Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:5]2[C:6]3[CH:25]=[CH:24][CH:23]=[N:22][C:7]=3[O:8][C:9]3([CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]3)[C:4]2=[CH:3][CH:2]=1.[ClH:26].O1CCOCC1>C(Cl)Cl.CO>[ClH:26].[N:1]1[N:5]2[C:6]3[CH:25]=[CH:24][CH:23]=[N:22][C:7]=3[O:8][C:9]3([CH2:10][CH2:11][NH:12][CH2:13][CH2:14]3)[C:4]2=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ncccc1-n1nccc12
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: c1cnc2c(c1)-n1nccc1C1(CCNCC1)O2
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl spiro[piperidine-4,4′-pyrazolo[1,5-d]pyrido[2,3-b][1,4]oxazine]-1-carboxylate (35 mg, 0.10 mmol) in CH2Cl2 (1 mL) and MeOH (0.1 mL) was added HCl in dioxane (256 μL of 4 M, 1.02 mmol) and the mixture was stirred at 40° C. for 4 hours. The reaction mixture was evaporated and the hydrochloric acid salt of the product was used without further purification. ESI-MS m/z calc. 242.1. found 243.5 (M+1)+. Retention time: 0.32 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].CO[C:16](=O)[C:17]1C=C(N(CCC)CCC)C=CC=1N.S(Cl)(Cl)=O>C(O)C>[CH2:16]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12])[CH3:17]
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CCCN(CCC)c1ccc(N)c(C(=O)OC)c1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 48 h

Procedure:
5-Chloro-2-nitro-benzoic acid (compound A′) (10.0 g) was dissolved in ethanol (100 ml). Thionyl chloride (20 ml) was added dropwise to the solution at 0° C., and the mixture was then heated under reflux with stirring for 48 hr. After the completion of the reaction, the reaction solution was concentrated under the reduced pressure. Distilled water was added to the residue, and the mixture was neutralized with a saturated aqueous sodium hydrogencarbonate solution under ice cooling. The cooled solution was subjected to separatory extraction with ethyl acetate. The organic layer was dried over sodium sulfate and was then concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a chloroform-methanol system to give 5-chloro-2-nitro-benzoic acid ethyl ester as a useful intermediate (11.0 g, yield 97%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:13])=[C:7]([CH:12]=1)C(OC)=O)=O.[CH3:14][O:15][C:16]1[CH:25]=[CH:24][C:19]2[N:20]=[C:21]([NH2:23])[S:22][C:18]=2[CH:17]=1.[P:26]([O-:33])([O:30][CH2:31]C)[O:27][CH2:28]C>C1(C)C=CC=CC=1>[OH:13][C:6]1[CH:7]=[CH:12][C:3]([CH:1]([P:26](=[O:33])([O:30][CH3:31])[O:27][CH3:28])[NH:23][C:21]2[S:22][C:18]3[CH:17]=[C:16]([O:15][CH3:14])[CH:25]=[CH:24][C:19]=3[N:20]=2)=[CH:4][CH:5]=1
Reactant: COc1ccc2nc(N)sc2c1
Reactant: CCOP([O-])OCC
Reactant: COC(=O)c1cc(C=O)ccc1O
Solvent: Cc1ccccc1
Product: COc1ccc2nc(NC(c3ccc(O)cc3)P(=O)(OC)OC)sc2c1

Procedure:
The mixture of 4-hydroxybenzaldehyde (2) (0.067 g, 5 mmol) and Mg(ClO4)2 (0.12 g, 5 mol %) was stirred for 10-15 minutes in anhydrous toluene (5 mL), after which time 6-methoxybenzo[d]thiazol-2-amine (1) (0.1 g, 5 mmol) and diethyl phosphite (0.076 g, 5 mmol) were added, and the reaction mixture was refluxed for 3 hours followed by usual workup and chromatographic purification [silica gel:EtOAc-Dichloromethane (8.5:1.5) as eluent] afforded the dimethyl ((4-hydroxyphenyl)((6-methoxybenzo[d]thiazol-2-yl)amino)methyl)phosphonate as colorless solid.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1.[OH-:12].[Na+].O.[CH3:15]O>O>[CH3:15][O:12][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1
Reactant: CO
Reactant: Clc1nc2c(Cl)cccc2s1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: COc1nc2c(Cl)cccc2s1
Yield: 92.4 %

