Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:11]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][CH:12]=1>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:17]([C:10]1[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]=1[CH3:1])[C:14]1[CH:15]=[CH:16][C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:12][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1cc2ccccc2[nH]1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Product: Cc1[nH]c2ccccc2c1C(c1ccc(-c2ccccc2)cc1)c1c(C)[nH]c2ccccc12

Procedure:
The compound Bis(2-methylindol-3-yl)-(1,1′-biphenyl-4-yl)methane was prepared following procedure A, starting from 2-methyl indole and 4-biphenyl carboxaldehyde. LC: Tr 2.71 min, MS: 427 (M+H)+
Reaction SMILES: Br[C:2]1[C:3](=[O:35])[N:4]([CH2:19][C@H:20]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5](=[O:18])[N:6]([CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[C:7]=1[CH3:8].[F:36][C:37]1[C:42]([O:43][CH3:44])=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O>C1C=CC=CC=1.CCO.COCCOC.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>[C:31]([O:30][C:28]([NH:27][C@H:20]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:19][N:4]1[C:3](=[O:35])[C:2]([C:38]2[CH:39]=[CH:40][CH:41]=[C:42]([O:43][CH3:44])[C:37]=2[F:36])=[C:7]([CH3:8])[N:6]([CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[C:5]1=[O:18])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: Cc1c(Br)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)C2CCCCC2)c(=O)n1Cc1c(F)cccc1F
Reactant: COc1cccc(B(O)O)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: COCCOC
Solvent: c1ccccc1
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3F)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)C3CCCCC3)c2=O)c1F
Temperature: 80 °C
Yield: 32.3 %

Procedure:
5-Bromo-3-[2(R)-tert-butoxycarbonylamino-2-cyclohexylethyl]-1-[2,6-difluorobenzyl]-6-methyl-pyrimidine-2,4(1H,3H)-dione 4b (1.0 g, 1.79 mmol) in benzene/EtOH/ethylene glycol dimethyl ether (20/2/22 mL) was added 2-fluoro-3-methoxyphenylboronic acid (382 mg, 2.24 mmol) and saturated Ba(OH)2/water (˜0.5 M, 15 mL). The reaction mixture was deoxygenated with N2 for 10 minutes, tetrakis(triphenylphosphine)palladium (0) (208 mg, 0.18 mmol) was added and the reaction mixture was heated at 80° C. overnight under N2. The reaction mixture was partitioned between brine and EtOAc. The organic layer was dried (sodium sulfate), evaporated, and purified by flash chromatography (silica, 30% EtOAc/hexanes) to give compound 4c (348 mg, 32.3%). MS (CI) m/z 502.2 (MH+-Boc).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH:6]1[C:12](=[O:13])[NH:11][C:10]2[CH:14]=[CH:15][C:16]3[C:21]([C:9]=2[CH2:8][CH2:7]1)=[CH:20][CH:19]=[CH:18][CH:17]=3>CS(C)=O>[N:1]([CH:6]1[C:12](=[O:13])[NH:11][C:10]2[CH:14]=[CH:15][C:16]3[C:21]([C:9]=2[CH2:8][CH2:7]1)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1Nc2ccc3ccccc3c2CCC1Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NC1CCc2c(ccc3ccccc23)NC1=O
Temperature: 80 °C
Yield: 65.1 %

Procedure:
To a suspension of sodium azide (0.55 g, 8.4 mmol) in DMSO (17 ml) was added 3-chloro-4-oxo-2,3,4,5-tetrahydro-1H-naphtho[2,1-b]azepine (1.6 g, 6.7 mmol) and the suspension was heated at 80° C. for 2.5 h. The hot reaction mixture was added on ice (30 g) and the precipitate was filtered and purified by chromatography on silica gel (200 g) using initially heptane as eluent and subsequently a mixture of heptane and ethyl acetate (1:1) to afford 1.1 g of 3-azido-4-oxo-2,3,4,5-tetrahydro-1H-naphtho[2,1-b]azepine.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]1([CH3:19])[CH2:16][O:15][C:14]([CH2:17][CH3:18])=[N:13]1>II>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[C:17]([C:14]1[O:15][CH2:16][C:12]([CH3:19])([CH3:11])[N:13]=1)[CH3:18]
Reactant: CCC1=NC(C)(C)CO1
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: II
Product: CC(=Cc1ccc(Cl)cc1Cl)C1=NC(C)(C)CO1

