Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][CH:26]=1)[O:7][C:8]1[C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)([OH:3])=[O:2].CO.[C:29](OCC)(=O)C>C(Cl)Cl>[CH3:29][O:2][C:1]([C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][CH:26]=1)[O:7][C:8]1[C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:3]
Reactant: CCOC(C)=O
Reactant: O=C(O)c1cccc(Oc2ncccc2OCCCc2ccncc2)c1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cccc(Oc2ncccc2OCCCc2ccncc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(3-Carboxyphenoxy)-3-[3-(pyridin-4-yl)propoxy]pyridine (0.20 g, 0.57 mmol) obtained in Example 52 is dissolved in methylene chloride (10 ml), and thereto are added 1-ethyl-3-(3′-dimethyl aminopropyl)carbodiimide.hydrochloride (0.13 g, 0.68 mmol) and methanol (0.10 ml), and the mixture is stirred at room temperature for 2 hours. To the reaction solution is added ethyl acetate (100 ml), and the mixture is washed with a saturated brine (30 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: chloroform/methanol) to give the title compound (0.17 g) as colorless oil.
Reaction SMILES: [H-].[Na+].[N:3]1[C:11]([NH2:12])=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[N:5][CH:4]=1.CS(O[CH2:18][C:19]1[S:23][C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[C:20]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])(=O)=O>CN(C=O)C>[C:29]1([CH3:34])[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[S:23][C:19]=1[CH2:18][N:7]1[CH:8]=[N:9][C:10]2[C:6]1=[N:5][CH:4]=[N:3][C:11]=2[NH2:12]
Reactant: Nc1ncnc2[nH]cnc12
Reactant: Cc1ccccc1-c1c(COS(C)(=O)=O)sc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1c(Cn2cnc3c(N)ncnc32)sc2ccccc12
Reaction time: 0.08 h
Yield: 67.3 %

Procedure:
NaH (60% in mineral oil, 16 mg, 0.39 mmol) was added in one portion to a mixture of 9H-purin-6-ylamine (49 mg, 0.36 mmol) in DMF (5 mL) at RT. After 5 min stirring, a solution of methanesulfonic acid 3-o-tolylbenzo[b]thiophen-2-ylmethyl ester from Example 27 (100 mg, 0.30 mmol) in DMF (1 mL) was added dropwise and stirring at RT was continued for 19 h. The reaction mixture was then quenched by addition of water and a solid formed. The precipitated was collected by filtration and was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc) affording 167 as a white solid (75 mg, 67%). LCMS: RT 4.13 min [M+H]+ 372.1. 1H NMR (DMSO, 400 MHz): δ 8.11 (1H, s), 7.96-7.88 (2H, m), 7.45-7.30 (6H, m), 7.23 (2H, s), 7.12-7.07 (1H, m), 5.46 (1H, d, J=16.2 Hz), 5.38 (1H, d, J=16.2 Hz), 1.99 (3H, s)
Reaction SMILES: [NH2:1]OS(O)(=O)=O.[OH:7][CH:8]([CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[OH-].[Na+]>O1CCCC1.O>[NH2:1][N:13]1[CH2:14][CH2:15][N:10]([CH2:9][CH:8]([OH:7])[CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:11][CH2:12]1
Reactant: NOS(=O)(=O)O
Reactant: CCCCCCCCCCCCCCCCCCOCC(O)CN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOCC(O)CN1CCN(N)CC1

Procedure:
A solution of hydroxylamine-O-sulfonic acid (0.17 g, 1.5 mmol) in 1:1 tetrahydrofuran-water (10 mL) is added dropwise to a mixture of 1-[2'-hydroxy-3'-octadecyloxypropyl]-piperazine (3.0 g, 7.3 mmol) and sodium hydroxide (0.29 g) in 1:1 tetrahydrofuran-water (30 mL) at 15° C. over a 30 minute period under a nitrogen atmosphere. The resultant mixture is stirred at 15° C. for 2 hours. Three additional portions of NaOH (0.29 g each) are then added to the mixture. The reaction mixture is extracted with dichloromethane, dried over NaOH, concentrated and chromatographed to afford 1-N-Amino-4-N-[2'-hydroxy-3'-octadecyloxypropyl]-piperazine.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:12][CH2:13][C:14]1([CH2:17]O)[CH2:16][CH2:15]1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH:10]1[O:12][CH2:13][C:14]2([CH2:16][CH2:15]2)[CH2:17][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCOCc1ccccc1
Reactant: OCC1(CO)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(COCC2OCC3(CC3)CO2)cc1
Temperature: 25 °C
Yield: 78.2 %

