Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:17])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C(O)(=[O:20])C>>[Br:1][C:2]1[C:3]([OH:17])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([CH3:16])=[O:20])=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: CSc1ccc(Nc2ncc(Br)c(O)n2)cc1
Reactant: CC(=O)O
Product: CS(=O)c1ccc(Nc2ncc(Br)c(O)n2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
11 g of 5-bromo-2-[4-(methylsulfanyl)phenylamino]pyrimidin-4-ol is suspended in 110 ml of glacial acetic acid. While being cooled with ice water, 4.6 ml of a 30% solution of hydrogen superoxide is added in drops. The mixture is stirred for 18 hours at room temperature and then suctioned off. The filter cake is washed twice with water and once with ethanol and dried at 60° C. in a vacuum. 8.75 g (75.7% of theory) of the product with a melting point of 240° C. (decomposition) is obtained.
Reaction SMILES: [CH2:1]1[CH:16]2[N:4]([CH2:5][CH2:6][C:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[NH:9][C:8]=32)[CH2:3][CH2:2]1.[H-].[Na+].[CH3:19]I>CN(C)C=O>[CH3:19][N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]2[CH2:6][CH2:5][N:4]3[CH:16]([C:8]1=2)[CH2:1][CH2:2][CH2:3]3
Reactant: c1ccc2c3c([nH]c2c1)C1CCCN1CC3
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c2c(c3ccccc31)CCN1CCCC21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,3,5,6,11,11b-Hexahydro-1H-indolizino[8,7-b]-indole (8.49 g.) is stirred for 1 hour at 25°C. in dimethylformamide (200 ml.) containing sodium hydride (2.11 g. of a 50% mineral oil dispersion). Methyl iodide (6.25 g.) in dimethylformamide (25 ml.) is added and the mixture is stirred at 25°C. for 16 hours. The dimethylformamide is distilled off, and the residue is dissolved in chloroform and washed with aqueous potassium bicarbonate and water, and dried. The product is chromatographed on neutral alumina to give 2,3,5,6,11,11b-hexahydro-11-methyl-1H-indolizino[8,7-b]indole as a clear oil (5.88 g.).
Reaction SMILES: C(OC(=O)[CH:5]([O:22][Si:23]([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C.[CH3:41][Mg]Br.[CH2:44]1[CH2:48][O:47]CC1>>[C:36]([Si:23]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[O:22][CH:5]([CH2:6][N:7]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:48]([CH3:44])([OH:47])[CH3:41])([CH3:39])([CH3:37])[CH3:38]
Reactant: CCOC(=O)C(CN(Cc1ccccc1)Cc1ccccc1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: C[Mg]Br
Reactant: C1CCOC1
Product: CC(C)(O)C(CN(Cc1ccccc1)Cc1ccccc1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 84 %

Procedure:
(8.0 g, 14.5 mmol) (RS)-2-(tert-Butyl-diphenyl-silanyloxy)-3-dibenzylamino-propionic acid ethyl ester (Example 95, step 1) was dissolved in THF (100 ml) and methylmagnesium bromide (3M in diethylether) (19.3 ml, 58 mmol, 4 equiv.) was drop wise at room temperature. The mixture was stirred for 3.5 hours at room temperature. The reaction mixture was extracted with saturated NaHCO3 solution and two times with EtOAc. The organic layers were extracted with brine, dried over Na2SO4 and evaporated to dryness. The desired (RS)-3-(tert-butyl-diphenyl-silanyloxy)-4-dibenzylamino-2-methyl-butan-2-ol (6.9 g, 84% yield) was obtained as a white solid, MS: m/e=538.5 (M+H+) and used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]2[CH2:12][NH:11][CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.Cl[C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:29])[C:19]([C:26]([OH:28])=[O:27])=[CH:20][N:21]2[CH2:24][CH3:25])=[CH:16][C:15]=1[F:30]>N1C=CC=CC=1>[Br:1][C:2]1[S:6][C:5]([CH:7]2[NH:8][CH2:9][CH2:10][N:11]([C:14]3[CH:23]=[C:22]4[C:17]([C:18](=[O:29])[C:19]([C:26]([OH:28])=[O:27])=[CH:20][N:21]4[CH2:24][CH3:25])=[CH:16][C:15]=3[F:30])[CH2:12]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(C2CNCCN2)s1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4ccc(Br)s4)C3)cc21

