Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH2:13][CH3:14])=[N:10][C:9](F)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][SH:35]>O>[Br:1][C:2]1[C:11]([O:12][CH2:13][CH3:14])=[N:10][C:9]([S:35][CH2:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[Cl:27])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: SCc1ccccc1Cl
Reactant: CCOc1nc(F)c2ncccc2c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1nc(SCc2ccccc2Cl)c2ncccc2c1Br
Temperature: 100 °C
Yield: 64.9 %

Procedure:
To a 5 mL microwave reactor vial was added 5-bromo-6-ethoxy-8-fluoro-1,7-naphthyridine (100 mg, 0.37 mmol), a large excess of K2CO3, followed by DMF (5 mL). (2-chlorophenyl)methanethiol (70 mg, 0.44 mmol) was then added to the mixture, the vessel was capped and heated under microwave irradiation for 20 min at 100° C. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The resultant residue was purified by silica gel to yield 5-bromo-8-(2-chlorobenzylthio)-6-ethoxy-1,7-naphthyridine as a pale yellow solid (100 mg, 0.24 mmol, 66%). 1H NMR (400 MHz, CDCl3): δ ppm 8.74 (d, J=2.64 Hz, 1H), 8.34 (d, J=7.47 Hz, 1H), 7.50-7.68 (m, 2H), 7.35-7.48 (m, 1H), 7.11-7.22 (m, 2H), 4.67 (s, 2H), 4.53 (q, J=7.03 Hz, 2H), 1.41 (t, J=7.03 Hz, 3H). LC/MS m/z 411 [M+H].
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]([CH3:16])=[CH2:15])[C:6]1=[O:17].[C:18]1([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[C:31]1([CH:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:25]2[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[N:7]([C:14]([CH3:16])=[CH2:15])[C:6]3=[O:17])[CH2:29][CH2:30]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: C=C(C)n1c(=O)n(CCCCl)c2ccccc21
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: C=C(C)n1c(=O)n(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc21

Procedure:
A mixture of 42.6 parts of 1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one, 38 parts of 1-(diphenylmethyl)piperazine, 48 parts of sodium carbonate and 400 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is cooled, water is cooled and the layers are separated. The 4-methyl-2-pentanone-phase is washed with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated, yielding 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one as a residue.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]#[N:9].[N+](C1C=CC([O:19][C:20]([C:22]2[C:30]3[S:29][C:28]([CH:31]4[CH2:33][CH2:32]4)=[N:27][C:26]=3[C:25]([O:34][CH3:35])=[CH:24][CH:23]=2)=O)=CC=1)([O-])=O>CN(C)C=O.C[Si](C)(C)[N-][Si](C)(C)C.[Na+]>[C:8]([C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[NH:1][C:20]([C:22]1[C:30]2[S:29][C:28]([CH:31]3[CH2:33][CH2:32]3)=[N:27][C:26]=2[C:25]([O:34][CH3:35])=[CH:24][CH:23]=1)=[O:19])#[N:9]
Reactant: Cn1ncc(C#N)c1N
Reactant: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2sc(C3CC3)nc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2c(C#N)cnn2C)c2sc(C3CC3)nc12
Yield: 49.8 %

Procedure:
Starting from 5-amino-1-methyl-1H-pyrazole-4-carbonitrile (90 mg) in dimethyl formamide (30 ml), sodium hexamethyldisilazide in tetrahydrofbran (1.08 ml, 1.0 M), and 2-cyclopropyl-4-methoxybenzothiazole-7-carboxylic acid 4-nitrophenyl ester (200 mg). Purification by flash chromatography (eluent 10% methanol in dichloromethane) to yield the title compound as an off-white solid (95 mg). TLC Rf 0.30 (10% methanol in dichloromethane); Mpt 259-260° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[N:7]([CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:8][C:9]1[CH:14]=[CH:13][C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][O:37][C:38](=[O:44])[C:39](I)=[CH:40][O:41][CH3:42].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>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.O>[CH3:36][O:37][C:38](=[O:44])[C:39]([C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:35])[CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:10][CH:11]=1)=[CH:40][O:41][CH3:42]
Reactant: COC=C(I)C(=O)OC
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC=C(C(=O)OC)c1ccc(CN(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Yield: 91.3 %

