Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH3:12])[CH:6]=[C:5]2[CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[O:24][CH3:25].[CH:26]1([CH2:31][C:32](O)=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27]1.Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:26]1([CH2:31][C:32]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH2:11][CH3:12])[CH:6]=[C:5]3[CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=2[O:24][CH3:25])=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(O)CC1CCCC1
Reactant: CCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(N)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(NC(=O)CC3CCCC3)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
A mixture of the ester (H) described above (used without further characterization) (4.43 g), cyclopentylacetic acid (1.85 g), 4-(dimethylamino)pyridine (1.76 g), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.26 g), was dissolved in methylene chloride (100 ml), under an atmosphere of nitrogen, and stirred at room temperature for 18 hours. The mixture was poured into 1M hydrochloric acid (25 ml), the separated aqueous layer extracted with dichloromethane (2×100 ml), the combined organic extracts washed with water, brine, dried (MgSO4) and evaporated. The residual oil was crystallized from ethanol to give off-white needles which were recrystallized from methylene chloride/hexane to give methyl 4-[5-(2-cyclopentylacetamido)-1-ethylindol-3-ylmethyl]-3-methoxybenzoate (I) as a white powder (5.12 g, 87%); mp 144°-146° C.; partial NMR (250 MHz, DMSO-d6): 1.17(m, 2H), 1.32(t, 3H), 1.4-1.8(m, 6H), 2.25(m, 3H), 3.82(s, 3H, OCH3), 3.92(s, 3H, OCH3), 3.97 (s, 2H, ArCH2), 4.09(q, 2H, CH2CH3), 9.61(s, 1H, NH).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Mg]Cl)(C)C.[C:27]([O:31][C:32](=[O:54])[N:33]([C:45]1[CH:50]=[CH:49][C:48]([CH:51]=[O:52])=[C:47]([F:53])[N:46]=1)[CH2:34][C:35]1[CH:36]=[N:37][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:39][CH:40]=1)([CH3:30])([CH3:29])[CH3:28].[Cl-].[NH4+]>O1CCCC1>[C:27]([O:31][C:32](=[O:54])[N:33]([C:45]1[CH:50]=[CH:49][C:48]([CH:51]([C:12]2[C:13]3[C:14](=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=3)[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:11]=2)[OH:52])=[C:47]([F:53])[N:46]=1)[CH2:34][C:35]1[CH:36]=[N:37][C:38]([C:41]([F:43])([F:42])[F:44])=[CH:39][CH:40]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: COc1cnc2c(c1)c(I)cn2S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(F)(F)F)nc1)c1ccc(C=O)c(F)n1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cnc2c(c1)c(C(O)c1ccc(N(Cc3ccc(C(F)(F)F)nc3)C(=O)OC(C)(C)C)nc1F)cn2S(=O)(=O)c1ccccc1
Temperature: -25 °C
Yield: 58.2 %

Procedure:
To 1-benzenesulfonyl-3-iodo-5-methoxy-1H-pyrrolo[2,3-b]pyridine (575, 0.326 g, 0.000788 mol) in tetrahydrofuran (3.00 mL) at −45° C. under nitrogen, isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 0.380 mL) was added slowly. The reaction was allowed to warm to −25° C. in 30 minutes, and then cooled to −45° C. followed by adding (6-fluoro-5-formyl-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (565, 80.0 mg, 0.20 mmol, prepared as described in Example 60, Scheme 176) in tetrahydrofuran (1.0 mL). The reaction was allowed to warm to room temperature over 2 hours. The reaction was poured into aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (576, 0.080 g, 60%). MS (ESI) [M+H+]+=688.1.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]([N+:14]([O-:16])=[O:15])=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.[CH:23](=O)[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1.O>N1CCCCC1>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([CH:23]=[CH:1][C:2]2[N:3]=[C:4]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[N:7]=2)=[CH:25][CH:26]=1
Reactant: Cc1nc(N2CCOCC2)c([N+](=O)[O-])c(N2CCOCC2)n1
Reactant: COc1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: O
Product: COc1ccc(C=Cc2nc(N3CCOCC3)c([N+](=O)[O-])c(N3CCOCC3)n2)cc1
Yield: 34.3 %

