Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[NH:5][CH3:6].Br.Br[CH:13]([C:15]1[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]2[C:24]=1[O:23][C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:21][C:20]2=[O:31])[CH3:14]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:5]([CH3:6])[CH:13]([C:15]2[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]3[C:24]=2[O:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:21][C:20]3=[O:31])[CH3:14])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: CNc1ccc(F)c(Cl)c1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Br
Product: CC(c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1ccc(F)c(Cl)c1
Yield: 53.5 %

Procedure:
3-chloro-4-fluoro-N-methylaniline (260 mg, 1.63 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (200 mg, 0.41 mmol, as described in Example 3.03), using an analgous procedure to that described in Example 3.00, to afford 8-(1-((3-chloro-4-fluorophenyl) (methyl)amino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (107 mg, 53.7%) as a white solid. Mass Spectrum: M+H+ 488. NMR Spectrum: (DMSOd6) 1.55 (d, 3H), 2.63 (s, 3H), 2.91 (s, 3H), 3.01 (s, 3H), 3.20-3.29 (m, 2H), 3.30-3.37 (m partially hidden by H2O, 2H), 3.42-3.49 (ms, 2H), 3.49-3.57 (m, 2H), 5.54 (s, 1H), 5.55 (q, 1H), 6.79 (dd, 1H), 6.98 (dd, 1H), 7.23 (dd, 1H), 7.68 (d, 1H), 7.87 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])(=[O:20])=[O:19])=[CH:16][CH:17]=1
Reactant: COc1ccccc1N
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)Nc2ccccc2OC)cc1
Yield: 90.1 %

Procedure:
Using o-anisidine (1.0 ml, 8.55 mmol) and 4-methoxybenzenesulfonyl chloride (1.78 g, 8.55 mmol), the procedure of Reference Example 2 was repeated to obtain 2.26 g (90.1%) of the title compound in the form of colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:12]([O-])=O)[C:3]=1[OH:15]>[Fe].C(O)(=O)C>[NH2:12][C:4]1[C:3]([OH:15])=[C:2]([Cl:1])[CH:10]=[C:9]([Cl:11])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1c(Cl)cc(Cl)c(O)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1c(O)c(Cl)cc(Cl)c1C(=O)O
Temperature: 80 °C
Yield: 94.3 %

Procedure:
A mixture of 4,6-dichloro-3-hydroxy-2-nitrobenzoic acid (1-6) (700 mg, 2.78 mmol), iron powder (400 mg, 7.16 mmol) and glacial acetic acid (13 mL) was heated at 80° C. for 50 minutes, cooled, and the solids filtered off. The filtrate was concentrated to a brown solid. Subsequent SiO2-gel column chromatography (ethyl acetate/HOAc, 100:1-100:3) gave 2-amino-4,6-dichloro-3-hydroxybenzoic acid (1-8) as a light brown solid (582 mg, 94%). —1H NMR (DMSO-d6): δ 6.68 (s); this is consistent with the literature.4
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:13][C:14]([F:32])([F:31])[C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH2:30])=[CH:24][CH:23]=2)=[N:19][CH:20]=1.C(N(CC)CC)C>C(O)C>[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][N:3]=[C:2]2[NH:30][CH2:29][CH2:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:32])([F:13])[F:31])=[CH:20][N:19]=2)=[CH:27][CH:26]=1
Reactant: NCCc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: Fc1cccc2c(Cl)ncnc12
Solvent: CCO
Solvent: CCN(CC)CC
Product: Fc1cccc2c(NCCc3ccc(Oc4ccc(C(F)(F)F)cn4)cc3)ncnc12
Yield: 58.4 %

