Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([OH:14])=[O:13])=[CH:5]2.S(=O)(=O)(O)O.[C:20](=O)(O)[O-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14][CH3:20])=[O:13])=[CH:5]2
Reactant: O=C(O)c1cnc2ccc(Br)cc2c1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cnc2ccc(Br)cc2c1
Temperature: 85 °C
Reaction time: 96 h

Procedure:
To a solution of 6-bromoquinoline-3-carboxylic acid (3 g, 11.9 mmol), in methanol (55 mL) was added sulfuric acid (0.32 mL, 6 mmol). The reaction was stirred at 85° C. for 96 h. The reaction was then cooled to room temperature and saturated sodium bicarbonate solution was added until pH=7. On neutralization, methyl 7-bromo-2-naphthoate precipitated as a solid which was collected by suction filtration (Int-1, 2.77 g, 97%). LC-MS: (FA) ES+ 266; 1H NMR (400 MHz, d6-DMSO) δ ppm 9.33 (d, J=2.1 Hz, 1H), 9.01 (d, J=2.1 Hz, 1H), 8.53 (t, J=1.3, 1.3 Hz, 1H), 8.07-8.01 (m, 2H), 3.95 (s, 3H).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([N:12]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]4[N:38]=[CH:37][C:36]([CH2:39][CH2:40][C:41]([O:43]CC)=[O:42])=[CH:35][C:34]=4[CH2:46][OH:47])[CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:13])=[O:11])=O)(C)(C)C.[OH-].[Na+].[ClH:50]>CCO.C1COCC1>[ClH:50].[ClH:50].[NH2:8][CH2:9][C:10]([N:12]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:28][CH2:29][N:30]([C:33]4[N:38]=[CH:37][C:36]([CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[CH:35][C:34]=4[CH2:46][OH:47])[CH2:31][CH2:32]3)=[N:25][CH:26]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:13])=[O:11]
Reactant: CCOC(=O)CCc1cnc(N2CCN(c3ncc(-c4cccc(CN(C)C(=O)CNC(=O)OC(C)(C)C)c4)cn3)CC2)c(CO)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(Cc1cccc(-c2cnc(N3CCN(c4ncc(CCC(=O)O)cc4CO)CC3)nc2)c1)C(=O)CN
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Ethyl 3-[6-(4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazin-1-yl)-5-(hydroxymethyl)pyridin-3-yl]propanoate (222 mg) was dissolved in EtOH (1 ml) and THF (2 ml), and a 1 M aqueous NaOH solution (1 ml) was added thereto, followed by stirring at room temperature for 5 hours. To the reaction mixture was added 1 M hydrochloric acid (1 ml), and the solvent was evaporated under reduced pressure. To the obtained residue was added water, followed by extraction with CHCl3. The organic layer was dried over MgSO4, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH). The product was dissolved in dioxane (2 ml), and 4 M hydrogen chloride/dioxane (0.8 ml) was added thereto. After stirring at room temperature overnight, the precipitated solid was collected by filtration to obtain 3-[6-{4-[5-(3-{[glycyl(methyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}-5-(hydroxymethyl)pyridin-3-yl]propionic acid dihydrochloride (203 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:23])[NH:14][C:15]1[CH:20]=[CH:19][C:18](Br)=[CH:17][C:16]=1[Cl:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:23])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[S:25][CH3:24])=[CH:17][C:16]=1[Cl:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(Br)cc1Cl
Reactant: CSc1ccccc1B(O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CSc1ccccc1-c1ccc(NC(=O)C2CCCN2C(=O)OC(C)(C)C)c(Cl)c1

Procedure:
2-(4-Bromo-2-chloro-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1 g, 2.5 mmol), 2-(methylthio)benzene boronic acid (0.5 g, 3 mmol), and tetrabutylammonium bromide (40 mg, 0.12 mmol) were combined in 10 mL toluene, added 2 mL of a 2M aqueous Na2CO3 solution followed by tetrakistriphenylphosphine palladium(0) (0.14 g, 0.12 mmol). Heated reaction at reflux for 5 hours, cooled, dissolved in EtOAc (150 mL), washed with water (3×50 mL), brine (50 mL), dried with MgSO4, filtered, and concentrated. Purified on a silica gel column eluted using an automated system with gradient of 0-50% EtOAc in hexanes over 40 minutes. Combined and concentrated pure fractions to yield title compound as a white foam. (1.01 g, 91%) APCI (AP−): 445.1, 447.1 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].OS(O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].[CH3:23][CH2:24]O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:23][CH3:24])=[O:10]
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)Cc1ccccc1Cl
Yield: 97 %

