cl2 (5.0 mL). After 2 hr, the solution was evaporated and washed with EtOAc, filtered, and concentrated to give the corresponding 2-Bromo-6-(4-morpholin-4-yl-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.21 g, 0.4 mmol) as brown solid in 80% yield.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[CH3:26][C:27]1[CH:31]=[C:30]([CH2:32][C:33](O)=[O:34])[O:29][N:28]=1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:33](=[O:34])[CH2:32][C:30]5[O:29][N:28]=[C:27]([CH3:26])[CH:31]=5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: Cc1cc(CC(=O)O)on1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: Cc1cc(CC(=O)N[C@H]2CC[C@H](CCN3CCC(c4cccc5c4OCO5)CC3)CC2)on1

Procedure:
The title compound, light yellow solid (23 mg, 72.4%), MS (ISP) m/z=454.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25.7 mg, 0.07 mmol) and 2-(3-methylisoxazol-5-yl)acetic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:16])=[C:13]([OH:15])[CH:14]=1.Cl>CCO.CCOC(C)=O>[Cl:16][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:14][C:13]=1[OH:15]
Reactant: Clc1ncccn1
Reactant: Nc1ccc(Cl)c(O)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: Oc1cc(Nc2ncccn2)ccc1Cl
Yield: 36.7 %

Procedure:
2-Chloropyrimidine (1.5 g, 13.3 mmol), 5-amino-2-chlorophenol (318 mg, 2.2 mmol) and 37% HCl solution (1.1 mL, 13.3 mmol) in 10% aqueous EtOH solution (10 mL) was stirred at 90° C. for 24 h. Afterwards, 2-chloropyrimidine (1.5 g, 13.3) was added and after 24 h, the reaction mixture was diluted with AcOEt and washed with 5% aqueous K2CO3 solution and brine. The organic phase was dried over Na2SO4, concentrated and the crude product (179 mg, 36% yield) was used for the next step without additional purification.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH3:12][O:13][CH:14]([O:23][CH3:24])[C:15]1[CH:16]=[C:17]([Br:22])[C:18]([CH3:21])=[N:19][CH:20]=1.C([O-])(O)=O.[Na+].[OH-].[Na+]>C(Cl)Cl>[CH3:24][O:23][CH:14]([O:13][CH3:12])[C:15]1[CH:16]=[C:17]([Br:22])[C:18]([CH3:21])=[N+:19]([O-:9])[CH:20]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(OC)c1cnc(C)c(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(OC)c1cc(Br)c(C)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
m-CPBA (242 mg, 1.052 mmol) was added to a suspension of 5-[bis(methyloxy)methyl]-3-bromo-2-methylpyridine (129.5 mg, 0.526 mmol) and NaHCO3 (133 mg, 1.579 mmol) in DCM (5 ml). The mixture was stirred at room temperature overnight. To the resulting white suspension was added DCM and 1N NaOH. The organic phase was extracted twice,
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[C:4]([CH2:12]N(C)C)=[CH:5][NH:6]2.[C-:16]#[N:17].[K+]>CN(C=O)C.O>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[C:4]([CH2:12][C:16]#[N:17])=[CH:5][NH:6]2
Reactant: [C-]#N
Reactant: Cc1cc(C)c2c(CN(C)C)c[nH]c2c1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c2c(CC#N)c[nH]c2c1

Procedure:
A solution of [(4,6-dimethyl-1H-indol-3-yl)methyl]dimethylamine from Step A (98.0 mg, 0.484 mmol) and potassium cyanide (315 mg, 4.84 mmol) in DMF (2 mL) and H2O (2 mL) was heated at 100° C. for 2 h. The reaction mixture was partitioned between EtOAc (20 mL) and saturated NaCl (10 mL). The layers were separated and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the crude product by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH-100:0 to 98:2, gave the title compound. MS: m/z=185 (M+1).
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]3[C:13](=[CH:14][C:4]=2[N:3]=1)[CH:12]=[CH:11][CH:10]=[CH:9]3.[SH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.O>C(O)C.[OH-].[Na+]>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][S:15][C:2]1[NH:6][C:5]2[CH:7]=[C:8]3[C:13](=[CH:14][C:4]=2[N:3]=1)[CH:12]=[CH:11][CH:10]=[CH:9]3
Reactant: Clc1nc2cc3ccccc3cc2[nH]1
Reactant: SCc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: c1ccc(CSc2nc3cc4ccccc4cc3[nH]2)nc1
Yield: 51.4 %

Procedure:
0.92 g of 2-chloro-1H-naphth[2,3-d]imidazole and 0.57 g of 2-mercaptomethylpyridine were heated under reflux for 18 hours in 15 ml of ethanol and 4.5 ml of 1 N caustic soda. 50 ml of water were added to the reaction solution, which was then extracted twice with a total amount of 50 ml of ethyl acetate. The organic phases were washed with saturated sodium chloride solution, dried over magnesium sulphate, and evaporated to dryness on a rotary evaporator. Crystallisation from 50 ml of acetonitrile provided 0.68 g of 2-[(2-pyridylmethyl)thio]-1H-naphth[2,3-d]imidazole having a m.p. of 169°-170°.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH:18]([CH3:20])[CH3:19])=[CH:11][C:12]([CH3:17])([CH3:16])[O:13]2)=[CH:8][C:7]=1/[C:21](/[CH3:29])=[C:22](/[F:28])\[C:23](OCC)=[O:24])[CH2:2][CH2:3][CH3:4].[H-].C([Al+]CC(C)C)C(C)C>>[CH2:1]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH:18]([CH3:19])[CH3:20])=[CH:11][C:12]([CH3:17])([CH3:16])[O:13]2)=[CH:8][C:7]=1/[C:21](/[CH3:29])=[C:22](/[F:28])\[CH2:23][OH:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc2c(cc1/C(C)=C(/F)C(=O)OCC)C(C(C)C)=CC(C)(C)O2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: CCCCOc1cc2c(cc1/C(C)=C(/F)CO)C(C(C)C)=CC(C)(C)O2

