Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][NH:9][C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([C@@H:20]([NH:31][C:32]([C:34]1[CH:43]=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=1)=[O:33])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:19])=[O:11])C1C=CC=CC=1>C(#N)C>[OH:8][NH:9][C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([C@@H:20]([NH:31][C:32]([C:34]1[CH:43]=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=1)=[O:33])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:19])=[O:11]
Reactant: O=C(CCCCCNC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)c1ccc2ccccc2c1)NOCc1ccccc1
Solvent: CC#N
Product: O=C(CCCCCNC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)c1ccc2ccccc2c1)NO
Yield: 7 %

Procedure:
Using an analogous method (J15F), the title compound was prepared from naphthalene-2-carboxylic acid[1-(5-benzyloxycarbamoyl-pentylcarbamoyl)-2-(1H-indol-3-yl)-ethyl]-amide (19/98). Yield 7%, foam. 1H NMR (DMSO-d6, HMDSO), δ: 1.10-1.60 (m, 6H); 1.93 (t, 2H, J=7.4 Hz); 2.95-3.30 (m, 4H); 4.65-4.83 (m, 1H); 6.92-7.10 (m, 2H); 7.23 (s, 1H); 7.30 (d, 1H, J=7.6 Hz); 7.53-7.66 (m, 2H); 7.71 (d, 1H, J=7.0 Hz); 7.84-8.04 (m, 4H); 8.09 (br t, 1H, J=5.2 Hz); 8.42 (s, 1H); 8.60 (d, 1H, J=8.2 Hz); 8.68 (br s, 1H); 10.34 (s, 1H); 10.77 (s, 1H). HPLC analysis on Symmetry C8 column: impurities 2.5% (column size 3.9×150 mm; mobile phase acetonitrile −0.1M phosphate buffer (pH 2.5), 40:60; detector UV 220 nm; sample concentration 0.25 mg/ml, flow rate 1.5 ml/min). Anal. Calcd for C28H30N4O4*H2O: C, 66.65; H, 6.39; N, 11.10. Found: C, 66.69; H, 6.00; N, 11.01.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[CH3:28])[C:5]2[CH:11]=[CH:10][C:9](=[O:12])[N:8]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[C:6]=2[N:7]=1.[H-].[Na+].[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1>O1CCCC1>[F:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[N:8]1[C:6]2[N:7]=[C:2]([NH:1][C:34]([CH:31]3[CH2:33][CH2:32]3)=[O:35])[N:3]=[C:4]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[CH3:28])[C:5]=2[CH:11]=[CH:10][C:9]1=[O:12]
Reactant: O=C(Cl)C1CC1
Reactant: Cc1cc(F)ccc1-c1nc(N)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(NC(=O)C2CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 0.33 h

Procedure:
To a solution of the product of Example 230(a), 2-amino-8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one (100 mg, 0.26 mmol) in 3 mL of tetrahydrofuran was added NaH (19 mg, 0.78 mmol). The mixture was stirred for 20 min at 23°, a soln of cyclopropanecarbonyl chloride (27 mg, 0.26 mmol) in tetrahydrofuran (1 mL) was added. The resulting mixture was heated to solvent reflux for 16 h to give the crude material, which was purified by preparative hplc to afford 25 mg (21%). LC-MS: 451.2 (MH+, m/z), 2.14 (Rt, min).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:15])[CH:10]2[NH2:14])[C:7]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])(=[O:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[S:38]1[CH2:43][CH2:42][S:41][CH:40]=[C:39]1[CH2:44][C:45](O)=[O:46]>CN(C)C=O>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:15])[CH:10]2[NH:14][C:45](=[O:46])[CH2:44][C:39]2[S:38][CH2:43][CH2:42][S:41][CH:40]=2)[C:7]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)C2SC1
Reactant: O=C(O)CC1=CSCCS1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)CC3=CSCCS3)C2SC1
Temperature: 20 °C
Reaction time: 5 h
Yield: 62.2 %