Procedure:
A mixture of benzyloxyacetaldehyde (5 g, 33.3 mmol), 1,1-bis(hydroxymethyl)cyclopropane (4.08 g, 40 mmol), p-toluenesulfonic acid monohydrate (287 mg, 1.51 mmol) and toluene (70 ml) was refluxed for 2 hours while removing water by the Dean-Stark apparatus. After the reaction mixture was cooled to room temperature, triethylamine (4 ml) was added to the reaction mixture and the solvent was distilled off. The residue was purified by silica gel column chromatography (silica gel: 200 g, elution solvent: ethyl acetate/heptane=5/95 to 1/9) to obtain the title compound (6.1 g, yield: 78.2%) as a light yellow oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=[O:4])=[O:3].[CH2:19](Br)[CH2:20][CH2:21][CH3:22]>>[CH2:19]([N:16]1[CH2:15][CH2:14][N:13]([C:7]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)[CH2:18][CH2:17]1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCBr
Reactant: COc1ccc(N2CCNCC2)cc1S(C)(=O)=O
Product: CCCCN1CCN(c2ccc(OC)c(S(C)(=O)=O)c2)CC1

Procedure:
Beginning with 1-(3-Methanesulfonyl-4-methoxy-phenyl)-piperazine and n-Bu-Br, the title compound was recovered by the procedure described in Example 2; MS m/z (rel. intensity, 70 eV)) 326 (M+, 32), 284 (16), 283 (bp), 70 (58), 56 (23).
Reaction SMILES: [CH2:1]([N:3]1[C:16]2[CH:15]=[CH:14][C:13]([CH:17]=O)=[CH:12][C:11]=2[S:10][C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[C:19]1([NH:25][NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO>[C:19]1([NH:25][N:26]=[CH:17][C:13]2[CH:14]=[CH:15][C:16]3[N:3]([CH2:1][CH3:2])[C:4]4[C:9]([S:10][C:11]=3[CH:12]=2)=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCN1c2ccccc2Sc2cc(C=O)ccc21
Reactant: NNc1ccccc1
Solvent: CO
Product: CCN1c2ccccc2Sc2cc(C=NNc3ccccc3)ccc21

Procedure:
10-Ethylphenothiazine-3-carbaldehyde (3 g, 0.012 mol) was dissolved in 30 ml of methanol under mild heating. A solution of 1.9 g (0.018 mol) of N-phenylhydrazine in methanol was added to the cooled reaction mixture. Next, the reaction mixture was refluxed for 0.5 hour. The precipitated product was filtered, washed with a large amount of methanol, and then dried. The yield of yellowish crystals of 10-ethylphenothiazine-3-carbaldehyde N-phenylhydrazone (C21H19N3S, FW=345.00) was 3 g (75%).
Reaction SMILES: C([O:14][C:15]1[C:24]2[N:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]([C:25](O)=[O:26])=[C:17]2[CH2:28][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[C:30](=[O:31])[C:16]=12)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2:40][C:41]1[S:42][CH:43]=[N:44][N:45]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[S:42]1[CH:43]=[N:44][N:45]=[C:41]1[NH:40][C:25]([C:18]1[C:19]2[CH:20]=[CH:21][CH:22]=[N:23][C:24]=2[C:15]([OH:14])=[C:16]2[C:30](=[O:31])[N:29]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH2:28][C:17]=12)=[O:26]
Reactant: O=C(O)c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Reactant: Nc1nncs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nncs1)c1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Temperature: 25 °C
Reaction time: 15 h
Yield: 38.9 %