Procedure:
A 3 g portion of 2-(5-bromo-2-thienyl)piperazine was suspended in 8 ml of dry pyridine. An 820 mg portion of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was added and the mixture was heated in a pressure bottle, under argon, at 120°-130° C. for 18 hours, then cooled, filtered and evaporated to dryness. The residue was evaporated from toluene and this residue purified by chromatography, eluting with chloroform:water saturated methanol (9:1). The appropriate fractions were combined, evaporated and recrystallized from dimethylformamide-ether, giving 440 mg of the desired product, mp 233°-235° C. (dec.).
Reaction SMILES: CC1N=C(N2CCN(C3C=CC=CC=3)C2=O)SC=1C(OCC)=O.[C:24]([C:27]1[S:31][C:30]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:39]=[C:40]([CH:45]=[CH:46][CH:47]=3)[C:41]([O:43]C)=[O:42])[C:33]2=[O:48])=[N:29][C:28]=1[CH3:49])(=[O:26])[CH3:25]>>[C:24]([C:27]1[S:31][C:30]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:39]=[C:40]([CH:45]=[CH:46][CH:47]=3)[C:41]([OH:43])=[O:42])[C:33]2=[O:48])=[N:29][C:28]=1[CH3:49])(=[O:26])[CH3:25]
Reactant: COC(=O)c1cccc(CN2CCN(c3nc(C)c(C(C)=O)s3)C2=O)c1
Agent: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Product: CC(=O)c1sc(N2CCN(Cc3cccc(C(=O)O)c3)C2=O)nc1C
Yield: 89 %

Procedure:
Following the procedure as described in Example 6, making variations as required to replace ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate with methyl 3-((3-(5-acetyl-4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)methyl)benzoate, the title compound was obtained as a white solid in 89% yield: MS (ES+) m/z 360.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[Cl:16])[C:12]([F:18])([F:17])[O:11][C:10]3([F:20])[F:19])[N:5]=[C:4]([C:21]#[N:22])[CH:3]=1.[F:23][C:24]([F:29])([F:28])[S:25]([O-])=O.[Na+].S(C1C=CC(C)=CC=1)(O)(=O)=O.CNC.S(Cl)(Cl)=O>C1(C)C=CC=CC=1.O>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[Cl:16])[C:12]([F:18])([F:17])[O:11][C:10]3([F:20])[F:19])[N:5]=[C:4]([C:21]#[N:22])[C:3]=1[S:25][C:24]([F:29])([F:28])[F:23]
Reactant: N#Cc1cc(N)n(-c2cc3c(cc2Cl)C(F)(F)OC3(F)F)n1
Reactant: O=S([O-])C(F)(F)F
Agent: CNC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: N#Cc1nn(-c2cc3c(cc2Cl)C(F)(F)OC3(F)F)c(N)c1SC(F)(F)F
Temperature: 55 °C
Reaction time: 10 h
Yield: 46.2 %

Procedure:
To a suspension wherein 5-amino-1-(6-chloro-1,1,3,3-tetrafluoro-1,3-dihydroisobenzofuran-5-yl)-3-cyanopyrazole (665 mg, 2.00 mmol), sodium trifluoro-methanesulfinate (624 mg, 4.00 mmol) and dimethylamine tosylate (1.086 g, 5.00 mmol) are in toluene (5 ml), thionyl chloride (476 mg, 2.00 mmol) was added dropwise under ice cooling over a period of about 10 minutes and stirred at 50 to 60° C. for 10 hours. After allowing time to cool, the reaction solution was poured into water, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography to give 400 mg of 5-amino-1-(6-chloro-1,1,3,3-tetrafluoro-1,3-dihydroisobenzofuran-5-yl)-3-cyano-4-trifluoromethylsulfenylpyrazole.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:32])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:23]=4[O:30][CH3:31])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:33][NH2:34]>>[Cl:32][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:23]=2[O:30][CH3:31])[C:15]2[O:14][CH:13]([CH2:12][NH:34][CH3:33])[CH2:17][C:16]=2[CH:18]=1
Reactant: COc1cccc(-c2cc(Cl)cc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)c1OC
Reactant: CN
Product: CNCC1Cc2cc(Cl)cc(-c3cccc(OC)c3OC)c2O1