Procedure:
3-Acetoxymethyl-7-amino-2(t-butoxycarbonyl)-8-oxo-5-thia-1-aza-bicyclo[4,2,0]oct-2-ene (11.2 g.) and dicyclohexylcarbodiimide (7.8 g.) are added to a solution of (5,6-dihydro-1,4-dithiin-2-yl)acetic acid (6 g.) in dimethylformamide (50 cc.). The reagents are left in contact for 5 hours, with stirring, at a temperature of about 20° C. and then the solid is filtered off. The filtrate is taken up in ethyl acetate (300 cc.) and is washed with an aqueous solution of sodium bicarbonate, N hydrochloric acid and then with water. After drying over sodium sulphate, it is treated with decolourizing charcoal and concentrated to dryness under reduced pressure (20 mm.Hg). A residue (20 g.) is obtained and is chromatographed on silica (330 g.). Elution is effected using a mixture (10 liters) of ethyl acetate and cyclohexane (1-3 by volume), and the eluates are concentrated to dryness under reduced pressure (20 mm.Hg). 3-Acetoxymethyl-2-(t-butoxycarbonyl)-7-[(5,6-dihydro-1,4-dithiin-2 -yl)acetamido]-8-oxo-5-thia-1 -aza-bicyclo-[4,2,0]oct-2-ene (10.3 g.), melting at 80° C., is thus obtained.
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13]C)=[C:9]([Cl:15])[CH:8]=2)=[N:4][C:3]=1C(F)(F)F.[OH-].[Na+].Br>CC(O)=O>[Br:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([Cl:15])[CH:8]=2)[NH:4][CH:3]=1
Reactant: COc1ccc(-c2nc(C(F)(F)F)c(Br)[nH]2)cc1Cl
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Oc1ccc(-c2nc(Br)c[nH]2)cc1Cl
Reaction time: 4 h
Yield: 52.2 %

Procedure:
A mixture of 56 (7.4 g, 0.021 mol) and 10% NaOH (200 ml) was heated at reflux with stirring. After 4 hours, the solution was cooled, extracted with CH2Cl2 (2 X), acidified with concentrated HC1, cooled and filtered to yield 100% of crude acid. The crude acid (6.9 g, 0.021 mol), AcOH (40 ml) and 48% HBr (160 ml) were heated at reflux with stirring. After 15 hours, the solution was concentrated to dryness and the residue treated with NaHCO3. The mixture was concentrated to dryness and the residue combined with silica gel and chromatographed on silica gel and the product eluted with 5% CH3OH-CHCl3 to yield 3.0 g (53%) of 57, m.p. 225°-27° C. (CH3CN). Analysis calculated for C9H6N2BrC10.
Reaction SMILES: C([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[C:16]#[C:17][C:18]([CH3:24])([CH3:23])[C:19]([O:21][CH3:22])=[O:20])(=O)CCC>C(#N)C>[CH3:23][C:18]([C:17]1[NH:6][C:7]2[C:8]([CH:16]=1)=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=2)([CH3:24])[C:19]([O:21][CH3:22])=[O:20]
Reactant: CCCC(=O)Nc1ccc([N+](=O)[O-])cc1C#CC(C)(C)C(=O)OC
Solvent: CC#N
Product: COC(=O)C(C)(C)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 25 °C
Yield: 22.6 %

Procedure:
To a deoxygenated solution of methyl 4-(2-butyramido-5-nitrophenyl)-2,2-dimethylbut-3-ynoate (1.8 g, 5.4 mmol) in acetonitrile (30 mL) was added Pd(CH3CN)2Cl2 (0.42 g, 1.6=mmol) under N2. The mixture was heated at reflux for 24 h. After cooling the mixture to ambient temperature, the solid was filtered off and washed with EtOAc (50 mL×3). The filtrate was evaporated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=30/1) to give methyl 2-methyl-2-(5-nitro-1H-indol-2-yl)propanoate (320 mg, 23%). 1H NMR (400 MHz, CDCl3) δ 9.05 (brs, 1H), 8.52 (d, J=2.0 Hz, 1H), 8.09 (dd, J=2.0, 8.8 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 6.54 (d, J=1.6 Hz, 1H), 3.78 (d, J=9.6 Hz, 3H), 1.70 (s, 6H).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9].S(Cl)([Cl:18])=O>N1C=CC=CC=1.C(Cl)Cl>[Cl:18][CH2:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C(C)Oc1cccc(CO)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(C)Oc1cccc(CCl)c1
Yield: 88.8 %