Procedure:
2-[2-(2,4-Dichlorophenyl)-1-methylethenyl]-4,4 -dimethyl-2-oxazoline (P-2016) was prepared by reacting 2,4-dichlorobenzaldehyde with 4,4-dimethyl-2-ethyl-2-oxazoline in the presence of iodine catalyst.
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[C:27]([C:30]1[N:31]2[CH:37]=[N:36][CH:35]=[C:32]2[S:33][CH:34]=1)(=[O:29])[CH3:28]>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:36]3[CH:35]=[C:32]4[S:33][CH:34]=[C:30]([C:27](=[O:29])[CH3:28])[N+:31]4=[CH:37]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Reactant: CC(=O)c1csc2cncn12
Product: CC(=O)c1csc2cn(CC3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)c[n+]12
Yield: 14.2 %

Procedure:
The same procedure as in Example 1 was repeated except that 104 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 95 mg of 3-acetylimidazo[5,1-b]thiazole were used, thereby obtaining 15.7 mg of the title compound.
Reaction SMILES: [C:1]1([C:7](=[O:16])[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17]Br>O1CCOCC1>[Br:17][CH:8]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:16]
Reactant: O=C(CCc1ccccc1)c1ccccc1
Reactant: BrBr
Solvent: C1COCCO1
Product: O=C(c1ccccc1)C(Br)Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1,3-diphenylpropan-1-one (compound 2) (7.0 mmol) in 25 ml of anhydrous dioxane, a solution of bromine (7.0 mmol) in 10 ml of dioxane was slowly added dropwise over 30 min. The reaction mixture was left to stir at room temperature for 24 hrs to form 2-bromo-1,3-diphenylpropan-1-one (compound 3). Solvent was removed in vacuo. The 2-bromo-1,3-diphenylpropan-1-one product formed was determined by 1H NMR to be sufficiently pure to be used in the next step.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH3:58][C:59]1([CH3:65])[CH2:63][NH:62][C:61](=[O:64])[CH2:60]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O.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]>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([N:62]2[CH2:63][C:59]([CH3:65])([CH3:58])[CH2:60][C:61]2=[O:64])[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: CC1(C)CNC(=O)C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1c(N2CC(C)(C)CC2=O)nc2cc(F)cc(F)c2c1Cl
Temperature: 100 °C

Procedure:
2,4-dichloro-5,7-difluoro-3-methylquinoline (1.50 g, 6.20 mmol), XantPhos (540 mg, 0.93 mmol), 4,4-dimethylpyrrolidin-2-one (700 mg, 6.20 mmol), cesium carbonate (2.80 g, 8.70 mmol), 3 A activated molecular sieves (1.0 g) and Pd2(dba)3 (280 mg, 0.31 mmol) were slurried in 1,4-dioxane (21 mL). The reaction was heated in an oil bath at 100° C. for 1 h. After this time the reaction was cooled to rt, diluted with EtOAc and filtered over a pad of Celite™. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, 0 to 30% EtOAc:DCM as eluant) to give 1-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-4,4-dimethylpyrrolidin-2-one. Mass Spectrum (ESI) m/e=325.1 (M+1).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1)([O-:12])=[O:11]>O.[OH-].[Na+].C1C=CC=CC=1>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5])=[O:21])=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: O=C(O)C[C@H](NC(=O)Nc1ccc([N+](=O)[O-])cc1)C(=O)O
Reaction time: 2 h
Yield: 79.4 %

