Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]([NH:9][C:10]2[C:11](=[CH:15][C:16]([S:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[C:12](O)=O)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[NH4+].[OH-].O=P(Cl)(Cl)[Cl:31]>>[CH:1]([N:4]1[C:8]2=[N:9][C:10]3[C:11]([C:12]([Cl:31])=[C:7]2[CH:6]=[N:5]1)=[CH:15][C:16]([S:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])(=[O:21])=[O:20])=[CH:17][CH:18]=3)([CH3:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCN(CC)S(=O)(=O)c1ccc(Nc2ccnn2C(C)C)c(C(=O)O)c1
Agent: [NH4+]
Agent: [OH-]
Product: CCN(CC)S(=O)(=O)c1ccc2nc3c(cnn3C(C)C)c(Cl)c2c1
Temperature: 25 °C

Procedure:
A mixture of N-(1-isopropylpyrazol-5-yl)-5-(diethylaminosulfonyl) anthranilic acid (12.0 g, 0.031 mol) and POCl3 (80 ml) is refluxed for 6 hours. The reaction mixture is cooled to room temperature, and then is poured into ice water and neutralized with concentrated NH4OH. The mixture is extracted with CH2Cl2 and the CH2Cl2 layer is dried over MgSO4 and evaporated to dryness. The residue is purified by column chromatography on silica gel eluting with CH2Cl2 /ether (9/1) to afford 10 g of crude 1-isopropyl-6-(diethylaminosulfonyl)-4-chloro-1H-pyrazolo[3,4-b]quinoline.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[S:10][CH:11]=[C:12]([CH2:14][OH:15])[N:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:17]1[N:22]=[CH:21][C:20]([C:23](OC)=[O:24])=[CH:19][CH:18]=1.O>CN(C)C=O>[C:3]1([C:9]2[S:10][CH:11]=[C:12]([CH2:14][O:15][C:17]3[N:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=3)[N:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: OCc1csc(-c2ccccc2)n1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCc1ccc(OCc2csc(-c3ccccc3)n2)nc1
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
Sodium hydride (60%, oily, 1.40 g) was added to a solution of 2-phenyl-4-thiazolylmethanol (6.69 g) and methyl 6-chloro-3-pyridinecarboxylate (6.01 g) in N,N-dimethylformamide (100 ml) at 0° C., and the mixture was stirred for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. Lithium aluminium hydride (1.33 g) was added to a solution of the residue in tetrahydrofuran (150 ml) at 0° C., which was stirred at room temperature for 10 minutes. Sodium sulfate decahydrate (11.3 g) was added to the reaction mixture, which was stirred for 30 minutes at room temperature. The precipitate was removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain 6-(2-phenyl-4-thiazolylmethoxy)-3-pyridylmethanol (5.81 g, yield 56%) as colorless crystals from the fraction eluted with tetrahydrofuran. This was recrystallized from tetrahydrofuran-hexane. Melting point: 134–135° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.C([Li])(C)(C)C.[CH3:14][C:15]1([CH3:46])[CH:24]=[C:23](OS(C(F)(F)F)(=O)=O)[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:33]#[C:34][C:35]3[CH:45]=[CH:44][C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:37][N:36]=3)[CH:21]=2)[S:16]1>C1COCC1.CCCCC.[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:33]#[C:34][C:35]4[CH:45]=[CH:44][C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:37][N:36]=4)[CH:21]=3)[S:16][C:15]([CH3:14])([CH3:46])[CH:24]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Br)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CC(C)(C)S3)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CC(C)(C)S3)nc1
Temperature: 25 °C