Procedure:
A mixture of (3-tert-butoxycarbonylamino-propyl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-carbamic acid tert-butyl ester (6.00 g, 12.25 mmol), 2-iodo-3-methoxy-acrylic acid methyl ester (4.45 g, 18.38 mmol), K3PO4 (7.79 g, 36.75 mmol), Pd(PPh3)4 (0) (0.68 g, 0.61 mmol), dioxane (60 mL) and water (12 mL) was degassed and heated at 80° C. for 20 h under argon atmosphere. The reaction mixture was diluted with EtOAc (500 mL), washed with water (300 mL) and brine (300 mL). The organic solution was concentrated and purified by flash chromatography (0%-30% EtOAc in heptane) to give desired product (5.35 g, 91%) as brown oil. 1NMR (300 MHz, CDCl3): δ 7.56 (s, 1H), 7.30 (d, J=8.1 Hz, 2H), 7.20 (br.d, 2H), 5.20 (br.s, 0.5H), 4.62 (br.s, 0.5H), 4.39 (br, 2H), 3.86 (s, 3H), 3.74 (s, 3H), 3.27 (m, 2H), 3.08 (m, 2H), 1.62 (m, 2H), 1.50 (br.d, 9H), 1.43 (s, 9H). LCMS (EI) m/z: 501 (M+Na+).
Reaction SMILES: [Cl:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[C@H:6]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[CH2:21]=O>C(O)=O>[Cl:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[C@H:6]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:7][N:8]([CH3:21])[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: C=O
Reactant: COc1cc2c(cc1Cl)CCNC[C@H]2c1ccccc1
Solvent: O=CO
Product: COc1cc2c(cc1Cl)CCN(C)C[C@H]2c1ccccc1