Procedure:
A mixture of 4-chloro-8-fluoroquinazoline (1.82 g, 0.01 mol), 2-(4-(5-trifluoromethyl-2-pyridinyloxy)-phenyl)ethylamine (2.82 g, 0.01 mol), triethylamine (1.1 g, 0.011 mol) and ethanol (50 mL) was heated under reflux for three hours and allowed to cool. Solvent was evaporated under reduced pressure, and the residue dissolved in dichloromethane. This was washed with 0.5M sodium hydroxide solution and water, and dried over anhydrous sodium sulphate. Evaporation of the solvent under reduced pressure and recrystallization from ethyl acetate:hexane gave 2.5 g of product. MP 152° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[N+:11]([O-])([OH:13])=[O:12]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)c1ccc(F)cc1
Solvent: ClC(Cl)Cl
Product: CC(=O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: -10 °C
Reaction time: 4 h

Procedure:
13.8 g of 4'-fluoroacetophenone (provided from Tokyo Chemical Industry Co., Ltd.) were added in two portions to 100 ml of fuming nitric acid cooled to -10° C. with agitation. After the mixture was warmed to room temperature, the agitation was continued for further 4 hours. This mixture was poured into 1.0 liter of ice water and was extracted with 500 ml of ethyl acetate. The organic layer was dried and the solvent was distilled off under a reduced pressure. The residue was purified by a column chromatography (9/1-4/1: n-hexane/ethyl acetate) twice, whereby 4.16 g of the above-identified were obtained. Rf=0.50 (chloroform).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[F:27]C1C=CC=CC=1C1CCC2C(=CC=C(O)C=2)O1>>[F:27][C:26]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([O:10][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=3)[CH:12]=2)[O:17]1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: Oc1ccc2c(c1)CCC(c1ccccc1F)O2
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2F)O3)nc1

