Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[O:8][CH:7]([C:14]([F:17])([F:16])[F:15])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2.[C:23]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:23][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[O:8][CH:7]([C:14]([F:17])([F:15])[F:16])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(O)cc(OC)c2OC1C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1=Cc2cc(OC)cc(OC)c2OC1C(F)(F)F
Temperature: 55 °C
Yield: 48.5 %

Procedure:
The ethyl 6-hydroxy-8-methoxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate (0.1 g, 0.31 mmole) and K2CO3 (0.23 g, 1.64 mmole) was suspended in acetone (5.0 mL). lodomethane (0.44 g, 3.1 mmole) was added and heated to 55 ° C. for 3 hrs. The contents were filtered through a plug of celite and washed with acetone. The solution was concentrated in vacuo to give a yellow solid (0.05 g, 50%). GCMS m/z 332.0 (M+). LCMS m/z 333.0 (M+H). 1H NMR (CDCl3/400 MHz) 7.64 (s, 1H), 6.54 (s, 1H), 6.32 (s, 1H), 5.68 (q, 1H, J=7.0 Hz), 4.28 (m, 2H), 3.85 (s, 3H), 3.75 (s, 3H), 1.32 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][O:6][CH2:5][CH2:4][NH:3]1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:12][C:13]1[N:18]=[C:17]([N:3]2[CH2:4][CH2:5][O:6][CH2:7][C:2]2([CH3:1])[C:8]([O:10][CH3:11])=[O:9])[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=1
Reactant: COC(=O)C1(C)COCCN1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)C1(C)COCCN1c1nc(Cl)ncc1[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 16 h
Yield: 100.5 %

Procedure:
Methyl 3-methylmorpholine-3-carboxylate (4.21 g, 26.4 mmol) was dissolved in THF (60 ml) to form a clear solution. 2,4-Dichloro-5-nitropyrimidine (5.13 g, 26.4 mmol) was added and the solution was cooled to −10° C. Diisopropylethylamine (6.93 ml, 39.7 mmol) was added while the temperature was maintained at −8 to −10° C. The reaction was stirred for 4 hours at 0° C. and for 16 hours at room temperature. The solvent was removed under reduced pressure. EtOAc (120 ml) was added and the mixture was washed with water (3×30 ml). The organic solution was concentrated to afford 8.4 g of crude methyl 4-(2-chloro-5-nitropyrimidin-4-yl)-3-methylmorpholine-3-carboxylate as an oil. The crude material was used in the next step without further purification. MS [M+H] calculated for C11H13ClN4O5, 317. found, 317
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[S:18][C:17]([C:19]([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[C:24](=[O:32])[NH:25][C:26]3=[O:31])=[O:20])=[CH:16][CH:15]=1.O[CH:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Cl:13][C:14]1[S:18][C:17]([C:19]([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[C:24](=[O:32])[N:25]([CH:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]2)[C:26]3=[O:31])=[O:20])=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=C(Nc1cccc2c1C(=O)NC2=O)c1ccc(Cl)s1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)CC1
Reaction time: 2 h

Procedure:
At room temperature, 0.12 ml (0.76 mmol) of diethyl azodicarboxylate (DEAD) is added dropwise to a suspension of 150 mg (0.49 mmol) of 5-chloro-N-(1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl)-2-thiophenecarboxamide, 148 mg (0.73 mmol) of tert-butyl 4-hydroxytetrahydro-1(2H)-pyridinecarboxylate and 199 mg (0.76 mmol) of triphenylphosphine in 1.95 ml of absolute THF. After 2 h at room temperature, the mixture is concentrated and the residue is separated by chromatography on silica gel (dichloromethane/methanol mixture) and the product is isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=O)[C:6]([C:14]([F:17])([F:16])[F:15])=[N:5]2.P(Br)(Br)[Br:19]>>[Br:19][C:7]1[C:6]([C:14]([F:17])([F:16])[F:15])=[N:5][C:4]2[C:9](=[CH:10][C:11]([Cl:12])=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: O=c1[nH]c2cc(Cl)c(Cl)cc2nc1C(F)(F)F
Reactant: BrP(Br)Br
Product: FC(F)(F)c1nc2cc(Cl)c(Cl)cc2nc1Br
Temperature: 140 °C

