Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH2:31][CH2:32][OH:33])=[C:20](OCC4C=CC=CC=4)[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CO.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]4[O:33][CH2:32][CH2:31][C:19]=4[C:17]=3[O:18]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(OCc4ccccc4)c(CCO)c3O2)cc1
Agent: [Pd]
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4c(c3O2)CCO4)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 2.3 g (4.9 mmole) of [(2R)-7-(benzyloxy)-8-(2-hydroxyethyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate in 100 mL of methanol was added to a slurry of 0.40 g of 10% palladium on carbon in 30 mL of methanol in 500 mL Parr hydrogenation bottle. The mixture was treated with 50 psi of hydrogen on a Parr shaker for 15 hours. The catalyst was then removed by filtration through celite and the filtrate concentrated in vacuum to 1.72 g of a yellow oil. The oil was dissolved in 100 mL of benzene, 2.1 g (8.0 mmole) of triphenylphosphine and 1.6 g (8.0 mmole) of diisopropylazodicarboxylate added and the mixture stirred at room temperature for 3 days. The solvent was then removed in vacuum and the residue column chromatographed on silica gel with methylene chloride as eluant to give 1.25 g of the (R)-enantiomer of the title compound as a white solid, m.p. 95-96° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:17])=O.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: O=S(Cl)Cl
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: O=C(Cl)c1cc([N+](=O)[O-])c(F)cc1Cl

Procedure:
22.3 g (0.1 mol) of 2-chloro-4-fluoro-5-nitrobenzoic acid 16.8 g (0.14 mol) of thionyl chloride 0.1 g (0.00036 mol) of triphenyl phosphine oxide Yield*: 46.5 g (>99% of theory) of the title compound as a solution in chlorobenzene * In these examples, the yield was determined by means of 19F-NMR with internal standard. Fluoride value: 0.01 g/l
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([C:10](=O)[CH2:11][CH3:12])[C:6](=O)[CH2:7][CH3:8])=[O:4].[Cl:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([Cl:25])[C:16]=1[NH:26][NH2:27]>C(O)C>[Cl:14][C:15]1[CH:20]=[C:19]([C:21]([F:23])([F:22])[F:24])[CH:18]=[C:17]([Cl:25])[C:16]=1[N:26]1[C:10]([CH2:11][CH3:12])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:6]([CH2:7][CH3:8])=[N:27]1
Reactant: CCC(=O)C(C(=O)CC)C(=O)OC
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: CCO
Product: CCc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(CC)c1C(=O)OC
Yield: 43 %

Procedure:
A solution of 7.5 g (40 mmol) of the compound of step A and 11.85 g (48 mmol) of 2,6-dichloro-4-trifluoromethylphenyl hydrazine in 50 mL of ethanol was heated at reflux for 8 hours. The ethanol was removed by evaporation and the residues were partitioned between ethyl acetate and dilute hydrogen chloride. The organic extracts were dried and evaporated to give the desired product in 43% yield as a maroon oil. 1H-NMR (CDCl3) δ 1.08 (3H, t, J=7), 1.24 (3H, t, J=7), 2.22 (2H, q, J=7), 2.58 (4H, q. J=7), J=7), 3.86 (3H, s), 7.46 (2H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[C:15]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[N:14]([CH3:38])[N:13]=2)=[N:6][CH:7]=1.C[OH:40]>>[Br:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[C:15]([NH:24][S:25]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([CH3:35])([CH3:37])[CH2:36][OH:40])=[CH:32][CH:33]=3)(=[O:26])=[O:27])[N:14]([CH3:38])[N:13]=2)=[N:4][CH:3]=1
Reactant: CO
Reactant: Cc1ccc(-c2c(OCCOc3ncc(Br)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: Cc1ccc(-c2c(OCCOc3ncc(Br)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)CO)cc2)cc1
Reaction time: 48 h

