Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10](O)[C@H:9]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:30])CC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([F:30])[C@H:9]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H]1C(=O)OCc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](F)[C@H]1C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 5 h
Yield: 89 %

Procedure:
The title compound was prepared in a similar manner as described by J. A. Hodges et al., J. Amer. Chem. Soc. 2005, 127, 15923-15932: To a solution of (2S,3R)-3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (490 mg, 1.53 mmol) in CH2Cl2 (30 mL), cooled to −78° C., was added dropwise DAST (1.01 mL, 7.62 mmol). The reaction mixture was stirred at −78° C. for 5 h, and then was allowed to warm to RT and stirred overnight. After cooling to 0° C., the reaction was quenched with MeOH, followed by addition of aqueous NaHCO3 solution. Volatiles were removed under reduced pressure and the residue was taken up in EtOAc. The organics were washed with aqueous NaHCO3 (3×), water and brine, dried (Phase separator) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc/c-hexane 1:9) to give the title compound (89% purity by HPLC/215 nm). MS (LC/MS): 346 [M+Na]+, 268 [MH−tBu]+, 224 [MH−Boc]+; tR (HPLC conditions b): 5.31 min.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[CH:9][CH:10]=2)[O:5][CH2:4]1.[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:18]=1[C:19](Cl)=[O:20]>N1C=CC=CC=1>[Cl:26][C:23]1[CH:24]=[CH:25][C:17]([O:16][CH3:15])=[C:18]([CH:22]=1)[C:19]([NH:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[CH:9][CH:10]=2)[O:5][CH2:4]1)=[O:20]
Reactant: COc1ccc2c(c1)OCC(N)C2
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc2c(c1)OCC(NC(=O)c1cc(Cl)ccc1OC)C2
Temperature: 60 °C
Reaction time: 1 h

Procedure:
15.1 g (70 mmol) of 3-amino-7-methoxychroman hydrochloride (Eur. J. Med. Chem. 11 (1976), 251-256) were dissolved in 80 ml of pyridine, and 14.8 g of 2-methoxy-5-chlorobenzoyl chloride were added at 0° C. The mixture was stirred at room temperature for 1.5 hours and at 60° C. for 1 hour. The cooled reaction mixture was partitioned between water and methylene chloride. The aqueous phase was extracted three times with methylene chloride. The combined organic phases were washed with 2N hydrochloric acid, water and bicarbonate solution. After drying and evaporation of the organic phase, the residue was dissolved in a little toluene and the product was precipitated with excess diethyl ether. 3-(5-chloro-2-methoxybenzamido)-7-methoxychroman of melting point 92°-93° C. was obtained.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15]C)=O)[CH:11]=2)[NH:6][CH:5]=1)([O-:3])=[O:2].O.[NH2:18][NH2:19]>CCO>[N+:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([NH:18][NH2:19])=[O:15])[CH:11]=2)[NH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NN
Reactant: COC(=O)c1ccc2[nH]cc([N+](=O)[O-])c2c1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc2[nH]cc([N+](=O)[O-])c2c1
Temperature: 25 °C
Yield: 50 %