Procedure:
Reflux for 4 hours, a solution of 52.0 g (0.18 moles) of the product of step C in a mixture of 96 ml of 37% formaldehyde and 144 ml of 90% formic acid. Distill almost to dryness at 100° C. under reduced pressure (about 100 mm). Dissolve the residue in a mixture of 500 ml of 1 N sodium hydroxide and 500 ml of ethyl ether with cooling and stirring. Separate the ether layer, dry over anhydrous sodium sulfate, and evaporate to give (S)-7-chloro-8-methoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine as a colorless solid. Obtain an analytically pure sample by crystallization from ethyl ether, m.p. 91°-92° C., [α]D26 =+47.3° (c=1, ethanol).
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:24])=[CH:9][C:10]([O:22][CH3:23])=[CH:11][C:12]=3[C@:13]32[N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)=[CH:4][CH:3]=1.Cl.[F:26][C:27]1([F:33])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:26][C:27]1([F:33])[CH2:32][CH2:31][N:30]([C:2]2[CH:15]=[C:14]3[C:5]([O:6][C:7]4[C:8]([F:24])=[CH:9][C:10]([O:22][CH3:23])=[CH:11][C:12]=4[C@:13]43[N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]4)=[CH:4][CH:3]=2)[CH2:29][CH2:28]1
Reactant: FC1(F)CCNCC1
Reactant: COc1cc(F)c2c(c1)[C@]1(COCC(N)=N1)c1cc(Br)ccc1O2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(F)c2c(c1)[C@]1(COCC(N)=N1)c1cc(N3CCC(F)(F)CC3)ccc1O2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A vial was charged with (S)-7′-bromo-4′-fluoro-2′-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (200 mg, 0.509 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl-t-butylether adduct (18.53 mg, 0.025 mmol), 4,4-difluoropiperidine hydrochloride (160 mg, 1.017 mmol) and 1 ml of THF. The mixture was cooled to 0° C. and LHMDS (1M in THF) (2035 μL, 2.035 mmol) was added, and the vial was sealed and stirred at RT for 2 hr. At this point more chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-t-butylether adduct (18.53 mg, 0.025 mmol), (18.53 mg, 0.025 mmol) was added followed by LHMDS solution (1 ml) and stirring continued for another hour. The mixture was quenched by addition of 2 ml of water and extracted with EtOAc. The combined organic fractions were concentrated and purified by chromatography [5-50% DCM/MeOH/NH4OH (90:10:1)] to afford (S)-7′-(4,4-difluoropiperidin-1-yl)-4′-fluoro-2′-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine as yellowish foam. Step 2: To a solution of (S)-7′-(4,4-difluoropiperidin-1-yl)-4′-fluoro-2′-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (130 mg, 0.300 mmol) in DCM (3 ml) boron tribromide (0.085 ml, 0.900 mmol) was added dropwise at room temperature and the mixture was stirred for 3 hrs at RT. The reaction was quenched by addition of MeOH (˜1 ml), stirred for 10 min, then neutralized by addition of 25% NH4OH. The homogeneous mixture was concentrated in vacuo and extracted with EtOAc. The organic layer was washed with brine and concentrated in vacuo to give after trituration with DCM off white solid. The solid was redissolved in 3 ml of DMF, cesium carbonate (195 mg, 0.600 mmol) and potassium iodide (14.94 mg, 0.090 mmol) were added and then 3-bromomethyll-3-methyloxetane (0.054 ml, 0.330 mmol) was added dropwise. The mixture was stirred at RT for 4 hrs. The mixture was diluted with water (10 ml) and extracted with EtOAc. The combined organic layers was washed twice with water, then with brine and concentrated in vacuo. The residue was purified by chromatography [10-80% DCM/MeOH/NH4OH (90:10:1) in DCM] to afford (S)-7′-(4,4-difluoropiperidin-1-yl)-4′-fluoro-2′-((3-methyloxetan-3-yl)methoxy)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][Cl:7].[ClH:11].Cl.[CH2:13]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[ClH:7].[ClH:11].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][N:25]1[CH2:26][CH2:27][N:22]([CH2:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:23][CH2:24]1
Reactant: COc1cccc(CCl)c1
Reactant: O=C(CN1CCNCC1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cccc(CN2CCN(CC(=O)c3ccccc3)CC2)c1
Yield: 53.8 %

Procedure:
A mixture of 3-methoxybenzylchloride (0.5 g, 2.15 mmol), N-phenacyl piperazine dihydrochloride (0.6 g, 2.15 mmol) and K2CO3 (1.04 g, 7.52 mmol) in 30 ml of acetone was treated according to general preparation 2 to give 0.46 g of compound (IV-25), yield 54%. M+ 324.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:37])[CH2:19][CH2:20][NH:21][C:22]([C:24]3[N:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])[O:27][C:28]=3[CH3:29])=[O:23])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[OH-].[Na+]>C1COCC1.O>[Cl:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:26]1[O:27][C:28]([CH3:29])=[C:24]([C:22]([NH:21][CH2:20][CH2:19][C:18]([NH:17][C:14]2[CH:13]=[CH:12][C:11]([C@H:8]3[CH2:9][CH2:10][C@H:5]([CH2:4][C:3]([OH:38])=[O:2])[CH2:6][CH2:7]3)=[CH:16][CH:15]=2)=[O:37])=[O:23])[N:25]=1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4ccccc4Cl)oc3C)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2Cl)nc1C(=O)NCCC(=O)Nc1ccc([C@H]2CC[C@H](CC(=O)O)CC2)cc1
Reaction time: 24 h