Procedure:
4.56 g (0.0568 mol) of L-aspartic acid are dissolved in water by addition of sodium hydroxide until a pH close to 10 is obtained. A solution of 10 g (0.0568 mol) of 4-nitrophenyl isocyanate in 50 cm3 of benzene is then added at room temperature. The solution is stirred vigorously for two hours whilst maintaining the pH at around 10 by successive addition of a concentrated sodium hydroxide solution. The weak precipitate formed is eliminated by filtration and the filtrate is washed with 3×50 cm3 of ethyl ether. The aqueous phase is then acidified and extracted with ethyl acetate, which makes it possible to obtain, after drying over anhydrous sodium sulfate and after concentration, 13.4 g (yield 76%) of a yellow solid of which the melting point is 118°-120° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]([C:11](=[O:13])[CH3:12])([OH:10])[CH2:6][CH2:5]1)(=[O:3])C.ClC([O:17][CH2:18][CH:19]=[CH2:20])=O.[H-].[K+]>Cl.O1CCCC1.O.C(OCC)(=O)C>[C:11]([C:7]1([OH:10])[CH2:8][CH2:9][N:4]([C:1]([O:17][CH2:18][CH:19]=[CH2:20])=[O:3])[CH2:5][CH2:6]1)(=[O:13])[CH3:12]
Reactant: CC(=O)N1CCC(O)(C(C)=O)CC1
Reactant: C=CCOC(=O)Cl
Agent: Cl
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1CCC(O)(C(C)=O)CC1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
1,4-Diacetyl-4-hydroxypiperidine (0.2 g) was dissolved in 1N hydrochloric acid (4 ml) and the solution was heated at 100° C. for 15 hours. After cooling to 0° C., the reaction mixture was diluted with a mixture of tetrahydrofuran (10 ml) and water (10 ml). To the mixture was added dropwise at 0° C. a solution of allyl chloroformate (0.15 ml) in tetrahydrofuran (2 ml) while adjusting pH to around 10 with aqueous potassium hydride. After stirring at 0° C. for 30 minutes, the reaction mixture was diluted with a mixture of ethyl acetate and water. The organic layer was separated, washed in turn with water and brine, and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (10 g) eluting with a mixture of n-hexane and ethyl acetate (9:1-1:1, V/V) to give 4-acetyl-1-allyloxycarbonyl-4-hydroxypiperidine (0.26 g).
Reaction SMILES: [CH2:1]1[N:12]2[C:13]3[C:9]([C@@H:10]4[CH2:17][NH:16][CH2:15][CH2:14][C@@H:11]42)=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:4][S:3][CH2:2]1.Cl[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1>>[F:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH2:20][CH2:19][N:16]2[CH2:15][CH2:14][C@@H:11]3[N:12]4[CH2:1][CH2:2][S:3][CH2:4][C:5]5[CH:6]=[CH:7][CH:8]=[C:9]([C:13]4=5)[C@@H:10]3[CH2:17]2)=[CH:24][CH:25]=1
Reactant: Fc1ccc(OCCCCl)cc1
Reactant: c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCSC2
Product: Fc1ccc(OCCCN2CC[C@H]3[C@@H](C2)c2cccc4c2N3CCSC4)cc1

Procedure:
The title compound of EXAMPLE 5 was prepared from (7bR,11aS)-1,2,7b,8,9,10,11,11a-octahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole and 1-(3-chloropropoxy)-4-fluorobenzene following the procedure described in EXAMPLE 4. 1H NMR(CDCl3, 300 MHz): δ 7.0-6.78 (m, 6H) 6.65 (t, 1H, J=7.3 Hz), 3.95 (t, 2H, J=6.2 Hz), 3.84 (dd, 2H, J=16.4 Hz), 3.59 (m, 2H), 3.25 (m, 2H), 3.15 (m, 2H), 2.85 (m, 2H), 2.65 (m, 2H), 2.45 (m, 4H), 2.30 (m, 2H) ppm. LRMS (ES)+: 399 (M+H)+.
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]1[CH2:17][CH2:16][N:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]1>CC(C)=O.C(=O)(O)[O-].[Na+].C(OCC)C>[CH3:1][S:2][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]1[CH2:17][CH2:16][N:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)NN1CCC(c2ccccc2CCl)CC1
Reactant: C[S-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: CSCc1ccccc1C1CCN(NC(=O)OC(C)(C)C)CC1
Reaction time: 6 h
Yield: 52.4 %

