Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]([Br:22])[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOC(C)=O.[H][H]>[Pt]=O.CCO>[CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]([Br:22])[C:9]1=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c(Br)c(C#Cc2ccccc2)ccn1Cc1ccccc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=c1c(Br)c(CCc2ccccc2)ccn1Cc1ccccc1

Procedure:
A mixture of 1-benzyl-3-bromo-4-(phenylethynyl)pyridin-2(1H)-one (0.3 g), and platinum oxide (0.05 g) in a solvent mixture of EtOAc (10.0 mL) and EtOH (10.0 mL) was stirred in an atmosphere of hydrogen at 15 psi in a Fischer porter bottle for 45 min. The catalyst was removed by filtration, and filtrate was concentrated. The resulting residue was purified by silica gel flash chromatography using 25% EtOAc in hexanes as the eluent. The appropriate fractions (visualized under an UV lamp) were combined and concentrated under reduced pressure. 1H-NMR (CD3OD) δ: 7.56 (d, 1H, J=6.8 Hz), 7.31-7.17 (m, 10H), 6.24 (d, 1H, J=6.8 Hz), 5.19 (s, 2H), 2.96 (m, 2H), and 2.91 (m, 2H); ES-MS m/z=368 (MH+); HR-MS m/z (MH+) calcd C20H19NOBr 368.0650, found 368.0630.
Reaction SMILES: [C:1]1([C:13](=[O:18])[CH2:14][C:15]([NH2:17])=[O:16])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.C[O:20][C:21](=O)[C:22]([C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=O.CC(C)([O-])C.[K+].Cl>O1CCCC1.C(OCC)(=O)C.O>[C:1]1([C:13]([C:14]2[C:15](=[O:16])[NH:17][C:21](=[O:20])[C:22]=2[C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:26][CH:25]=2)=[O:18])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: COC(=O)C(=O)c1c[nH]c2ccccc12
Reactant: NC(=O)CC(=O)c1cn2c3c(cccc13)CCC2
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C1NC(=O)C(c2c[nH]c3ccccc23)=C1C(=O)c1cn2c3c(cccc13)CCC2
Yield: 78.6 %