Procedure:
9-Benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid 213 (0.02 g, 0.0386 mmol) was dissolved in 0.3 mL of dimethylformamide. To this was added 2-amino-1,3,4-thiadiazole (0.0078 mL, 0.0772 mmol), diisopropylethylamine (0.027 mL, 0.1544 mmol), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.03 g, 0.0772 mmol) and stirred at room temperature. After 15 hours, starting material was consumed. Purified by reverse phase HPLC (0.1% TFA, H2O/ACN) to give 7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid [1,3,4]thiadiazol-2-ylamide 320 (0.0066 g, 0.015 mmol, 40%.) 1H NMR (CDCl3) δ 9.02 (dd, 1H), 8.81 (s, 1H), 8.65 (d, 1H), 7.65 (dd, 1H), 7.38 (dd, 2H), 7.05 (dd, 2H), 4.74 (s, 2H), 4.64 (s, 2H.) MS: 436 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])=[CH:4][C:3]=1[CH:21]=[O:22].[CH2:23](O)[CH2:24][CH2:25][OH:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[N:10]([CH3:19])[C:9]2=[O:20])=[CH:4][C:3]=1[CH:21]1[O:26][CH2:25][CH2:24][CH2:23][O:22]1
Reactant: OCCCO
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C=O)c2)c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C3OCCCO3)c2)c1=O

Procedure:
A solution of 3.5 g of 3-[4-chloro-3-formylphenyl]-2,4-dioxo-1-methyl-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine, 0.8 g of 1,3-propanediol and 0.2 g of p-toluenesulfonic acid in 100 ml of anhydrous dichloromethane was boiled for 5 hours under a water separator. The solution was washed with 10% strength sodium bicarbonate solution and water, dried over sodium sulfate and evaporated down. The residue was chromatographed over silica gel (7:3 cyclohexane/ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[C:9]3=[CH:19][CH:20]=[CH:21][N:8]3[CH2:7][C:6]=2[CH:22]=1.[Br:23]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Br:23][C:21]1[N:8]2[C:9]([CH:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[O:11][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:22][C:6]=3[CH2:7]2)=[CH:19][CH:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1CCC(C2Oc3ccc(Cl)cc3Cn3cccc32)CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCC(C2Oc3ccc(Cl)cc3Cn3c(Br)ccc32)CC1

Procedure:
A solution of 7-chloro-11-[(1-methyl)piperidin-4-yl]-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (5.5 g; 0.017 mole) and N-bromosuccinimide (3.7 g; 0.021 mole) in 150 ml of tetrahydrofuran was stirred for 20 hours at ambient temperature. The reaction mixture was then diluted with ethyl acetate and washed twice with a dilute Na2SO3 solution and once with water and dried (saturated NaCl solution, anhydrous MgSO4).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([CH2:13][OH:14])[CH2:10][CH:9]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:41][C:42]1[CH:43]=[C:44](O)[CH:45]=[CH:46][CH:47]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][O:14][C:46]2[CH:45]=[CH:44][CH:43]=[C:42]([Cl:41])[CH:47]=2)[CH2:10][C@H:9]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)C1CC(CO)CN1C(=O)OC(C)(C)C
Reactant: Oc1cccc(Cl)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1C[C@H](COc2cccc(Cl)c2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.4 %

Procedure:
To a solution of 4-hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid di-tert-butyl ester (Preparation 45, 132 mg, 0.44 mmol), triphenylphosphine (172 mg, 0.66 mmol) and 3-chlorophenol (0.069 ml, 0.66 mmol) in tetrahydrofuran (5 ml) at 0° C. under a nitrogen atmosphere was added diisopropylazodicarboxylate (0.129 ml; 0.66 mmol) dropwise and allowed to stir to room temperature over 18 hours. The solvent was removed under reduced pressure and the residue purified by chromatography on silica gel, eluting with 10% ethyl acetate/heptane to give the title compound as a colourless gum (66 mg, 37%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5](O)=O.[NH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[NH2:21]>P(Cl)(Cl)(Cl)=O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]1[NH:21][C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[N:14]=1
Reactant: Nc1ccncc1N
Reactant: COc1ccc(C(=O)O)c(OC)c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2nc3cnccc3[nH]2)c(OC)c1