Procedure:
By the method of Example 1, Step H, 1.98 g (0.0095 mole) of methyl 2-(3-hydroxymethylphenoxy)propionate and 1.24 g (0.0105 mole) of thionyl chloride were reacted in the presence of five drops of pyridine in 40 mL of methylene chloride, yielding 1.93 g of methyl 2-(3-chloromethylphenoxy)propionate as a yellow liquid. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: [OH-].[Li+].[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=1)[C:12]([O:14]C)=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4]>O.CO>[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])=[O:9])([CH3:5])([CH3:6])[CH3:4]
Reactant: COC(=O)[C@H](Cc1ccc(OC(C)C)cc1)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reaction time: 24 h
Yield: 90 %

Procedure:
Lithium hydroxide (160 mg, 6.8 mmol) in water (10 mL) was added to a solution of (S)-methyl 2-(tert-butoxycarbonylamino)-3-(4-isopropoxyphenyl)propanoate in methanol (30 mL). The reaction was stirred for 24 h., and was concentrated under reduced pressure to remove the methanol. The remaining water layer was adjusted to pH=3 using 1 N HCl aqueous solution, and was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude product (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-isopropoxyphenyl)propanoic acid (1 g, 90%). Analytical LCMS (M+H-Boc)+: m/z=223.9.
Reaction SMILES: [C:1]([C:9]1[C:19]([N+:20]([O-:22])=[O:21])=[C:18]([OH:23])[C:17]([O:24]C)=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.[Cl-].[Al+3].[Cl-].[Cl-].Cl>N1C=CC=CC=1>[C:1]([C:9]1[C:19]([N+:20]([O-:22])=[O:21])=[C:18]([OH:23])[C:17]([OH:24])=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(OC)c(O)c([N+](=O)[O-])c1C(=O)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(O)c(O)c([N+](=O)[O-])c1C(=O)c1ccccc1
Temperature: 77 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
To a mixture of ethyl 2-benzoyl-4-hydroxy-5-methoxy-3-nitrobenzoate (reference example 18-1) (806 mg) and ethyl acetate (10 mL) were added aluminum chloride (610 mg) and pyridine (0.889 mL). The mixture was stirred at 77° C. for 2 hours. After cooling to room temperature, 2 mol/L hydrochloric acid was added to the mixture. The separated organic layer was washed with brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was triturated with hexane:diethyl ether=4:1 to give the title compound (430 mg).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:11].[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:12][CH2:10][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([CH3:11])[C:2]=1[Cl:1])[C:6]#[N:7]
Reactant: Cc1cc(C#N)cc(C)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(C#N)cc(CBr)c1Cl
Temperature: 25 °C
Yield: 66.6 %

Procedure:
A mixture of 4-chloro-3,5-dimethyl-benzonitrile (1.011 g, 6.10 mmol), N-bromosuccinimide (1.087 g, 6.10 mmol) and benzoyl peroxide (0.074 g, 0.305 mmol) in carbon tetrachloride (30 mL) was heated to reflux for 4 hr. The reaction mixture was cooled to room temperature and filtered. The filtrate was purified by flash column chromatography (silica gel, 0 to 30% ethyl acetate/hexane) to give 3-bromomethyl-4-chloro-5-methyl-benzonitrile as an impure white solid (0.9938 g, 66%), which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]2[C:5]([S:6](=[O:21])(=[O:20])[C:7]3[CH:8]=[C:9]([C:17](O)=[O:18])[CH:10]=[CH:11][C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C[N:27](C)C=O>>[F:1][C:2]1[CH:15]=[C:14]2[C:5]([S:6](=[O:21])(=[O:20])[C:7]3[CH:8]=[C:9]([C:17]([NH2:27])=[O:18])[CH:10]=[CH:11][C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccc(F)cc1C2=O
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: NC(=O)c1ccc2c(c1)S(=O)(=O)c1ccc(F)cc1C2=O