Procedure:
6,7-Dichloro-3-trifluoromethyl-1H-quinoxalin-2-one (500 mg, 1.8 mmol) was dissolved in phosphorus tribromide (2.0 ml), and the solution was heated at 140° C. for 16 hours. The reaction mixture was cooled to room temperature, before it was poured out on ice (100 g) and extracted with dichloromethane. The organic phase was separated and dried with anhydrous sodium sulphate, then taken to dryness by rotary evaporation to leave a pale brown powder.
Reaction SMILES: C(Cl)Cl.[CH2:4]([CH:6]([C:9]1[C:10]2[N:11]([C:16]([C:20]3[O:21][CH:22]=[CH:23][C:24]=3[CH3:25])=[C:17]([CH3:19])[N:18]=2)[N:12]=[C:13]([CH3:15])[CH:14]=1)[CH2:7][CH3:8])[CH3:5].C1C(=O)N([Br:33])C(=O)C1>O>[Br:33][C:22]1[O:21][C:20]([C:16]2[N:11]3[N:12]=[C:13]([CH3:15])[CH:14]=[C:9]([CH:6]([CH2:7][CH3:8])[CH2:4][CH3:5])[C:10]3=[N:18][C:17]=2[CH3:19])=[C:24]([CH3:25])[CH:23]=1
Reactant: CCC(CC)c1cc(C)nn2c(-c3occc3C)c(C)nc12
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClCCl
Product: CCC(CC)c1cc(C)nn2c(-c3oc(Br)cc3C)c(C)nc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.5 %

Procedure:
A CH2Cl2 solution (4 mL) of 8-(1-ethyl-propyl)-2,6-dimethyl-3-(3-methyl-furan-2-yl)-imidazo[1,2-b]pyridazine (32.4 mg, 0.11 mmol) is cooled to 0° C. under a CaSO4 drying tube and treated with NBS (20.1 mg, 0.11 mmol). After 15 minutes at 0° C., the mixture is warmed to room temperature. After an additional 10 minutes, the reaction mixture is poured into H2O (25 mL) and extracted into CH2Cl2 (2×25 mL). The combined organic extracts are washed with aq. brine, dried over Na2SO4, filtered, and concentrated. The crude product is purified by chromatography using hexane-ethyl acetate gradient (100% hexane to 10% ethyl acetate in hexane) to elute the title compound (26.3 mg, 64% yield) as a solid. ES-MS (m/z): calc'd for C18H22BrN3O: 375.1; found 376.2 (M+H); 1H NMR (400 mHz, CDCl3): δ 6.72 (s, 1H), 6.40 (s, 1H), 3.34 (m, 1H), 2.56 (s, 3H), 2.49 (s, 3H), 2.07 (s, 3H), 1.93-1.77 (m, 4H), 0.89 (t, J=7.5 Hz, 6H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:16][C:15]([CH3:18])([CH3:17])[C:14](=[O:19])[N:13]([CH3:20])[C:12]3[C:7]2=[N:8][C:9]([NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=2[O:31][CH3:32])=[N:10][CH:11]=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:33]1([CH:38]2[CH2:43][CH2:42][CH:41]([NH2:44])[CH2:40][CH2:39]2)[CH2:37][CH2:36][CH2:35][CH2:34]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([N:6]2[CH2:16][C:15]([CH3:17])([CH3:18])[C:14](=[O:19])[N:13]([CH3:20])[C:12]3[C:7]2=[N:8][C:9]([NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([NH:44][CH:41]4[CH2:40][CH2:39][CH:38]([N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[CH2:43][CH2:42]4)=[O:28])=[CH:24][C:23]=2[O:31][CH3:32])=[N:10][CH:11]=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Reactant: NC1CCC(N2CCCC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCC(N3CCCC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C