Procedure:
A mixture of 2,4 dimethoxybenzoic acid (2.5 g) and 3,4-diaminopyridine (1.5 g) was ground to a fine powder and added portionwise to phosphorus oxychloride (50 ml) with stirring. The mixture was stirred and heated under reflux for 2.5 hours before excess phosphorus oxychloride was removed in vacuo. The residue was cooled, water (20 ml) added and the pH adjusted to 7 with ammonium hydroxide to yield a pale yellow solid which was collected, washed with water and dried. The solid was recrystallised twice from aqueous ethanol to yield a cream coloured crystalline solid m.p. 195°-198°.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Cl:4][C:5]1[C:6]([C:15]([N:17]([CH:26]([C:30]2[CH:39]=[CH:38][C:33]3[O:34][CH2:35][CH2:36][O:37][C:32]=3[CH:31]=2)[C:27]([NH2:29])=[O:28])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:16])=[N:7][C:8](S(C)(=O)=O)=[N:9][CH:10]=1>C1COCC1>[Cl:4][C:5]1[C:6]([C:15]([N:17]([CH:26]([C:30]2[CH:39]=[CH:38][C:33]3[O:34][CH2:35][CH2:36][O:37][C:32]=3[CH:31]=2)[C:27]([NH2:29])=[O:28])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:16])=[N:7][C:8]([NH:3][CH2:1][CH3:2])=[N:9][CH:10]=1
Reactant: CCN
Reactant: Cc1ccc(CN(C(=O)c2nc(S(C)(=O)=O)ncc2Cl)C(C(N)=O)c2ccc3c(c2)OCCO3)cc1
Solvent: C1CCOC1
Product: CCNc1ncc(Cl)c(C(=O)N(Cc2ccc(C)cc2)C(C(N)=O)c2ccc3c(c2)OCCO3)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
Ethylamine was passed through an ice-cold solution of the sulfone from example 243 (0.15 g, 0.28 mmol) in THF (3 ml) for 20 minutes. After 2 hours at room temperature, the solvent was evaporated. The residue was dissolved in ethyl acetate (10 ml) and the solution was washed with water (10 m[), saturated NaHCO3 solution (2×10 ml), brine (10 ml), dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel (10 g) eluting with a gradient of pentane-ethyl acetate from 90110 to 30/70 in 10% increments of ethyl acetate to give the title compound as a foam 107 mg, (76%).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:12]3[N:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[N:9]=[C:8]2[NH:18][CH3:19])=[CH:4][CH:3]=1.[CH3:22]C(C)([O-])C.[K+].CI>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:12]3[N:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[N:9]=[C:8]2[N:18]([CH3:22])[CH3:19])=[CH:20][CH:21]=1
Reactant: CNc1nc(=O)c2cccnc2n1Cc1ccc(F)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(C)c1nc(=O)c2cccnc2n1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 10.0 g. of powdered 1-(4'-fluorobenzyl)-2-methylamino-pyrido[2,3-d]pyrimidin-4(1H)-one in 300 ml. of tetrahydrofuran is added portionwise over the course of 5 minutes 4.8 g. of potassium t-butoxide and the resulting mixture is stirred at room temperature for 45 minutes. There is then added 6.5 g. of methyl iodide followed by stirring at room temperature for two days. The resulting mixture is filtered through celite and the filtrate evaporated to dryness. The residue is dissolved in 100 ml. of methylene chloride, washed twice with water, dried, filtered and evaporated to dryness. The residue is dissolved in a small amount of chloroform and filtered through a 650 ml. filter column using silica and chloroform. The combined product containing fractions are evaporated to dryness, the residue dissolved in 50 ml. of methylene chloride and ether added while warming on a steam bath to obtain 1-(4'-fluorobenzyl)-2-dimethylamino-pyrido[2,3-d]pyrimidin-4(1H)-one, m.p. 167°-170°C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5](O)=[CH:6][CH:7]=1.ClC1C=CC=CC=1.C([O-])(=O)C.[K+].[N+:22]([O-])(OCCC(C)C)=O>C(OC(=O)C)(=O)C>[NH:1]1[C:2]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=[N:22]1
Reactant: CC(C)CCO[N+](=O)[O-]
Reactant: Cc1cc(O)ccc1N
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: Clc1ccccc1
Product: c1ccc2[nH]ncc2c1