Procedure:
A solution of 4-methylbromobenzene (280.0 mg, 1.64 mmol) in 2.0 mL of THF was cooled to -78° C. and tert-butyllithium (209.5 mg, 3.27 mmol, 1.9 ml of a 1.7M solution in pentane) was added to give a yellow solution. After 30 minutes a solution of ZnCl2 (680.0 mg, 5.0 mmol) in 4.0 mL THF was slowly added via cannula. The resulting solution was warmed to room temperature and transferred via cannula to a solution of ethyl 6-(2,2-dimethyl-4-trifluoromethanesulfonyloxy-(2H)-thiochromen-6-ylethynyl)-nicotinate (Compound 239, 120.0 mg, 0.24 mmol) and tetrakis(triphenylphosphine)palladium(0) (20.0 mg, 0.02 mmol) in 2.0 mL THF. This solution was heated to 50° C. for 2 hours, cooled to room temperature, and the reaction quenched by the addition of saturated aqueous NH4Cl. The solution was extracted with EtOAc and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound, 80.0 mg (76%), was isolated by column chromatography (10 to 15% EtOAc/hexanes) as a colorless solid. 1H NMR (300 MHz, CDCl3) δ: 9.15 (1H, d, J=2.2 Hz), 8.23 (1H, dd, J=2.1, 8.0 Hz), 7.51 (1H, d, J=8.1 Hz), 7.40-7.32 (3H, m), 7.18 (4H, m), 5.83 (1H, s), 4.40 (2H, q, J=7.1 Hz), 2.40 (3H, s), 1.47 (6H, s), 1.40 (3H, t, J=7.1 Hz).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:12][NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Br[CH2:23][C:24]([O:26][CH2:27]C)=[O:25]>ClCCl>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:12][N:11]1[CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COCC2CN2)cc1
Reactant: CCOC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CN1CC1COCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold (−78° C.) solution of 2-[(benzyloxy)methyl]aziridine (0.42 g, 2.57 mmol) and N,N-diisopropylethylamine (0.5 mL, 2.90 mmol) in dichloromethane (15 mL) under an atmosphere of nitrogen, ethyl bromoacetate (0.39, 2.5 mmol) was added over a period of 1 h. The resultant mixture was allowed to slowly warm up to room temperature and stirred overnight. The resultant mixture was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a mixture of 70% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][C:8]=2[CH:9]=1)=[O:4].Cl[CH2:16][C:17]1[S:21][C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[N:19][C:18]=1[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([S:14][CH2:16][C:17]3[S:21][C:20]([C:22]4[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=4)=[N:19][C:18]=3[CH3:32])=[CH:10][C:8]=2[CH:9]=1)=[O:4]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Reactant: COC(=O)c1cc2cc(S)ccc2o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1cc2cc(SCc3sc(-c4ccc(C(F)(F)F)cc4)nc3C)ccc2o1
Temperature: 60 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
A mixture of 5-mercapto-benzofuran-2-carboxylic acid methyl ester (300 mg, 1.4 mmol) and 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (550 mg, 1.9 mmol) was dissolved in 5 ml anhydrous acetonitrile followed by addition of cesium carbonate (700 mg, 2.1 mmol). The reaction was then stirred at 60° C. for 2 hours, filtered and concentrated in vacuo. Purification by flash column chromatography (gradient elution: 5% EtOAc/hexanes to 45% EtOAc/hexanes), gave the title compound (410 mg, 61%) as a pale yellow solid. M.p. 132–133° C.; IR (thin film) cm−1: 1173; 400 MHz 1H NMR (DMSO-d6) δ 7.95 (d, 2H, J=8.1 Hz), 7.79 (s, 1H), 7.74 (d, 2H, J=8.1 Hz), 7.65 (m, 2H), 7.51 (d, 1H, J=9.0 Hz), 4.44 (s, 2H), 3.82 (s, 3H); MS m/z 464 (M+1); Annl. Calc'd for C22H16F3N1O3S2 C, 57.01; H, 3.48; N, 3.02; found: C, 56.94; H, 3.44; N, 2.84.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[C:4]([F:27])[CH:3]=1.Cl.[NH2:29][OH:30].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:29]\[OH:30])=[C:4]([F:27])[CH:3]=1
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1F
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1F

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-2-fluoro-phenyl)-3-o-tolyl-propionyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=443.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C:6](=[O:8])[C:5]2[S:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:4]=2[S:3]1(=[O:17])=[O:16].[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[H-].[Na+].Cl>CN(C)C=O>[OH:8][C:6]1[C:5]2[S:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:4]=2[S:3](=[O:17])(=[O:16])[N:2]([CH3:1])[C:7]=1[C:25]([NH:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:26]
Reactant: CN1CC(=O)c2sc3ccccc3c2S1(=O)=O
Reactant: O=C=Nc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(C(=O)Nc2ccccc2)=C(O)c2sc3ccccc3c2S1(=O)=O
Temperature: 27 °C
Reaction time: 2 h