Procedure:
2,4-Dichlorobenzothiazole (10.21 g, 0.05 mole) and 94% sodium hydroxide (8.30 g, 0.075 mole) were added to a 50 (V/V) % water/methanol mixed solvent (150 c.c.), and the mixture was heated under reflux for 30 minutes. After cooling, water (100 c.c.) was added to the reaction solution, followed by ice-cooling. The deposited crystals were filtered and washed with water to obtain 9.22 g of 2-methoxy-4-chlorobenzothiazole. Yield 92.4%, purity 100%, m.p. 55°-57° C.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([Cl:19])[C:13]=1[CH2:20][C:21]([NH:23][C:24]1[C:25]([C:30]([OH:32])=O)=[N:26][CH:27]=[CH:28][N:29]=1)=[O:22].O([CH2:41][CH:42]([F:44])[F:43])S(C(F)(F)F)(=O)=O.Cl>O1CCCC1>[F:43][CH:42]([F:44])[CH2:41][N:23]1[C:24]2=[N:29][CH:28]=[CH:27][N:26]=[C:25]2[C:30]([OH:32])=[C:20]([C:13]2[C:14]([Cl:19])=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=2[Cl:11])[C:21]1=[O:22]
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: O=C(Cc1c(Cl)ccc(Cl)c1Cl)Nc1nccnc1C(=O)O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1c(-c2c(Cl)ccc(Cl)c2Cl)c(O)c2nccnc2n1CC(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hexamethyldisilazide (“NaHMDS”) (1M in THF) (1.4 ml) was added dropwise to a solution of 3-[2-(2,3,6-trichloro-phenyl)-acetylamino]-pyrazine-2-carboxylic acid (Example 3.1) (0.225 g) in anhydrous tetrahydrofuran (10 ml) over a period of 10 minutes. Then difluoroethyl triflate (0.270 g) was added dropwise and the reaction mixture was allowed to stir at ambient temperature for 30 minutes. Then the reaction mixture was heated to reflux for 6 hours. The reaction mixture was allowed to cool to ambient temperature and acidified by addition of aqueous hydrochloric acid (1M). The mixture was concentrated. The residue was dissolved in diethyl ether and washed with aqueous hydrochloric acid (1M). The acid solution was extracted with ethyl acetate. The combined organic fractions were dried over magnesium sulfate and concentrated. The residue was purified by reverse phase HPLC to give Compound No. B11 of Table B (0.034 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([CH3:14])[CH2:9][CH2:10][NH:11][C:12](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])[C:19]([Cl:33])=[CH:18][N:17]=1.Cl>C(O)(C)C.O1CCOCC1>[Cl:33][C:19]1[C:20]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])=[N:21][C:16]([NH:1][C:2]2[C:7]3[N:8]([CH3:14])[CH2:9][CH2:10][NH:11][C:12](=[O:13])[C:6]=3[CH:5]=[CH:4][CH:3]=2)=[N:17][CH:18]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1CCNC(=O)c2cccc(N)c21
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2cccc3c2N(C)CCNC3=O)ncc1Cl
Temperature: 110 °C
Yield: 6.3 %