Procedure:
The title compound was prepared (0.046 g, 34%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.172 g, 0.36 mmol) and methylamine (0.112 g, 3.6 mmol). mp 105-107° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1Cl)([O-:3])=[O:2].[NH2:14][C@@H:15]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:16][C:17]([O:19][CH3:20])=[O:18].C(N(CC)CC)C>CO>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:14][C@@H:15]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:16][C:17]([O:19][CH3:20])=[O:18])([O-:3])=[O:2]
Reactant: COC(=O)C[C@@H](N)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)C[C@@H](Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])c1ccccc1

Procedure:
To a solution of 2,4-dinitrochlorobenzene (5.1 g, 25 mmol) in methanol (60 mL) was added methyl (3R)-3-amino-3-phenylpropanoate (3.75 g, 21 mmol, prepared according to Davies et. al., Tetrahedron Asymm., 1991, 183) and triethylamine (2.9 mL, 21 mmol). The mixture was brought to reflux, heating in total for 5 hours, and was then cooled and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (95:5), to afford the title compound, [LCMS (Method C, Mobile Phase I) RT=3.22 mins, MH+ 346].
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]([CH:17]2[C:26]([CH3:28])([CH3:27])[CH:25](O)[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:30]([O:32][CH3:33])=[O:31])[CH:23]=3)[NH:18]2)[CH:14]=[CH:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]([CH:17]2[C:26]([CH3:28])([CH3:27])[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:30]([O:32][CH3:33])=[O:31])[CH:23]=3)[NH:18]2)[CH:14]=[CH:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cccc(C(=O)OCc3ccccc3)c1)N2
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)OCc3ccccc3)c1)N2
Temperature: 25 °C
Yield: 75.6 %