Procedure:
2-[2-(2-Fluorophenyl)chroman-6-yloxy]-5-nitropyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 390 mg of 2-(2-fluorophenyl)chroman-6-ol. The product was purified by column chromatography using heptane-ethyl acetate (4:1) as an eluant. 1H NMR (400 MHz, CDCl3) δ: 9.04 (d, 1H, J 2.8 Hz), 8.60 (dd, 1H, J 9.1, 2.8 Hz), 7.56 (m, 1H), 7.43 (m, 1H), 7.30-7.22 (m, 2H), 7.20 (d, 1H, J 9.1 Hz), 7.02 (d, 1H, J 2.8 Hz), 6.98 (dd, 1H, J 8.7, 2.8 Hz), 6.91 (d, 1H, J 8.7 Hz), 5.37 (dd, 1H, J 10.4, 2.3 Hz), 3.04 (ddd, 1H, J −17.0, 11.5, 6.0 Hz), 2.82 (ddd, 1H, J −17.0, 5.1, 2.8 Hz), 2.18 (m, 1H), 2.08 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Li]CCCC.CCCCCC.CON(C)[C:24]([C@@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]1)=[O:25]>C1COCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3]([CH3:9])=[C:2]([CH:7]=1)[C:24]([C@@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]1)=[O:25]
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Cc1ccc(F)cc1Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a solution of 2-bromo-4-fluoro-1-methylbenzene (10.6 g, 0.056 mol) in anhydrous THF (150 mL) at −78° C. under nitrogen was added dropwise a solution of 2.5 M n-BuLi in hexane (22 mL, 0.056 mol). After stirring for 1 hr at −78° C., a solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (10 g, 0.037 mol) in anhydrous THF (120 mL) was added dropwise, After addition, the reaction mixture was allowed to warm to rt and stirred for 2 hr. The mixture was quenched with saturated NH4Cl (100 mL) solution and extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to provide crude (R)-tert-butyl 3-(5-fluoro-2-methylbenzoyl)piperidine-1-carboxylate (10.5 g, yield 88%), which was used in the next step without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:23][C:24]1[S:25][CH:26]=[CH:27][CH:28]=1>C(OCC)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[N:14]([CH2:23][C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: BrCc1cccs1
Reactant: CCOC(=O)N1CCC(c2c[nH]c3cc(F)ccc23)CC1
Solvent: CCOCC
Product: CCOC(=O)N1CCC(c2cn(Cc3cccs3)c3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
This compound was prepared following the procedure described in example 13 (part B) starting with 4 g (13.8 mmol) of 4-(6-fluoro-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester (example 24, part A) and 16 mL of (16 mmol) of a freshly prepared 1M solution in ethyl ether of 2-bromomethyl-thiophene. The reaction mixture was stirred at room temperature for 18 hours. After standard work-up, 5.42 g (100% of yield) of 4-(6-fluoro-1-thiophen-2-ylmethyl-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[CH2:11]([O:13][C:14]1[O:15][C:16](=[O:28])[C:17]2[CH:27]=[C:26]3[C:21]([CH:22]=[CH:23][CH:24]=[CH:25]3)=[CH:20][C:18]=2[N:19]=1)[CH3:12]>C1C=CC=CC=1>[C:5](/[C:4](=[C:16](\[C:17]1[C:18]([NH:19][C:14]([O:13][CH2:11][CH3:12])=[O:15])=[CH:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=1)/[OH:28])/[C:3]([O:9][CH3:10])=[O:8])(=[O:6])[CH3:7]
Reactant: CCOc1nc2cc3ccccc3cc2c(=O)o1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)Nc1cc2ccccc2cc1/C(O)=C(\C(C)=O)C(=O)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a dispersion of sodium hydride (95%) (1.00 g, 41.7 mmol, 2.1 equiv) in anhydrous benzene (250 ml) under nitrogen was added dropwise methyl acetoacetate (6.5 ml, 7.00 g, 60.3 mmol, 3.1 equiv) and the mixture was stirred at room temp for 1 hour. 2-ethoxy-4H-naphtho[2,3-d][1,3]oxazin-4-one (1-2) (4.72 g, 19.5 mmol, 1.0 equiv) was added and the reaction continued stirring at room temperature for 20 hours. The reaction was quenched with water and the organic layer was separated, and extracted three times with water. The emulsion and combined aqueous layers were made acidic with conc. HCl and stirred for 20 hours. The solid precipitate was filtered and dried to yield methyl (2Z)-2-acetyl-3-{3-[(ethoxycarbonyl)amino]-2-naphthyl}-3-hydroxyprop-2-enoate (1-3) as a yellow solid. LRMS m/z (M+H) 358.3 found, 358.1 required.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][CH:6]=1)=[O:4].[N-:15]=[N+:16]=[N-:17].[Na+].[Na+].[Cl-]>CC(C)=O>[N:15]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][CH:6]=1)=[O:4])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)c1ccc(C(=O)CBr)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)c1ccc(C(=O)CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
To a solution of the product of Example 1A (985 mg, 3.86 mmol) in 45 mL acetone was added NaN3 (0.505 g, 7.07 mmol), and the mixture stirred overnight at room temperature. The reaction mixture was poured into saturated NaCl solution and extracted with dichloromethane. The extracts were washed with saturated NaCl solution, dried over Na2SO4, and concentrated in vacuo to afford the title compound as a yellow oil (715 mg, 85%). 1H NMR (DMSO-d6) δ 7.88 (d, 2H, J=8.5 Hz), 7.57 (d, 2H, J=8.5 Hz), 4.86 (s, 2H), 1.31 (s, 9H); MS (ESI+) m/z 218 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[C:18]([NH2:20])=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[S:24][C:25]([Cl:28])=[CH:26][CH:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][C:23]2[S:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[C:18]([NH2:20])=[O:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: NC(=O)[C@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: Clc1ccc(CBr)s1
Product: NC(=O)[C@H]1CCCC[C@H]1N(Cc1ccc(Cl)s1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 38 %