Procedure:
Streptomyces rimosus subsp. rimosus ATCC10970 maintained on a quarter strength ATCC172 agar slope was inoculated as a loopful of spores into a 300 ml Erlenmeyer flask containing 50 ml of AS-7H inoculum medium. This was allowed to incubate for 2 days at 28° C., 200 rpm on an Infors Multitron™ Shaker with 1″ throw. 2 mls of this inoculum medium was then transferred to each of sixteen 300 ml Erlenmeyer flask containing 50 ml of AP-5H production medium and incubated under the same conditions for a further 24 hours. At this point 20 mg of N-[3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-4-(tert-butyl)benzenesulfonamide (GB Patent Application No 9917858.4) dissolved in 0.5 ml of methanol was added to each of the flasks and the fermentation allowed to continue under the same conditions for a further 6 hours. Each flask was then extracted with 200 mls of ethyl acetate and the combined ethyl acetate solubles concentrated to dryness to give a gum solid, 1.4 g.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([S:17]([N:1]2[CH2:8][CH2:7][CH2:6][CH:2]2[C:3]([OH:5])=[O:4])(=[O:19])=[O:18])=[CH:15][CH:16]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N2CCCC2C(=O)O)cc1

Procedure:
Proline is reacted with 4-methoxybenzenesulfonyl chloride in dichloromethane in the presence of triethylamine, to give 1-[(4-methoxyphenyl)sulfonyl]-2-pyrrolidinecarboxylic acid.
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.[CH:18]([CH:21]1[CH2:26][CH2:25][O:24][C:23](=[O:27])[N:22]1[C:28](=[O:39])[CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])([CH3:20])[CH3:19].C(N(C(C)C)CC)(C)C.[CH2:49]([N:55]1[C:59]([CH:60]=[O:61])=[CH:58][N:57]=[CH:56]1)[CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]>ClCCl>[CH2:49]([N:55]1[C:59]([C@@H:60]([OH:61])[C@@H:29]([C:28]([N:22]2[C@H:21]([CH:18]([CH3:20])[CH3:19])[CH2:26][CH2:25][O:24][C:23]2=[O:27])=[O:39])[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:58][N:57]=[CH:56]1)[CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: CCCCCCn1cncc1C=O
Reactant: COC(=O)CC/C=C\CCC(=O)N1C(=O)OCCC1C(C)C
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCn1cncc1[C@@H](O)[C@H](C/C=C\CCC(=O)OC)C(=O)N1C(=O)OCC[C@H]1C(C)C
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
A 1M solution of dibutylboron triflate in dichloromethane (1.56 ml) was added to a solution of the product of step (iv) (422 mg, 1.42 mmol) in dry dichloromethane (9 ml) at 5° C. under argon, followed by diisopropylethylamine (0.295 ml, 1.7 mmol). The reaction mixture was stirred at 5° C. for 30 minutes and then cooled to -78° C. A solution of the product of step (iii) (280 mg, 1.56 mmol) in dichloromethane (2 ml) was added dropwise. The mixture was stirred at -78° C. for 30 minutes before being allowed to warm to room temperature. The reaction was quenched by the addition of pH7.2 phosphate buffer solution (1.36 ml) followed by hydrogen peroxide (0.4 ml, 30% w/v aqueous solution). The mixture was stirred for 30 minutes and then poured into water and extracted three times with dichloromethane. The combined extracts were dried (MgSO4), filtered, and evaporated. The residue was purified by column chromatography, eluting with ethyl acetate, to give methyl (7S,4Z)-7-[(S)-(1-hexylimidazol-5-yl)hydroxymethyl]-8-[(S)-4-isopropyl-2-oxo-1,3-oxazinan-3-yl]-8-oxo-oct-4-enoate (450 mg, 66% yield) as an oil;
Reaction SMILES: [CH2:1]([S:8][C:9]([CH3:38])([CH:33](OC)[O:34]C)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[N:23]([CH3:32])[S:24]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)(=[O:26])=[O:25])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>CC(C)=O>[CH2:1]([S:8][C:9]([CH3:38])([CH:33]=[O:34])[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[N:23]([CH3:32])[S:24]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)(=[O:26])=[O:25])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)C(C)(CNC(=O)c1cc2cccc(N(C)S(=O)(=O)c3cccs3)c2[nH]1)SCc1ccccc1
Solvent: O
Solvent: CC(C)=O
Product: CN(c1cccc2cc(C(=O)NCC(C)(C=O)SCc3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Yield: 90.2 %