Procedure:
To a solution of methyl 2-(3-(benzyloxycarbonyl)phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (14.0 g, 31.4 mmol, 1.0 eq.), triethylsilane (10.6 g, 91.4 mmol, 2.91 eq.) in dichloromethane (240 mL), which was placed in a drop funnel, under nitrogen below 0° C. over 1 h. colorless solution turned yellow gradually. The resulting mixture was allowed to warm back to room temperature naturally overnight. Thin layer chromatography (Petroleum ether:ethyl acetate=3:1) showed the reaction was complete. The reaction mixture was basified with solid sodium carbonate to pH=7 and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (Petroleum ether: ethyl acetate=10:1) to give 10.2 g of methyl 2-(3-(benzyloxycarbonyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a yellow oil, yield: 75.6%. MS (ESI+APCI) M+1=430.2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:17][C:18]1[CH:23]=[C:22]([CH2:24]Cl)[CH:21]=[C:20]([Cl:26])[CH:19]=1.Cl>CN(C)C=O.C(OCC)C>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:10][O:11][CH2:24][C:22]1[CH:23]=[C:18]([Cl:17])[CH:19]=[C:20]([Cl:26])[CH:21]=1)[C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(=O)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NC(COCc1cc(Cl)cc(Cl)c1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N-t-butoxycarbonyl-D-serine (10.0 g, 48.7 mol) in N,N-dimethylformamide (150 mL) at about 0° C. was added sodium hydride (4.0 g, 60% dispersion in mineral oil, 99.84 mmol) portionwise. The mixture was stirred for about 30 minutes, and then a solution of 1,3-dichloro-5-chloromethyl-benzene (9.5 mL, 48.7 mmol) in ethyl ether (40 mL) was added. The reaction was allowed to slowly warm to room temperature overnight. The reaction was then quenched with 1 N NaOH, the mixture extracted three times with dichloromethane. The combined organic layers were then washed three times with water, 1 N HCl, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give crude product. The original basic aqueous layer was then acidified to about pH 4 with 1 N HCl, and the mixture was extracted three times with dichloromethane. These three organic layers were combined and washed three times each with water and brine then dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give an additional 620 mg of crude product. Both product fractions were combined and purified by silica gel chromatography using 5% methanol/chloroform as eluent and yielded the title compound of part 1-E (12.39 g, 70%): −APcl MS (M−1)−363, (M−3)−361; 1H NMR=400 MHz (CDCl3) δ: 7.13 (arom, s, 3H), 5.42 (NH, d, 1H), 4.50 (CHCO2H, m, 1H), 4.45 (PhCH2O, s, 2H), 3.82 (CH2OBz, d of d, 2H), 1.43 (BOC, s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([CH3:22])=[CH:15][C:3]=1[NH:4][S:5]([C:8]1[CH:14]=[CH:13][C:11]([CH3:12])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[O-2].[Ca+2].[CH2:25]([OH:28])[CH2:26]Br.O>CN(C=O)C>[NH2:1][C:2]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([CH3:22])=[CH:15][C:3]=1[N:4]([CH2:26][CH2:25][OH:28])[S:5]([C:8]1[CH:9]=[CH:10][C:11]([CH3:12])=[CH:13][CH:14]=1)(=[O:7])=[O:6]
Reactant: OCCBr
Reactant: Cc1ccc(S(=O)(=O)Nc2cc(C)cc([N+](=O)[O-])c2N)cc1
Agent: [Ca+2]
Agent: [O-2]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N(CCO)c2cc(C)cc([N+](=O)[O-])c2N)cc1

Procedure:
0.087 mol (28 g) of 2-amino-3-nitro-5-methyl-N-tosylaniline is dissolved in 85 ml of DMF heated beforehand on a boiling water-bath. 9.7 g of quicklime are then added and 0.174 mol (21.75 g) of glycol bromohydrin is then introduced gradually, in the course of 30 minutes and whilst stirring, the heating on the boiling water-bath being maintained. After 11/2 hours, the reaction medium is filtered hot and the filtrate is then poured into 250 ml of iced water. The expected product precipitates. It is filtered off, washed with water and dried in vacuo. After recrystallisation from acetic acid and drying in vacuo, it melts at 201° C.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([O:19]C)=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:24]=1)([CH3:3])[CH3:2].O.[Li+].[OH-].Cl>C1COCC1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([OH:19])=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:24]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cccc(Nc2ncnc3nc(C(C)C)ccc23)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1ccc2c(Nc3cccc(C(=O)O)c3)ncnc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 149.2 %

Procedure:
The product from Example 7A (1.0 g, 3.26 mmol) was dissolved in THF (12.0 mL) and water (12.0 mL) and LiOH (390 mg, 16.29 mmol) was added and the reaction was stirred at room temperature overnight. Reaction was neutralized with 1 N HCl and extracted with ethyl acetate. Dried over Na2SO4, filtered and concentrated to give the title compound (1.5 g).
Reaction SMILES: [CH:1]1[C:13]2[C:12]3([C:25]4[CH:24]=[C:23]([CH2:26][OH:27])[CH:22]=[CH:21][C:20]=4[C:19]4[C:14]3=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:28][OH:29]>C1(C)C=CC=CC=1.[O-2].[Cr+6].[O-2].[O-2]>[CH:24]1[C:25]2[C:12]3([C:13]4[CH:1]=[C:2]([CH:28]=[O:29])[CH:3]=[CH:4][C:5]=4[C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]=2[CH:21]=[CH:22][C:23]=1[CH:26]=[O:27]
Reactant: OCc1ccc2c(c1)C1(c3ccccc3-2)c2ccccc2-c2ccc(CO)cc21
Agent: [Cr+6]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: O=Cc1ccc2c(c1)C1(c3ccccc3-2)c2ccccc2-c2ccc(C=O)cc21
Yield: 40.4 %