Procedure:
To a solution of 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-oxo-propionamide (2.0 g, 8.3 mmol) and (1H-indol-3-yl)-oxo-acetic acid methyl ester (1.8 g, 8.8 mmol) in anhydrous tetrahydrofuran (40 ml) at room temperature was added potassium tert-butoxide (26 ml, 26.0 mmol; 1M solution in tetrahydrofuran). After 45 minutes concentrated hydrochloric acid (10 ml) was added. Water (500 ml) was added to the mixture which was then extracted with ethyl acetate (350 ml). The organic layer was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue obtained was sonicated with ethyl acetate (50 ml) to afford 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carbonyl)-4-(1H-indol-3-yl)-pyrrole-2,5-dione as an orange solid (2.58 g). M.p.=>300° C.; 400 MHz 1H NMR (DMSO-d6) δ: 11.99 (s, 1H), 11.12 (s, 1H), 8.18 (s, 1H), 8.13 (s, 1H), 7.93 (m, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.18 (m, 1H), 7.06-7.01 (m, 2H), 6.85 (m, 1H), 4.11 (m, 2H), 2.90 (m, 2H), 2.08 (m, 2H); LCMS: 396 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([NH2:19])[CH:13]=2.[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][C@H:31]2[C:36](O)=[O:37])(=[O:29])=[O:28])=[CH:23][CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([NH:19][C:36]([C@@H:31]1[CH2:32][CH2:33][CH2:34][CH2:35][N:30]1[S:27]([C:24]1[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=1)(=[O:29])=[O:28])=[O:37])[CH:13]=2
Reactant: COc1nccc(Cl)c1-c1cc2ccc(N)cc2[nH]1
Reactant: O=C(O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1nccc(Cl)c1-c1cc2ccc(NC(=O)[C@@H]3CCCCN3S(=O)(=O)c3ccc(F)cc3)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 2-(4-chloro-2-methoxy-pyridin-3-yl)-1H-indol-6-ylamine (35 mg, 0.13 mmol) in CH2Cl2 (5 mL) was added (S)-1-(4-fluoro-benzenesulfonyl)-piperidine-2-carboxylic acid (37 mg, 0.13 mmol) and HATU (49 mg, 0.13 mol). The solution was stirred at 25° C. for 1 h and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (70/30 hexanes/ethyl acetate) afforded (S)-1-(4-fluoro-benzenesulfonyl)-piperidine-2-carboxylic acid[2-(4-chloro-2-methoxy-pyridin-3-yl)-1H-indol-6-yl]-amide (60 mg, 86%) as a white solid. MH+ 543.0.
Reaction SMILES: [N:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]=[C:3]([C:9]([O:11]CC)=O)[CH2:2]2.Cl.[CH3:15][NH:16][O:17][CH3:18].N1C=CC=CC=1>Cl>[N:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]=[C:3]([C:9]([N:16]([O:17][CH3:18])[CH3:15])=[O:11])[CH2:2]2
Reactant: CNOC
Reactant: CCOC(=O)C1=CC2CCN(C1)C2
Agent: Cl
Solvent: c1ccncc1
Product: CON(C)C(=O)C1=CC2CCN(C1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
A solution of (±)ethyl 1-azabicyclo[3.2.1]oct-3-en-3-yl carboxylate (D6) (1.9 g, 10.5 mmole) in 5M hydrochloric acid (25 ml) was heated at 100° C. for 7h. The reaction was concentrated in vacuo and dried by co-distillation with toluene. The resulting brown solid (2.0 g) was suspended in thionyl chloride (20 ml) and heated under reflux until all the acid had dissolved (approx. 10 minutes). After concentrating the reaction in vacuo, residual traces of volatile material were removed by co-distillation with toluene, and the residue was finally dried under high vacuum. A suspension of the acid chloride in absolute chloroform (50 ml) was treated with N,O-dimethylhydroxylamine hydrochloride (1.13 g, 11.5 mmole) and cooled in an ice-salt bath. Pyridine (4.2 ml, 5.3 mmole) was added dropwise with good stirring over a period of 1h. The reaction was allowed to warm to room temperature and stirred overnight. After cooling in an ice bath, the reaction was quenched with a saturated aqueous solution of potassium carbonate (25 ml). The aqueous layer was extracted with chloroform (3×25 ml), and the combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give an oil which was extracted into ether, and then distilled on a kugelrohr (175° C./0.2 mmHg) to afford the title compound (D8) as a pale yellow oil (1.1 g, 54%) which solidified on cooling.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9](=[O:20])[C:8](=[CH:21]O)[CH:7]1[CH3:23])=[O:5])[CH3:2].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1C=CC=CC=1>[C:25]1([NH:24][CH:21]=[C:8]2[C:9](=[O:20])[C:10]3[C:15](=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=3)[N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]2[CH3:23])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CO)C1C
Solvent: c1ccccc1
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CNc2ccccc2)C1C

Procedure:
Starting with 3.2 g. of 3-hydroxymethylene-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-quinoline carboxylic acid ethyl ester and 1.0 g. an aniline in 30 ml. of benzene and employing the reaction procedures of Example 5 provides 3.2 g. of the desired product as a yellow oil.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:8][N:7]([C:9]2[C:18]([F:19])=[C:17]3[C:12]([C:13](=[O:25])[C:14]([C:22]([OH:24])=[O:23])=[CH:15][N:16]3[CH2:20][CH3:21])=[CH:11][C:10]=2[F:26])[CH2:6][CH2:5][O:4]1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.[I-].[Na+]>CN(C)C=O>[CH2:20]([N:16]1[C:17]2[C:12](=[CH:11][C:10]([F:26])=[C:9]([N:7]3[CH2:6][CH2:5][O:4][CH:3]([CH2:2][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:8]3)[C:18]=2[F:19])[C:13](=[O:25])[C:14]([C:22]([OH:24])=[O:23])=[CH:15]1)[CH3:21]
Reactant: C1CCNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCOC(CCl)C3)c(F)c21
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCOC(CN4CCCC4)C3)c(F)c21
Temperature: 150 °C
Reaction time: 7 h

