Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N)C1C=CC=CC=1.[CH:9]1([CH2:12][NH2:13])[CH2:11][CH2:10]1.[F:14][C:15]1[CH:38]=[CH:37][C:18]([CH2:19][N:20]([CH3:36])[C:21]2[N:26]=[C:25]([C:27]3[S:28][C:29]([C:33](O)=[O:34])=[C:30]([CH3:32])[N:31]=3)[CH:24]=[N:23][CH:22]=2)=[CH:17][CH:16]=1>>[CH:9]1([CH2:12][NH:13][C:33]([C:29]2[S:28][C:27]([C:25]3[CH:24]=[N:23][CH:22]=[C:21]([N:20]([CH2:19][C:18]4[CH:37]=[CH:38][C:15]([F:14])=[CH:16][CH:17]=4)[CH3:36])[N:26]=3)=[N:31][C:30]=2[CH3:32])=[O:34])[CH2:11][CH2:10]1
Reactant: NCC1CC1
Reactant: Cc1nc(-c2cncc(N(C)Cc3ccc(F)cc3)n2)sc1C(=O)O
Solvent: NCc1ccccc1
Product: Cc1nc(-c2cncc(N(C)Cc3ccc(F)cc3)n2)sc1C(=O)NCC1CC1
Yield: 75 %

Procedure:
Following the procedure described in Example 1 (Part A), making variations as required to replace benzylamine with cyclopropane-methyl-amine to react with 2-{6-[(4-fluoro-benzyl)-methyl-amino]-pyrazin-2-yl}-4-methyl-thiazole-5-carboxylic acid, the title compound was obtained in 75% yield. 1H NMR (400 MHz, CD2Cl2) δ 8.58 (s, 1H), 8.05 (s, 1H), 7.25-7.31 (m, 2H), 6.98-7.05 (m, 2H), 5.95 (bs, 1H), 4.82 (s, 2H), 3.21-3.26 (m, 2H), 3.15 (s, 3H), 2.70 (s, 3H), 1.00-1.10 (m, 1H), 0.50-0.57 (m, 2H), 0.22-0.28 (m, 2H); MS (ES+) m/z 412.3 (M+1), Rt=1.52 min.
Reaction SMILES: [Cl:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:8](OCC)=[O:9].CC(C)([O-])C.[K+:18]>C1COCC1>[Cl:1]/[C:2](/[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:8]/[O-:9].[K+:18]
Reactant: CCOC(=O)CCl
Reactant: CCOC=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C(Cl)=C\[O-]
Temperature: 10 °C
Reaction time: 24 h
Yield: 90.2 %

Procedure:
A mixture of ethyl 2-chloroacetate (110.0 g; 897.6 mmol) and ethyl formate (73.14 g; 987.4 mmol) was added slowly to a suspension of potassium t-butoxide (110.8 g; 987.4 mmol) in THF (1000 mL) at −5° C. (maintaining the temperature<10° C.) with mechanical stirring. The mixture was stirred at ambient temperature for 24 hours. The solids were collected by filtration and washed with THF (200 mL) and acetonitrile (200 mL). The material was dried under vacuum to give the product (152.7 g) which was used without further purification.
Reaction SMILES: OC1C2C=CC=CC=2S(=O)(=O)N(C)C=1C(NC1C=CC=CN=1)=O.[Na].[S:25]1([C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:29](=[O:30])[NH:28]1)(=[O:27])=[O:26].Cl[CH2:38][C:39]([O:41][CH:42]([CH3:44])[CH3:43])=[O:40]>CN(C)C=O>[O:30]=[C:29]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=2[S:25](=[O:26])(=[O:27])[N:28]1[CH2:38][C:39]([O:41][CH:42]([CH3:44])[CH3:43])=[O:40]
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: CC(C)OC(=O)CCl
Agent: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)CN1C(=O)c2ccccc2S1(=O)=O