Procedure:
2.67 g. of 3,4-dihydro-2-methyl-4-oxo-2H-[1]benzothieno[2,3-e]-1,2-thiazine 1,1-dioxide are dissolved in 40 ml. of absolute dimethylformamide and 1.2 ml. of phenylisocyanate are added. The solution obtained is added dropwise at 4° C. within 30 minutes to a suspension of 600 mg. of a 55% sodium hydride dispersion in paraffin in 10 ml. of dimethylformamide. The mixture is stirred for a further 1 hour at 4° C. and subsequently for 2 hours at 27° C. and then stirred into 400 ml. of ice/water. The solution obtained is acidified with concentrated hydrochloric acid. The precipitate is filtered off under suction, washed with water and dissolved in methylene chloride. The resulting solution is dried over sodium sulfate and evaporated. The residue is stirred with 30 ml. of methanol. The insoluble components are digested with acetonitrile, filtered off under suction and dried for 4 hours at 100° C./11 Torr. The 4-hydroxy-2-methyl-N-phenyl-2H-[1]benzothieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide obtained melts at 261°-263° C.
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH2:11][C@@H:10]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:8][C:7]=2[CH:31]=1.[Br:32]N1C(=O)CCC1=O>CO.O>[ClH:1].[Br:2][C:3]1[CH:4]=[C:5]([Br:32])[C:6]2[N:12]([CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH2:11][C@@H:10]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:8][C:7]=2[CH:31]=1
Reactant: CS(=O)(=O)N1Cc2cc(Br)ccc2N(Cc2cccnc2)C[C@H]1Cc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Solvent: O
Solvent: CO
Product: CS(=O)(=O)N1Cc2cc(Br)cc(Br)c2N(Cc2cccnc2)C[C@H]1Cc1ccccc1
Reaction time: 1 h
Yield: 39.1 %

Procedure:
To a stirred solution of the compound (200 mg) of Example 16 in methanol and water (7.5 mL/0.5 mL), was added N-bromosuccinimide (73 mg). The mixture was allowed to stir for 1 h, and solvent was removed. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes) to give a solid (90 mg, 35%). (M+H): 564.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].Cl.[Cl:7][C:8]1[CH:9]=[C:10]([C@@H:14]([OH:36])[CH2:15][NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH:19]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31](OCC)=[O:32])=[CH:25][CH:24]=3)[CH2:18]2)[CH:11]=[CH:12][CH:13]=1>>[Cl:7][C:8]1[CH:9]=[C:10]([C@@H:14]([OH:36])[CH2:15][NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH:19]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[O:32])=[CH:25][CH:24]=3)[CH2:18]2)[CH:11]=[CH:12][CH:13]=1
Reactant: COCCN
Reactant: CCOC(=O)COc1ccc(C2CCCC(NC[C@H](O)c3cccc(Cl)c3)C2)cc1
Agent: Cl
Product: COCCNC(=O)COc1ccc(C2CCCC(NC[C@H](O)c3cccc(Cl)c3)C2)cc1
Temperature: 25 °C
Reaction time: 71 h
Yield: 98.6 %

Procedure:
2-Methoxyethylamine (320 mg) was added to the (1R)-1-(3-chlorophenyl)-2-[3-(4-ethoxycarbonylmethoxyphenyl) cyclohexylamino]ethanol hydrochloride (trans-H) obtained in Example 28 (100 mg), and the mixture was stirred at room temperature for 71 hours. The reaction solution was separated and purified by silica gel column chromatography (chloroform:methanol=10:1) to obtain 97 mg of (2R)-2-[4-[3-[2-(3-chlorophenyl)-2-hydroxyethylamino]cyclohexyl]phenoxy]-N-(2-methoxyethyl) acetamide (90% yield).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([CH:10](O)[CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:13]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.N12CCCN=C1CCCCC2>O1CCCC1>[C:1]([C:5]1[N:6]=[C:7](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:13]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(CC(O)c2nc(C(C)(C)C)cs2)ccn1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)Nc1cc(/C=C/c2nc(C(C)(C)C)cs2)ccn1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 71.7 %