Procedure:
Sodium thiomethoxide (0.220 g) tetra-n-butylammonium bromide (0.100 g) and tert-butyl 4-(2-chloromethylphenyl)piperidinecarbamate (0.867 g) were combined in acetone (20 mL) under nitrogen and stirred for 6 h, then heated under reflux for 90 min. The reaction was diluted with aqueous sodium bicarbonate and diethyl ether. The organic phase was dried and evaporated and the residue purified by chromatography (6:1 hexanes:ethyl acetate) to give tert-butyl 4-(2-methylthiomethylphenyl)piperidinecarbamate (0.471 g) as a yellow oil. MS: m/z222 (M-Boc). 1H NMR (CDCl3) δ 7.18 (m, 4H, Ar—H), 3.68 (s, 2H, Ar—CH2—S), 3.04 (m, 1H), 2.80 (m,3H), 2.04 (s, 3H, S—CH3), 1.70 (m, 5H), 1.49 (s, 9H). This material was N-deprotected with HCl according to the conditions described for Example 21d to afford 4-(2-methylthiomethylphenyl)piperidine. 1H NMR (CDC13) δ 7.30 (m, 4H, Ar—H), 3.77 (s, 2H), 3.63 (m, 2H), 3.10 (m, 3H), 2.25 (m, 2H), 2.04 (s, 3H, S—CH3), 1.95 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(=O)C.[CH:11]([C:13]1[CH:14]=[CH:15][C:16]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:17]([CH:27]=1)[C:18]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[O:19])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.ClCCl>[N:1]1([CH2:11][C:13]2[CH:14]=[CH:15][C:16]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:17]([CH:27]=2)[C:18]([NH:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[O:19])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=Cc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(Nc1cccnc1)c1cc(CN2CCOCC2)ccc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Morpholine (26 uL, 0.30 mmol) and acetic acid (17 ul, 0.30 mmol) were added to a solution of 5-formyl-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in Example 66; 100 mg, 0.301 mmol) in DCE (5 ml). The solution was stirred for 4 hours at 50° C. then sodium triacetoxyborohydride (96 mg, 0.45 mmol) was added. The reaction was stirred overnight. Saturated NaHCO3 solution (5 ml) was added and the mixture stirred for 5 minutes. The organic layer was then diluted with dichloromethane (5 ml) before being separated and dried (MgSO4). The solvent was removed in vacuo and the residue purified by MDAP to yield the title compound. 40 mg.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>C1C=CC=CC=1.O.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[C:12]([C:9]1[C:10](=[O:11])[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][C:7](=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:8]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: CCOC(=O)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C=C1C=C(C(C)(C)C)C(=O)C(C(C)(C)C)=C1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
In benzene (150 mL) was dissolved Intermediate 10 (6.7 g, 22.9 mmol) and this treated with a solution of potassium hydroxide (13.9 g [85%], 210 mmol) and potasium ferricyanide (K3Fe(CN)6) (15.2 g, 46 mmol) in water (150 mL). The mixture stirred under nitrogen atmosphere at 40° C. for 2 hours. The benzene layer then separated, washed with brine (100 mL) and dried over magnesium sulfate. The solvent was evaporated in vacuo to give a red oil, 6.1 g (92%), which was used as is.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1>>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:3]=1
Reactant: Brc1cccnc1
Reactant: NCc1cccnc1
Product: c1cncc(CNc2cccnc2)c1
Yield: 82.6 %