Procedure:
A mixture of N-[2-(benzylthio)-3,3-dimethoxy-2-methylpropyl]-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (1.00 g), Amberlyst (registered trade mark) 15 ion exchange resin (0.20 g), water (0.1 ml) and-acetone (10 ml) was stirred overnight at room temperature. The insoluble substance was removed by filtration, and the filtrate was concentrated to give the title compound (0.83 g, yield 92%) as colorless crystals. melting point 149-150° C.
Reaction SMILES: Cl[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH2:14]([O:16][C:17](=[O:25])[CH2:18]N1CCNCC1)[CH3:15].O.Cl>CN(C)C=O>[CH2:14]([O:16][C:17]([CH2:18][CH:9]1[CH2:5][CH2:4][N:3]([C:2]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=2)[CH2:2][CH2:10]1)=[O:25])[CH3:15]
Reactant: CCOC(=O)CN1CCNCC1
Reactant: O=C(O)c1cnc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC1CCN(c2ncc(C(=O)O)cc2[N+](=O)[O-])CC1
Temperature: 130 °C
Yield: 162.2 %

Procedure:
A mixture of 2.00 g (9.87 mmol) of 6-chloro-5-nitro-nicotinic acid and 2.03 g (11.8 mmol) of piperazin-1-yl-acetic acid ethyl ester in N,N-dimethylformamide (10 mL) are heated to 130° C. in a microwave reactor for 1 hour. The resulting dark mixture is poured into water which forms a precipitate. The pH of the mixture is adjusted to approximately pH 2 by adding concentrated hydrochloric acid. The precipitated solid is collected by filtration, washed with water, and dried under reduced pressure to give 2.70 g (81.1%) of 4-ethoxycarbonylmethyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[SH:7].C(NC(C)C)(C)C.[F:15][C:16]([F:20])=[C:17]([F:19])[F:18]>CN(C)C=O>[F:15][C:16]([F:20])([S:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH:17]([F:19])[F:18]
Reactant: FC(F)=C(F)F
Reactant: Sc1ccccn1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: FC(F)C(F)(F)Sc1ccccn1
Temperature: 50 °C
Yield: 296.6 %

Procedure:
A mixture of 42 grams of 2-pyridinethiol, 1-oxide, 150 ml of dimethylformamide and 36 grams of diisopropylamine in a stainless steel pressure vessel was pressurized with 4.95 grams of tetrafluoroethylene at -20° C. and heated to 50° C. for 6 hours with rocking. After cooling to ambient temperature, the pressure vessel was vented and the resulting reaction solution was poured into 300 ml of ice water. The aqueous reaction mixture was extracted four times, using 300 ml of diethyl ether each time. The combined diethyl ether extracts were washed three times, using 500 ml of cold water each time. After washing the diethyl ether solution once with 500 ml of saturated aqueous sodium chloride solution, the diethyl ether solution was dried over 100 grams of anhydrous sodium sulfate and evaporated under reduced pressure of 300 mm Hg to 49.6 grams of a semisolid. The semisolid was crystallized from 1-chlorobutane to yield 31 grams of 2-(1,1,2,2-tetrafluoroethylthio)pyridine, 1-oxide melting 67.5°-68.5° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[C:32](=[O:36])[N:31]([C:37]1([CH3:45])[CH2:42][CH2:41][C:40](=[O:43])[NH:39][C:38]1=[O:44])[C:30]2=[O:46].CCOC(C)=O>CN(C)C=O>[CH3:45][C:37]1([N:31]2[C:30](=[O:46])[C:29]3[C:33](=[CH:34][CH:35]=[C:27]([CH2:26][NH:25][C:9]([C:6]4[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][N:7]=4)=[O:11])[CH:28]=3)[C:32]2=[O:36])[CH2:42][CH2:41][C:40](=[O:43])[NH:39][C:38]1=[O:44]
Reactant: CC1(N2C(=O)c3ccc(CN)cc3C2=O)CCC(=O)NC1=O
Reactant: CSc1ccc(C(=O)O)nc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2(C)CCC(=O)NC2=O)C3=O)nc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 57.5 %