Procedure:
The tert-butyl N-(4-{2-[4-(tert-butyl)-1,3-thiazol-2-yl]-2-hydroxyethyl}-2-pyridyl)carbamate (1.80 g, 4.77 mmol) obtained in (C) was dissolved in anhydrous tetrahydrofuran (20 ml), added with triethylamine (2.33 ml, 16.7 mmol) and methanesulfonyl chloride (738 μl, 9.54 mmol), and stirred at 0° C. for 3.5 hours. After insoluble solids were removed, the reaction mixture was washed with tetrahydrofuran, and the solvent was evaporated under reduced pressure. The residue was dissolved in toluene (30 ml), added with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.07 ml, 7.15 mmol), and refluxed by heating for 1 hour. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1→2:1, v/v) to obtain the title compound (1.23 g, 72%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]=O)=[CH:11][C:6]=2[N:5]([CH2:14]C)[C:4]1=[O:16])C.N[C@H](C(O)=O)C.[N+:23]([CH2:26][CH3:27])([O-:25])=[O:24]>C(O)CCC>[CH3:1][N:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]=[C:26]([N+:23]([O-:25])=[O:24])[CH3:27])=[CH:11][C:6]=2[N:5]([CH3:14])[C:4]1=[O:16]
Reactant: CCn1c(=O)n(CC)c2cc(C=O)ccc21
Reactant: CC[N+](=O)[O-]
Agent: C[C@H](N)C(=O)O
Solvent: CCCCO
Product: CC(=Cc1ccc2c(c1)n(C)c(=O)n2C)[N+](=O)[O-]
Temperature: 115 °C
Reaction time: 2 h

Procedure:
1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carbaldehyde (2.48 g, 13.1 mmol, obtained using the same procedure used for 1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carbaldehyde) in n-butanol (25 mL) was treated with □-alanine (298.0 mg) and nitroethane (1.85 mL). The mixture was heated to 115° C. for 4 hours, more nitroethane (0.5 mL) was added and the heating was continued for 2 hours. The reaction was allowed to cool, was filtered and washed with ether then dried to give 1,3-Dimethyl-5-(2-nitro-propenyl)-1,3-dihydro-benzoimidazol-2-one (2.229 g).
Reaction SMILES: CC1CCCC(C)N1.Cl[CH:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21])[C:11]([OH:13])=[O:12].[OH-].[Na+].Cl>CN(C=O)C>[NH:21]1[C:16]2[C:15](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12]
Reactant: Nc1ccccc1CC(Cl)C(=O)O
Agent: CC1CCCC(C)N1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)[C@@H]1Cc2ccccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
(+)-α-Chloro-2-aminobenzenepropanoic acid 2,6-dimethylpiperidine salt (1.25 g., 4.00 mmol) was added to magnetically stirred N sodium hydroxide (4 ml.) under nitrogen. The solution was stirred under nitrogen overnight at room temperature. The pH was adjusted to a value between 2 and 3 (pH paper) with conc. hydrochloric acid while cooling in ice. The crystalline precipitate was collected and washed with several aliquots of ice cold water. The product was dried briefly under vacuum over phosphorus pentoxide and then stirred with ether. The product was dried over phosphorus pentoxide at 56° C. for several hours under oil pump vacuum to give 0.48 g. (74%) of the title compound, m.p. 155°-157° C., [α]D25 +36.09° (c 0.87, DMF).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12](Cl)(=[O:15])[CH2:13][CH3:14].Cl>N1C=CC=CC=1>[C:12]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:15])[CH2:13][CH3:14]
Reactant: COC(=O)c1ccnc(N)c1
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCC(=O)Nc1cc(C(=O)OC)ccn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
To a stirred solution of methyl 2-aminoisonicotinate (1.00 g, 6.57 mmol) in pyridine (22 mL) is added propionyl chloride (0.69 mL, 7.89 mmol) at 0° C. After stirring at 0° C. for 2 hours, the reaction mixture is poured into 2M hydrochloric acid (100 mL) and extracted with ethyl acetate (100 mL). The organic layer is dried over sodium sulfate, and concentrated under reduced pressure to give 1.07 g (78% yield) of the title compound as a yellow solid. This material is used for the next reaction (Step-2) without further purification.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][S:9]([NH2:12])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[C:16]([F:23])[CH:15]=1.O.Cl>O1CCOCC1>[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:12][S:9]([CH:8]=[CH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:10])=[O:11])=[O:19])=[C:16]([F:23])[CH:15]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1F
Reactant: NS(=O)(=O)C=Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C(NS(=O)(=O)C=Cc1ccccc1)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
To a solution of 2-phenyl-ethenesulfonic acid amide (500 mg, 2.7 mmol) in dioxane (25 ml) sodium hydride (197 mg, 55% dispersion in mineral oil) were added and the mixture was stirred at room temperature for 30 minutes. 4-Chloro-2-fluoro-benzoyl chloride (527 mg, 2.7 mmol) were added and the mixture was stirred at room temperature overnight. After addition of water (50 ml) the pH was adjusted to 7 with 1 N HCl and the mixture was extracted with ethyl acetate (3 times 50 ml). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Preparative HPLC (RP18, methanol-water-gradient) returned the title compound (730 mg, 79% yield) as a white solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[N:10]1([C:17](=[O:19])[CH3:18])[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:17]([N:10]1[CH2:16][CH2:15][CH2:14][N:13]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:12][CH2:11]1)(=[O:19])[CH3:18]
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(=O)N1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CCCN(c2ccc(C=O)cc2)CC1
Temperature: 120 °C
Yield: 69.6 %