Procedure:
The synthesis method shall be explained concretely, and in order, below. A solution of 2-methyl-4,6-dimorpholino-5-nitropyrimidine (1.13 g, 3.65 mmol) and p-anisaldehyde (3.50 ml, 29.3 mmol) in piperidine (5 ml) was agitated under heating for 4 hours at 130 degrees Celsius. Water was added, and extraction was carried out 2 times using ethyl acetate. After washing the organic layer with saturated saline, drying was done with MgSO4, and the solvent was distilled away under reduced pressure. Purification was done by silica gel chromatography (hexane:ethyl acetate=1:1), and 535 mg of 2-[2-(4-methoxyphenyl)vinyl]-4,6-dimorpholino-5-nitropyrimidine (yield 58%) was obtained. The NMR data for the obtained 2-[2-(4-methoxyphenyl)vinyl]-4,6-dimorpholino-5-nitropyrimidine is shown below.
Reaction SMILES: [CH2:1]([C:4]1[C:5](Cl)=[N:6][CH:7]=[N:8][C:9]=1[CH3:10])[CH2:2][CH3:3].O.[NH2:13][NH2:14].[CH3:15]CO>>[CH3:10][C:9]1[N:8]=[CH:7][N:13]2[N:14]=[CH:15][N:6]=[C:5]2[C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: CCO
Reactant: CCCc1c(C)ncnc1Cl
Reactant: NN
Solvent: O
Product: CCCc1c(C)ncn2ncnc12
Temperature: 100 °C

Procedure:
A mixture of 4-chloro-6-methyl-5-propyl-pyrimidine (101) (500 mg, 2.93 mmol) and hydrazine monohydrate (880 mg, 17.6 mmol) in EtOH (15 mL) is heated in a sealed tube at 100° C. overnight. On cooling, the solvent is removed and to the residue is added water (15 mL). The solid is filtered and washed with water (5 mL) and ether (10 mL). The solid is then heated in acetic acid (10 mL) in a sealed tube at 110° C. overnight. The excess acetic acid is removed under vacuum. The residue is neutralized with aqueous sodium bicarbonate and then extracted with ethyl acetate. On drying, the solvent is removed to give the product (168).
Reaction SMILES: [F:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:16][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:3]3[N:4]([CH3:7])[N:5]=[CH:6][C:2]=3[F:1])[CH:9]=2)=[O:26])=[CH:20][CH:19]=1
Reactant: COc1ccc(N)cc1-c1c(F)cnn1C
Reactant: O=C=Nc1ccc(Br)cc1
Product: COc1ccc(NC(=O)Nc2ccc(Br)cc2)cc1-c1c(F)cnn1C
Yield: 60 %

Procedure:
3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 4-bromophenylisocyanate, in a similar manner as described in Example 1.68, providing 27 mg (60% yield) of Compound 85: LCMS m/z (%)=421 (M+H81Br, 100), 419 (M+H79Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.24 (s, 1H), 8.13 (s, 1H), 7.63 (dd, J1=9.0 Hz, J2=2.6 Hz, 1H), 7.51 (d, J=8.8 Hz, 2H), 7.48 (d, J=2.8 Hz, 1H), 7.42 (d, J=8.8 Hz, 2H), 7.38 (d, JH,F=4.4 Hz, 1H), 7.13 (d, J=9.2 Hz, 1H), 3.83 (s, 3H), 3.65 (s, 3H). 19F NMR (376 MHz, acetone-d6) δ: −177.39 (d, JH,F=5.3 Hz, 1F).
Reaction SMILES: ClCCl.[CH3:4][Si:5]([CH3:36])([C:32]([CH3:35])([CH3:34])[CH3:33])[O:6][CH2:7][C@H:8]1[C@H:12]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH2:11][C@@H:10]([OH:20])[C@@H:9]1[CH2:21][CH2:22][C@H:23]([OH:31])[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28].C(N(CC)CC)C.[S:44](Cl)([CH3:47])(=[O:46])=[O:45]>O>[CH3:36][Si:5]([CH3:4])([C:32]([CH3:33])([CH3:35])[CH3:34])[O:6][CH2:7][C@H:8]1[C@H:12]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH2:11][C@@H:10]([O:20][S:44]([CH3:47])(=[O:46])=[O:45])[C@@H:9]1[CH2:21][CH2:22][C@H:23]([O:31][S:44]([CH3:47])(=[O:46])=[O:45])[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)CCC[C@@H](O)CC[C@@H]1[C@@H](CO[Si](C)(C)C(C)(C)C)[C@H](OC2CCCCO2)C[C@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)CCC[C@H](CC[C@@H]1[C@@H](CO[Si](C)(C)C(C)(C)C)[C@H](OC2CCCCO2)C[C@H]1OS(C)(=O)=O)OS(C)(=O)=O
Reaction time: 2 h