Procedure:
9-Amino-1-methyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (#) (40 mg, 0.21 mmol) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (#) (68 mg, 0.23 mmol) were combined in isopropanol (1 mL). 4 N HCl in dioxane (57 μL) was added, and the resulting mixture was heated to 110° C. in the microwave for 20 min. The resulting mixture was filtered, washed with CH2Cl2 and acetone. The ppt was dissolved in H2O, neutralized with NaHCO3, and extracted with EtOAc, dried over MgSO4, filtered, and concentrated. The resulting residue was purified with silica gel chromatography (0-10% MeOH in CH2Cl2) to obtain 2-[5-Chloro-2-(1-methyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)pyrimidin-4-ylamino]-N-methyl-benzamide as a white solid (6 mg, 5%). mp 282-284° C.; LCMS: m/z=452.22 (M+H+), 1H NMR (400 MHz, CDCl3) δ 11.30 (s, 1H), 8.41 (d, J=8.8 Hz, 1H), 8.06 (s, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.49 (d, J=7.6 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.26 (m, 1H), 7.06 (m, 1H), 6.88 (m, 1H), 6.69 (m, 1H), 6.21 (m, 1H), 4.43 (m, 1H), 3.55 (m, 2H), 3.42 (m, 2H), 3.18 (s, 3H), 3.02 (m, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:18][OH:19].O>CO>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[N:18]\[OH:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: O/N=C\c1ccc(OCc2ccccc2)cc1

Procedure:
To 4-(benzyloxy)benzaldehyde (12.9 g) in MeOH (129 ml), Hydroxylamine hydrochloride (6.34 g) was added and the reaction mixture was refluxed for 3 hours and then cooled. The reaction mixture was concentrated to obtain pale brown residue. To this residue, water was added and it was extracted with EtOAc. Organic layer was collected, dried over Na2SO4 and concentrated to obtain off white solid, which was crystallized from DCM-Petroleum ether to obtain the title compound as white solid. Yield: 11.5 g (83%); 1HNMR (DMSO-d6; 300 MHz): δ 10.98 (s, 1H), 8.06 (s, 1H), 7.53 (d, 2H), 7.33-7.46 (m, 5H), 7.05 (d, 2H), 5.13 (s, 2H).
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][N:7]1[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2.CN(C)CCN(C)C.[CH:29](N1CCCCC1)=[O:30].Cl>C(OCC)C>[CH3:6][N:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([CH:29]=[O:30])[C:13]=2[S:14][C:15]2[C:20]1=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: CN1c2ccccc2Sc2ccccc21
Reactant: O=CN1CCCCC1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CN1c2ccccc2Sc2c(C=O)cccc21
Temperature: 0 °C
Reaction time: 18 h
Yield: 74.4 %

Procedure:
21.7 ml of tert-butyllithium solution (1.4M in pentane) were slowly added dropwise under argon at -78° to a solution of 5.0 g (23.4 mmol) of 10-methylphenothiazine in 10 ml of absolute diethyl ether and 7 ml of freshly distilled N,N,N',N'-tetramethylethylenediamine. The reaction mixture was subsequently brought slowly to room temperature, stirred for 18 hours, then cooled to 0° and thereupon treated with 3.90 ml (35.1 mmol) of N-formylpiperidine. The reaction mixture was stirred at room temperature for 2 hours and then poured into 50 g of ice, 50 ml of 0.1N aqueous hydrochloric acid solution and 1.50 ml of diethyl ether. The aqueous phase was extracted twice with 100 ml of diethyl ether and the combined organic fractions were dried over magnesium sulphate and concentrated. The residue was chromatographed on 500 g of silica gel with ethyl acetate/hexane (1:3), whereafter, after recrystallization from ethyl acetate/hexane, 4.20 g (74.4%) of 10-methylphenothiazine-4-carbaldehyde were obtained as a yellow solid of m.p. 103°.
Reaction SMILES: [N+:1]([C:4]1[C:9](=O)[NH:8][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:9]1[N:8]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(=O)[nH]c1C(=O)OCC
Product: CCOC(=O)c1cc([N+](=O)[O-])c(Cl)nc1C(=O)OCC
Temperature: 80 °C
Yield: 73.9 %