Procedure:
A process for manufacturing 4-hydroxy-2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide, of formula I, ##STR6## which comprises the following reaction sequence: reacting saccharin sodium with isopropyl chloroacetate in dimethylformamide to obtain isopropyl 3-oxo-1,2-benzoisothiazoline-2-acetate 1,1-dioxide, of formula II ##STR7## reacting the isopropyl 3-oxo-1,2-benzoisothiazoline-2-acetate 1,1-dioxide of formula II with sodium isopropylate in isopropanol at a temperature between 60° C. and the boiling point of the solvent, for a time between 15 minutes and 3 hours, to produce an intermediate of formula III ##STR8## methylating the intermediate of formula III in an aqueous-alcoholic basic medium with dimethyl sulfate to produce an intermediate compound of formula IV ##STR9## condensing the intermediate compound of formula IV with 2-aminopyridine in xylene to obtain a final product of formula I.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([CH:8]([C:14](=O)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=O)=[CH:4][CH:3]=1.[N:25]1([NH2:30])[CH:29]=[CH:28][CH:27]=[CH:26]1.C(OCC)(=O)C.O>C(O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:15]([C:14]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([C:5]2[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=2)[C:26]2[N:25]([CH:29]=[CH:28][CH:27]=2)[N:30]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nn1cccc1
Reactant: CCOC(=O)C(C(=O)Cc1ccccc1)C(=O)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1c(Cc2ccccc2)nn2cccc2c1-c1ccc(F)cc1
Yield: 51.9 %

Procedure:
A mixture of ethyl 2-(4-fluorobenzoyl)-3-oxo-4-phenylbutanoate (1.4 g), 1H-pyrrol-1-amine (350 mg), and p-toluenesulfonic acid monohydrate (41 mg) in ethanol (10 ml) was refluxed for 5 hours. The mixture was partioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:4) to give ethyl 2-benzyl-4-(4-fluorophenyl)pyrrolo[1,2-b]pyridazine-3-carboxylate (828 mg) as an oil.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][N:6]2[CH:9]=[C:10]([CH2:12][S:13]C(=N)N)[N:11]=[C:5]2[CH:4]=1.[OH-].[Na+]>O>[CH3:2][C:3]1[CH:8]=[CH:7][N:6]2[CH:9]=[C:10]([CH2:12][SH:13])[N:11]=[C:5]2[CH:4]=1
Reactant: Cc1ccn2cc(CSC(=N)N)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccn2cc(CS)nc2c1
Yield: 78.6 %

Procedure:
A mixture of S-(7-methylimidazo[1,2-a]pyridin-2-ylmethyl)isothiourea hydrochloride (7.7 g) and sodium hydroxide (1.2 g) in water (54 ml) was refluxed for 2 hours and the reaction mixture was extracted with ethyl acetate. The extract was washed with water, and dried over magnesium sulfate. The solvent was evaporated in vacuo to give 7-methylimidazo[1,2-a]pyridin-2-ylmethanethiol (4.2 g).
Reaction SMILES: CN(C(ON1N=NC2[CH:12]=[CH:13][CH:14]=[N:15][C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.N1CCCC1.[Br:39][C:40]1[CH:41]=[N:42][C:43]([N:46]2[C:54]3[C:49](=[CH:50][CH:51]=[C:52]([C:55]([OH:57])=O)[CH:53]=3)[C:48]([S:58][CH3:59])=[CH:47]2)=[N:44][CH:45]=1>CN(C=O)C>[Br:39][C:40]1[CH:45]=[N:44][C:43]([N:46]2[C:54]3[C:49](=[CH:50][CH:51]=[C:52]([C:55]([N:15]4[CH2:14][CH2:13][CH2:12][CH2:10]4)=[O:57])[CH:53]=3)[C:48]([S:58][CH3:59])=[CH:47]2)=[N:42][CH:41]=1
Reactant: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)O)ccc12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCCC3)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
HATU (3.1 g, 8.24 mmol), diisopropylethylamine (3.6 ml, 20.6 mmol) and pyrrolidine (0.6 g, 8.24 mmol) were added to an ice cooled suspension of 1-(5-bromopyrimidin-2-yl)-3-(methylthio)-1H-indole-6-carboxylic acid (2.5 g, 6.86 mmol) in DMF (20 mL). The resulting mixture was stirred at room temperature for 16 h and then quenched with crushed ice. The precipitating solid was filtered off, washed with water and dissolved in dichloromethane. The organic phase was dried over sodium sulfate and evaporated. White solid. Yield: 2.1 g (73% of theory)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[NH:9][C:8]([C:13]2[C:17]([NH:18][C:19](=[O:28])[C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[F:27])=[CH:16][NH:15][N:14]=2)(C(O)=O)[NH:7][CH:6]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN([CH:46]=[O:47])C>ClCCl>[F:27][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([F:26])[C:20]=1[C:19]([NH:18][C:17]1[C:13]([C:8]2[NH:9][C:5]3[CH2:4][CH2:3][CH2:2][NH:1][C:46](=[O:47])[C:6]=3[N:7]=2)=[N:14][NH:15][CH:16]=1)=[O:28]
Reactant: CN(C)C=O
Reactant: NCCCC1=CNC(C(=O)O)(c2n[nH]cc2NC(=O)c2c(F)cccc2F)N1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C1NCCCc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 13 %