Procedure:
4-Amino-m-cresol is suspended in acetic anhydride and chlorobenzene in the presence of potassium acetate, isoamyl nitrate is added to the suspension at 70° C. to 100° C., preferably about 80° C., and the mixture is stirred to form an indazole skeleton. The intermediate thus obtained is dissolved in hydrochloric acid-methanol, and the mixture is preferably stirred at room temperature to deacetylate the compound.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[C:7]([C:10]1[NH:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)(=[O:9])[CH3:8].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[C:7]([C:10]1[N:11]([CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)(=[O:9])[CH3:8]
Reactant: CC(=O)c1nc2ccccc2[nH]1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(=O)c1nc2ccccc2n1C1CCCCO1
Reaction time: 24 h

Procedure:
Dihydropyran (20.5 mL) as added dropwise to a solution of 2-acetylbenzoimidazole (32 g) and p-toluenesulfonic acid (2 g) in dichloromethane (280 mL) at reflux. The reaction mixture was stirred at this temperature for 24 hours, then cooled and the insoluble materials were filtered off. The filtrate was concentrated to give 2-acetyl-1-(tetrahydropyran-2-yl)-benzoimidazole as an amber oil (51.8 g). TLC: dichloromethane:methanol, 97:3) RF=0.80.
Reaction SMILES: [Br-].[NH2:2][CH2:3][CH2:4][CH2:5][N+:6]([CH2:9][CH2:10][NH:11][C:12]([C:14]1[C:19]([NH2:20])=[N:18][C:17]([NH2:21])=[C:16]([Cl:22])[N:15]=1)=[O:13])([CH3:8])[CH3:7].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][CH:25]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.[F:58][P-:59]([F:64])([F:63])([F:62])([F:61])[F:60]>CN(C=O)C>[F:58][P-:59]([F:64])([F:63])([F:62])([F:61])[F:60].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([NH:2][CH2:3][CH2:4][CH2:5][N+:6]([CH2:9][CH2:10][NH:11][C:12]([C:14]2[C:19]([NH2:20])=[N:18][C:17]([NH2:21])=[C:16]([Cl:22])[N:15]=2)=[O:13])([CH3:7])[CH3:8])=[O:32])=[CH:26][CH:25]=1
Reactant: C[N+](C)(CCCN)CCNC(=O)c1nc(Cl)c(N)nc1N
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Br-]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[N+](C)(CCCNC(=O)Cc1ccc(Cl)cc1)CCNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (3-amino-propyl)-{2-[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-ethyl}-dimethyl-ammonium bromide (Intermediate M) (0.25 g, 0.63 mmol), (4-chloro-phenyl)-acetic acid (0.11 g, 0.64 mmol), N-methylmorpholine (0.25 mL, 2.27 mmol) and HATU (0.24 g, 0.63 mmol) in anhydrous DMF (8 mL) is stirred under a nitrogen atmosphere at RT for 16 h. The reaction mixture is concentrated in vacuo and is purified by column chromatography (basic alumina, 0-4% MeOH in DCM) to afford the title compound. M+ 468. 1H NMR (400 MHz, DMSO-d6) δ 8.22 (1H, t), 8.14 (1H, t), 7.45 (2H, br), 7.32 (2H, d), 7.24 (2H, d), 7.08 (2H, br), 3.57-3.51 (2H, m), 3.43 (2H, s), 3.42-3.25 (4H, m), 3.12-3.03 (2H, m), 3.02 (6H, s), 1.86-1.78 (2H, m).
Reaction SMILES: [CH3:1][C:2]1[C:6]([OH:7])=[C:5]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[S:4][C:3]=1[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15].C(N(CC)CC)C.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCOCC1>[CH3:1][C:2]1[C:6]([O:7][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:5]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[S:4][C:3]=1[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15]
Reactant: Cc1c(C(=O)OC(C)C)sc(C(=O)OC(C)C)c1O
Reactant: O=C(Cl)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)OC(C)C)sc(C(=O)OC(C)C)c1OC(=O)c1ccccc1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
A mixture of di-isopropyl 3-methyl-4-hydroxy-2,5-thiophene-dicarboxylate (656 g, 2.30 mol), triethylamine (297 g, 2.98 mol) and dioxane (2 l) was cooled with ice to about 10° C. The solution was added, while stirring, with benzoyl chloride (351 g, 2.5 mol) over about 10 minutes, followed by further stirring for 30 minutes at room temperature. After removing the precipitate of triethylamine hydrochloride salt by filtration, the solution was distilled in vacuo to remove dioxane. Toluene was then added to the remaining residue, and the solution was washed with 5% aqueous sodium bicarbonate and water, and then dried over MgSO4. The solvent was removed by distillation to give almost pure di-isopropyl 3-methyl-4-benzoyloxy-2,5-thiophene dicarboxylate (851 g, 95%). nD10 1.5499.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH:10](O)[CH2:9][N:8]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:7]=1)=[O:5])[CH3:2].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:45]([SH:47])[CH3:46].O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH:10]([S:47][CH2:45][CH3:46])[CH2:9][N:8]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(O)c2c1[nH]c1ccccc21
Reactant: CCS
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(SCC)c2c1[nH]c1ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 1.5 %