Procedure:
Diethyl 1,6-dihydro-5-nitro-6-oxo-2,3-pyridinedicarboxylate (26.23 g, 0,092 mol) is partially dissolved under N2 atmosphere in 250 mL of phosphorous oxychloride and the mixture is heated to 80° C. for 15 hours. The mixture is cooled and concentrated and the resulting oil dissolved in ethyl acetate and washed with water, 10% K2CO3 and brine. The organic layer is dried over MgSO4, filtered and the solvent removed to yield a solid which is recrystallized from absolute ethanol/water to give 20.65 g of the produce as a brown solid in 73.9% yield, having a melting point of 84.5°-86° C.
Reaction SMILES: O.[OH-].[Li+].[N:4]1[C:5]([CH2:13][O:14][C:15]2[CH:36]=[CH:35][C:18]([CH2:19][O:20]/[N:21]=[C:22](/[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)\[CH2:23][CH2:24][C:25]([O:27]C)=[O:26])=[CH:17][CH:16]=2)=[CH:6][N:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=12.O.Cl>O1CCCC1.CO>[N:4]1[C:5]([CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:19][O:20]/[N:21]=[C:22](/[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)\[CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:35][CH:36]=2)=[CH:6][N:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=12
Reactant: COC(=O)CC/C(=N\OCc1ccc(OCc2cn3ccccc3n2)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CC/C(=N\OCc1ccc(OCc2cn3ccccc3n2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
Lithium hydroxide monohydrate (53.0 mg) was added to a solution of methyl E-4-[4-(imidazo[1,2-α]pyridin-2-ylmethoxy)benzyloxyimino]-4-phenylbutyrate (280 mg) in tetrahydrofuran (6 ml)-water (4 ml)-methanol (4 ml) and stirred at room temperature for 2 hours. 1N hydrochloric acid (1.3 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E4-[4-(imidazo[1,2-α]pyridin-2-ylmethoxy)benzyloxyimino]-4-phenylbutyric acid (206 mg, yield 76%) as colorless crystals. m.p. 180-182° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=1>CN(C=O)C.O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[CH:6][CH:5]=1
Reactant: Oc1ccc(Br)cc1
Reactant: Cc1cc(Cl)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(Br)cc2)ccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
To a solution of NaH (60% in mineral oil) (0.13 g, 3.25 mmol) in DMF (5 ml) was added commercially available 4-bromophenol (0.50 g, 2.89 mmol) and the reaction was stirred at room temperature for 10 minutes. Then, 4-chloro-2-picoline (0.30 g, 2.40 mmol) was added and the resulting reaction mixture was then microwaved at 150° C. for 10 minutes. After cooling, the mixture was diluted with water and extracted with Et2O. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue thus obtained was purified by flash chromatography (DCM) to yield intermediate 25 (0.52 g, 81%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:4][OH:5].C([O:12][C:13]([C:15]1[CH:20]=[CH:19][N:18]=[N:17][C:16]=1Cl)=O)C>COCCOC>[CH2:8]([O:7][C:3]([C:4]1[O:5][C:16]2[N:17]=[N:18][CH:19]=[CH:20][C:15]=2[C:13]=1[OH:12])=[O:6])[CH3:9]
Reactant: CCOC(=O)c1ccnnc1Cl
Reactant: CCOC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1oc2nnccc2c1O
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (44.7 mmol) in 100 mL 1,2-dimethoxyethane was added ethyl glycolate (43 mmol) under ice cooling and stirring. The ice bath was removed and stirring was continued at RT. After 30 min, a solution of 3-chloropyridazine-4-carboxylic acid ethyl ester (17.2 mmol) in 40 mL 1,2-dimethoxyethane was slowly added and the mixture was heated to 75° C. for 2 h. The solvent was then evaporated off and the residual solid was redissolved in aq. NaHCO3 solution and EtOAc. The aqueous layer was acidified with AcOH and extracted with DCM (3×). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by CC (KP-SIL™ from Biotage) using EtOAc/MeOH (1/1) gives the desired product as brown solid;
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([Cl:20])[C:11]=1[C:21]1[NH:22][CH:23]=[CH:24][N:25]=1.O>CN(C)C=O>[Br:1][C:24]1[N:25]=[C:21]([C:11]2[C:12]([Cl:20])=[CH:13][C:14]([C:16]([F:17])([F:18])[F:19])=[CH:15][C:10]=2[Cl:9])[NH:22][CH:23]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: FC(F)(F)c1cc(Cl)c(-c2ncc[nH]2)c(Cl)c1
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(Cl)c(-c2nc(Br)c[nH]2)c(Cl)c1
Reaction time: 7 h
Yield: 13.1 %