Procedure:
The titled compound was prepared in 38% yield from (1S,2R)-2-(4-chlorobenzenesulfonylamino)-cyclohexanecarboxylic acid amide (75 mg, 0.237 mmol) and 2-bromomethyl-5-chloro-thiophene (83 mg, 0.498 mmol) according to the procedure described in Example 3: 1H NMR (400 Mz, CDCl3) δ 7.72 (d, 2 H, J=6.6), 7.59 (d, 2 H, J=8.9), 7.39 (br s, 1 H), 6.88 (d, 1 H, J=3.7), 6.79 (br s, 1 H), 4.69 (s, 2 H), 3.83 (dt, 1 H, Jd=12.7, J=3.7), 2.71 (m, 1 H), 2.52 (m, 1 H), 1.79–1.69 (m, 2 H), 1.61 (m, 1 H), 1.49–1.22 (m, 3 H), 1.11 (m, 1 H); MS m/e 469.1 (M+Na)+.
Reaction SMILES: [C:1]([C:3]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH2:4][CH2:5][C:6]([OH:8])=O)#[N:2].Cl[C:25]1C=CC(C(C#N)(CCC(O)=O)CCC(O)=O)=CC=1.O1CCCC1.CC(C)([O-])C.[K+]>C(O)(=O)C>[C:11]([CH:10]1[CH2:9][C:3]([C:1]#[N:2])([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[CH2:4][CH2:5][C:6]1=[O:8])([O:13][CH3:25])=[O:12]
Reactant: N#CC(CCC(=O)O)(CCC(=O)O)c1ccc(Cl)cc1
Reactant: COc1ccc(C(C#N)(CCC(=O)O)CCC(=O)O)cc1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C1CC(C#N)(c2ccc(OC)c(OC)c2)CCC1=O
Yield: 94 %

Procedure:
Following the procedure of Example 1, Part B, but substituting 34.25 gm. (0.098 mole) of the dimethyl ester of 4-cyano-4-(3.4-dimethoxyphenyl)pimelic acid (prepared in Part A, above) for the dimethyl ester of 4-(p-chlorophenyl)-4-cyanopimelic acid and using 640 ml. of the tetrahydrofuran, 22.0 gm. (0.196 mole) of the potassium tert-butoxide and 155 ml. of the 2.5 N of the aqueous acetic acid instead of the 700 ml. the 24.4 gm. (0.218 mole), and the 175 ml. respectively, there is prepared 29.2 gm. (94% yield) of 2-carbomethoxy-4-cyano-4-(3,4-dimethoxyphenyl)cyclohexanone as crystals having a melting range of 110° to 113° C. An analytical sample recrystallized from a mixture of ethyl acetate and cyclohexane melts in the range of 112.5° to 114.5° C.
Reaction SMILES: [CH:1]1([C@:7]([OH:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][N:19]([CH3:25])[CH2:20][C:21]#[C:22][CH2:23][NH2:24].O>C(Cl)(Cl)Cl>[CH3:18][N:19]([CH3:25])[CH2:20][C:21]#[C:22][CH2:23][NH:24][C:8](=[O:10])[C:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CN(C)CC#CCN
Reactant: O=C(O)[C@@](O)(c1ccccc1)C1CCCCC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN(C)CC#CCNC(=O)C(O)(c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.9 %

Procedure:
A mixture of (S)-(+)-2-cyclohexyl-2-hydroxy-2-phenylacetic acid (1.13 g, 80% ee) and N,N'-carbonyldiimidazole (0.77 g) in chloroform (5 ml) was stirred at room temperature for 2 hours. After an addition of 4-dimethylamino-2-butynylamine (0.54 g), the mixture was stirred at the same temperature for an additional hour, then the mixture was poured into water, and extracted with ethyl acetate. The extract was washed with water and the organic layer was extracted with 1N-hydrochloric acid. The acidic solution was adjusted to pH 13 with aqueous solution of sodium hydroxide and extracted with ethyl acetate. The extract was washed with sodium chloride aqueous solution, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of chloroform and methanol (10:1) as an eluent to give (-)-N-(4-dimethylamino-2-butynyl)-2-cyclohexyl-2-hydroxy-2-phenylacetamide (0.60 g, 88% ee).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].S(Cl)(Cl)=O.[CH3:14]O>>[NH2:1][C@@H:2]([C:3]([SH:6])([CH3:5])[CH3:4])[C:7]([O:9][CH3:14])=[O:8]
Reactant: CO
Reactant: CC(C)(S)[C@H](N)C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H](N)C(C)(C)S
Yield: 100 %