Procedure:
A mixture of 397 mg of 7-(2-chloromethylmorpholino)-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 156 mg of pyrrolidine, 150 mg of sodium iodide and 15 ml of dimethylformamide is stirred at 150° C. for 7 hours. The reaction mixture is concentrated under reduced pressure and to the residue is added water followed by extracting with chloroform. The organic layer is washed with water, dried over anhydrous magnesium sulfate and then the solvent is distilled off to give 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-[2-(1-pyrrolidinylmethyl)morpholino]quinoline-3-carboxylic acid.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[CH:9][CH:10]=[C:11]([C:12]3[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=3)[N:5]2[N:4]=1.C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35][CH2:36][CH2:37][S:38](Cl)(=[O:40])=[O:39]>CN(C)C=O.CCOC(C)=O.O>[O:39]=[S:38]1(=[O:40])[CH2:37][CH2:36][CH2:35][N:18]1[C:14]1[CH:13]=[C:12]([C:11]2[N:5]3[C:6]([CH:7]=[N:8][C:3]([S:2][CH3:1])=[N:4]3)=[CH:9][CH:10]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CSc1ncc2ccc(-c3cccc(N)c3)n2n1
Reactant: O=S(=O)(Cl)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc2ccc(-c3cccc(N4CCCS4(=O)=O)c3)n2n1
Reaction time: 8 h
Yield: 46.5 %

Procedure:
3-(2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenylamine (0.795 g, 3.10 mmol) was dissolved in N,N-Dimethylformamide (12.0 mL) and N,N-Diisopropylethylamine (1.50 mL, 8.61 mmol). Potassium carbonate (1.28 g, 9.30 mmol) was added, followed by 3-Chloropropane-1-sulfonyl chloride (0.450 mL, 3.70 mmol) and stirred overnight. After 24 h, a second aliquot of N,N-Diisopropylethylamine (2.00 mL, 11.5 mmol) and 3-Chloropropane-1-sulfonyl chloride (0.50 mL, 4.1 mmol) was added and stirred additionally. When conversion had reached ca. 90%, the mixture was treated with water (40 mL) and EtOAc (40 mL). The layers were separated, the aq. extr. with EtOAc (3×20 mL) and the comb. org. diluted with hexane (20 mL) and washed with water (30 ml) and brine (30 mL). After drying over sodium sulfate, the mixture was filtered and conc. in vacuo and applied to a 25 g ISCO loading cartridge. Purification on ISCO (40 g column, 10-70% EtOAc:Hex) afforded 7-[3-(1,1-Dioxido-1,2-thiazolidin-2-yl)phenyl]-2-(methylsulfanyl)pyrrolo[2,1-f][1,2,4]triazine (0.52 g; Yield=46%) as a yellow solid. 1H-NMR (CDCl3): 8.74 (s, 1H), 8.06 (s, 1H), 7.86 (d, 1H, J=7.9 Hz), 7.47 (m, 1H), 7.28 (m, 1H), 7.27 (s, 1H), 7.12 (d, 1H, J=4.8 Hz), 6.89 (d, 1H, J=4.8 Hz), 3.86 (t, 2H, J=6.5 Hz), 3.42 (t, 2H, J=7.4 Hz), 2.62 (s, 3H), 2.58 (m, 2H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]1([CH2:17][O:18][C:19]([N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([OH:27])[C@H:22]2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:11]1([CH2:17][O:18][C:19]([N:21]2[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[CH:22]2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:20])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H](O)[C@H]1c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCCN(C(=O)OCc2ccccc2)C1c1ccccc1
Temperature: -75 °C
Reaction time: 0.25 h
Yield: 98.3 %