Procedure:
To a suspension of methyl 3-nitro-1H-indole-5-carboxylate (2.0 g, 9.09 mmol) in EtOH (40 mL) was added hydrazine hydrate (6 mL) and the reaction mixture was heated to reflux for 30 h. The mixture was cooled to RT and EtOH was removed in vacuo. Petroleum ether was added to the residue to get a yellow precipitate. The precipitate was filtered, washed with petroleum ether (3×40 mL) and dried to afford 3-nitro-1H-indole-5-carbohydrazide (1.0 g, 50%) as a yellow solid. MS (ESI, pos. ion) m/z: 221.0 (M+1); 1H NMR (300 MHz, DMSO-d6): δ 9.83 (s, 1H), 8.71 (s, 1H), 8.57 (s, 1H), 7.77 (dd, 1H, J=8.7, 1.2 Hz), 7.58 (d, 1H, J=8.7 Hz), 4.49 (brs, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[N:17]([CH3:21])[N:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:27]([O:29][CH2:30][CH3:31])=[CH2:28])CCC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:30]([O:29][C:27]([C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[N:17]([CH3:21])[N:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1)=[CH2:28])[CH3:31]
Reactant: Cn1ncc2cc(Cc3cnc4ccc(Cl)nn34)ccc21
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=C(OCC)c1ccc2ncc(Cc3ccc4c(cnn4C)c3)n2n1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A suspension of 6-chloro-3-((1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazine (180.0 mg, 36% pure, 0.22 mmol), tributyl(1-ethoxyvinyl)stannane (94 mg, 0.26 mmol) and Pd(PPh3)4 (25.1 mg, 0.02 mmol) in 10 mL DMF was flashed with nitrogen, then heated at 110° C. and stirred overnight. Solvent was removed under reduced pressure, the residue was diluted with DCM, washed sequentially with KF solution and water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (DCM:MeOH=20:1) to give the title compound which contains some triphenylphosphine oxide impurity and used in the next step without further purification (49 mg, 47%, 70% pure). LCMS (method A): [MH]+=334, tR=5.71 min.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:16][CH3:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]2([CH2:16][CH3:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH2:27][CH2:26]1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: CCC1(CCCCCl)C(=O)Nc2ccccc21
Product: CCC1(CCCCN2CCN(c3ccccc3Cl)CC2)C(=O)Nc2ccccc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 starting from 3-(4-chlorobutyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 1-(2-chlorophenyl)-piperazine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[NH2:41][C:42]1[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[C:44]([O:52][CH2:53][CH3:54])[CH:43]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10][C@H:9]2[C:28]([NH:41][C:42]2[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[C:44]([O:52][CH2:53][CH3:54])[CH:43]=2)=[O:30])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CCOc1cc(N)ccc1C(=O)OC
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: ClCCl
Product: CCOc1cc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)ccc1C(=O)OC
Reaction time: 1.5 h
Yield: 107.4 %

Procedure:
To a solution of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (60.8 mg, 0.13 mmol) in dichloromethane (3 mL) were added DIPEA (89.0 mg, 0.69 mmol), methyl 4-amino-2-ethoxybenzoate (50.9 mg, 0.26 mmol) and HATU (90.8 mg, 0.24 mmol). (The acid, DIPEA, and HATU were added in thirds at 20 min intervals). After 90 min, the reaction was diluted with dichloromethane, washed with water and saturated sodium chloride and purified by silica gel chromatography with ethyl acetate and hexanes to give racemic methyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-2-ethoxybenzoate (90 mg, with minor impurity) as a light brown oil.
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][C@@H:10]1[NH:19][C:20]([C:22]1[S:23][C:24]2[CH2:25][N:26]([CH3:31])[CH2:27][CH2:28][C:29]=2[N:30]=1)=[O:21])=[O:7])(C)(C)C.Cl.[Cl:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38](C(O)=O)=[CH:37]2>O1CCOCC1>[ClH:33].[Cl:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38]([C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][C@@H:10]1[NH:19][C:20]([C:22]1[S:23][C:24]3[CH2:25][N:26]([CH3:31])[CH2:27][CH2:28][C:29]=3[N:30]=1)=[O:21])=[O:7])=[CH:37]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: COC(=O)[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@H]1CC[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1

Procedure:
(1R*,2S*,4S*)-N1-tert-Butoxycarbonyl-4-methoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine was treated with a 4N dioxane solution of hydrochloric acid and then condensed with 5-chloroindole-2-carboxylic acid in a similar manner to Example 118 to obtain the title compound.
Reaction SMILES: [S:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][NH:4][CH2:3][CH2:2]1.[Br:12][CH2:13][C:14](Cl)=[O:15]>C(N(CC)CC)C>[Br:12][CH2:13][C:14]([N:4]1[CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:1][CH2:2][CH2:3]1)=[O:15]
Reactant: c1ccc2c(c1)CNCCS2
Reactant: O=C(Cl)CBr
Solvent: CCN(CC)CC
Product: O=C(CBr)N1CCSc2ccccc2C1
Yield: 42.1 %

Procedure:
2,3,4,5-Tetrahydro-1,4-benzothiazepine (4.8 g), triethylamine (5.9 g) and bromoacetyl chloride (5.5 g) were reacted in the same manner as in Experimental Example 1 to give 4-bromoacetyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (3.5 g).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[H-].[Na+].[CH:16]([Si:19](Cl)([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])([CH3:18])[CH3:17].O>CN(C)C=O>[CH3:1][N:2]([CH3:13])[CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]([Si:19]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:16]([CH3:18])[CH3:17])[CH:5]=1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(CN(C)C)c2cccnc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Dimethyl-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-amine 109 (5.0 g, 28 mmol), was dissolved in N,N-dimethylformamide (80.0 mL) and sodium hydride (60% dispersion in mineral oil, 1.25 g, 31.4 mmol) was added, followed by triisopropylsilyl chloride (6.3 mL, 30.0 mmol). The reaction was stirred at room temperature for 12 hours, then poured into water and extracted with ethyl acetate. The organic portion was washed with brine, dried over sodium sulfate, concentrated and purified with silica gel chromatography to give the compound (110, 6.5 g, 70%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][CH2:6][NH:7][C:8](=O)[O:9]CC.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O=P(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[F:16])[C:8](=[O:9])[NH:7][CH2:6][CH2:5]2
Reactant: CCOC(=O)NCCc1ccc(F)c(F)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: O=C1NCCc2cc(F)c(F)cc21
Yield: 20 %