Procedure:
To a methanol (18 mL, 1.14 M) solution containing L-penicillamine (3.0 g, 20.11 mmol, 1.0 eq) was added thionyl chloride (1.5 mL, 20.7 mmol, 1.03 eq). The resulting mixture was heated to reflux for 18 hr and the solvent removed in vacuo. The resulting clear semi-solid was used in the next step without further purification. Isolated 3.28 g (20.1 mmol, 100% yield).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].[CH3:12][N:13](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[O:11]=[C:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:2]([C:12]#[N:13])[C:3]=2[CH2:4][CH2:5]1
Reactant: O=C1CCc2c(Br)cccc21
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cccc2c1CCC2=O
Temperature: 165 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-2,3-dihydro-1H-inden-1-one (1.00 g, 4.74 mmol) in 5 mL of DMF was added Zn(CN)2 (556 mg, 4.74 mmol) and Pd(PPh3)4 (77 mg, 0.14 mmol), and the reaction mixture was stirred under microwave irradiation for 1 h at 165° C. The solvent was removed in vacuum to afford the crude compound, which was purified via column chromatography to afford 1-oxo-2,3-dihydro-1H-indene-4-carbonitrile.
Reaction SMILES: [CH2:1]([NH:4][S:5]([C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-])=O)[C:9]=1[OH:18])(=[O:7])=[O:6])[CH:2]=[CH2:3].O.O.[Sn](Cl)Cl>C(O)C>[CH2:1]([NH:4][S:5]([C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([NH2:15])[C:9]=1[OH:18])(=[O:7])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: C=CCNS(=O)(=O)c1c(Cl)ccc(N)c1O
Yield: 84.6 %

Procedure:
A solution of N-allyl-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (25 mg, 0.09 mmol) and tin (II) chloride dihydrate (101 mg, 0.44mmol) in 5 mL of ethanol was stirred at room temperature. The mixture was concentrated, the residue was diluted with ethyl acetate and 10% aq. NaHCO3. The organic layer was dried over Na2SO4 and concentrated to give the crude product (20 mg) which was carried on to the next step without purification. EI-MS (m/z) 263.1, 265.2 (M−).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][C:3]=1[C:12]1[CH:20]=[C:19]2[C:15]([C:16]3([CH2:25][CH2:24][CH2:23][CH2:22]3)[C:17](=[O:21])[NH:18]2)=[CH:14][CH:13]=1.[CH3:26][C:27](C)(C)C([O-])([O-])[O-].O>C(O)(=O)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[O:7][C:26]([CH3:27])=[N:9][N:8]=2)=[CH:4][C:3]=1[C:12]1[CH:20]=[C:19]2[C:15]([C:16]3([CH2:25][CH2:24][CH2:23][CH2:22]3)[C:17](=[O:21])[NH:18]2)=[CH:14][CH:13]=1
Reactant: CC(C)(C)C([O-])([O-])[O-]
Reactant: Cc1ccc(C(=O)NN)cc1-c1ccc2c(c1)NC(=O)C21CCCC1
Solvent: CC(=O)O
Solvent: O
Product: Cc1nnc(-c2ccc(C)c(-c3ccc4c(c3)NC(=O)C43CCCC3)c2)o1
Temperature: 150 °C
Reaction time: 3 h
Yield: 34.8 %

Procedure:
A stirred mixture of 4-methyl-3-(2′-oxospiro[cyclopentane-1,3′-indoline]-6′-yl)benzohydrazide (preparation 53, 0.05 g, 0.16 mmol) and trimethylorthoacetate (0.04 mL, 0.19 mmol) in acetic acid (1 mL) were heated to 150° C. in a sealed tube. After 3 hours, the mixture was cooled, poured into water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried (MgSO4) and evaporated in vacuo. Purification of the residue by flash chromatography (1:1 hexanes/ethyl acetate) gave the title compound (0.02 g, 35%) as a white solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][SH:6].[CH3:9][O:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15](Cl)=[N:14][CH:13]=1>C1COCC1>[F:3][C:4]([F:8])([F:7])[CH2:5][S:6][C:15]1[N:14]=[CH:13][C:12]([C:11]([O:10][CH3:9])=[O:19])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: FC(F)(F)CS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(SCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.2 %