Procedure:
Dimethyl sulfoxide (9.1 mL, 10.0 g, 128.6 mmol) in dichloromethane (50 mL) was added slowly to a cooled (-75° C.) solution of oxalyl chloride (6.9 mL, 10.2 g, 80.4 mmol) in dichloromethane (500 mL). The mixture was stirred at -75° C. for 15 min., then (2R,3R)-1-(phenylmethoxycarbonyl)-2-phenylpiperidin-3-ol (Description 79, 20.0 g, 64.3 mmol) was added slowly. The mixture was stirred at -75° C. for 1 h., then triethylamine (27 mL, 19.5 g, 192.9 mmol) was added. The mixture was stirred at -75° C. for 1 h., then at room temperature overnight. The mixture was washed with aqueous citric acid (1M), aqueous sodium hydrogen carbonate, water, and brine, dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a yellow oil (19.56 g, 98%). 1H NMR (250 MHz, CDCl3) δ7.39-7.20 (10 H, m), 5.74 (1 H, br s), 5.17 (2 H, br s), 4.13 (1 H, br s), 3.40 (1 H, br m), 2.47 (2 H, m), and 1.94 (2 H, m).
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[OH-].[CH2:26]([N+:28]([CH2:33][CH3:34])([CH2:31][CH3:32])[CH2:29][CH3:30])[CH3:27]>O>[C:1]([O-:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[CH2:26]([N+:28]([CH2:33][CH3:34])([CH2:31][CH3:32])[CH2:29][CH3:30])[CH3:27]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: CC[N+](CC)(CC)CC
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]
Temperature: 70 °C

Procedure:
A mixture of 100 g water, 8.95 g of behenic acid (20 mmole), and 8.0 g of a 35 weight % solution of tetraethylammonium hydroxide was heated to 70° C. with stirring. Then an additional 0.16 g of the tetraethylammonium hydroxide solution was added to adjust the pH to 8.3 (˜20 mmole total). The resulting opalescent solution was freeze dried to yield a white free-flowing powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([CH2:14][CH3:15])[CH2:7][NH:8][C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>CC(C)=O.O>[CH2:1]([O:3][C:4]([CH:6]([CH2:14][CH3:15])[CH2:7][N:8]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:5])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C(CC)CN[C@@H](C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(CC)CN(C(=O)OCc1ccccc1)[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of N-[2-(ethoxycarbonyl)butyl]alanine (2.2 g, 10 mmol) and potassium carbonate (2.2 g, 16 mmol) in a mixture of acetone (30 mL) and water (2.5 mL) was added benzyl chloroformate (2.0 mL, 2.4 g, 14 mmol) at 0-5° C. After stirring for 2 h at ambient temperature the solid was filtered off, the solvent was evaporated, the residue was stirred with cold aqueous sodium hydroxide solution [prepared from ice (20 g) and aqueous sodium hydroxide solution (1N, 40 mL)] and extracted with ethyl acetate (40 mL). The aqueous layer was acidified with an aqueous solution of hydrochloric acid 1/1 (20 mL) and the mixture was extracted with ethyl acetate (40 mL). After drying and evaporation N-[2-(ethoxycarbonyl)butyl]-N-benzyloxycarbonylalanine (1.66 g, 47%) was obtained as a yellow oil which can be used in the next reaction without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:20]([C:21]([OH:23])=O)[CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][N:25](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN>CN(C=O)C.C(OCC)(=O)C>[CH3:24][NH:25][C:21]([C@@H:20]1[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[CH2:19]1)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:23]
Reactant: CC(C)(C)OC(=O)N1Cc2[nH]c3ccccc3c2C[C@@H]1C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)[C@H]1Cc2c([nH]c3ccccc23)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.9 %