Procedure:
Using an analogous reaction procedure and workup as described in example 1 for the preparation of intermediate I-1d above, ethyl 3,4-difluorophenethylcarbamate (I-49c: 5 g, 21.8340 mmol) in POCl3 (43.6 mL) was reacted with P2O5 (6.19 g, 43.6681 mmol) at 110° C. for 2 hours to afford the crude product. Purification by column chromatography on silica gel (50% ethyl acetate in hexane) afforded 800 mg of the product (18.91% yield).
Reaction SMILES: [C:1]([CH:3]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[CH2:4][CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)#[N:2]>[Ni].CCO.[OH-].[NH4+]>[Cl:20][C:15]1[CH:14]=[C:13]([CH:3]([CH2:1][NH2:2])[CH2:4][CH2:5][O:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: N#CC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: NCC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Reaction time: 24 h
Yield: 54.5 %

Procedure:
Raney nickel (38 g) was placed in a stainless steel bottle and EtOH (100 ml) was added followed by a solution of 2-(3-cyano-3-(3,4-dichlorophenyl)propyl)oxytetrahydropyran (138 g, 0.44 mol) in EtOH (1100 ml) and concentrated ammonium hydroxide (600 ml). The bottle was then shaken under an atmosphere of hydrogen gas (53 psi) and when the pressure fell below 35 psi the flask was repressurised. After 24 h the pressure remained constant so the reaction mixture was filtered through Celite™ and concentrated. Water was added, the mixture was extracted with DCM and then dried (Na2SO4) and concentrated to give 2-(3-(3,4-dichlorophenyl)-4-aminobutyl)oxytetrahydropyran as an oil (75 g, 0.24 mol).
Reaction SMILES: Cl[C:2]([C:7]1[CH:8]=[CH:9][C:10]2[O:19][C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH2:12][C:11]=2[CH:20]=1)([CH3:6])[C:3]([OH:5])=[O:4].[OH-].[Na+]>[Ni].[H][H]>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]2[CH2:12][C:11]3[CH:20]=[C:7]([CH:2]([CH3:6])[C:3]([OH:5])=[O:4])[CH:8]=[CH:9][C:10]=3[O:19][C:14]=12
Reactant: CC(Cl)(C(=O)O)c1ccc2c(c1)Cc1cccnc1O2
Reactant: [H][H]
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Product: CC(C(=O)O)c1ccc2c(c1)Cc1cccnc1O2
Yield: 58.7 %

Procedure:
A mixture of 2.9 g of 2-chloro-2-(5H-[1]benzopyrano[2,3-b]pyridin-7-yl)propionic acid, 40 ml of 0.5 N aqueous sodium hydroxide solution and 1 g of Raney nickel is stirred in a hydrogen stream at ordinary pressure and temperature, until absorption of 230 ml of hydrogen is attained. The RAney nickel is then filtered off, and the filtrate is neutralized with hydrochloric acid. The crystalline precipitate is filtered off, washed with water, and recrystallized from aqueous dioxane to give 1.5 g of 2-(5H-[1]benzopyrano-[2,3-b]pyridin-7-yl)propionic acid melting at 183°-184°C.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=2)[C:6]([C:16]([OH:18])=O)=[CH:5]1)([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:55][C:56]1[S:57][CH:58]=[CH:59][N:60]=1>C(Cl)Cl>[S:57]1[CH:58]=[CH:59][N:60]=[C:56]1[NH:55][C:16]([C:6]1[C:7]2[C:12](=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[N:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)=[O:18]
Reactant: CC(C)n1cc(C(=O)O)c2ccc([N+](=O)[O-])cc21
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)n1cc(C(=O)Nc2nccs2)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 4.9 %