Procedure:
A mixture of 2-(2-chlorophenyl)acetic acid (10 g, 58.6 mmol) in EtOH (Volume: 152 ml) was treated with H2SO4 (1.719 ml, 32.2 mmol). The result mixture was refluxed overnight. The heat was removed, and the reaction mixture was concentrated. The resulting oil was dissolved in EtOAc and CAREFULLY treated with aqueous Na2CO3 (3.47 g, 32.8 mmol) (CAUTION: Gas evolution) until the solution remained basic and no further gas evolution was seen. The EtOAc layer was then removed and the aqueous layer was again extracted two times with EtOAc. The combined organic layers were then washed with brine, dried over Na2SO4 and concentrated in vacuo to obtain ethyl 2-(2-chlorophenyl)acetate (11.32 g, 57.0 mmol, 97% yield). LC-MS (M+H)+=199.1. 1H NMR (500 MHz, CD3OD) δ 7.41 (ddd, J=16.8, 5.6, 3.5 Hz, 1H), 7.35 (dd, J=5.5, 3.7 Hz, 1H), 7.28 (dd, J=5.8, 3.7 Hz, 2H), 4.17 (q, J=7.0 Hz, 2H), 3.80 (s, 2H), 1.26 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.I[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:17]
Reactant: OCCc1ccc(F)cc1
Reactant: CCOC(=O)CI
Agent: [Ag+]
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=S(=O)([O-])C(F)(F)F
Product: CCOC(=O)COCCc1ccc(F)cc1

Procedure:
In analogy to the procedure described in example 78.1, 2-(4-fluoro-phenyl)-ethanol was reacted with ethyl iodoacetate in the presence of silver trifluoromethanesulfonate and 2,6-di-tert-butylpyridin to give [2-(4-fluoro-phenyl)-ethoxy]-acetic acid ethyl ester as colorless liquid. 1H NMR (CDCl3): 1.28 (t, J=7.2 Hz, 3H), 2.92 (t, J=7.0 Hz, 2H), 3.73 (t, J=7.0 Hz, 2H), 4.07 (s, 2H), 4.22 (q, J=7.2 Hz, 2H), 6.97 (m, 2H), 7.21 (m, 2H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]1[O:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[N:10]([C:21](=[O:34])[C:22]2[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=2)[CH2:9]1)(=O)=O.Cl.[C:36]1([C:42]2([C:48]([NH2:50])=[O:49])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])O.[Na+].[I-].[K+].[Cl-].[Na+]>CN(C)C=O>[Cl:20][C:15]1[CH:14]=[C:13]([CH:11]2[N:10]([C:21](=[O:34])[C:22]3[CH:23]=[C:24]([O:32][CH3:33])[C:25]([O:30][CH3:31])=[C:26]([O:28][CH3:29])[CH:27]=3)[CH2:9][C@@H:8]([CH2:7][CH2:6][N:45]3[CH2:44][CH2:43][C:42]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)([C:48]([NH2:50])=[O:49])[CH2:47][CH2:46]3)[O:12]2)[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2C[C@@H](CCOS(C)(=O)=O)OC2c2ccc(Cl)c(Cl)c2)cc(OC)c1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2C[C@@H](CCN3CCC(C(N)=O)(c4ccccc4)CC3)OC2c2ccc(Cl)c(Cl)c2)cc(OC)c1OC
Temperature: 80 °C
Yield: 70.6 %

Procedure:
150 mg (0.28 mmole) of 2-[(5R)-(3,4-dichlorophenyl)-3-(3,4,5-trimethoxybenzoyl)oxazolidin-5-yl]ethanol methanesulfonate [prepared as described in step (g) above] and 75 mg (0.31 mmole) of 4-phenylpiperidine-4-carboxamide hydrochloride were dissolved in 3 ml of anhydrous dimethylformamide, and 71 mg (0.85 mmole) of sodium hydrogencarbonate and 70 mg (0.42 mmole) of potassium iodide were added to the resulting solution. The mixture was then heated under a nitrogen atmosphere at 80° C. for 6 hours. At the end of this time, 50 ml of a saturated aqueous solution of sodium chloride were added to the reaction mixture, which was then extracted three times, each time with 50 ml of ethyl acetate. The combined organic extracts were then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel thin-layer chromatography, using a 10:1 by volume mixture of methylene chloride and methanol as the developing solvent, to give 127 mg (yield 71%) of the title compound as a white amorphous substance.
Reaction SMILES: C(O)(=O)C.O.[CH2:6]([NH:13][C:14]1[C:19]([N+:20]([O-])=O)=[CH:18][N:17]=[C:16]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]2)[N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C.ClCCl.[Fe]>[NH2:20][C:19]1[C:14]([NH:13][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:15][C:16]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]2)=[N:17][CH:18]=1
Reactant: CCOC(=O)C1CCN(c2ncc([N+](=O)[O-])c(NCc3ccccc3)n2)CC1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1CCN(c2ncc(N)c(NCc3ccccc3)n2)CC1
Yield: 68.7 %