Procedure:
To a solution of (R)-2-(tert-butoxycarbonyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid (SM1-B, 10 g, 32 mmol) in DMF (100 ml) was added HATU (15.5 g, 42 mmol), followed by DIEA (12.4 g, 96 mmol) while the temperature was maintained below 0° C. After stirring for 2 h at this temperature, methylamine (2M in THF, 32 mL, 63 mmol) was added. The reaction mixture was warmed to rt and stirred for 16 h. The solution was diluted with ethyl acetate (500 mL); washed with water (200 mL), 0.1 M hydrochloride (100 mL), saturated NaHCO3 (100 mL), and brine (100 mL); dried over Na2SO4; and concentrated and purified by column chromatography (DCM:MeOH=200:1) to give product (2-B) (10 g, 96%) as a white solid. LC-MS (M+H)+=330.
Reaction SMILES: [CH3:1][N:2]([CH2:26][CH:27]=[CH2:28])[S:3]([C:6]1[CH:11]=[C:10]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])[CH:9]=[CH:8][C:7]=1[Cl:25])(=[O:5])=[O:4].IC.[H][H]>[Pd].C(OCC)(=O)C>[CH3:1][N:2]([CH2:26][CH2:27][CH3:28])[S:3]([C:6]1[CH:11]=[C:10]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])[CH:9]=[CH:8][C:7]=1[Cl:25])(=[O:4])=[O:5]
Reactant: [H][H]
Reactant: C=CCN(C)S(=O)(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CI
Product: CCCN(C)S(=O)(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
A mixture of 1.6 g of N-methyl-N-(2-propenyl)-2-chloro-5-(3,6-dihydro-3-methyl-4-trifluoromethyl-2,6-dioxo-1(2H)-pyrimidinyl)benzenesulfonamide (Compound #29), prepared by process C from Compound #28 and iodomethane, 100 ml of ethyl acetate and 200 mg of 5% palladium/carbon catalyst was hydrogenated in a Paar® apparatus at 28 psi of hydrogen. After 30 minutes, the catalyst was filtered and solvent removed from the filtrate by rotary evaporation. The glassy residue was treated with ethanol to give 1.4 g of the title compound as a light gray powder, m.p. 143.5°-145° C.
Reaction SMILES: [OH:1][C@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[Br:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28]2>>[Br:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])/[C:28]/2=[CH:14]\[C:11]1[NH:10][C:7]2[CH2:8][CH2:9][N:4]([CH2:3][C@H:2]([OH:1])[CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:5](=[O:16])[C:6]=2[C:12]=1[CH3:13]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CC2
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: Cc1c(/C=C2\C(=O)Nc3ccc(Br)cc32)[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CC2
Yield: 50 %

Procedure:
The title compound was prepared under the same conditions as described in step 6 of Example 1 with (R)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 1f obtained from step 5 of Example 1 and 5-bromo-1,3-dihydro-indol-2-one as starting materials to give (R,Z)-2-(5-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 4 (24 mg, yield 50%) as a yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)(=[O:13])=[O:12])[CH2:7][CH2:6]1)=[O:4].[F:24][C:25]([F:38])([F:37])[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33]C(O)=O)=[CH:28][CH:27]=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>C(Cl)Cl>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[S:11]([N:8]1[CH2:9][CH2:10][N:5]([C:3]([CH:2]2[CH2:33][CH:32]2[C:29]2[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:37])[F:38])=[CH:31][CH:30]=2)=[O:4])[CH2:6][CH2:7]1)(=[O:13])=[O:12]
Reactant: O=C(O)CCc1ccc(C(F)(F)F)cc1
Reactant: O=C(CCl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C1CC1c1ccc(C(F)(F)F)cc1)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Reaction time: 8 h