Procedure:
To a solution of 4-[(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]-3-methoxy-benzoic acid (Intermediate 236; 83 mg, 0.19 mmol) in DMF (3 mL) was added a solution of 4-pyrrolidin-1-ylcyclohexan-1-amine (Intermediate 237; 78 mg, 0.46 mmol). DIPEA (100 uL, 0.57 mmol) was added, followed by HATU (107 mg, 0.28 mmol). The resultant mixture was stirred at ambient temperature for 2 hours. The reaction mixture was evaporated to a gum, which was partitioned between DCM (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL). The organic phase was separated by gravity elution through a PTFE filter cup and evaporated to an amber gum which was purified by base modified reverse phase preparative HPLC to yield the title compound as an off white solid (34 mg, 30%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Cl.[CH3:22][O:23]C(=O)[C@H](CO)N.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH:16]([CH2:22][OH:23])[NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1noc(C)c1Cn1cc(N2C(=O)NC(CO)C2=O)cn1
Temperature: 25 °C
Yield: 5.5 %

Procedure:
4-((4-isocyanato-1H-pyrazol-1-yl)methyl)-3,5-dimethylisoxazole (example 10-1) (784 mg, 3.6 mmol), serine methyl ester hydrochloride (672 mg, 4.32 mmol) and triethylamine (1 mL, 7.2 mmol) were refluxed in toluene (16 mL) for 8 hours. The reaction was allowed to cool to room temperature and then the solution was concentrated on the rotovap. The product was purified by reverse phase HPLC (5 to 95% acetonitrile in H2O:16 minute gradient) to afford 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5-(hydroxymethyl)imidazolidine-2,4-dione as a white solid (60 mg, 25%). 1H NMR (CDCl3, 400 MHz): δ (s, 3H), 2.40 (s, 3H), 3.13-3.07 (m, 1H), 3.94-3.93 (d, J=4 Hz, 2H), 4.21-4.19 (t, J=4 Hz, 1H), 5.03 (s, 2H), 6.68 (bs, 1H), 7.87 (s, 1H), 7.99 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 3 μM.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[NH:10][C:9](=O)[CH:8]=2)[CH:2]=1.P(Cl)(Cl)([Cl:22])=O.P(Cl)(Cl)(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>>[Cl:22][C:9]1[CH:8]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(-c2cccnc2)nc(-c2ccccn2)[nH]1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1cc(-c2cccnc2)nc(-c2ccccn2)n1
Temperature: 0 °C

Procedure:
To 6-pyridin-3-yl-2-pyridin-2-yl-3H-pyrimidin-4-one (1 eq, 0.26 mmol, 0.035 g) under inert atmosphere, is added dropwise phosphorus oxychloride (15 eq, 3.9 mmol, 0.36 ml) followed by cautious addition of phosphorus pentachloride (1 eq, 0.26 mmol, 0.054 g). After 4 hours at reflux, the reaction mixture is added slowly to ice/water. The pH is adjusted to pH 7 using NaHCO3 and the aqueous portion is extracted with EtOAc. The combined organic extracts are separated, washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography eluting with 0-100% MeOH in DCM to afford 4-chloro-6-pyridin-3-yl-2-pyridin-2-yl-pyrimidine as a white solid; [M+H]+=269/271.
Reaction SMILES: [O:1]=[C:2]1[NH:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]=3)=[CH:7][CH:8]=2)[NH:3]1>C1COCC1.[Pd]>[O:1]=[C:2]1[NH:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=2)[NH:3]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)NC(=O)NC3)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3c(c2)NC(=O)NC3)CC1
Reaction time: 12 h
Yield: 72.7 %