Procedure:
Following General Procedure L, ethyl (2E)-3-(7-butoxy-4-isopropyl-2,2-dimethyl-2H-chromen-6-yl)-2-fluoro-but-2-enoate (Compound 74, 133 mg, 0.34 mmol) and diisobutylaluminum hydride (1 M in hexanes, 1.37 mL, 1.37 mmol) were reacted to give the title compound as a colorless oil after purification by flash chromatography (silica gel, 1:9 ethyl acetate/hexane).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13].[CH3:19][N:20]([CH3:33])[CH2:21][CH2:22][C@@H:23]([NH2:32])[CH2:24][S:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:33][N:20]([CH3:19])[CH2:21][CH2:22][C@@H:23]([NH:32][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])[CH2:24][S:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CN(C)CC[C@@H](N)CSc1ccccc1
Reactant: NS(=O)(=O)c1ccc(F)c(S(=O)(=O)C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CN(C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Yield: 82 %

Procedure:
A solution of 4-fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide (685 mg, 2.3 mmol), (R)—N1,N1-dimethyl-4-phenylsulfanyl-butane-1,3-diamine (500 mg, 2.3 mmol), and DIPEA (0.78 mL, 4.5 mmol) in DMA (18.8 mL) was heated to 100° C. for 6 hours. The reaction was cooled to room temperature and diluted with EtOAc/heptanes (1:1, 50 mL). This solution was washed with water, the layers were separated, and the aqueous layer was extracted with EtOAc/heptanes (1:1) (50 mL×3). The combined organic layers were washed with water and brine, dried over MgSO4, and concentrated to afford the title compound as a yellow solid (965 mg, 82% yield). MS (ESI) m/e (M+H+): 512.2
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[C:6]=2[N:7]=1.[CH:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21]>O>[CH:20]([N:22]1[CH2:27][CH2:26][N:25]([C:2]2[N:3]=[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:5]3[N:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[C:6]=3[N:7]=2)[CH2:24][CH2:23]1)=[O:21]
Reactant: O=CN1CCNCC1
Reactant: CSc1ncnc2c(N3CCOCC3)nc(Cl)nc12
Solvent: O
Product: CSc1ncnc2c(N3CCOCC3)nc(N3CCN(C=O)CC3)nc12

Procedure:
10.4 gm (0.035 mol) of 2-chloro-8-methylthio-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p. 179°-180° C.) were heated with 28.5 gm (0.25 mol) of N-formyl-piperazine at about 100° C. for 30 minutes. The resulting solution was taken up in about 300 ml of water, whereby the reaction product was obtained as yellowish precipitate. The precipitate was suction-filtered off, washed with water and dried at 70° C.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([C:11]([OH:13])=O)[NH:2]1.[O-:14][C:15]#[N:16].[K+].Cl>C(O)(=O)C.O>[C:11]1(=[O:13])[CH:3]2[N:2]([CH2:1][C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:4]2)[C:15](=[O:14])[NH:16]1
Reactant: O=C(O)C1Cc2ccccc2CN1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=O)N2Cc3ccccc3CC12
Reaction time: 18 h
Yield: 49.3 %

Procedure:
To a suspension of 53.1 g (0.30 mole) of 1,2,3.4-tetrahydroisoquinoline-3-carboxylic acid in 1000 ml glacial acetic acid was added quickly a solution of 48.6 g (0.60 mole) of potassium cyanate in 150 ml water. The mixture was stirred and heated on a steam bath at 90°-95° for 90 min and all solids dissolved. 3N hydrochloric acid (2400 ml) was added and the resulting solution was stirred and refluxed for 20 hr. The solution was filtered while hot through a coarse sintered glass funnel to remove mechanical impurities and the filtrate was stored in the refrigerator for 18 hrs to deposit 44 g of the crude product. Recrystallization from 1400 ml alcohol gave 29.9 g (49%) of the cyclized material, m.p. 225°-231°. Further recrystallization from alcohol gave the analytical sample, m.p. 227°-230°.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14]([CH:17]=O)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2].[F:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[CH2:32][C:33](=[O:39])[NH:34]2>>[CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14](/[CH:17]=[C:32]3\[C:33](=[O:39])[NH:34][C:35]4[C:31]\3=[C:30]([C:24]3[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=3[F:22])[CH:38]=[CH:37][CH:36]=4)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2]
Reactant: CCN(CC)CCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Product: CCN(CC)CCN1CCCc2[nH]c(/C=C3\C(=O)Nc4cccc(-c5cccc(F)c5F)c43)c(C)c2C1=O
Yield: 61.4 %

Procedure:
The title compound was prepared under the same conditions as described in step 10 of Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 1j obtained from step 9 of Example 1 and 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one 6d as starting materials to obtain (Z)-5-(2-diethylamino-ethyl)-2-[4-(2,3-difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 6 (43 mg, yield 61.4%) as a yellow solid.