Procedure:
To a stirred solution of 2-chloro-1-(4-(naphthalen-2-ylsulfonyl)piperazin-1-yl)ethanone (compound 4, 0.086 g, 0.27 mmol) and 3-(4-(trifluoromethyl)phenyl)propanoic acid (60 mg, 0.27 mmol) in dry DCM (20 mL), DIPEA (72 mg, 1.37 mmol) followed by HATU (208 mg, 0.55 mmol) was added at room temperature and stirred overnight. The mixture was then diluted with DCM washed with water (2×10 mL) & brine (2×10 mL). The organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield the title compound AGI-604 (0.118 g, 90.07%) as solid.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13](C1C=CC=CC=1)[C:14](=[O:16])[O-])(=[O:12])=[O:11].[NH2:24][C:25]1[N:30]=[C:29]([CH2:31][CH3:32])[N:28]=[C:27]([O:33][CH3:34])[N:26]=1>O1CCOCC1.C(OCC)(=O)C>[F:23][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([NH:24][C:25]1[N:30]=[C:29]([CH2:31][CH3:32])[N:28]=[C:27]([O:33][CH3:34])[N:26]=1)=[O:16])(=[O:11])=[O:12]
Reactant: O=C([O-])N(c1ccccc1)S(=O)(=O)c1ccccc1OC(F)F
Reactant: CCc1nc(N)nc(OC)n1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCc1nc(NC(=O)NS(=O)(=O)c2ccccc2OC(F)F)nc(OC)n1
Temperature: 0 °C
Yield: 80.5 %

Procedure:
A solution of 5.4 g of N-(2-difluoromethoxyphenylsulfonyl)phenylcarbamate and 2.42 g of 2-amino-4-ethyl-6-methoxy-1,3,5-triazine in 60 ml of dioxane is refluxed for 5 hours and then poured into 600 ml of ice-water. The precipitate is taken up in ethyl acetate. The ethyl acetate phase is washed with water, dried and concentrated. The residual oil is dissolved in ethyl acetate and washed 5 times with saturated sodium bicarbonate solution. The combined aqueous phases are acidified with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase is dried and evaporated to dryness. Recrystallisation from methanol yields 5.1 g of N-(2-difluoromethoxyphenylsulfonyl)-N'-(4-ethyl-6-methoxy-1,3,5-triazin-2-yl)urea with a melting point of 114°-116° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[C:16]([C:17]2[NH:18][C:19]3[C:24]([C:25]=2[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:23][CH:22]=[C:21]([C:32]([O:34][CH3:35])=[O:33])[CH:20]=3)=[CH:15][CH:14]=[CH:13][N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:37][CH2:38][O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C=O)C>[CH2:40]([O:39][CH2:38][CH2:37][N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[C:21]([C:32]([O:34][CH3:35])=[O:33])[CH:20]=2)[C:25]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:17]1[C:16]1[C:11]([O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[N:12][CH:13]=[CH:14][CH:15]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccnc3OCc3ccccc3)[nH]c2c1
Reactant: BrCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccnc3OCc3ccccc3)n(CCOCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.3 %

Procedure:
To a suspension of NaH (14 mg of 60% dispersion in mineral oil, 0.354 mmol) in DMF (2 mL), methyl 2-(2-(benzyloxy)pyridin-3-yl)-3-cyclohexyl-1H-indole-6-carboxylate (130 mg, 0.295 mmol) was added and the reaction mixture was stirred at rt for 15 min. Benzyl 2-bromoethyl ether (0.052 mL, 0.325 mmol) was then added, and the reaction mixture was stirred at rt overnight before being quenched by the addition of water. The resultant mixture was extracted with ethyl acetate (2×20 mL) and the organic layers were combined, washed with 1N HCl solution, and then dried (MgSO4), filtered and concentrated under vacuum. The residue was then purified by Prep. reverse phase HPLC to give the title compound as light yellow solid (83.5 mg, 49% yield). MS m/z 575(MH+); 1H NMR (500 MHz, CDCl3) δ ppm 1.21–1.31 (m, 3 H) 1.69–1.90 (m, 7 H) 2.53 (m, 1 H) 3.65 (m, 1 H) 3.72 (m, 1 H) 3.92 (s, 3 H) 4.17 (m, 1 H) 4.27 (m, 1 H) 4.32 (s, 2 H) 5.21 (s, 2 H) 6.18 (t, J=6.87 Hz, 1 H) 7.07–7.12 (m, 2 H) 7.21–7.36 (m, 9 H) 7.41 (dd, J=6.71, 2.14 Hz, 1 H) 7.74 (dd, J=8.54, 1.22 Hz 1 H) 7.78 (m, J=8.55 Hz, 1 H) 8.12 (s, 1 H).