Procedure:
An anhydrous dichloromethane (323 mL) solution of the compound 7 (38.0 g) and triethylamine (44 mL) was cooled to around −60° C. in a dry ice-methanol bath, and mesyl chloride (15 mL) was added dropwise over about 20 minutes. The bath was changed to an ice bath, the mixture was stirred for 2 hours, and the reaction mixture was then added to cold water (600 mL), and extracted with a mixed solution of hexane (600 mL) and ethyl acetate (600 mL). The organic layer was washed with 1 M hydrochloric acid (290 mL) and a saturated saline (300 mL×3 times), dried with anhydrous sodium sulfate, and then concentrated to obtain a titled compound (44.7 g) having the following physical property values.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:19]=[C:18]2[C:10]([C:11]3[C:12]([C:20]([OH:22])=[O:21])=[CH:13][CH:14]=[CH:15][C:16]=3[CH2:17]2)=[CH:9][CH:8]=1)([OH:3])=[O:2].[CH:23](OCC)=[O:24].CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[CH:23]([CH:17]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:20]([OH:22])=[O:21])[C:11]=2[C:10]2[C:18]1=[CH:19][C:7]([CH2:6][CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:8][CH:9]=2)=[O:24]
Reactant: CCOC=O
Reactant: O=C(O)CCCc1ccc2c(c1)Cc1cccc(C(=O)O)c1-2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=CC1c2cc(CCCC(=O)O)ccc2-c2c(C(=O)O)cccc21
Temperature: 25 °C
Reaction time: 17 h

Procedure:
In a dry argon-purged flask with a reflux condenser, 7-(3-carboxy-propyl)-4-fluorenecarboxylic acid (4.0 g, 0.0135 mol) was dissolved in anh. DMF (120 mL) at 40° C. Ethyl formate (40 mL, stored over K2CO3 anh.) was added followed by addition of potassium tert-butoxide 95% (12.8 g, 0.108 mol, added in 2 portions). The reaction was stirred at about 40° C.-50° C. for four hours with the addition of anh. DMF (80 mL), anhydrous THF (5 mL) and ethyl formate (25 mL) at various intervals to aid solubility. The reaction was then stirred another 17 hours at room temperature. The ethyl formate was evaporated at reduced pressure. The reaction was quenched with water (150 mL) and acidified to pH 2 with concentrated HCl. The product was twice extracted with ethyl acetate (600 mL then 200 mL). The combined organic layers were washed 3 times with brine, dried over sodium sulfate, filtered and evaporated to dryness. The crude product (4.7 g, ˜100%, purity 80%) contained some unreacted starting material. 1H-NMR (d6-DMSO): δ (ppm) 11.4 (s, 1H, formyl); 8.3-7.0 (m, 7H, Ar); 2.7 (m, 2H, CH2); 2.3 (m, 2H, CH2); 1.9 (m, 2H, CH2).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[ClH:13].Cl.Cl.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1.C(N(CC)CC)C>C(Cl)Cl>[OH2:3].[OH2:3].[ClH:33].[ClH:13].[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:23]2[CH2:22][CH2:21][N:20]([CH2:19][CH2:18][CH2:17][NH:16][C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=3)=[O:12])[CH2:25][CH2:24]2)=[CH:28][CH:29]=1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CC(=O)c1ccc(N=C=O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(NC(=O)NCCCN2CCN(Cc3ccc(Cl)cc3)CC2)cc1
Product: O
Yield: 230.3 %