Procedure:
1.3 ml of acetic acid, 1.3 ml of distilled water and 1.40 g of iron were added to a suspension of 0.90 g of ethyl 1-[4-benzylamino-5-nitropyrimidin-2-yl)-4-piperidinecarboxylate (Reference Example 6) in 50 ml of ethanol and the reaction solution was refluxed for 5 hours. The dark blue solution was filtered to remove the insoluble substance, and concentrated under reduced pressure to obtain the thin yellow oily product. The resulting product was dissolved in dichloromethane and washed with 10% sodium carbonate(50 ml×2). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 0.57 g of the title compound as a oily product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19](O)=[O:20])=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:53]([N:55]1[N:59]=[N:58][C:57]([CH2:60][N:61]2[C:66]3[CH:67]=[C:68]([C:70]4[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=4)[S:69][C:65]=3[C:64](=[O:76])[N:63]([CH:77]3[CH2:82][CH2:81][NH:80][CH2:79][CH2:78]3)[C:62]2=[O:83])=[N:56]1)[CH3:54].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[C:18]([C:19]([N:80]4[CH2:81][CH2:82][CH:77]([N:63]5[C:64](=[O:76])[C:65]6[S:69][C:68]([C:70]7[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=7)=[CH:67][C:66]=6[N:61]([CH2:60][C:57]6[N:58]=[N:59][N:55]([CH2:53][CH3:54])[N:56]=6)[C:62]5=[O:83])[CH2:78][CH2:79]4)=[O:20])[CH:22]=[CH:23][CH:24]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)O)c1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nnn(CC)n5)c4=O)CC3)c1)=N[C@@H]1CCSC[C@H]21

Procedure:
In analogy to the procedure described for example 14 3-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (120 mg; compound C8) is reacted with HBTU (120 mg), 1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (132 mg; compound B39) and DIPEA (0.16 ml) in DCM (10 ml). After purification by flash column chromatography (silica gel, eluent: EtOAc) the title compound is obtained as a solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C@@H:13]([O:24]COC)[CH2:14][CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:7][C:6]=1[NH:28][C:29](=[O:45])[CH2:30][CH:31]1[C:44]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[O:38][C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)([CH3:4])([CH3:3])[CH3:2].Cl>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C@@H:13]([OH:24])[CH2:14][CH2:15][CH2:16][CH2:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)=[CH:7][C:6]=1[NH:28][C:29](=[O:45])[CH2:30][CH:31]1[C:44]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[O:38][C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCO[C@@H](CCCCC1CCCCC1)CCc1ccc(C(C)(C)C)c(NC(=O)CC2c3ccccc3Oc3ccccc32)c1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(CC[C@@H](O)CCCCC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
A mixture of 1.20 g (1.96 mmol) of (S)-N-{2-t-butyl-5-[7-cyclohexyl-3-(methoxymethoxy)heptyl]phenyl}-2-(9H-xanthen-9-yl)acetamide (prepared as described in Preparation 43) in 12 ml of a 4N solution of hydrogen chloride in dioxane was stirred for 30 minutes and then the solvent was removed by distillation under reduced pressure. The pH of the residue was brought to 7 by adding an aqueous solution of sodium hydrogencarbonate, and the resulting mixture was extracted twice with ethyl acetate. The combined extracts were washed with a saturated aqueous solution of sodium chloride. The washed extracts were dried, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.9 g of the title compound as an oil. This oil was triturated with hexane and the resulting crystallized product was collected, to give 0.83 g (yield 75%) of the title compound as crystals.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[C:8]([NH2:23])=[N:9][C:10]([CH:20]2[CH2:22][CH2:21]2)=[N:11][C:12]=1[CH:13]([O:17]CC)[O:14][CH2:15][CH3:16].S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].C(=O)(O)[O-].[Na+]>C(#N)C>[NH2:23][C:8]1[N:9]=[C:10]([CH:20]2[CH2:22][CH2:21]2)[N:11]=[C:12]([C:13]([O:14][CH2:15][CH3:16])=[O:17])[C:7]=1[Cl:6]
Reactant: CCOC(OCC)c1nc(C2CC2)nc(N)c1Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: CC#N
Product: CCOC(=O)c1nc(C2CC2)nc(N)c1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 55 %