Procedure:
To a solution of 3-(4-fluorobenzoyl)-1-hydroxy-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester (60 mg, 0.3 mmol) in DCM (2 mL) was added trifluoromethanesulfonic anhydride (50 mL, 0.6 mmol) at 0° C. and the mixture was stirred for 1 hour at 0° C. Ethanethiol (34 mL, 0.9 mmol) was added and the reaction mixture was stirred overnight at 20° C. Water was added and organic layer was separated. The aqueous layer was extracted with DCM. The combined organic layer was then washed with water and dried over MgSO4. Evaporation of solvent gave a crude product, which was purified by column chromatography on silica gel, eluted with MeOH-DCM (1:19) to give the title compound (2 mg); 1NMR (CDCl3): δ 8.59 (1H, s), 8.77 (1H, d), 7.54 (2H, m), 7.36 (1H), 7.19 (1H, m), 7.06 (2H, m), 6.73 (1H, s), 4.41 (2H, m), 4.21-4.30 (3H, m), 2.59-2.69 (2H, m), 1.28 (3H, t), 1.19 (3H, t). MS (ES): 439 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:19]=[C:18]([F:20])[C:7]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=2)=[C:6]([F:21])[CH:5]=1.[BH4-].[Na+]>CO>[F:21][C:6]1[CH:5]=[C:4]([CH2:3][CH2:2][NH:1][CH2:2][CH2:3][CH:4]([CH3:19])[CH3:5])[CH:19]=[C:18]([F:20])[C:7]=1[O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=1
Reactant: NCCc1cc(F)c(Oc2ccc(C(N)=O)cn2)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCNCCc1cc(F)c(Oc2ccc(C(N)=O)cn2)c(F)c1

Procedure:
Combine 3-methyl-butylaldehyde (26 μl, 0.24 mmol), amine from step 6 above and 3 A molecular sieves (900 mg) in methanol (3 mL), stir the mixture at room temperature overnight. Add NaBH4 (45 mg, 1.20 mmol) and stir at room temperature for 3 hours. Filtrate the mixture over celite and eliminate the solvent. Submit the crude to a SCX column to obtain a solid witch was further purified by HPLC (Column: X-Terra MS C18. A=10 Mm NH4HCO3 pH8/B=CH3CN. Gradient mode: from 30 to 70% B. Flow rate: 1 mL/min) to obtain the title compound (42 mg). Electrospray MS M+1 ion=364. 1H-NMR (metanol-d4, 300 MHz): 8.60 (d, 1H, J=2.0 Hz), 8.32 (dd, 1H, J=2.2 and 8.5 Hz), 7.19 (d, 1H, J=8.7 Hz), 7.01-6.98 (m, 2H), 2.85 (m, 4H), 2.63 (m, 2H), 1.62 (m, 1H), 1.42 (q, 1H, J=7.3 Hz), 0.92 (d, 6H, J=6.5 Hz).