Procedure:
A mixture of 4-fluorobenzaldehyde (1.56 g, 12.6 mmol), 1-(1,4-diazepan-1-yl)ethanone (1.5 g, 10.5 mmol), and K2CO3 (1.74 g, 12.6 mmol) in DMF (10 mL) were heated at 120° C. for 20 hours. The mixture was cooled to room temperature and diluted with water. The mixture was extracted with ethyl acetate and the organic phase washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 50% ethyl acetate/hexanes to 100% ethyl acetate to 10% methanol/ethyl acetate, to afford 4-(4-acetyl-1,4-diazepan-1-yl)benzaldehyde (1.8 g, 70%).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:7][CH2:6][CH:5]([N:8]2[CH2:11][CH2:10][CH:9]2[C:12]([O:14]C)=[O:13])[CH2:4][CH2:3]1.O.[OH-].[Li+:19]>>[CH3:1][C:2]1([CH3:16])[CH2:7][CH2:6][CH:5]([N:8]2[CH2:11][CH2:10][CH:9]2[C:12]([O-:14])=[O:13])[CH2:4][CH2:3]1.[Li+:19]
Reactant: COC(=O)C1CCN1C1CCC(C)(C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC1(C)CCC(N2CCC2C(=O)[O-])CC1

Procedure:
The reaction of methyl 1-(4,4-dimethylcyclohexyl)azetidine-2-carboxylate 19C and lithium hydroxide monohydrate yielded lithium 1-(4,4-dimethylcyclohexyl)azetidine-2-carboxylate as a light yellow solid (quant). MS ISP (m/e): 212.2 (100) [(M+H)]+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([NH:25]C(=O)OC(C)(C)C)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].O1CCC(=O)CC1.C1(=O)CCCCC1.Cl>C(O)C>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([NH2:25])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(NC(=O)OC(C)(C)C)CCOCC1
Agent: Cl
Agent: O=C1CCOCC1
Solvent: O=C1CCCCC1
Solvent: CCO
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(N)CCOCC1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, a mixture of tert-Butyl {4-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydropyran-4-yl}carbamate (3.0 g, prepared according to the general methods of Parts A through F of Example 54 using tetrahydro-4H-pyran-4-one in lieu of cyclohexanone in Part A), hydrochloric acid (12.2 mL of 2.8 M in ethanol), and ethanol (18 mL) was heated at reflux for 4 hours. The reaction mixture was allowed to cool to ambient temperature and was then concentrated under reduced pressure. The residue was combined with isopropanol (100 mL). A solid was isolated by filtration to provide 2.56 g of 4-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydropyran-4-amine as a tan solid.
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[CH3:12][O:13][CH2:14][C:15]1[C:20]([CH2:21][O:22][CH3:23])=[CH:19][CH:18]=[CH:17][C:16]=1[OH:24].COCC1C(COC)=C([N+]([O-])=O)C=CC=1O>C(#N)C.O>[CH3:12][O:13][CH2:14][C:15]1[C:20]([CH2:21][O:22][CH3:23])=[CH:19][CH:18]=[C:17]([N+:8]([O-:11])=[O:9])[C:16]=1[OH:24]
Reactant: O=[N+]([O-])O
Reactant: COCc1cccc(O)c1COC
Agent: COCc1c(O)ccc([N+](=O)[O-])c1COC
Solvent: CC#N
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COCc1ccc([N+](=O)[O-])c(O)c1COC
Reaction time: 0.67 h
Yield: 54.6 %

Procedure:
Acetyl nitrate obtained by mixing acetic anhydride (306 mg, 3.0 mmol) with fuming nitric acid (189 mg, 3.0 mmol) at 0° C. was dropped into a solution of 2,3-bis(methoxymethyl)phenol (483 mg, 2.65 mmol) in acetonitrile (5 ml) at 0° C. followed by stirring for 40 minutes. The reaction solution was diluted with water and extracted with ether. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom to provide a 2:1 mixture (329 mg; yield 54%) of 2,3-bis(methoxymethyl)-6-nitrophenol and 2,3-bis(methoxymethyl)-4-nitrophenol as yellow solid. This was used in the next reaction without separation and purification.