Procedure:
A solution of N-bromosuccinimide (0.63 g, 0.0036 mol) in dimethylformamide (dried over 4Å molecular sieve, 18 ml) was added dropwise with stirring to a solution of 2-(2,6-dichloro-4-trifluoromethylphenyl)-imidazole (1.0 g, 0.0036 mol) in dimethylformamide (dried over 4Å molecular sieve, 18 ml) and stirred for 7 hours. The mixture was poured into water (180 ml) and extracted with dichloromethane (5×30 ml). The combined extracts were washed with water (3×50 ml), dried over anhydrous sodium sulphate and evaporated to dryness. The residue was purified by mplc on silica eluted with a mixture of ethyl acetate and petroleum spirit (bp 60°-80° C.) (3:5) to give 4-bromo-2-(2,6-dichloro-4-trifluoromethylphenyl)-imidazole (0.17 g), m.p. 224°-225° C., as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11](=[O:22])([O:17][C:18]([CH3:21])(C)C)OC(C)(C)C.Cl.O1CCO[CH2:26][CH2:25]1>>[CH2:18]([O:17][C:11]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[O:22])[CH2:21][CH2:25][CH3:26]
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cl
Product: CCCCOC(=O)Nc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 7.5 h

Procedure:
4-Aminobenzoic acid (5.0 g, 36.46 mmol) was dissolved in a mixed solvent of 1,4-dioxane/1N sodium hydroxide (1/1, 50 ml), and a 1,4-dioxane solution (9.5 g, 43.75 mmol/25 ml) of di-t-butyl carbonate was added dropwise to the solution under cooling with ice water. The mixture was stirred at room temperature. After 7.5 hours, additional di-t-butyl carbonate (1.5 g) was added to continue stirring. After 24 hours, 6N hydrochloric acid was added to the reaction mixture to acidify it, and the solvent was then distilled off under reduced pressure. The resultant residue was dissolved in ethyl acetate, and the solution was washed 4 times with water and once with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 9.28 g (39.10 mmol) of 4-butoxycarbonylaminobenzoic acid as a crude product. This compound was dissolved together with benzyl alcohol (4.23 g, 39.10 mmol) and N,N-dimethylaminopyridine (478 mg, 3.91 mmol) in N,N-dimethylformamide (100 ml), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.99 g, 46.92 mmol) was added to the solution under cooling with ice water. The mixture was stirred at room temperature for 8 hours. The reaction mixture was diluted with ethyl acetate, washed with water (twice), a 10% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography on silica gel (toluene:ethyl acetate=20:1) to obtain 4.09 g (12.5 mmol) of a benzyl ester. The thus-obtained ester was dissolved in ethyl acetate (70 ml), and 4N hydrochloric acid/ethyl acetate (70 ml) was added to the solution. The mixture was stirred at room temperature. After 1.5 hours, additional 4N hydrochloric acid/ethyl acetate (70 ml) was added to continue stirring. After 1 hour, the reaction was stopped, and solids deposited were collected by filtration. The thus-obtained solids were suspended in ethyl acetate, and the suspension was ultrasonically washed and then filtered to obtain 2.86 g of the title compound.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[C:5]([C:13](=O)[CH2:14][C:15](=O)[CH:16]([CH3:18])[CH3:17])=[CH:4][CH:3]=1.C(=O)(O)O.[NH2:25][C:26]([NH2:28])=[NH:27]>>[NH2:28][C:26]1[N:27]=[C:13]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=3)[C:2]([F:1])=[CH:3][CH:4]=2)[CH:14]=[C:15]([CH:16]([CH3:18])[CH3:17])[N:25]=1
Reactant: N=C(N)N
Reactant: CC(C)C(=O)CC(=O)c1ccc(F)c2ccc(F)cc12
Agent: O=C(O)O
Product: CC(C)c1cc(-c2ccc(F)c3ccc(F)cc23)nc(N)n1
Temperature: 150 °C
Yield: 34.7 %