Procedure:
To a stirred solution of 5-(3-amino-propyl)-2-[4-(2,6-difluoro-benzoylamino)-1H-pyrazol-3-yl]-1H-imidazole carboxylic acid (200 mg, 0.51 mmoles) in DMF (10 ml) and dichloromethane (10 ml) was added EDC (118 mg, 0.62 mmoles), HOBt (84 mg, 0.62 mmoles) and NEM (260 μl, 2.04 mmoles). The solution was stirred at ambient temperature for 48 hours and then partitioned between EtOAc and water. The organic portion was dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by flash column chromatography [silica, 3% MeOH in DCM to 5% to 10%] to give 2,6-difluoro-N-[3-(4-oxo-1,4,5,6,7,8-hexahydro-1,3,5-triaza-azulen-2-yl)-1H-pyrazol-4-yl]-benzamide as a pale yellow solid (10 mg, 13%). (LC/MS: Rt 1.93, [M+H]+ 372.99).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[O:19][C:20]2[C:25]([C:26](=[O:28])[CH:27]=1)=[C:24]([O:29][CH3:30])[CH:23]=[C:22]([O:31][CH3:32])[C:21]=2[C@@H:33]1[CH2:37][CH2:36][N:35]([CH3:38])[C@H:34]1[CH2:39][OH:40].C([O-])(O)=O.[Na+]>C(Cl)Cl.C(N(CC)CC)C>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[O:19][C:20]2[C:25]([C:26](=[O:28])[CH:27]=1)=[C:24]([O:29][CH3:30])[CH:23]=[C:22]([O:31][CH3:32])[C:21]=2[C@@H:33]1[CH2:37][CH2:36][N:35]([CH3:38])[C@H:34]1[CH:39]=[O:40]
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccccc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(OC)c2c(=O)cc(-c3ccccc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dimethyl sulfoxide (1.8 mL, 25.3 mmol) in methylene chloride (20 mL) was added to a stirred solution of oxalyl chloride (840 μL, 9.84 mmol) in dry methylene chloride (120 mL) dropwise at −50° C. The reaction mixture was stirred for 30 min. Compound of example 7, (2.0 g, 4.65 mmol) in methylene chloride (20 mL) was added dropwise to the reaction mixture. The resulting mixture was further stirred for 30 min. Triethylamine was added dropwise at −50° C. and the reaction mixture was warmed to room temperature and basified with NaHCO3 solution (10 mL). Reaction mixture was extracted with methylene chloride, organic layer was washed with water, brine and dried (anhydrous Na2SO4) to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14](O)[CH3:15]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:14][CH3:15])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CCO
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Yield: 93 %