Procedure:
A solution of 4-acetylphenyl isocyanate (1.61 g; 10 mmole) in methylene chloride (100 ml) was added to a solution of 1-(3-aminopropyl)-4-(4-chlorobenzyl)piperazine trihydrochloride (3.77 g; 10 mmole), methylene chloride (50 ml) and triethylamine (4.3 ml; 31 mmole). The resulting mixture was refluxed 3 hours, washed with aqueous sodium bicarbonate, dried (sodium sulfate), and the product precipitated with ethereal hydrochloric acid. Recrystallization from ethanol provided the title compound (4.13 g; 82% yield) as a white powder, m.p. >197° C. (slow dec.).
Reaction SMILES: C(O)(=O)C.C(O[CH:8](OCC)[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:13][CH:12]=1)C.[ClH:24].[OH:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[OH:35])[CH2:29][CH2:30][NH2:31]>Cl.O>[ClH:24].[S:17]([C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH:8]2[C:32]3[C:28](=[CH:27][C:26]([OH:25])=[C:34]([OH:35])[CH:33]=3)[CH2:29][CH2:30][NH:31]2)=[CH:16][CH:15]=1)(=[O:19])(=[O:20])[NH2:18]
Reactant: CCOC(COc1ccc(S(N)(=O)=O)cc1)OCC
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: NS(=O)(=O)c1ccc(OCC2NCCc3cc(O)c(O)cc32)cc1
Temperature: 110 °C
Yield: 73.5 %

Procedure:
To a mixture of acetic acid (23 ml), water (6.6 ml) and concentrated hydrochloric acid (15 drops) was added (4-sulfamoylphenoxy) acetaldehyde diethyl acetal (2.3 g), and the mixture was heated for 20 minutes at 110°C. To the solution was added 3,4-dihydroxyphenethylamine hydrochloride (1.2 g), and the mixture was heated for 3.5 hours at the same temperature. After the reaction, the reaction mixture was concentrated to dryness under reduced pressure. The residue was crystallized by adding acetone, and the crystals were recrystallized from a mixed solvent of methanol and acetone to give 1-(4-sulfamoylphenoxy)methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.8 g), mp 270°C (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])(=[O:20])=[O:19])=[O:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.N1C(C)=CC=CC=1C.Cl[C:40]([O:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:41]>ClCCl>[CH2:43]([O:42][C:40]([NH:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])(=[O:20])=[O:19])=[O:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)=[O:41])[CH2:44][CH2:45][CH3:46]
Reactant: CCCCOC(=O)Cl
Reactant: Cc1ccccc1S(=O)(=O)NC(=O)c1ccc2c(ccn2Cc2cccc(N)c2)c1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCCCOC(=O)Nc1cccc(Cn2ccc3cc(C(=O)NS(=O)(=O)c4ccccc4C)ccc32)c1
Reaction time: 3 h

Procedure:
The amine (Example 4) (0.17 g) was dissolved in dichloromethane (5 ml) and 2,6-lutidine (50 μl) and stirred as n-butyl chloroformate (55 μl) was added over 2 minutes. The reaction mixture was stirred for 3 hours, diluted with dichloromethane and washed with 0.5N hydrochloric acid, then water. The organic extract was dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo. Purification by flash chromatography on silica, eluting with 0-5% ethyl acetate in dichloromethane, yielded N-{1-[3-(n-butoxycarbonylamino)benzyl] indol-5-ylcarbonyl}-2-methylbenzene sulphonamide as a gum.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:7]=[C:6]([OH:17])[C:3]=1[CH:4]=O.[N+:18](CC)([O-])=O.C(O)(=O)C>O>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:7]=[C:6]([OH:17])[C:3]=1[C:4]#[N:18]
Reactant: O=Cc1c(O)cc(OCc2ccsc2)cc1F
Reactant: CC[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1c(O)cc(OCc2ccsc2)cc1F
Temperature: 25 °C
Yield: 25.3 %