Procedure:
A solution of 1-isopropyl-6-nitro-1H-indole-3-carboxylic acid (200 mg, 0.81 mmol) in methylene chloride (4 mL) and N,N-diisopropylethylamine (0.32 mL, 1.85 mmol) at 25° C. was treated with benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluoro-phosphate (463 mg, 1.05 mmol). The reaction was stirred at 25° C. for 20 min. At this time, the reaction was treated with 2-aminothiazole (186 mg, 1.85 mmol) and was stirred at 25° C. for 24 h. At this time, the reaction mixture was partitioned between water (50 mL) and ethyl acetate (50 mL) and was treated with a 1N aqueous hydrochloric acid solution (25 mL). The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was dissolved in a hot solution of 1/1 hexanes/ethyl acetate and then filtered. The filtrate was cooled in the freezer for 1 h. At this time, the resulting solid was collected by filtration. The filtrate was concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded 1-isopropyl-6-nitro-1H-indole-3-carboxylic acid thiazol-2-ylamide (13 mg, 4.9%) as a yellow solid: mp 236-239° C.; EI-HRMS m/e calcd for C15H14N4O3S (M+) 330.0786, found 330.0792.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6](=[O:12])[O:5][C:4]1=[O:13].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH2:14]([N:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6](=[O:12])[O:5][C:4]1=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=c1[nH]c2sccc2c(=O)o1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1oc(=O)n(Cc2ccccc2)c2sccc12
Temperature: 0 °C
Yield: 73.5 %

Procedure:
NaH (60% dispersion in mineral oil, 1.0 g, 0.025 mol) was added to a solution of 1H-thieno[2,3-d][1,3]oxazine-2,4-dione (56) (3.53 g, 0.021 mol) in anhydrous DMF stirred at 0° C. under argon. The solution was stirred for 15 minutes before adding benzyl bromide (2.97 mL, 0.025 mol). The solution was allowed to come to room temperature and further stirred for 12 hours. The solution was poured into ice water and the precipitated solid was collected by vacuum filtration to yield 4.0 g (74%) of 1-benzyl-1H-thieno[2,3-d][1,3]oxazine-2,4-dione. 1H-NMR (DMSO-d6) δ 5.13 (s, 2H), 7.22 (d, J=5.6 Hz, 1H), 7.28 (d, J=5.6 Hz, 1H), 7.30-7.45 (m, 5H) ppm; EIMS m/z 260 (M+1).
Reaction SMILES: N[N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.O.[ClH:12].[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=O>C(O)(C)C>[ClH:12].[CH:8]1[CH:7]=[CH:6][C:5]2[CH2:4][CH2:3][N:2]3[C:10]=2[C:9]=1[C:17]1[CH2:18][NH:13][CH2:14][CH2:15][C:16]=13
Reactant: NN1CCc2ccccc21
Reactant: O=C1CCCCN1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: c1cc2c3c(c1)c1c(n3CC2)CCNC1
Yield: 72.9 %

Procedure:
A mixture of 1-amino-2,3-dihydroindole (1.0 g, 5.9 mmol), piperidone hydrochloride monohydrate (0.91 g, 5.9 mmol) and isopropanol (29 mL) was brought to reflux for 4 hours. The resulting brown solid was filtered and washed with cold diethylether (20 mL) and dried under Vacuum, affording the title compound (1.01 g, 74%). 1H NMR (CD3OD, 300 MHz) δ7.15 (d, 1H, J=7.7 Hz), 6.85-6.96 (m, 2H), 4.39-4.50 (m, 4H), 3.75 (t, 2H, J=7.3 Hz), 3.57 (t, 2H, J=6.2 Hz), 3.15 (t, 2H, J=6.2 Hz) ppm.
Reaction SMILES: B(F)(F)F.C([NH:12][C@@H:13]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:14](O)[CH2:15][Si](C)(C)C)(OC(C)(C)C)=O.[OH-].[Na+]>CCOCC.C(Cl)Cl>[C:22]1([CH2:21][C@H:13]([NH2:12])[CH:14]=[CH2:15])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(O)C[Si](C)(C)C
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: C=C[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
35.6 ml (0.28 mol) of an approximately 48% solution of boron trifluoride in ether are added at 5° C., over a period of 10 min, to a solution of 18.8 g (0.055 mol) of 3(S)-(Boc-amino)-2(R,S)-hydroxy-4-phenyl-1-trimethylsilyl-butane in 420 ml of methylene chloride. The reaction mixture is then stirred at RT for 16 h, cooled to 10°0 C. and, over a period of 20 min, 276 ml of a 4N sodium hydroxide solution are added. The aqueous phase is removed and extracted twice with 400 ml of methylene chloride each time. The combined organic extracts are washed with brine and dried over sodium sulfate. The title product is further used without additional purification. TLC Rf (C)=0.15; IR (methylene chloride) (cm-1): 3370, 3020, 2920, 1640, 1605.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(Cl)Cl.CN1CCOCC1.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[S:32](Cl)(=[O:34])=[O:33]>>[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[S:32]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:33])=[O:34]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: COC(=O)c1cccc(N)c1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)c1cccc(NS(=O)(=O)c2ccc3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
To 5.0 g (33 mmol) of the methyl 3-aminobenzoate (11) prepared in Example 1 in 70 mL of methylene chloride containing 4.0 mL (36 mmol) of N-methylmorpholine was added 7.49 g (33 mmol) of 2-naphthalenesulfonyl chloride. After stirring at room temperature overnight, the reaction mixture was quenched with 1N HCl (100 mL). The suspension was dissolved in ca. 250 mL of THF and enough ether was added to induce phase separation. The organic extract was washed with saturated sodium chloride solution (2×). The organic phase was dried (MgSO4), and concentrated to give 11.0 g (97% yield) of the title compound as a pale yellow solid: 1H-NMR (200 MHz; DMSO-d6) δ 8.46 (s, 1H), 8.13 (t, 2H), 7.99 (d, 1H), 7.55-7.75 (m, 5H), 7.43 (dd, 21H), 7.38 (d, 1H), 3.79 ppm (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[C:13]([F:16])([F:15])[F:14].[CH3:17][N:18]([CH3:24])[CH:19]1[CH2:23][CH2:22][NH:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:17][N:18]([CH3:24])[CH:19]1[CH2:23][CH2:22][N:21]([CH2:2][C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=2[C:13]([F:16])([F:15])[F:14])[CH2:20]1
Reactant: COC(=O)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: CN(C)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(CN2CCC(N(C)C)C2)c(C(F)(F)F)c1
Yield: 59.6 %