Procedure:
Using the general procedure, 3-bromopyridine (96 μL, 1.0 mmol) was coupled with 3-(aminomethyl)pyridine (153 μL, 1.5 mmol) at 90° C. for 20 h. Purification of the crude product by column chromatography on silica gel using dichloromethane(saturated with ammonia)/methanol (15:1) as eluent afforded the desired product as a light yellow liquid (153 mg, 83% yield). Rf=0.4 (dichloromethane(saturated with ammonia)/methanol=10:1).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:23][C:24]([O:26]C)=[O:25])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:28](=[O:30])[NH2:29])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C(O)C>[I:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:23][C:24]([OH:26])=[O:25])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:28](=[O:30])[NH2:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(I)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1cccc2c1c1c(OCC(=O)O)cccc1n2Cc1cccc(I)c1
Temperature: 25 °C
Reaction time: 43 h
Yield: 44.5 %

Procedure:
A suspension of the {9-[(3-iodophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (15 mg, 0.03 mM) and 0.03 mL (0.03 mM) of 1 N NaOH in 5 mL of ethanol was stirred for 43 hours at 25° C., then cooled in an ice-bath. The resultant white precipitate was collected by filtration, washed with a small amount of EtOH, then dried in vacuo to afford 6.5 mg (43%) of the {9-[(3-iodophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt as a white powder. 1H NMR (DMSO-d6) δ 7.6-7.0 (m, 11H), 6.6 (d, 1H, J=8 Hz), 5.7 (s, 2H), and 4.35 (s, 2H). IR (KBr, cm−1) 3456, 3416, 3335, 1735, 1638, 1617, 1580, 1499, 1452, 1431, 1431, 1329, 1255, 1157, 772, 764, and 717. MS (ES) m/e 407, 409, 411.
Reaction SMILES: C1(N2CCN3C(CC4(C5C=CC=CC=5)CCCC4)=NC(=O)C(O)=C3C2=O)CC1.C([O:36][C:37]1[C:42](=[O:43])[N:41]=[C:40]([CH2:44][C:45]2([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[CH2:49][CH2:48][CH2:47][CH2:46]2)[N:39]2[CH2:56][CH2:57][N:58]([CH:61]3[CH2:64][CH2:63][CH2:62]3)[C:59](=[O:60])[C:38]=12)C1C=CC=CC=1>>[CH:61]1([N:58]2[CH2:57][CH2:56][N:39]3[C:40]([CH2:44][C:45]4([C:50]5[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=5)[CH2:49][CH2:48][CH2:47][CH2:46]4)=[N:41][C:42](=[O:43])[C:37]([OH:36])=[C:38]3[C:59]2=[O:60])[CH2:62][CH2:63][CH2:64]1
Reactant: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccccc4)CCCC3)n2CCN1C1CCC1
Agent: O=C1c2c(O)c(=O)nc(CC3(c4ccccc4)CCCC3)n2CCN1C1CC1
Product: O=C1c2c(O)c(=O)nc(CC3(c4ccccc4)CCCC3)n2CCN1C1CCC1
Yield: 42.1 %

Procedure:
This compound was prepared following the same method as described for 2-cyclopropyl-9-hydroxy-6-(1-phenyl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (287) from 9-benzyloxy-2-cyclobutyl-6-(1-phenyl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (294) (140 mg, 0.29 mmol). The product was obtained as a white solid (48 mg, 42.14%).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[CH3:17][C:18]1[O:19][CH:20]=[CH:21][C:22]=1/[CH:23]=[CH:24]/[C:25](Cl)=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1>>[CH3:16][O:15][C:13]1[CH:12]=[CH:11][C:3]2[N:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=3)[C:25](/[CH:24]=[CH:23]/[C:22]3[CH:21]=[CH:20][O:19][C:18]=3[CH3:17])=[N:1][C:2]=2[CH:14]=1
Reactant: COc1ccc(Nc2ccccn2)c(N)c1
Reactant: Cc1occc1/C=C/C(=O)Cl
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Product: COc1ccc2c(c1)nc(/C=C/c1ccoc1C)n2-c1ccccn1
Yield: 16 %