Procedure:
A mixture of 2-fluoro-6-hydroxy-4-(3-thienylmethoxy)benzaldehyde (1 g), nitroethane (0.6 g) sodium acetate (0.66 g) and glacial acetic acid (1 mL) is heated at reflux for 2 hours. The reaction mixture is cooled to ambient temperature, water (50 mL) is added and the mixture is extracted three times with ethyl acetate (50 mL). The combined organic phases are washed with saturated brine (50 mL), dried over magnesium sulphate, filtered and concentrated under reduced pressure to leave a brown oil. The residue is purified by flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (1:2 v/v). Fractions homogeneous in the required product are combined and evaporated to give 2-fluoro-6-hydroxy-4-(3-thienylmethoxy)benzonitrile (250 mg), as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[NH:4][C:3]=1[C:14]([O:16][CH3:17])=[O:15].[OH-].[Na+].S(OC)(O[CH3:24])(=O)=O>O>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:12])(=[O:13])[N:4]([CH3:24])[C:3]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Temperature: 25 °C

Procedure:
To a suspension of 90 grams (0.352 moles) of methyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide in 450 ml proprietory alcohol there is added a solution of 15.5 grams (0.3875 moles) of sodium hydroxide in 450 ml of water at a temperature of less than 20°C. 53.4 Grams (0.423 moles) of dimethyl sulphate is added while stirring, at 25°C. and the mixture is then allowed to stir for about 15 hours. It is cooled to 10°C. and filtered. The cake is washed with water, followed by a 50% alcohol/water wash, and dried. Yield is 90 grams (95%) m.p. 162.5°-164°C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[C:4]([C:10]([OH:12])=[O:11])[CH:3]=1.[CH3:13][C:14](O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]([OH:12])=[O:11])[C:5]2[N:6]([C:13]([CH3:14])=[N:9][N:8]=2)[N:7]=1
Reactant: NNc1nnc(Cl)cc1C(=O)O
Reactant: CC(=O)O
Product: Cc1nnc2c(C(=O)O)cc(Cl)nn12
Temperature: 100 °C
Yield: 73 %

Procedure:
A suspension of 6-chloro-3-hydrazinylpyridazine-4-carboxylic acid (4.8 g; crude product) in AcOH (100 mL) was heated at 100° C. for 3 h. The mixture was cooled to room temperature and concentrated to remove the solvent. Then the residue was washed by petroleum ether (50 mL) and recrystallized from MeOH to give the pure 6-chloro-3-methyl-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylic acid (4.0 g, 73% yield over two steps). 1H NMR (300 MHz, DMSO-d6): δ 7.2 (s, 1H), 2.66 (s, 3H). LRMS [M+H]+: 212 m/z.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([OH:12])[CH:6]=[C:5]2[OH:13].CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O.[F:32][C:33]([F:43])([F:42])[C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1.C(O)C>N1C=CC=CC=1>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([OH:12])[C:6]([CH2:38][C:37]1[CH:36]=[CH:35][C:34]([C:33]([F:32])([F:42])[F:43])=[CH:41][CH:40]=1)=[C:5]2[OH:13]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: Oc1cc(O)c2cc(I)ccc2n1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Solvent: c1ccncc1
Solvent: CCO
Product: Oc1nc2ccc(I)cc2c(O)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 105 °C
Reaction time: 6 h

Procedure:
To a suspension of 6-iodoquinoline-2,4-diol (498.2 g, 1.736 mol) and diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (439.6 g, 1.736 mol) in pyridine (3.5 L) was added 4-(trifluoromethyl)benzaldehyde (332.4 g, 1.909 mol). The resulting mixture was warmed with stirring to 105° C. for a period of 6 h. After cooling to room temperature, the heterogeneous mixture was treated with ethanol (4.6 L). White solids were isolated through filtration, washed with 57:43 ethanol:pyridine (800 mL), and dried in a vacuum oven at 65° C. The title compound was obtained in a 1:0.92 ratio with pyridine and used directly in the subsequent step.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[OH:10][CH2:11][CH:12]([CH2:14]O)[OH:13].S(=O)(=O)(O)O>CCOCC>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[O:10][CH2:11][CH:12]([OH:13])[CH2:14][O:5]1
Reactant: OCC(O)CO
Reactant: O=Cc1ccccc1F
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: OC1COC(c2ccccc2F)OC1
Temperature: 25 °C
Yield: 45.5 %