Procedure:
A stirred mixture of 5-methylsulfanyl-pyridine-2-carboxylic acid (0.34 g, 2.00 mmol) and CDI (0.34 g, 2.10 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 2 h, 5-aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)isoindole-1,3-dione hydrochloride (0.68 g, 2.00 mmol) was added and the mixture was heated at 40° C. for 2 h. The mixture was cooled to rt and EtOAc (75 mL) was added. The organic layer was washed with sat. aq. NaHCO3 (3×100 mL) then concentrated in vacuo. The crude residue was purified by column chromatography (0-5% gradient, MeOH/CH2Cl2, 0-5% gradient, product eluted after 4.7 min). The product fractions were combined, concentrated and the residue was triturated in MeCN (50 mL) for 1.5 h. The product was isolated by filtration and dried in vacuo to give 5-methylsulfanyl-pyridine-2-carboxylic acid [2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.52 g, 57% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 4.89 min (98.54%); mp: 210-212° C.; 1H NMR (DMSO-d6) δ 1.88 (s, 3H), 1.97-2.12 (m, 1H), 2.53-2.78 (m, 6H), 4.62 (d, J=6.2 Hz, 2H), 7.68-7.90 (m, 4H), 7.91-8.04 (m, 1H), 8.52 (d, J=1.7 Hz, 1H), 9.51 (t, J=6.3 Hz, 1H), 11.01 (s, 1H); 13C NMR (DMSO-d6) δ 13.93, 21.02, 28.57, 29.09, 42.35, 58.73, 121.75, 122.05, 123.15, 129.59, 131.34, 133.53, 133.82, 139.65, 145.00, 145.90, 147.39, 164.07, 167.73, 167.88, 172.15; LCMS: MH=453; Anal Calcd for C22H20N4O5S: C, 58.40; H, 4.46; N, 12.38. Found: C, 58.24; H, 4.33; N, 12.16.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[C:3]([NH:5][CH2:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:8])=[O:4].[Cl:29][C:30]1[CH:40]=[CH:39][C:33]([CH:34]=[CH:35][C:36](O)=[O:37])=[CH:32][CH:31]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:29][C:30]1[CH:31]=[CH:32][C:33](/[CH:34]=[CH:35]/[C:36]([NH:1][C@@H:2]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:3]([NH:5][CH2:6][C:7]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH2:13][CH2:14]2)=[O:8])=[O:4])=[O:37])=[CH:39][CH:40]=1
Reactant: O=C(O)C=Cc1ccc(Cl)cc1
Reactant: N[C@@H](Cc1ccccn1)C(=O)NCC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccc(Cl)cc1)N[C@@H](Cc1ccccn1)C(=O)NCC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.7 %