Procedure:
To a suspension of 4-fluoro-3-nitrobenzoic acid (150 g, 0.810 mol) in ethanol (1000 ml), concentrated sulfuric acid (25 ml) was added dropwise, and the mixture was heated under reflux for 8 hours. After being allowed to cool, the mixture was concentrated under a reduced pressure, and water was added thereto under stirring. The precipitate was separated by filtration, washed with water and then subjected to through circulation drying to give the title compound (160 g, 93%) as a yellow solid.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Cl)[CH:3]=1.[H-].[Na+].[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][C@@H:21]([OH:24])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].O>CN(C=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][C@@H:21]([O:24][CH2:8][C:4]2[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=2)[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: ClCc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](OCc2cccnc2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54.7 %

Procedure:
A suspension of 3-picolylchloride hydrochloride (1.84 g, 11.2 mmol) in DMF (50 ml) was added to a stirred slurry of sodium hydride (60% dispersion in oil, 0.45 g, 11.2 mmol) in DMF at 0° C. under nitrogen. The mixture was stirred at 0° C. for 0.25 h and then added to a mixture of (3R)-N-tert-butyloxycarbonylpyrrolidin-3-ol (2.0 g, 10.7 mmol) and sodium hydride (60% dispersion in oil, 0.45 g, 11.2 mmol) in DMF at 0° C. under nitrogen (mixture stirred for 0.2 h at 0° C. prior to the addition). The reaction mixture was stirred at room temperature for 2.5 h. Water (200 ml) was added and the mixture extracted with ethyl acetate (1×200 ml), dried (Na2SO4) and evaporated in vacuo. The crude product was chromatographed on silica gel, eluting with Et2 O/MeOH (95:5), to give the desired product (1.63 g, 55%), δ (250 MHz, d4 -MeOH), 1.46 (9H, s, OC(Me)3), 1.95-2.18 (2H, m, CH2), 3.34-3.51 (4H, m, 2 of CH2), 4.22 (1H, m, CHOCH2Ar), 4.59 (2H, s, OCH2Ar), 7.43 (1H, dd, J=4.7 and 7.8 Hz, Ar--H), 7.48 (1H, d, J=7.9 Hz, Ar--H), 8.45-8.51 (2H, m, 2 of Ar--H).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-])=O)=[CH:9][CH:10]=2)[N:5]([C:15](=[O:17])[CH3:16])[CH2:4][CH2:3]1>CO.[Pd]>[NH2:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([CH3:18])([CH3:1])[CH2:3][CH2:4][N:5]2[C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=1
Reactant: CC(=O)N1CCC(C)(C)c2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Product: CC(=O)N1CCC(C)(C)c2ccc(N)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The mixture of 1-(4,4-dimethyl-7-nitro-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.97 g) and Pd/C (10 wt %, 0.20 g) in 10 ml of MeOH was placed under H2 and stirred at RT for 2 h then filtered through a pad of Celite. Removal of the solvents gave 1-(7-amino-4,4-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone as an off-white viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=O.[NH2:12]C(N)=O>ClCCl.CO>[Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]#[N:12]
Reactant: NC(N)=O
Reactant: O=C(O)c1ccc(Cl)cc1Br
Solvent: CO
Solvent: ClCCl
Product: N#Cc1ccc(Cl)cc1Br

Procedure:
588 mg (2.5 mmol) of 2-bromo-4-chlorobenzoic acid and 300 mg of urea are dissolved in dichloromethane/methanol and concentrated onto 364 mg of alumina (neutral) on a rotary evaporator. The residue is microwaved at 150° C. for a total of 60 min. After cooling, the residue is stirred with ethyl acetate and water, filtered, and the aqueous phase is separated. The organic phase is washed with a sodium hydrogen carbonate solution, dried over sodium sulfate, concentrated on a rotary evaporator and then dried under high vacuum. The product (383 mg, 80% pure, 57% of theory.) is reacted further without additional purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[CH:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)([CH3:29])[CH3:28].C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=2)[CH:12]=[C:13]([O:15][C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([CH:27]([CH3:29])[CH3:28])[CH:35]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)c1cccc(B(O)O)c1
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(CC(C)C)c1cc(Oc2cccc(C(C)C)c2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.2 %