Procedure:
Sulfuric acid (1.97 g, 20 mmol) was added dropwise to 5-chloro-2-cyclopropyl-6-(diethoxymethyl)-4-pyrimidinamine (i.e. the product of Example 6) (2.71 g, 10 mmol) in acetonitrile (27.5 mL) at room temperature. The temperature rose to 35° C. When the mixture had cooled to 29° C. ammonium persulfate (0.5 g, 2.21 mmol) was added in one portion. After stirring for 20 h at room temperature the mixture was poured into saturated aqueous sodium bicarbonate solution (100 mL). The mixture was extracted with ethyl acetate (2×70 mL). The combined extracts were dried and evaporated to leave the product as an off-white solid (1.32 g, 55% yield). Product purified by chromatography on silica gel (eluted with 40:60 ethyl acetate-hexanes) followed by washing with hydrochloric acid (1 N) melted at 93-95° C.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH2:9][NH:8][C:7]2[CH:10]=[C:11]([Cl:18])[C:12]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:13][C:6]=2[S:5]1(=[O:20])=[O:19].[N-:21]=[N+]=[N-].[Na+]>CN(C=O)C>[NH2:21][CH2:2][CH2:3][N:4]1[CH2:9][NH:8][C:7]2[CH:10]=[C:11]([Cl:18])[C:12]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:13][C:6]=2[S:5]1(=[O:20])=[O:19]
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)NCN(CCBr)S2(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NCCN1CNc2cc(Cl)c(S(N)(=O)=O)cc2S1(=O)=O
Reaction time: 44 h

Procedure:
Combine the product of step A (12.2 g) with sodium azide (3.9 g) in DMF (200 ml). Stir 44 hours, extract with ethyl acetate, wash with water, dry the organic layer over MgSO4 and concentrate. Dissolve the resultant residue in ethanol (150 ml), add 5.0 g 10% Pd/C and hydrogenate at 3 atm for 4 hours. Filter and concentrate the filtrate to obtain 2-(2-aminoethyl)-6-chloro-3,4-dihydro-1, 1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazine.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[NH2:9][C:10]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>>[CH3:19][C:16]1[CH:15]=[C:11]([C:12]([OH:14])=[O:13])[C:10]2[NH:9][C:2]3[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=3[C:18]=2[CH:17]=1
Reactant: O=C1CCCCC1Br
Reactant: Cc1ccc(N)c(C(=O)O)c1
Product: Cc1cc(C(=O)O)c2[nH]c3c(c2c1)CCCC3
Yield: 55 %

Procedure:
Under the conditions of Example 60, 2-bromocyclohexanone is reacted with the methyl ester of 2-amino-5-methylbenzoic acid; after recrystallization from cyclohexane, the methyl ester of 3-methyl-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid is obtained in a 55% yield, m.p. 111° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[NH:10][CH:11]=[CH:12][N:13]=2)=[C:6]([OH:8])[CH:7]=1.CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][CH2:27]Br>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[N:13]([CH:12]=[CH:11][N:10]=3)[CH2:26][CH2:27][O:8][C:6]=2[CH:7]=1
Reactant: Oc1cc(F)ccc1-c1ncc[nH]1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc2c(c1)OCCn1ccnc1-2
Temperature: 90 °C
Reaction time: 3 h
Yield: 67.6 %