Procedure:
To a suspension of (2S)-2-amino-N-[2-[4-(4-chlorophenyl)-1-piperazinyl]-2-oxoethyl]-3-(2-pyridyl)propanamide (29 g) and 4-chlorocinnamic acid (13.1 g) in N,N-dimethylformamide (230 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (15.2 g) and N-hydroxybenzotriazole (10.7 g) at 0° C. The mixture was stirred at room temperature for 20 hours. The reaction mixture was poured into ice-cold saturated aqueous sodium hydrogencarbonate solution and the resulting solid was collected by filtration. The solid was washed successively with saturated aqueous sodium hydrogencarbonate solution and water. The solid was crystallized from water:ethanol (1:9 (v/v)) to give the title compound (34 g) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[N:10][C:9]=2[CH2:20]O)=[CH:4][C:3]=1[F:22].S(Cl)([Cl:25])=O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[N:10][C:9]=2[CH2:20][Cl:25])=[CH:4][C:3]=1[F:22]
Reactant: O=S(Cl)Cl
Reactant: OCc1nc(-c2ccc(F)cc2)oc1-c1ccc(Cl)c(F)c1
Solvent: C1CCOC1
Product: Fc1ccc(-c2nc(CCl)c(-c3ccc(Cl)c(F)c3)o2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5-(4-chloro-3-fluorophenyl)-2-(4-fluoro-phenyl)-4-hydroxymethyloxazole (965 mg) and thionyl chloride (1.1 ml) in tetrahydrofuran (30 ml) was stirred at 0° C. for 30 minutes, followed by stirring at room temperature for 2 hours. Additional thionyl chloride (1.1 ml) was added to the mixture and the mixture was refluxed for one hour. The reaction mixture was concentrated under reduced pressure. The remaining volatiles were removed by evaporation with toluene, and further dried under reduced pressure to obtain a crude product of 5-(4-chloro-3-fluorophenyl)-4-chloromethyl-2-(4-fluoro-phenyl)oxazole (925 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]([CH3:15])[C:12](=[O:16])[NH:11][C:10]2[CH:17]=[N:18][C:19]([Cl:21])=[N:20][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:23].[H-].[Na+]>CN(C)C=O>[CH2:1]([N:8]1[CH2:14][CH:13]([CH3:15])[C:12](=[O:16])[N:11]([CH3:23])[C:10]2[CH:17]=[N:18][C:19]([Cl:21])=[N:20][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CN(Cc2ccccc2)c2nc(Cl)ncc2NC1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CN(Cc2ccccc2)c2nc(Cl)ncc2N(C)C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
To an ice cooled mixture of 1.38 g (0.0046 mole) of (rac)-9-benzyl-2-chloro-7-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-42), 0.43 mL (0.0068 mole) of iodomethane and 15 mL of dimethylformamide was added 0.27 g (0.0068 mole) of a 60% oil dispersion of sodium hydride. The mixture was stirred at 0 degrees for 2 hours and then partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed successively with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with hexanes-ethyl acetate (100:0-60:40) to give 1.36 g of (rac)-9-benzyl-2-chloro-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one as white powder (VII-42).
Reaction SMILES: [Cl:1][CH2:2][S:3]([NH:6][C:7]1[CH:12]=[C:11]([N:13]2[C:22](=[O:23])[CH:16]3[CH2:17][CH:18](O)[CH2:19][CH2:20][N:15]3[C:14]2=[O:24])[C:10]([F:25])=[CH:9][C:8]=1[Cl:26])(=[O:5])=[O:4].C(N(S(F)(F)[F:33])CC)C>ClCCl>[Cl:1][CH2:2][S:3]([NH:6][C:7]1[CH:12]=[C:11]([N:13]2[C:22](=[O:23])[C@@H:16]3[CH2:17][C@@H:18]([F:33])[CH2:19][CH2:20][N:15]3[C:14]2=[O:24])[C:10]([F:25])=[CH:9][C:8]=1[Cl:26])(=[O:5])=[O:4]
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C1C2CC(O)CCN2C(=O)N1c1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Solvent: ClCCl
Product: O=C1[C@@H]2C[C@@H](F)CCN2C(=O)N1c1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the title compound of Example 11, Step A (771 mg, 1-80 mmol) in dichloromethane (10 mL) was added dropwise diethylaminosulfur trifluoride (0.48 mL, 3.60 mmol) at 0° C. The reaction was stirred at 0° C. for 1 hour, quenched with cold water, and extracted with dichloromethane. The combined organic layers were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The title compound of Step A, a compound of this invention, was isolated by flash chromatography (332 mg) as a foam melting at 60-64° C. 1H NMR (CDCl3) 87.7 (d, 1H), 7.4 (d, 1H), 7.1 (br s, 1H), 5.28 and 5.12 (two br s, 1 H), 4.6 (s, 2H), 1H), 4.2 (dd, 1H), 3.3 (ddd, 1H), 2.65 (m, 1H), 2.2 (m, 1H), 1.9-1.6 (m, 2H).
Reaction SMILES: [N:1]([CH:4]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[C:8]2[CH2:16][N:17]([CH3:20])[CH2:18][CH2:19][C:7]1=2)=[N+]=[N-].[Cl-].[NH4+]>C(O)C.O.[Zn]>[CH3:20][N:17]1[CH2:18][CH2:19][C:7]2[N:6]([CH2:5][CH:4]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[NH2:1])[C:14]3[CH:13]=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=3[C:8]=2[CH2:16]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(N=[N+]=[N-])c2ccc(F)cc2)CCN(C)C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(N)c2ccc(F)cc2)CCN(C)C1
Temperature: 100 °C
Yield: 78.7 %