Procedure:
Trans-{4-[4-(3-{[2-(2-chlorophenyl)-5-methyloxazole-4-carbonyl]amino}propionylamino)phenyl]cyclohexyl}acetic acid methyl ester (80 mg, 0.149 mmol) was put into THF/water (20 mL, 3:1) solvent, and NaOH (44.61 mg, 1.115 mmol) was added thereto. The mixture was stirred for 24 hours, THF was removed, and pH of the mixture was adjusted to be 2-3 with 1N hydrochloric acid. The reaction mixture was extracted with EtOAC (3×100 mL), washed with brine and dried with anhydrous sodium sulfate, and the solvent was removed. The obtained crude material was crystallized with acetonitrile to obtain a compound (77 mg, 98%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=2[CH:7]=[C:6]([CH:16]=O)[CH:5]=1)[CH3:2].Cl.Cl.[CH2:20]([NH:22][C:23](=[O:37])[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[C:26]([CH3:36])[CH:25]=1)[CH3:21]>>[CH2:1]([O:3][C:4]1[C:9]2[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=2[CH:7]=[C:6]([CH2:16][N:33]2[CH2:32][CH2:31][N:30]([C:27]3[CH:28]=[CH:29][C:24]([C:23]([NH:22][CH2:20][CH3:21])=[O:37])=[CH:25][C:26]=3[CH3:36])[CH2:35][CH2:34]2)[CH:5]=1)[CH3:2]
Reactant: CCOc1cc(C=O)cc2c1OC(C)C(=O)N2
Reactant: CCNC(=O)c1ccc(N2CCNCC2)c(C)c1
Agent: Cl
Product: CCNC(=O)c1ccc(N2CCN(Cc3cc4c(c(OCC)c3)OC(C)C(=O)N4)CC2)c(C)c1

Procedure:
Using 398B and N-ethyl-3-methyl-4-(piperazin-1-yl)benzamide-2HCl in the general procedure for reductive aminations, the title compound was obtained as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (t, J=7.07 Hz, 3H) 1.32 (t, J=6.95 Hz, 3H) 1.40 (d, J=6.57 Hz, 3H) 2.26 (s, 3H) 2.51-2.59 (m, 4H) 2.88 (br. s., 4H) 3.19-3.29 (m, 2H) 3.42 (s, 2H) 3.98-4.09 (m, 2H) 4.55-4.64 (m, 1H) 6.51 (d, J=1.52 Hz, 1H) 6.63 (d, J=1.52 Hz, 1H) 7.02 (d, J=8.34 Hz, 1H) 7.55-7.69 (m, 2H) 8.26 (t, J=5.56 Hz, 1H) 10.57 (s, 1H). ESI-MS: m/z 467.4 (M+H)+. mp 199.8-199.9° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:6](=[O:7])[C:5]2=[CH:11][C:12]=1[S:13](=[O:16])(=[O:15])[NH2:14].[NH3:17]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([NH2:8])=[O:10])[C:5]([C:6]([NH2:17])=[O:7])=[CH:11][C:12]=1[S:13](=[O:16])(=[O:15])[NH2:14]
Reactant: N
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)NC2=O
Product: NC(=O)c1cc(Cl)c(S(N)(=O)=O)cc1C(N)=O

Procedure:
A solution of 4-chloro-5-sulfamoylphthalimide (21.3 g., 0.076 mole) and 250 ml. of liquid ammonia was stirred at room temperature while permitting ammonia to evaporate. Water was added to residual material, the pH adjusted to 7 with hydrochloric acid and precipitated material collected to provide 14.5 g. (63%) of hydrated 4-chloro-5-(sulfamoyl)-1,2-benzenedicarboxamide, m.p. 270°-275° C.
Reaction SMILES: [SH:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:15](OC(=O)C)(=[O:17])[CH3:16].Cl>C(O)(=O)C>[C:15]([S:1][C:2]1[C:10]([C:11]([F:12])([F:13])[F:14])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1cccc(C(F)(F)F)c1S
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)Sc1c(C(=O)O)cccc1C(F)(F)F