Procedure:
1-(4,7-difluoronaphth-1-yl)-4-methylpentane-1,3-dione (0.114 g, 0.5 mmol) was combined with guanidine carbonate (0.180 g, 0.5 mmol) and heated to 150° C. for 6 hours. The reaction was cooled to room temperature and directly purified by column chromatography to give 2-amino-4-(4,7-difluoronaphth-1-yl)-6-isopropylpyrimidine (0.052 g, 34%), m.p. 103-105° C.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]2[C:7]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=[CH:10][C:3]1=2.[OH-].[Na+].[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[CH:20]=[CH2:21]>>[S:2]1[CH:6]=[CH:5][C:4]2[C:7]([N:11]3[CH2:16][CH2:15][N:14]([CH2:21][CH2:20][C:19]([O:23][CH2:24][CH3:25])=[O:22])[CH2:13][CH2:12]3)=[CH:8][CH:9]=[CH:10][C:3]1=2
Reactant: c1cc(N2CCNCC2)c2ccsc2c1
Reactant: C=CC(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)CCN1CCN(c2cccc3sccc23)CC1
Temperature: 25 °C
Yield: 83.4 %

Procedure:
5.05 g (19.8 mmol) of 1-benzo[b]thiophen-4-yl-piperazine hydrochloride was added to an aqueous solution of sodium hydroxide, and the mixture was extracted with dichloromethane. The extraction solution was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in 50 ml of ethanol and ethyl acrylate (2.44 ml, 21.8 mmol) was added thereto, and then the reaction mixture was refluxed with heating for 4 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Diisopropyl ether was added to the residue and insoluble matter precipitated was obtained by filtration, washed with diisopropyl ether, and dried to obtain ethyl 3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propionate (5.26 g) as white powder.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12](Cl)[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:19][NH2:20]>>[CH2:1]([O:8][CH2:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([NH:19][NH2:20])[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(Cl)c(COCc2ccccc2)n1
Reactant: NN
Solvent: O
Product: NNc1ccc(Cl)c(COCc2ccccc2)n1
Temperature: 120 °C

Procedure:
A sealable flask is charged with 2-(benzyloxymethyl)-3,6-dichloropyridine as prepared in Step 2 (950 mg, 3.5 mmol), hydrazine hydrate (1 mL) is added, and the reaction is heated to 120° C. overnight. After cooling the solids are collected by filtration to provide 2-(benzyloxymethyl)-3-chloro-6-hydrazinylpyridine.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH:15]=[C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:7]1)=[O:5])C.[OH-].[Na+].O>C(O)C>[ClH:30].[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:15][O:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1
Reactant: CCOC(=O)[C@@H]1CCCN(CCOC=C(c2ccccc2C)c2ccccc2Cl)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1C(=COCCN1CCC[C@@H](C(=O)O)C1)c1ccccc1Cl
Product: Cl
Yield: 165.7 %

Procedure:
(R)-1-[2-[[2-(2-Chlorophenyl)-2-(2-methylphenyl)ethenyl]oxy]ethyl]-3-piperidine carboxylic acid ethyl ester (4.1 g, 0.0096 mol) (prepared as described in Method D) was dissolved in ethanol (100 ml) and 18 N sodium hydroxide solution (10 ml) was introduced. After stirring the solution at room temperature for 1 h water (500 ml) was added, and the solution was washed with diethyl ether (2 × 100 ml). The pH of the aqueous phase was adjusted to 1 using 2 N hydrochloric acid solution and extracted with dichloromethane (4 × 200 ml). The combined extracts were dried (M ), evaporated and the residue was crystallized from toluene/trace methanol to provide the title compound (3.47 g, 87%) as a white crystalline solid, m.p. 231°-234°.