Procedure:
To a solution of sodium hydride (60% dispersion in mineral oil, 90 mg, 2.25 mmol) in anhydrous THF (40 mL) at 0 C was added 2,2,2-trifluoro-ethanethiol (200 μL, 2.25 mmol) drop-wise under nitrogen. The resulting solution was stirred for 15 min and added to a solution of 6-chloro-nicotinic acid methyl ester (257 mg, 1.5 mmol) in anhydrous THF (40 mL) at 0 C drop-wise. The reaction mixture was allowed to warm to room temperature and stirring was continued for a further 3 h. The solution was quenched with water at 0 C and extracted into EtOAc (3×50 mL). Combined organics were washed with brine (20 mL), dried over magnesium sulfate, evaporated to dryness and purified by silica chromatography (25% EtOAc in heptane) to afford the title compound as a colourless oil (370 mg, 98%). Method C HPLC-MS: MH+ requires m/z=252. Found: m/z=252, Rt=1.41 min (94%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@@H:12]2[N:17]3[C:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]=[CH:20][C:19]=4[N:28]=[C:16]3[CH2:15][O:14][CH2:13]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:37])C=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C@@H:12]2[N:17]3[C:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N+:21]([O-:37])=[CH:20][C:19]=4[N:28]=[C:16]3[CH2:15][O:14][CH2:13]2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C[C@H]2COCc3nc4cnc5ccccc5c4n32)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1ccc(C[C@H]2COCc3nc4c[n+]([O-])c5ccccc5c4n32)cc1
Reaction time: 18 h
Yield: 100 %

Procedure:
4-[(11S)-10,11-Dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-ylmethyl]phenyl acetate (2.95 g, 7.91 mmol) was dissolved in 80 mL of CHCl3 and treated with MCPBA (2.33 g, 77% max). After stirring for 18 hours, the reaction was treated with 25 mL of a 2% Na2CO3 solution and the layers were separated. The aqueous layer was then extracted with CHCl3 (4×20 mL). The combined organic layers were washed with 20 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 4-{[(11S)-5-oxido-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]methyl}phenyl acetate (3.08 g) as a tan solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)=[CH:13][C:12]2=[O:24])=[CH:5][CH:4]=1.P(Br)(Br)[Br:26]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Br:26][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)=[CH:13][C:12]2=[O:24])=[CH:5][CH:4]=1
Reactant: BrP(Br)Br
Reactant: O=c1cc(OCc2cccs2)ccn1CCc1ccc(CO)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1cc(OCc2cccs2)ccn1CCc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 480 mg (1.41 mmol) 1-[2-(4-hydroxymethyl-phenyl)-ethyl]-4-(thiophen-2-ylmethoxy)-1H-pyridin-2-one (example 2.1a) in 5.0 mL of DCM is added 67 μL (0.70 mmol) phosphorus tribromide at 0° C. After warming to RT, the mixture is stirred 2 h at RT and is diluted with aqueous 5% NaHCO3-solution. The layers are separated and the aqueous phase is washed with DCM. The combined organic phase is washed with water, dried over MgSO4, filtered and the solvent is evaporated to afford the product.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-])=O)[CH2:9][CH2:8]1)=[O:6])[CH3:3]>C(O)C.[Pd]>[CH3:3][C:2]([CH3:22])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH2:19])[CH2:9][CH2:8]1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2N)CC1
Reaction time: 6 h

Procedure:
1-[1,1-Dimethylethoxycarbonyl]-4-(2-nitrophenyl)piperazine (PREPARATION 12, 7.61 g) is dissolved in ethanol (150 ml). Palladium on carbon (10%, 0.75 g) is added and the reaction is hydrogenated at 45 psi for 6 hr. The mixture is filtered thru celite and concentrated under reduced pressure to give the title compound.