Procedure:
To a solution of 5-(2-azido-2-(4-fluorophenyl)ethyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1 g, 2.75 mmol) in ethanol-water (40-5 mL) was added ammonium chloride (590 mg, 11.02 mmol) and zinc dust (716 mg, 11.02 mmol) and heated at 100° C. for 1 h. After complete conversion of starting material (TLC), ethanol was removed under reduced pressure and 50 mL additional water was added and extracted with DCM (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the crude product, which was purified by reverse phase HPLC to obtain 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(4-fluorophenyl)ethanamine (730 mg) as the TFA salt. 1H NMR (CD3OD, TFA salt): δ (ppm): 7.27 (m, 1H), 7.21 (m, 3H), 7.10 (m, 3H), 4.60 (m, 3H), 4.50 (m, 1H), 4.24 (m, 1H), 3.69 (m, 1H), 3.44 (m, 1H), 3.04 (m, 1H), 2.96 (s, 3H), 2.56 (m, 1H), 2.41 (s, 3H). Chiral HPLC separated the racemate into enantiomers II-11a-b.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].[F:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]2[CH:25]=[C:26](I)[S:27][C:20]=12)[NH2:14]>>[F:10][C:11]1[CH:12]=[C:13]([NH2:14])[CH:15]=[CH:16][C:17]=1[O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]2[CH:25]=[C:26]([C:3]#[C:2][CH2:1][N:4]3[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]3)[S:27][C:20]=12
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: C#CCN1CCCCC1
Product: Nc1ccc(Oc2ccnc3cc(C#CCN4CCCCC4)sc23)c(F)c1
Temperature: 50 °C
Yield: 82.7 %

Procedure:
Prepared from 1-(prop-2-ynyl)piperidine (24 mg, 0.19 mmol) and 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 6, Step A; 50 mg, 0.13 mmol) according to the procedure described for Example 6, Step B, except the reaction was heated at 50° C. for 5 hours. The crude was purified by preparative TLC [5% MeOH (containing 7N NH3) in CHCl3]. The product was obtained as a waxy solid (41 mg, 71%). 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J=6 Hz, 1H), 7.58 (s, 1H), 7.03 (t, J=9 Hz, 1H), 6.52 (m, 3H), 3.85 (br s, 2H), 3.56 (s, 2H), 2.60 (m, 4H), 1.66 (m, 4H), 1.47 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:10])=[C:4]([NH2:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:11]([N:14]=[C:15]=S)([CH3:13])[CH3:12].CC1C=CC(S([O-])(=O)=O)=CC=1.C[N+]1(CCN=C=NC2CCCCC2)CCOCC1>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]2[N:10]=[C:15]([NH:14][CH:11]([CH3:13])[CH3:12])[NH:9][C:4]=2[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Nc1cc(Cl)cc(Cl)c1N
Reactant: CC(C)N=C=S
Agent: C[N+]1(CCN=C=NC2CCCCC2)CCOCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccncc1
Product: CC(C)Nc1nc2c(Cl)cc(Cl)cc2[nH]1
Yield: 59.9 %

Procedure:
3,5-Dichloro-1,2-phenylenediamine (1.30 g, 7.32 mmol), isopropyl isothiocyanate (0.81 g, 8.00 mmol), 1-cyclohexyl-3-(2-morpholinoethyl) carbodiimide metho-p-toluenesulfonate (4.19 g, 9.89 mmol) and pyridine (25 mL) were used according to general procedure I. The product was recrystallized from 1,4-dioxane to afford 1.07 g (60%) of a white solid. Anal. calcd for C10H11Cl2N3-(0.25 C4H8O2): C, 49.64; H, 4.92; N, 15.79. Found: C, 49.54; H, 4.94; N, 15.79.