Procedure:
A mixture of 7-fluoro-9-oxo-3-thioxanthene carboxylic acid 10,10-dioxide (see example 6), 34.0 g (0.11 mol), and thionyl chloride, 130.9 g (1.10 mol), was heated at reflux for 2.0 hr. Dimethyl formamide, 1 ml, was added to the mixture, giving a solution which was heated at reflux overnight. The reaction was cooled, and a yellow crystalline solid, 27.85 g, was collected and washed with ether. A portion of the acid chloride, 5.0 g, was placed in concentrated NH4OH, 50 mL, and heated on a steam bath for 0.5 hr. The solid was filtered and washed with H2O and acetone to give 3.82 g of the amide. A small amount of the amide was recrystallized from DMF:MeOH/75:25 to provide 0.3 g of a light yellow crystalline 7-fluoro-9-oxothioxanthene-3-carboxamide 10,10-dioxide, m.p. 307°-310° C. TLC (CHCl3 /MeOH/9/1) Rf =0.45.
Reaction SMILES: CN(C)C=O.Br[CH:7]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=O.[NH2:26][C:27]1[CH2:31][CH2:30][CH2:29][N:28]=1>O>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]2[N:26]=[C:27]3[CH2:31][CH2:30][CH2:29][N:28]3[C:7]=2[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:11][CH:12]=1
Reactant: NC1=NCCC1
Reactant: COc1ccc(C(=O)C(Br)c2ccc(OC)cc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc3n(c2-c2ccc(OC)cc2)CCC3)cc1
Reaction time: 72 h

Procedure:
To 300 ml of dry N,N-dimethylformamide was added 30. g (0.09 mol) of 2-bromo-1,2-di(4-methoxyphenyl)ethanone and 19.5 g (0.27 mol) of 2-amino-4,5-dihydro-3H-pyrrole. The mixture was stirred for three days at 25° with the exclusion of moisture. The reaction mixture was poured into water and the aqueous suspension was extracted three times with methylene chloride. The organic extracts were combined and washed six times with water, then dried (K2CO3). The solvent was evaporated and the residue was recrystallized from chloroform-hexane and dried overnight (80° in vacuo) to give the title compound, m.p. 146°-147.5°.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5]([S:8][CH3:9])=[N:6][N:7]=1.[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([N:25]=[C:26]=[O:27])(=[O:24])=[O:23])=[O:15]>O1CCOCC1>[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([NH:25][C:26](=[O:27])[NH:1][C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5]([S:8][CH3:9])=[N:6][N:7]=1)(=[O:23])=[O:24])=[O:15]
Reactant: CSc1nnc(N)c(=O)n1C
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nnc(SC)n(C)c1=O
Yield: 73.1 %

Procedure:
3.42 g of 6-amino-4-methyl-3-methylthio-1,2,4-triazin-5-one are suspended in 100 ml of absolute dioxane, and 4.99 g of 2-methoxycarbonylphenylsulfonyl isocyanate are added at room temperature. The reaction proceeds slightly exothermically. After a reaction time of one hour at room temperature, the reaction has ended. The precipitate which has separated out is filtered off and washed with a small amount of dioxane. After drying, 6.0 g of 6-[3-(2-methoxycarbonylphenylsulfonyl)-ureido]-4-methyl-3-methylthio-1,2,4-triazin-5-one with a melting point of 186°-187° C. are thus obtained.
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4](N)[CH2:3][CH2:2]1.[ClH:12].[NH:13]1[CH2:19][CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[ClH:12].[CH2:3]1[N:4]2[C:5]3[C:10]([C:17]4[CH2:18][CH2:19][NH:13][CH2:14][CH2:15][C:16]=42)=[CH:9][CH:8]=[CH:7][C:6]=3[S:1][CH2:2]1
Reactant: NN1CCSc2ccccc21
Reactant: O=C1CCCNCC1
Agent: Cl
Product: c1cc2c3c(c1)c1c(n3CCS2)CCNCC1