Procedure:
 A solution of 380 mg of 9,9′-spirobifluorene-2,2′-dimethanol in 15 ml of toluene was admixed with 5 g of chromium(VI) oxide on graphite (Seloxcette, Alpha Inorganics) and refluxed under nitrogen for 48 hours. The mixture was then filtered with suction on a glass suction filter and the filtrate was evaporated. Chromatography on silica gel using chloroform and crystallization from methylene chloride/ether gave 152 mg of 9,9′-spirobifluorene-2,2′-dicarbaldehyde (mp. >300° C.) and
Reaction SMILES: S[CH2:2][C:3]1[N:7]2[C:8]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:9]=3[CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[O:11][CH2:12][C:6]2=[N:5][N:4]=1.[OH-:25].[Na+].Cl.[CH3:28]O>>[CH3:28][O:25][CH2:2][C:3]1[N:7]2[C:8]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:9]=3[CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[O:11][CH2:12][C:6]2=[N:5][N:4]=1
Reactant: SCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)OC2
Reactant: [OH-]
Reactant: CO
Agent: Cl
Agent: [Na+]
Product: COCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)OC2
Reaction time: 3 h
Yield: 92 %

Procedure:
To a solution of Compound 20 (0.85 g) prepared in Example 12 in methanol (100 ml) is added an aqueous solution of sodium hydroxide (10%)(4 ml), and the mixture is stirred for 3 hours, acidified with 10% hydrochloric acid, and concentrated. The residue is washed with water and chloroform to give Compound 21 (0.7 g) in 92% yield.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([Br:11])[CH:8]=[C:7]([O:12][CH2:13][P:14]([O:19]CC)([O:16]CC)=[O:15])[C:5]=2[N:6]=1.C[Si](Br)(C)C>C(Cl)Cl>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([Br:11])[CH:8]=[C:7]([O:12][CH2:13][P:14]([OH:19])([OH:16])=[O:15])[C:5]=2[N:6]=1
Reactant: CCOP(=O)(COc1cc(Br)cc2sc(N)nc12)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: Nc1nc2c(OCP(=O)(O)O)cc(Br)cc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-amino-4-diethylphosphonomethyloxy-6-bromobenzothiazole (1 mmole) in CH2Cl2 (4 mL) was treated with TMSBr (10 mmole) at 0° C. After stirred for 8 h at room temperature the reaction was evaporated to dryness and the residue was taken into water (5 mL). The resulting precipitate was collected via filtration and washed with water to give 2-amino-4-phosphonomethyloxy-6-bromobenzothiazole (34.1) as white solid. mp>220° C.(dec.). Anal. Calcd. for C8H8N2O4PSBr: C:28.34; H:2.38; N:8.26. Found: C:28.32; H:2.24; N:8.06.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:33])[N:9]2[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][C@H:17]([OH:20])[C@H:16]([CH2:21][NH:22]C(=O)OCC3C=CC=CC=3)[CH2:15]2)=[CH:4][CH:3]=1>CCO.[OH-].[OH-].[Pd+2]>[NH2:22][CH2:21][C@H:16]1[C@@H:17]([OH:20])[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH:6]=[CH:7][C:8]2=[O:33])[CH2:15]1
Reactant: O=C(NC[C@@H]1CN(CCn2c(=O)ccc3ccc(F)cc32)CC[C@@H]1O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: NC[C@@H]1CN(CCn2c(=O)ccc3ccc(F)cc32)CC[C@@H]1O
Reaction time: 2 h
Yield: 96.1 %