Procedure:
To a solution of compound 22 (0.8 g, 2.45 mmol) in THF (20 mL) was added Pd—C (10% wet basis, 0.15 g), and the mixture was subjected to hydrogenation in a Parr apparatus at 60 psi for 12 h. After filtering over the pad of celite, the solution was concentrated to get a brown oil material, which was resolved over silica column, eluting with hexanes:ethyl acetate (4:6) and then changing to (6:4) yielded 0.59 g (76%) of 23 as a light yellow gum. IR (KBr) νmax. cm−1: 3211, 3165 (NH), 3072 (Ar—H), 1698 (C═O), 1610, 1512, 1419 (C═C). 1H-NMR (500 MHz, CDCl3) δ=1.48 (s, 9H, (CH3)3C); 1.54 (m, 2H, CH2); 1.75-1.82 (m, 2H, CH2); 2.56 (m, 1H, CH); 2.76 (br. s, 2H, CH2); 4.23 (br. s, 2H, CH2); 4.44 (s, 2H, CH2); 6.58 (m, 2H, H-7, H-8); 7.30 (m, 1H, d, J=8.3 Hz, H-5); 13C NMR (125.7 MHz, CDCl3) δ=28.38 (CH3)3C), 32.50 (CH2), 42.87 (CH2), 43.30 (CH), 47.88 (CH2), 66.36 (CH2), 79.53 (CH3)3C), 93.98 (aromatic-C), 113.24 (aromatic-C), 116.97 (aromatic-C), 117.68 (aromatic-C), 132.41 (aromatic-C), 134.49 (aromatic-C), 149.82 (aromatic-C), 152.48 (C═O), 154.69 (C═O). Calculated (%) for C18H25N3O3(331.19); C, 65.23; H, 7.60; N, 12.68. found (%); C, 65.12; H, 7.69; N, 12.55.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15]([C:17]3[S:21][C:20]4[CH2:22][CH2:23][CH2:24][CH2:25][C:19]=4[CH:18]=3)=[O:16])[C:9]=2[CH3:26])[N:5]=[C:4]([O-])[C:3]1=[O:28].[Na+].P(Br)(Br)([Br:32])=O.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[Br:32][C:4]1[C:3](=[O:28])[N:2]([CH3:1])[CH:7]=[C:6]([C:8]2[C:9]([CH3:26])=[C:10]([NH:14][C:15]([C:17]3[S:21][C:20]4[CH2:22][CH2:23][CH2:24][CH2:25][C:19]=4[CH:18]=3)=[O:16])[CH:11]=[CH:12][CH:13]=2)[N:5]=1
Reactant: O=P(Br)(Br)Br
Reactant: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1-c1cn(C)c(=O)c([O-])n1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1-c1cn(C)c(=O)c(Br)n1
Yield: 49.9 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was purged with nitrogen and charged with 10 (6.55 g, 15.7 mmol) and anhydrous methylene chloride (60 mL). To the resulting suspension phosphorous oxybromide (9.95 g, 34.3 mmol) and N,N-dimethylformamide (190 mg, 2.60 mmol) were added and the reaction was then heated at reflux for 4 h. After this time the reaction mixture was poured into a 10% aqueous potassium carbonate solution (100 mL) and methylene chloride (75 mL) was added. The resulting suspension was filtered through. Celite 521 and the layers separated. The aqueous layer was extracted with methylene chloride (2×100 mL) and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was triturated with a 2:1 solution of ethyl acetate/hexanes (10 mL) and filtered. The filter cake was washed with the 2:1 ethyl acetate/hexanes solution (20 mL) and dried to a constant weight under vacuum to afford a 50% yield (3.59 g) of 11 as a light yellow solid: mp 240-241° C., 1H NMR (500 MHz, DMSO-d6) δ 9.86 (s, 1H), 7.98 (s, 1H), 7.67 (s, 1H), 7.28 (m, 3H), 3.57 (s, 3H), 2.76 (t, 2H, J=5.5 Hz), 2.61 (t, 2H, J=5.5 Hz), 2.18 (s, 3H), 1.76 (m, 4H); MS (ESI+) m/z 458 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[CH:15]([N:18]([C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O)[CH3:19])([CH3:17])[CH3:16].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>C(Cl)Cl>[CH:15]([N:18]([C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1)[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)N(C)c1ccccc1C=O
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)N(C)c1ccccc1CN1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl piperidin-4-ylcarbamate (262 mg, 1.31 mmol) (Aldrich) and 2-(N-isopropyl-N-methylamino)benzaldehyde (150 mg, 0.85 mmol) in CH2Cl2 (6 mL) was added Na(OAc)3BH (288 mg, 1.36 mmol) followed by AcOH (0.1 mL). This mixture was stirred for 3 h at RT. The reaction was quenched by adding 2M NaOH—H2O (5 mL) and stirred for 5 min. The mixture was then extracted with CH2Cl2 (2×25 mL), and the organic layer was washed with brine, and dried, and the solvent was removed. The crude material was purified by silica gel column chromatography eluting with 5% NH3-MeOH in CH2Cl2 gave Compound 221.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C@@H:14]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:15](=[O:21])[N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)(=[O:12])=[O:11])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[CH:35]=[CH2:36].O>CN(C)C=O>[CH2:36]([N:13]([C@@H:14]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:15](=[O:21])[N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:11])=[O:12])[CH:35]=[CH2:34]
Reactant: C=CCBr
Reactant: O=C([C@@H](NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1ccccc1)N1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN([C@H](C(=O)N1CCCC1)c1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.3 %