Procedure:
1,2,8,9,10,11-Hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3,4-hi]indole hydrochloride was prepared from 2,3-dihydro-4H-1,4-benzothiazin-4-amine and hexahydro-4H-azepin-4-one hydrochloride following the procedure of example 471, step A to give the 1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3,4-hi]indole hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH3:13])[CH:7]=[C:6]([F:14])[C:3]=1[CH2:4][OH:5].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28](Cl)=[O:29])[C@H:24]([CH2:31][CH3:32])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH3:13])[CH:7]=[C:6]([F:14])[C:3]=1[CH2:4][O:5][C:28]([N:25]1[CH2:26][CH2:27][N:22]([C:20]([O:19][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:21])[CH2:23][C@H:24]1[CH2:31][CH3:32])=[O:29]
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cl
Reactant: CCCOc1cc(F)c(CO)c(Cl)c1
Product: CCCOc1cc(F)c(COC(=O)N2CCN(C(=O)OC(C)(C)C)C[C@H]2CC)c(Cl)c1
Yield: 93 %

Procedure:
This compound was prepared from 2-chloro-6-fluoro-4-propoxy-benzylalcohol and (R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester according to the procedure described in Example 179 to give the product as a colorless oil (499 mg; 93%); MS (ISP): 476.3 (M+NH4)+.
Reaction SMILES: C([O-])=O.[NH4+].[CH3:5][O:6][C:7](=[O:28])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:15]2[CH2:20][CH2:19][N:18](CC3C=CC=CC=3)[CH2:17][CH2:16]2)=[N:10][CH:9]=1>C(O)C>[CH3:5][O:6][C:7](=[O:28])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[N:10][CH:9]=1
Reactant: COC(=O)c1ccc(NC2CCN(Cc3ccccc3)CC2)nc1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)c1ccc(NC2CCNCC2)nc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
Ammonium formate (4.9 g, 67.2 mmol) was added to a solution of (39) (4.2 g, 12.9 mmol) in 100 mL of absolute ethanol. The mixture was purged with argon then palladium (0.9 g, 5% on activated carbon) was added. The resulting mixture was heated to 80° C. and maintained at that temperature for 12 h. After cooling to 25° C., the mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was cooled to 0° C. and saturated Na2CO3 (100 mL) was added. The resulting mixture was stirred for 30 min at 0° C. then was extracted with EtOAc (3×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to give 2.6 g (86%) of the title compound; 1H NMR (CDCl3) δ 8.55 (s, 1H), 7.78 (d, 1H, J=8.9), 7.35 (d, 1H, J=7.3), 6.49 (d, 1H, J=8.9), 3.77 (m, 4H), 3.12 (s, 1H), 2.94 (m, 2H), 2.52 (m, 2H), 1.82 (m, 2H), 1.29 (m, 2H); 13C NMR (CDCl3) δ 165.7, 160.2, 150.8, 136.7, 112.7, 107.5, 51.1, 48.0, 45.0, 33.0; HRMS (FAB) m/z 236.1392 (M+H)+ (C12H17N3O2, requires 236.1399).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[C:22]([CH3:23])[C:16]=2[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cc1cccc(N)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1cccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Reaction time: 16 h
Yield: 98.2 %