Procedure:
A reactor is charged with 1.2 g (4.06 mmol) of the compound obtained in step 2, 0.55 g (4.88 mmol) of 3-dimethylaminopyrrolidine, 2.8 g (20.3 mmol) of potassium carbonate and 25 ml acetone. The mixture is heated for 6 hours at reflux. The solvent is evaporated under reduced pressure and 100 ml of water is then added. The obtained solution is extracted with 3*30 ml ethyl acetate. The organic phases are combined, dried on sodium sulphate and then evaporated under reduced pressure to give the expected product (0.8 g, 61%),
Reaction SMILES: [OH-].[K+].C(S([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])=[CH:10][N:9]=1)(=O)=O)C.[O:19]1CCCC1.Cl>O>[CH2:17]([S:14]([C:11]1[CH:12]=[CH:13][C:8]([OH:19])=[N:9][CH:10]=1)(=[O:16])=[O:15])[CH3:18]
Reactant: CCS(=O)(=O)c1ccc(S(=O)(=O)CC)nc1
Reactant: C1CCOC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCS(=O)(=O)c1ccc(O)nc1

Procedure:
A solution of potassium hydroxide (11.0 g, 196 mmol, 50%) in water was added to a suspension of 2,5-bis-ethanesulfonyl-pyridine (12.0 g, 45.6 mmol, prepared using the method described above) in water and tetrahydrofuran (100 mL, 1:1, v/v). After being heated at reflux for 1 hour, the mixture was acidified with 0.5 N hydrochloric acid to pH 3 and concentrated in vacuo to remove the solvent. The residue was triturated with boiling ethanol (150 mL) and filtered. The filtrates were concentrated in vacuo to afford the crude product which was used in the next step without further purification.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C@H:10]([NH:19]C(=O)C)[CH2:9][C@@H:8]1[CH2:23][CH3:24])=[O:6])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+]>Cl>[CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C@H:10]([NH2:19])[CH2:9][C@@H:8]1[CH2:23][CH3:24])=[O:6])([CH3:3])[CH3:2]
Reactant: CC[C@H]1C[C@@H](NC(C)=O)c2nc(OC)ccc2N1C(=O)OC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC[C@H]1C[C@@H](N)c2nc(OC)ccc2N1C(=O)OC(C)C
Temperature: 25 °C
Yield: 97.2 %

Procedure:
Heat at 80° C. a solution of (+/−)-cis-4-acetylamino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (100 mg, 0.298 mmol) in 5 N HCl (1 mL) for 4 h. Cool the reaction mixture to room temperature, pour the crude onto a saturated solution of sodium carbonate and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure, to afford the title compound (85 mg, 98%). MS (ES+): 277 (M−NH2).