Procedure:
A mixture of 2-fluorobenzaldehyde (24.8 g, 0.2, mole), glycerol (18.4 g, 0.2 mole) and 40% sulfuric acid (2 ml) was heated at 80°-100° C for 12 hours. The mixture cooled to room temperature and 100 ml of ether was added. The solution was washed with 2% potassium carbonate solution, dried over magnesium sulfate and concentrated under reduced pressure. The oil which remained (28.7 g) was distilled under 1 × 10-5 mm to give a product (18 g) which distilled at a pot temperature of 140°-145° C. This product was identified by infrared and elemental analysis as 5-hydroxy-2-(2-fluorophenyl)-1,3-dioxane.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:11][C:12]1[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C:13]=1[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[CH:26]=[C:27]([CH3:28])[C:21]=2[N:20]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:35][C:36]([CH3:38])=O.C1COCC1.[BH3-]C#N.[Na+]>CO>[OH:1][CH2:2][C@@H:3]([NH:11][C:12]1[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C:13]=1[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([N:29]3[CH2:30][CH2:31][N:32]([CH:36]([CH3:38])[CH3:35])[CH2:33][CH2:34]3)[CH:26]=[C:27]([CH3:28])[C:21]=2[N:20]=1)[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)=O
Reactant: Cc1cc(N2CCNCC2)cc2[nH]c(-c3c(N[C@H](CO)Cc4ccccc4)cc[nH]c3=O)nc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(N2CCN(C(C)C)CC2)cc2[nH]c(-c3c(N[C@H](CO)Cc4ccccc4)cc[nH]c3=O)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
To a solution of (S)-4-(1-hydroxymethyl-2-phenyl-ethylamino)-3-(4-methyl-6-piperazin-1-yl-1H-benzimidazol-2-yl)-1H-pyridin-2-one (25 mg, 0.054 mmol) in methanol (0.5 mL) was added acetone (0.25 mL) and 1 M THF solution of NaCNBH3 (0.2 mL). The reaction mixture was stirred at room temperature for 1 h and concentrated in vacuo. The residue was purified by prep. HPLC to yield the title compound (12 mg, 44%). 1H NMR (400 MHz, CD3OD) δ 7.10–7.24 (6H, m), 7.08 (1H, s), 7.06 (1H, s), 6.06 (1H, d, J=7.9 Hz), 3.58–4.01 (10H, m), 3.34 (1H, m), 3.14 (1H, m), 2.98 (1H, dd, J=5.9, 13.7 Hz), 2.83 (1H, dd, J=7.9, 13.7 Hz), 2.60 (3H, s), 1.44 (6H, d, J=6.7 Hz). LCMS (M+H)+ m/z 501 (t=1.80 min.).
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:13]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11][C:4]=2[NH:5][C:6]=1[C:7]([O:9]C)=[O:8].O.[OH-].[Li+].CO>C1COCC1>[Br:1][C:2]1[C:3]2[CH:13]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:12][CH2:11][C:4]=2[NH:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1[nH]c2c(c1Br)C(CCc1ccccc1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1[nH]c2c(c1Br)C(CCc1ccccc1)CC2

Procedure:
The title compound was synthesized from methyl 3-bromo-4-phenethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (68 mg, 0.20 mmol) and lithium hydroxide monohydrate (33 mg, 0.78 mmol in 3 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (6 mL) was used. The resulting product was purified by flash chromatography (Isco CombiFlash) eluting with a gradient of 0-80% EtOAc/Heptane to the title compound. 37 mg. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.68-1.80 (m, 1H), 2.08-2.22 (m, 2H), 2.55-2.71 (m, 4H), 2.71-2.83 (m, 1H), 3.00-3.08 (m, 1H), 7.10-7.16 (m, 1H), 7.17-7.28 (m, 4H); LCMS-MS (ESI+) 356.0 (M+Na); HPLC (UV=93.2%), (ELSD=100%).