Procedure:
2-Mercapto-3-trifluoromethyl-benzoic acid (4.0 g, 18 mmol), acetic anhydride (2.2 g, 22 mmol), and glacial acetic acid (6 ml) were refluxed 30 minutes, cooled and combined with dilute hydrochloric acid, thereby affording the product as a white crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:17](=[O:18])[O:16][C:14](=[O:15])[C:5]2=[C:6]([CH3:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:19](O)(=O)CC(O)=O>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:5](=[C:6]([CH3:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:14](=[O:15])[O:16][C:17]2([OH:18])[CH3:19]
Reactant: CCOC(=O)c1c(C)cc2c(c1C)C(=O)OC2=O
Reactant: O=C(O)CC(=O)O
Product: CCOC(=O)c1c(C)cc2c(c1C)C(=O)OC2(C)O
Temperature: 100 °C
Yield: 65 %

Procedure:
A mixture consisting of 4, 6-dimethyl-5-ethoxycarbonylbenzene-1,2-dicarboxylic acid anhydride (7.8 g. mp. 80°-81°C.), malonic acid (6.5g) dried by heating at 100°C. for 10 hr, and absolute pyridine (7 ml) was heated at 80° - 85°C. for 15 hr. After cooling, 10% aqueous hydrochloric acid was added, and the mixture was extracted with chloroform. The organic layer was washed with water, and extracted with saturated aqueous sodium bicarbonate solution. The sodium bicarbonate extract was made acidic with dilute hydrochloric acid, and further extracted with ethyl acetate. The extract was dried over MgSO4, and the solvent was removed. The resulting residue was recrystallized from ether ~ n-hexane to yield 5,7-dimethyl-6-ethoxycarbonyl-3-hydroxy-3-methylphthalide (5.4g, yield 62%) melting at 118° - 120°C.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][CH2:15][N:14]3[CH:18]=[N:19][CH:20]=[C:13]23)[CH2:9]1)C1C=CC=CC=1.Cl.[H][H]>CO.[Pd]>[NH:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][CH2:15][N:14]3[CH:18]=[N:19][CH:20]=[C:13]23)[CH2:9]1
Reactant: c1ccc(CN2CCC3(CCCn4cncc43)C2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: c1ncn2c1C1(CCC2)CCNC1

Procedure:
A solution of 1.00 mmol of 1′-benzyl-6,7-dihydro-5H-spiro[imidazo[1,5-a]pyridine-8,3′-pyrrolidine] in 5 ml of methanol is admixed with 1 mmol of 2M aqueous hydrochloric acid and 0.10 g of 10% Pd/C. The reaction mixture is hydrogenated with 1 bar of hydrogen at 22° C. for 18 hours. The reaction mixture is filtered over Hyflo and the filtrate is evaporated. The residue is taken up in ethyl acetate and the amine is liberated with saturated aqueous sodium carbonate solution. The phases are separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60 F) on the basis of the Rf value.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[NH2:18][C:19]1[S:23][C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[O:31][CH3:32])=[N:21][C:20]=1[CH3:33]>N1C=CC=CC=1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]2[S:23][C:19]([NH:18][C:9](=[O:11])[CH:8]=[CH:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:13][CH:12]=3)=[C:20]([CH3:33])[N:21]=2)=[C:25]([O:31][CH3:32])[CH:26]=1
Reactant: COc1cc(Cl)ccc1-c1nc(C)c(N)s1
Reactant: COc1ccc(C=CC(=O)O)cc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(C=CC(=O)Nc2sc(-c3ccc(Cl)cc3OC)nc2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13 %

Procedure:
4-Methoxycinnamic acid (178 mg, 1.0 mmol) and thionyl chloride (480 mg, 4.0 mmol) were heated under reflux for 2 hours. The excess thionyl chloride was distilled off. The resulting residue was dissolved in pyridine (1 ml). Under an ice cooling, the resulting solution was added to a solution of 5-amino-2-(4-chloro-2-methoxyphenyl)-4-methylthiazole (254 mg, 1.0 mmol) prepared in the Step 28-1-2 in pyridine (4 ml). After the removal of the ice bath, the mixture was stirred for 16 hours at a room temperature. To the mixture, 3.5% hydrochloric acid was added, and the resulting mixture was subjected to extraction with chloroform. The extract was washed with water. The washed product was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=30:1) to give the title compound (54 mg, 13%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:4]=1.[CH3:19][NH2:20]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:20][CH3:19])(=[O:11])=[O:10])=[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:4]=1
Reactant: CN
Reactant: COc1ccc(S(=O)(=O)Cl)c(N2CCOCC2)c1
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(OC)cc1N1CCOCC1
Reaction time: 15 h