Procedure:
To a stirred solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1 g, 0.00502 mole) in dry 1,2-dichloroethane (10 mL) (under an atmosphere of nitrogen for 10 minutes) was added 2,3-dimethylaniline (0.73 g, 0.00602 mole), acetic acid (0.301 g, 0.005 mole) and sodium triacetoxyborohydride (1.596 g, 0.00753 mole) portionwise with stirring. The stirring was continued at ambient temperature for a further 16 hours. The reaction mixture was basified with sodium bicarbonate solution and the product extracted with dichloromethane. The dichloromethane layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to as afford a transparent viscous liquid which was purified by column chromatography using neutral aluminium oxide (1% ethyl acetate in hexane) to afford 1.5 g (98%) of 4-(2,3-dimethyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (CDCl3): δ 7.0 (t, 1H), 6.6 (m, 2H), 4.1 (m, 2H), 3.5 (m, 1H), 3.0-2.9 (t, 2H), 2.3 (s, 3H), 2.1 (m, 2H), 2.0 (s, 3H), 1.5 (s, 9H), 1.4 (m, 2H). A solution of 4-(2,3-dimethyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.45 g, 0.00476 mole) in ethyl acetate.HCl (15 mL) was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was washed with ether and dried to afford 1.1 g (83) of (2,3-dimethyl-phenyl)-piperidin-4-yl-amine dihydrochloride. LCMS: 205.16 (M+1)+, 95.98%, 1H NMR (DMSO-d6): δ 9.4 (d, 1H), 9.0 (d, 1H), 7.3 (m, 3H), 3.7 (m, 2H), 3.3 (d, 2H), 3.1 (bs, 1H), 2.9 (m, 2H), 2.3 (d, 6H), 2.1 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12]([Sn](CCCC)(CCCC)CCCC)=[CH2:13])[CH3:10]>C1(C)C=CC=CC=1.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>[CH2:12]([O:11][C:9]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[CH2:10])[CH3:13]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Fc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=C(OCC)c1ccc(F)cc1

Procedure:
A solution of 10.0 g 4-Fluoro-iodobenzene, 21.1 g 1-Ethoxyvinyltributyltin and 2.6 g Tetrakis(triphenylphosphine)Palladium in 130 ml of Toluene was refluxed overnight under an argon atmosphere. The dark brown solution was filtered over filter aid and concentrated in vaccuo. The crude dark brown oil (7.49 g) was directly used in the next step.
Reaction SMILES: [H-].[Na+].[S:3](Cl)([C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:17]=[C:18]2[CH:24]=[CH:23][NH:22][C:19]2=[N:20][CH:21]=1>C1COCC1>[F:26][C:15]([F:14])([F:25])[C:16]1[CH:17]=[C:18]2[CH:24]=[CH:23][N:22]([S:3]([C:6]3[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=3)(=[O:5])=[O:4])[C:19]2=[N:20][CH:21]=1
Reactant: FC(F)(F)c1cnc2[nH]ccc2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(C(F)(F)F)cnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a stirred solution of sodium hydride (6.2 g, 156 mmol, 60% dispersion), tosyl chloride (27 g, 141.8 mmol), in anhydrous THF (200 mL) under a nitrogen atmosphere was added a solution of 5-trifluoromethyl-lH-pyrrolo[2,3-b]pyridine (26.38 g, 141.8 mmol) in THF (150 mL) dropwise at a rate which maintained the internal temperature of the reaction below 40° C. The reaction mixture was stirred overnight at room temperature and analysis by LCMS showed no starting material remained after this time. The reaction mixture was concentrated to remove most of THF and diluted with DCM and water. The organic layer was separated and the aqueous layer further extracted with DCM. The organic layers are combined and washed with brine, dried over magnesium sulphate and concentrated to a volume which was appropriate to load onto the top of a silica plug (300 mL) pre-wet with DCM, and the silica was washed with 2.5 L DCM. The filtrate was concentrated to give the product as a slightly brown solid (44.1 g, 92% yield).
Reaction SMILES: C([O:3][P:4]([C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[N+:26]([O-:28])=[O:27])[CH:12]=[CH:11][C:10]=1[N+:29]([O-:31])=[O:30])(=[O:8])[O:5]CC)C.Cl>C(O)C>[N+:29]([C:10]1[CH:11]=[CH:12][C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][C:17]=2[N+:26]([O-:28])=[O:27])=[CH:14][C:9]=1[P:4](=[O:3])([OH:5])[OH:8])([O-:31])=[O:30]
Reactant: CCOP(=O)(OCC)c1cc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])ccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Oc1ccc([N+](=O)[O-])c(P(=O)(O)O)c1

Procedure:
A mixture of 1.85 g of the 2-nitro-5-(2'-nitro-4'-trifluoromethylphenoxy)-phenylphosphonic acid diethyl ester obtained in Example 1, in 20 ml of ethanol, and 40 ml of 20% hydrochloric acid, is refluxed for 24 hours and then evaporated to dryness, affording as residue the monohydrate of the corresponding free phosphonic acid in the form of yellowish brown crystals in quantitative yield.