Procedure:
A solution of phenylmethyl ({(3R,4S)-1-[2-(7-fluoro-2-oxo-1(2H)-quinolinyl)ethyl]-4-hydroxy-3-piperidinyl}methyl)carbamate (525 mg; 1.16 mmol) in EtOH (100 mL) was added 20% Pd(OH)2/C (100 mg). The mixture was hydrogenated at 1 atm of H2 at ambient temperature for 2 h. The crude product was filtered through Celite, washed with ethanol and concentrated under reduced pressure to obtain the product as a pale yellow oil (356 mg; 96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.Br(O)(=O)=O.[NH2:47][C:48]1[S:49][C:50]([Br:53])=[CH:51][N:52]=1>C(Cl)(Cl)Cl.O>[Br:53][C:50]1[S:49][C:48]([NH:47][C:35]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][C:18]=2[F:23])=[O:41])=[N:52][CH:51]=1
Reactant: Nc1ncc(Br)s1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [O-][Br+2]([O-])O
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ncc(Br)s4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (30 mg) was dissolved in chloroform (3 ml) to prepare a solution. Triethylamine (0.3 ml) and a solution of triphosgene (27 mg) in chloroform (0.2 ml) were then added to the solution, and the mixture was stirred at room temperature for 30 min. Next, a solution of 2-amino-5-bromothiazole bromate (106 mg) in chloroform (0.6 ml) was added thereto, and the mixture was further stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The extract was washed with saturated brine and was dried over anhydrous sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give 5 mg of the title compound.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12](=[O:30])[N:13]([CH2:26][CH:27]2[CH2:29][CH2:28]2)[CH2:14][C:15]2[NH:16][C:17](=[O:25])[CH:18]3[CH2:24][O:23][CH2:22][CH2:21][CH:19]3[N:20]=2)[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>CO.O>[CH:27]1([CH2:26][N:13]([CH2:14][C:15]2[NH:16][C:17](=[O:25])[CH:18]3[CH2:24][O:23][CH2:22][CH2:21][CH:19]3[N:20]=2)[C:12]([CH2:11][N:8]2[CH2:7][CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]2)=[O:30])[CH2:28][CH2:29]1
Reactant: COC(=O)C1CCN(CC(=O)N(CC2=NC3CCOCC3C(=O)N2)CC2CC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1CCN(CC(=O)N(CC2=NC3CCOCC3C(=O)N2)CC2CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
To a solution of 1-{[cyclopropylmethyl-(4-oxo-3,4a,5,7,8,8a-hexahydro-4H-pyrano[4,3-d]pyrimidin-2-ylmethyl)-carbamoyl]-methyl}-piperidine-4-carboxylic acid methyl ester (0.6 g, 1.43 mmol, 1 eq.) in 3 mL of MeOH was added a solution of NaOH (0.13 g, 5.43 mmol, 3.8 eq.) in 3 mL of H2O. The resulting mixture was stirred at room temperature overnight. After 18 h, the reaction mixture was concentrated and treated with 1 N HCl to pH 5. The resulting mixture was freeze dried using lyophilizer to remove H2O. The resulting white solids were washed with dichloromethane/methanol and filtered to remove NaCl. The filtrate was concentrated to give the title compound as a white solid (0.53 g, 92%). Exact mass calculated for C23H31N4O3 407.2. MS (ESI) m/z 407.6 (M+H)+.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:26]=[CH:25][C:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[C:4]([F:27])[CH:3]=1.C(I)(I)[I:29].N(OC(C)(C)C)=O>O1CCCC1>[F:27][C:4]1[CH:3]=[C:2]([I:29])[CH:7]=[CH:6][C:5]=1[O:8][C:9]1[CH:26]=[CH:25][C:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:11]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Oc3ccc(N)cc3F)cc2CC1
Reactant: IC(I)I
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Oc3ccc(I)cc3F)cc2CC1

Procedure:
To a solution of 1,1-dimethylethyl 7-[(4-amino-2-fluorophenyl)oxy]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (E274, Step 2) (0.5 g, 1.34 mmol) and iodoform (1 g, 2.69 mmol) in tetrahydrofuran (10 ml) was added dropwise tert-butyl nitrite (0.32 ml, 2.69 mmol). The reaction was then heated at reflux for 1 hour, cooled and concentrated in vacuo and resulting residue was purified by column chromatography eluting with a mixture of ethyl acetate:pentane (1:10) to afford the title compound. MS (ES+) m/e 384 [M-COOtBu]+.