Procedure:
To a stirred solution of 4-methoxy-2-morpholin-4-yl-benzenesulfonyl chloride (37 mg; 0.13 mmol) in dry CH2Cl2 (1 mL) was added methylamine (0.16 mL of 2.0 M solution in tetrahydrofuran; 0.32 mmol) via syringe at room temperature under a nitrogen atmosphere. After stirring for 15 hours, the reaction was diluted with CH2Cl2 (25 mL), washed with water, saturated aqueous NaHCO3 and brine, then dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified via HPLC (Biotage with 2:1 hexanes/EtOAc) to provide the sulfonamide as a white solid (12.5 mg; 34%).
Reaction SMILES: C([O-])(=[O:3])C.[Na+].C(=O)(O)[O-].[Na+].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:32]=[CH:31][N:30]=[C:29]3[C:25]=2[N:26]=[C:27](Cl)[N:28]3[CH3:33])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CS(C)=O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:32]=[CH:31][N:30]=[C:29]3[C:25]=2[NH:26][C:27](=[O:3])[N:28]3[CH3:33])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(=O)[O-]
Reactant: Cn1c(Cl)nc2c(N3CCN(C(=O)OC(C)(C)C)CC3)ncnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: Cn1c(=O)[nH]c2c(N3CCN(C(=O)OC(C)(C)C)CC3)ncnc21
Temperature: 135 °C
Yield: 53.5 %

Procedure:
Sodium acetate (0.168 g) and sodium bicarbonate (0.100 g) were added to a solution of 4-(8-chloro-9-methyl-9H-purin-6-yl)-piperazine-1-carboxylic acid t-butyl ester (0.353 g) in dimethylsulfoxide (5 mL). This was then heated at 135° C. for 64 hours. The reaction solution was filtered, and was directly loaded onto a column for purification by reverse phase high performance liquid chromatography to give the title compound (0.179 g).
Reaction SMILES: [F:1][C:2]1[C:7](F)=[CH:6][C:5]([NH2:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([CH3:15])[CH3:14]>O>[F:1][C:2]1[C:7]([N:19]2[CH2:20][CH2:21][N:16]([CH:13]([CH3:15])[CH3:14])[CH2:17][CH2:18]2)=[CH:6][C:5]([NH2:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: CC(C)N1CCNCC1
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Solvent: O
Product: CC(C)N1CCN(c2cc(N)c([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C

Procedure:
4,5-Difluoro-2-nitrophenylamine (1.0 equivalent) and N-isopropyl piperazine were heated at 100° C. for 3 hours. The solution was then cooled to room temperature and diluted with water. The resulting precipitate was filtered and dried under vacuum to provide title compound product. LC/MS (m/z) 283.2 (MH+), Rt 1.56 minutes.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc2[nH]ncc12
Yield: 102 %

Procedure:
In a second step, to a suspension of 4-nitroindazole (3 g, 18.4 mmol) in EtOH (75 ml) was added Pd on carbon (10%, 1.5 g), the mixture was charged with H2 at 50 psi for 1 h, Pd on carbon was filtered off, and the filtrate was concentrated to give 4-aminoindazole (2.5 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][Cl:12])[CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc(Cl)n1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: ClCc1cccc(Cl)n1

Procedure:
6-Chloro-2-pyridylmethanol, 0.982 g (6.84 mmole) in 10 ml methylene chloride was treated with 0.814 g thionyl chloride at room temperature for one hour. The mixture was neutralized with saturated sodium bicarbonate solution, extracted with methylene chloride, the extracts dried and solvent evaporated to give 815 mg of product as colorless crystals. 1H-NMR(CDCl3)ppm (delta): 4.7 (s, 2H), 7.1-8.0 (m, 3H).