Procedure:
5-fluoro-2-(1H-imidazole-2-yl)phenol (0.90 g, 5.0 mmol) was dissolved in N,N-Dimethylformamide (40 mL, 500 mmol). Cesium carbonate (6.6 g, 20 mmol) was added, followed by 1,2-Dibromoethane (1.7 mL, 20 mmol) and heated at 90° C. with a vigreux condensation column attached for 3 hours. Complete by LCMS. Diluted with water and extracted with ethyl acetate. Acidified the aqueous layer to pH ˜5 with HCl and extracted with ethyl acetate. The combined organics were concentrated in vacuo and purified by flash chromatography on the ISCO 0-50% ethyl acetate in hexanes and concentrated in vacuo to give 9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.69 g, 67% yield)
Reaction SMILES: [CH2:1]([OH:13])[C@H:2]([OH:12])[C@@H:3]([OH:11])[C@H:4]([OH:10])[C:5]([C:7]([OH:9])=[O:8])=[O:6].OCC([C@H]([C@@H]([C@H](CO)O)O)O)=O.S(=O)(=O)(O)O.[Mn]([O-])(=O)(=O)=O>OC1[C@@H]([C@@H](O)CO)OC(=O)C=1O.CC(C)=O>[O:8]=[C:7]([OH:9])[C@H:5]([C@H:4]([C@@H:3]([C@H:2]([CH2:1][OH:13])[OH:12])[OH:11])[OH:10])[OH:6]
Reactant: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: CC(C)=O
Product: O=C(O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
2-keto-L-gulonic acid is an important intermediate in vitamin C manufacture. Condensation of L-sorbose with acetone in the presence of sulfuric acid followed by oxidation with permanganate and hydrolysis of the diisopropylidene derivative by boiling yields 2 keto-L-gulonic acid as described in Helv. Chim. Acta., 17, 311 (1934) and U.S. Pat. No. 2,301,811. The preparation of 2-keto-L-gulonic acid by careful oxidation of L-sorbose with nitric acid is claimed in British Pat. No. 443,901 and Dutch Pat. No. 59,584. The selective reduction of 2,5-diketogluconic acid to yield a mixture of 2-ketogluconic acid and 2-ketogulonic acid is described in co-pending application, Ser. No. 749,509 filed Oct. 10, 1976.
Reaction SMILES: Cl[C:2]1[C:10](=[O:11])[C:9]2[N:8]([CH3:12])[N:7]=[CH:6][C:5]=2[C:4](=[O:13])[C:3]=1[N:14]([C:18](=[O:20])[CH3:19])[CH:15]([CH3:17])[CH3:16].C(N)(C)C.[CH2:25]([OH:27])[CH3:26]>>[CH2:25]([O:27][C:2]1[C:10](=[O:11])[C:9]2[N:8]([CH3:12])[N:7]=[CH:6][C:5]=2[C:4](=[O:13])[C:3]=1[N:14]([C:18](=[O:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[CH3:26]
Reactant: CCO
Reactant: CC(=O)N(C1=C(Cl)C(=O)c2c(cnn2C)C1=O)C(C)C
Solvent: CC(C)N
Product: CCOC1=C(N(C(C)=O)C(C)C)C(=O)c2cnn(C)c2C1=O

Procedure:
6-Chloro-5-(N-acetyl-N-isopropylamino)-1-methyl-1H-indazole-4,7-dione (3 grams prepared by a similar method to that described in Example III) and isopropylamine (3 grams) in ethanol (25 milliliters) were heated together under reflux for 10 minutes. On cooling the reaction mixture a yellow-orange solid crystallized out, which was filtered off and dried to yield 6-ethoxy-5-(N-acetyl-N-isopropylamino)-1-methyl-1H-indazole-4,7-dione having a melting point of 154°-155° C.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[S:10][C:11]3[CH:17]=[C:16]([OH:18])[C:15]([F:19])=[CH:14][C:12]=3[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:27]([NH:29][CH3:30])=[O:28])[CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[CH:1]1([CH2:7][NH:8][C:9]2[S:10][C:11]3[CH:17]=[C:16]([O:18][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([C:27]([NH:29][CH3:30])=[O:28])[CH:22]=4)[C:15]([F:19])=[CH:14][C:12]=3[N:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: Oc1cc2sc(NCC3CCCCC3)nc2cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CNC(=O)c1cc(Oc2cc3sc(NCC4CCCCC4)nc3cc2F)ccn1
Temperature: 85 °C
Reaction time: 12 h
Yield: 4.3 %

Procedure:
To the solution of 2-(cyclohexylmethylamino)-5-fluorobenzo[d]thiazol-6-ol (25 mg, 0.089 mmol, 1.0 eq) in 2 mL of NMP was added 4-chloro-N-methylpicolinamide (18 mg, 0.107 mmol, 1.2 eq) and cesium carbonate (86 mg, 0.267 mmol, 3.0 eq) at room temperature. The reaction mixture was stirred at 85° C. for 12 hours, thereafter the mixture was purified on reverse phase HPLC giving 1.6 mg of product as TFA salt in ca. 3.5% yield. LC/MS (m/z) [415.1] (MH+)
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=O.COC1C=CC(/C=[C:36]2/[C:37]([NH:39][C:40]([S:42]/2)=[NH:41])=[O:38])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:41][C:40]1[S:42]/[C:36](=[CH:1]\[C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])/[C:37](=[O:38])[N:39]=1
Reactant: CCCCCCc1c(C#N)cnc2ccc(C=O)cc12
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCCCCc1c(C#N)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12

Procedure:
Similar procedure as described in example 38 was used, starting from 6-formyl-4-hexyl-quinoline-3-carbonitrile (example 52c), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-hexyl-quinoline-3-carbonitrile. LC-MS m/e 365 (MH+).