Procedure:
A mixture of 2-(5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (50 mg, 0.14 mmol), 3-isopropylphenyl boronic acid (45 mg, 0.27 mmol), copper acetate (26 mg, 0.14 mmol), triethylamine (57 μL, 0.4 mmol) and powdered 4 Å molecular sieves in DCM (1 mL) were stirred at room temperature for 2 days. The reaction mixture was concentrated in vacuo. Purification by flash chromatography (EtOAc:petroleum ether) give the title compound (32 mg, 48%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:13])[CH:3]=1.[C:14](OCC)(=[O:20])[C:15](OCC)=[O:16]>>[CH3:13][C:4]1[CH:3]=[C:2]2[C:11]([NH:12][C:14](=[O:20])[C:15](=[O:16])[NH:1]2)=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: CCOC(=O)C(=O)OCC
Reactant: COC(=O)c1cc(N)c(N)cc1C
Product: COC(=O)c1cc2[nH]c(=O)c(=O)[nH]c2cc1C
Temperature: 145 °C
Reaction time: 3 h

Procedure:
A mixture of 3.98 g of methyl 4,5-diamino-2-methylbenzoate and 40 mL of diethyl oxalate was stirred at 145° C. for 3 hours. After cooling to room temperature, the solid was collected by filtration, washed with diethyl ether, and dried under reduced pressure to obtain 4.75 g of methyl 7-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:10]([CH2:12][C:13]1[S:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]2)[CH:14]=1)[CH3:11])[CH3:9].[CH3:41][NH:42][CH2:43][CH3:44]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:39]([S:36]([N:33]1[CH2:34][CH2:35][CH:30]([C:21]2[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=[C:18]([C:15]4[CH:14]=[C:13]([CH2:12][N:10]([CH3:11])[CH2:8][CH2:9][C:43]5[CH:44]=[CH:3][CH:2]=[CH:41][N:42]=5)[S:17][CH:16]=4)[CH:19]=3)[NH:23][CH:22]=2)[CH2:31][CH2:32]1)(=[O:37])=[O:38])[CH3:40]
Reactant: CCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Reactant: CCNC
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)CCc5ccccn5)c4)cc23)CC1
Yield: 7.36 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting methyl[2-(2-pyridinyl)ethyl]amine (75 mg, 1.0 mmol) for N-methylethanamine to afford 5.0 mg of the title compound (7.36%).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17](=[CH2:37])[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1)=[O:19].[CH3:38][O:39][C:40]1[CH:45]=[CH:44][C:43](O)=[CH:42][CH:41]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:37][C:17](=[CH2:16])[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([C:32]([O:34][C:43]2[CH:44]=[CH:45][C:40]([O:39][CH3:38])=[CH:41][CH:42]=2)=[O:33])=[CH:35][CH:36]=1)=[O:19]
Reactant: C=C(C)C(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Reactant: COc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=C(C)C(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.4 %