Procedure:
To a stirred solution of 2-nitro-N-(2-oxo-1-(S)-phenyl-2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide (62.4 g, 160 mmol) in anhydrous dimethylformamide (300 cm3) was added potassium carbonate (44.3 g, 320 mmol). The mixture was stirred at ambient temperature for 10 minutes and allyl bromide (18.0 cm3, 208 mmol) was added dropwise over 10 minutes. The mixture was stirred for 16 hours at ambient temperature and poured into water (2000 cm3) to afford a white precipitate. The mixture was vacuum filtered, washed with water (3×200 cm3) and vacuum dried at 50° C. to constant weight to afford the title compound as a white solid (66.2 g, 96.2%) with a positive ion ESI (M−H)+430.2.
Reaction SMILES: C(N(CC)CC)C.[SH:8][CH2:9][C:10]([OH:12])=[O:11].[CH2:13]([CH:16]1[C:20](O)([CH3:21])[CH:19]=[CH:18][C:17]1=[O:23])[CH:14]=[CH2:15]>C1(C)C=CC=CC=1>[CH2:13]([C:16]1[C:17](=[O:23])[CH2:18][CH:19]([S:8][CH2:9][C:10]([OH:12])=[O:11])[C:20]=1[CH3:21])[CH:14]=[CH2:15]
Reactant: C=CCC1C(=O)C=CC1(C)O
Reactant: O=C(O)CS
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CCC1=C(C)C(SCC(=O)O)CC1=O
Reaction time: 1 h
Yield: 90.7 %