Procedure:
(E)-3-(2-Methyl-3-furyl)acrylic acid (0.30 g, 2 mmol) was dissolved into thionyl chloride (5 ml) and the mixture was heated to reflux for 80 min. Volatiles were removed by evaporation to give crude (E)-3-(2-methyl-3-furyl)acryloyl chloride. The titled compound was prepared from 2-amino-4-methoxy-N-(2-pyridyl)aniline (0.43 g, 2 mmol) and (E)-3-(2-methyl-3-furyl)acryloyl chloride obtained as above according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). Recrystallization from a mixture of isopropyl ether (3 ml) and ethyl acetate (3 ml) to give 0.10 g (16%) of the titled compound.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH:15]=[CH2:16])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[OH:25][CH:26]([C:28]1[S:32][C:31]([CH:33]=[O:34])=[N:30][CH:29]=1)[CH3:27].C(N(CC)CC)C.O1CCCC1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH2:15][CH2:16][C:33]([C:31]3[S:32][C:28]([CH:26]([OH:25])[CH3:27])=[CH:29][N:30]=3)=[O:34])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CC(O)c1cnc(C=O)s1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(O)c1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)s1
Yield: 93.7 %

Procedure:
A mixture of 4-[4-(cyclopropylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (1.00 g), 5-(1-hydroxyethyl)-1,3-thiazole-2-carbaldehyde (0.47 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (77 mg), triethylamine (0.16 mL), tetrahydrofuran (6 ml) and ethanol (6 mL) was stirred with heating under reflux for 2 hr. The reaction mixture was concentrated, the residue was subjected to basic silica gel column chromatography, and eluted with ethyl acetate, and the fraction was concentrated. The residue was subjected to silica gel column chromatography, and the title compound (1.36 g, yield 94%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (9:1, volume ratio). MS: 506 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=1)[CH3:2].N1C=CC=CC=1.[CH2:19]([S:22](Cl)(=[O:24])=[O:23])[CH2:20][CH3:21].O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][S:22]([CH2:19][CH2:20][CH3:21])(=[O:24])=[O:23])[CH:6]=1)[CH3:2]
Reactant: CCCS(=O)(=O)Cl
Reactant: CCOC(=O)c1cccc(N)c1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCS(=O)(=O)Nc1cccc(C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 3-amino-benzoic acid ethyl ester (74, 5.0 g, 0.030 mol) in methylene chloride (30.0 mL) were added pyridine (3.67 mL, 0.045 mol) and propane-1-sulfonyl chloride (3.75 mL, 33.0 mmol). The reaction was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The desired compound was isolated by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a white solid (75, 6.0 g, 74.1%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20]OS(C)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[NH:26]1[CH2:29][CH2:28][CH2:27]1>CC(N(C)C)=O.CCOCC.C([O-])([O-])=O.[Na+].[Na+]>[N:26]1([CH2:20][CH2:19][C:18]#[C:17][C:15]2[CH:14]=[CH:13][C:12]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=4)=[N:9][S:10][C:11]=3[CH:16]=2)[CH2:29][CH2:28][CH2:27]1
Reactant: C1CNC1
Reactant: CS(=O)(=O)OCCC#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: Brc1ccc(-c2nsc3cc(C#CCCN4CCC4)ccc23)cc1
Yield: 34.9 %

Procedure:
73 mg (0.16 mmol) Methanesulfonic acid 4-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl ester in 1 ml DMA were treated with 35 μl (0.5 mmol) azetidine for 48 h. The solution was diluted with ether and aqueous Na2CO3, the phases were separated and the inorganic layer was extracted with ether. The combined organic phases were washed with brine, dried over Na2SO4. Column chromatography on silica gel with a gradient CH2Cl2 to CH2Cl2:MeOH 8:1 gave 22.2 mg (33%) 6-(4-Azetidin-1-yl-but-1-ynyl)-3-(4-bromo-phenyl)-benzo[d]isothiazole as brown oil, MS: 397(MH+, 1Br).