Procedure:
6.8 g (33 mmol) of N,N′-dicyclohexylcarbodiimide were added at 0° C. while stirring to a solution of 7.8 g (25.4 mmol) of 4-[6-(2-methyl-acryloyloxy)-hexyloxy]-benzoic acid, 2.9 g (23.4 mmol) of 4-methoxy-phenol and 0.5 g of 4-(dimethyl-amino)-pyridine in 200 ml of dichloromethane. The reaction mixture was stirred at room temperature for a further 16 hours, then filtered and the filtrate was extracted twice with saturated K2CO3 solution. The combined organic phases were washed twice with saturated sodium chloride solution, dried over magnesium sulphate, filtered and subsequently concentrated. Chromatographic purification of the residue on silica gel with methylene chloride: acetone=19:1 and two-fold recrystallization of the fractions which were pure according to thin-layer chromatography from methyl alcohol gave 7.76 g of 4-methoxy-phenyl 4-[6-(2-methyl-acryloyloxy)-hexyloxy]-benzoate as a white solid. The substance is monotropic nematic, m.p. (C-l) 550C, (cl.p. (N-l) 35.7° C.). Mass spectrometric analysis yields the mol peak at m/e=412.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:26])=[CH:4][N:3]=1.[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Cl:26][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:33]([C:32]3[CH:35]=[CH:36][C:29]([O:28][CH3:27])=[CH:30][CH:31]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Nc1ncc(Cl)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(CC(=O)Nc5nccs5)CC4)c(Cl)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 2-[4-(2-amino-5-chloro-3-nitro-pyridin-4-yl)-piperazin-1-yl]-N-thiazol-2-yl-acetamide (0.040 g, 0.10 mmol), ethanol (3 ml), and p-methoxybenzaldehyde (0.019 g, 0.14 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.4 ml, 0.4 mmol). The reaction mixture was heated at 70° C. for 5 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 50% dichloromethane in ethyl acetate and then 2.5% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.012 g, 25%); 1H-NMR (500 MHz, DMSO-d6) 2.76 (br s, 4H, piperazine N(CH2)2), 3.40 (s, 2H, NCH2CO), 3.72 (br s, 4H, piperazine N(CH2)2), 3.83 (s, 3H, OCH3), 7.10 (d, J=8.79 Hz, 2H, 3,5-ArH or 2,6-ArH), 7.24 (d, J=3.51 Hz, 1H) and 7.50 (d, J=3.55 Hz, 1H) (thiazole 4-H, 5-H), 8.09 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.13 (d, 2H, J=8.76 Hz, 3,5-ArH or 2,6-ArH); 11.95 (s, 1H, CONH), 13.72 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[C:9]3[C:14]([C:15]=2[C:16](=[NH:18])[O-])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:26])[O:4][N:3]=1.[NH2:27][NH2:28]>CCO.CCOC(C)=O>[CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:19]3[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=3)[C:9]3[C:14]([C:15]=2[C:16](=[N:27][NH2:28])[NH2:18])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: NN
Reactant: Cc1noc(C)c1-c1c(C(=N)[O-])c2ccccc2n1-c1ccc(O)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1noc(C)c1-c1c(C(N)=NN)c2ccccc2n1-c1ccc(O)cc1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
2-(3,5-Dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indole-3-carbimidate (Example 184) was dissolved in EtOH and 10 eq hydrazine was added. The resulting mixture was stirred at 90° C. for 10 hours. The reaction mixture was diluted with EtOAc and washed with brine. The organic phase was evaporated to dryness in vacuo and then purified using reversed phase preparative HPLC. Fractions were combined, concentrated and the final product was identified by 1H-NMR and LC/MS. Purity was determined by analytical HPLC. ES/MS m/z: 362.21 (M+H), 360.28 (M−H); 1H NMR (methanol-d3, 500 MHz): 7.81 (m, 1H), 7.36-7.32 (m, 3H), 7.08 (m, 2H), 6.90 (m, 2H), 2.16 (s, 3H) and 1.96 (s, 3H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[N:12]=[C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH:25]=[N:24][N:23]=[N:22]4)=[N:19][CH:20]=3)[CH:10]=[N:9]2)[CH2:4][CH2:3]1.Cl[C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28]>>[N:21]1([C:18]2[N:19]=[CH:20][C:15]([O:14][CH2:13][C:11]3[CH:10]=[N:9][N:8]([CH:5]4[CH2:4][CH2:3][N:2]([C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])[CH2:7][CH2:6]4)[N:12]=3)=[CH:16][CH:17]=2)[CH:25]=[N:24][N:23]=[N:22]1
Reactant: c1cc(-n2cnnn2)ncc1OCc1cnn(C2CCNCC2)n1
Reactant: C=CCOC(=O)Cl
Agent: Cl
Product: C=CCOC(=O)N1CCC(n2ncc(COc3ccc(-n4cnnn4)nc3)n2)CC1

Procedure:
The title compound was synthesized from Intermediate 15 and allyl chloroformate in a manner similar to that described in Journal of Medicinal Chemistry 1998, 41, 4983-4994. 1H NMR (CDCl3): δ 9.46 (1H, s), 8.28 (1H, m), 8.04 (1H, m), 7.73 (1H, s), 7.61 (1H, m), 5.95 (1H, m), 5.40-5.20 (4H, m), 4.64 (3H, m), 4.24 (2H, m), 3.10 (2H, m), 2.16 (4H, m).