Procedure:
Into the same flask as used in Example 1, triethylamine (10 g), mercaptoacetic acid (30 g) and toluene (50 g) were charged, and 2-allyl-3-hydroxy-3-methyl-4-cyclopentenone (15.2 g) was dropwise added thereto at a temperature of 20° to 40° for 1 hour. Thereafter, the reaction mixture was stirred at a temperature of 50° to 70° C. for 4 hours. After completion of the reaction, the mixture was evaporated under reduced pressure. The residue was dissolved in a 5% aqueous solution of sodium bicarbonate (100 g), and undissolved materials were filtered off. The filtrate was treated with an acid and extracted with diethyl ether. Diethyl ether was evaporated off from the organic layer to obtain 2-allyl-3-methyl-4-carboxymethylthio-2-cyclopentenone (20.5 g). Yield, 90.5%. nD20 1.5567.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])[CH:3]=1.[C:13]([O:17][C:18](=[O:26])[NH:19][C:20]1[S:21][CH:22]=[C:23]([CH3:25])[N:24]=1)([CH3:16])([CH3:15])[CH3:14]>CCOC(C)=O>[C:13]([O:17][C:18](=[O:26])[NH:19][C:20]1[S:21][C:22]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]([C:9]#[N:10])([CH3:12])[CH3:11])[CH:3]=2)=[C:23]([CH3:25])[N:24]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: Cc1csc(NC(=O)OC(C)(C)C)n1
Reactant: CC(C)(C#N)c1cc(I)ccn1
Solvent: CCOC(C)=O
Product: Cc1nc(NC(=O)OC(C)(C)C)sc1-c1ccnc(C(C)(C)C#N)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
The title compound is prepared in analogy to the procedure described in Step 1.3, but using 2-(4-iodo-pyridin-2-yl)-2-methyl-propionitrile (Step 21.5) and (4-methyl-thiazol-2-yl)-carbamic acid tert-butyl ester (Step 18.4). The reaction mixture is stirred for 3 h at 100° C. Title compound: ESI-MS: 359.1 [M+H]+; TLC: Rf=0.47 (Hex/EtOAc, 1:1).
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][C:8]([NH2:14])=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH2:2]1.[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27](O)=[O:28])[CH2:26][CH2:25]3)=[CH:23][C:18]=2[O:17][CH2:16]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27]([NH:14][C:8]4[CH:7]=[C:6]5[C:11](=[CH:10][CH:9]=4)[NH:12][C:13]4[CH2:1][CH2:2][CH2:3][CH2:4][C:5]5=4)=[O:28])[CH2:25][CH2:26]3)=[CH:23][C:18]=2[O:17][CH2:16]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: Nc1ccc2[nH]c3c(c2c1)CCCC3
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(Nc1ccc2[nH]c3c(c2c1)CCCC3)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 70 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
2,3,4,9-Tetrahydro-1H-carbazol-6-amine (81.8 mg, 0.439 mmol) and 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (90.4 mg, 0.439 mmol) were dissolved in acetonitrile (3 mL) containing diisopropylethylamine (0.230 mL, 1.32 mmol) and a magnetic stir bar. O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (183 mg, 0.482 mmol) was added to the mixture and the resulting solution was allowed to stir for 16 h at 70° C. The solvent was evaporated and the crude product was then purified on 40 g of silica gel utilizing a gradient of 5-50% ethyl acetate in hexanes to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2,3,4,9-tetrahydro-1H-carbazol-6-yl)cyclopropanecarboxamide as a beige powder (0.115 g, 70%) after drying. ESI-MS calc. 374.2. found 375.3 (M+1)+. Retention time of 3.43 minutes. 1H NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.39 (s, 1H), 7.46 (d, J=1.8 Hz, 1H), 7.10-6.89 (m, 5H), 6.03 (s, 2H), 2.68-2.65 (m, 2H), 2.56-2.54 (m, 2H), 1.82-1.77 (m, 4H), 1.41-1.34 (m, 2H), 1.04-0.97 (m, 2H).
Reaction SMILES: C(O[C:5]1[C:6](=[O:20])[C:7](=[O:19])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)(C)C.[C:21]([NH2:26])([CH2:24][CH3:25])([CH3:23])[CH3:22]>>[F:18][C:15]([F:16])([F:17])[C:12]1[CH:11]=[CH:10][C:9]([C:8]2[C:7](=[O:19])[C:6](=[O:20])[C:5]=2[NH:26][C:21]([CH3:23])([CH3:22])[CH2:24][CH3:25])=[CH:14][CH:13]=1
Reactant: CCC(C)(C)N
Reactant: CC(C)Oc1c(-c2ccc(C(F)(F)F)cc2)c(=O)c1=O
Product: CCC(C)(C)Nc1c(-c2ccc(C(F)(F)F)cc2)c(=O)c1=O

Procedure:
In a manner similar to Example 1, Step 2, 3-isopropoxy-4-(4-trifluoromethyl-phenyl)-cyclobut-3-ene-1,2-dione (0.30 g, 1.056 mmol) and tert-amylamine (0.86 mL, 7.39 mmol) were converted to the title compound. Recrystallization from hot ethyl acetate afforded 0.250 g (76%) of compound as a tan solkd: m.p. 115.4-119° C. (dec); 1H NMR (DMSO-d6) δ8.60(br s,1H), 8.15(ABq, 2H), 7.86(ABq,2H), 1.81(q,2H), 1.43(s,6H), 0.88(s,3H); IR (KBr) 3170, 2980, 1770, 1720, 1580, 1310, 1170, 1125, 1060, 1010, 850 cm−1; MS (m/z) 311 [M+].
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([N:9]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:8])=[CH:5][C:4]=1[N+:25]([O-])=O>ClCCl.CO.[Pd]>[NH2:25][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:3]=1[NH:2][CH3:1])[C:7]([N:9]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:8]
Reactant: CCOC(=O)CCN(C(=O)c1ccc(NC)c([N+](=O)[O-])c1)c1ccccn1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc(NC)c(N)c1)c1ccccn1

Procedure:
The process disclosed in WO 98/37075 also involves the reduction of ethyl 3-(4-(methylamino)-3-nitro-N-(pyridin-2-yl)benzamido)propanoate (herein after referred as “nitro compound”) using Pd—C in a mixture of dichloromethane and methanol under hydrogen pressure to provide ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate (herein after referred as “diamine compound”).