Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[CH:15]([N:23]3[CH2:27][C:26]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[Cl:35])=[CH:25][C:24]3=[O:36])[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:9]2)[CH2:4][O:3]1.Cl.ClC1C=CC=CC=1OC1CN(C(CC2C=CC=CC=2)C(NC2C=CN(C[C@@H](O)CO)N=2)=O)C(=O)C=1>O1CCCC1.C(OCC)(=O)C>[Cl:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[O:28][C:26]1[CH2:27][N:23]([C@@H:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([NH:13][C:10]2[CH:11]=[CH:12][N:8]([CH2:7][C@@H:5]([OH:6])[CH2:4][OH:3])[N:9]=2)=[O:37])[C:24](=[O:36])[CH:25]=1
Reactant: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(Cc3ccccc3)N3CC(Oc4ccccc4Cl)=CC3=O)n2)O1
Agent: Cl
Agent: O=C(Nc1ccn(C[C@@H](O)CO)n1)C(Cc1ccccc1)N1CC(Oc2ccccc2Cl)=CC1=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccn(C[C@@H](O)CO)n1)[C@H](Cc1ccccc1)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-phenyl-propionic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.010 g, 0.017 mmol) in tetrahydrofuran (1 mL) was treated with 2N aqueous hydrochloric acid solution (1 mL). The reaction mixture was stirred at 25° C. for 3 h. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated to afford, 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-phenyl-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-propionamide (0.007 g, 82%) as an off-white powder: HR-ES-MS m/z calculated for C23H27ClN4O6 [M+H]+ 497.1587, observed 497.1586; 1H NMR (300 MHz, CDCl3) δ ppm 1.75 (br. s., 2H), 3.17 (dd, J=14.0, 8.8 Hz, 1H), 3.39 (dd, J=14.0, 6.9 Hz, 1H), 3.44-3.55 (m, 2H), 3.56-3.65 (m, 1H), 3.95-4.10 (m, 2H), 4.16 (d, J=18.1 Hz, 1H), 4.30 (d, J=18.1 Hz, 1H), 4.77 (s, 1H), 5.02 (t, J=7.8 Hz, 1H), 6.65 (d, J=1.8 Hz, 1H), 7.17 (dd, J=8.2, 1.8 Hz, 1H), 7.19-7.26 (m, 6H), 7.28-7.35 (m, 2H), 7.46 (dd, J=7.8, 1.5 Hz, 1H), 9.65 (s, 1H).
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[C:17]1([S:23]([N:3]2[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C1CCN(S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.2 %

Procedure:
To a solution of 4-piperidone monohydrate hydrochloride (4.59 g, 30 mmol), triethylamine (12.5 ml, 90 mmol) in CH2Cl2 (50 ml) was added benzenesulfonyl chloride (5.30 g, 30 mmol). The mixture was stirred at 25° C. for 16 h. After evaporation of solvents, the residue was triturated with water (100 ml), filtered, and further purified by recrystallization from hexanes/CH2Cl2 (3:1) to afford the desired ketone (5.97 g, 83%) as a colorless solid. mp 116-118° C.; 1H NMR (500 MHz, CDCl3) δ2.54 (t, J=6.4 Hz, 4H), 3.41(t, J=6.4 Hz, 4H). 7.58 (d, J=7.8 Hz, 2H), 7.63 (t, J=7.0 Hz, 1H), 7.81 (d, J=7.8 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:22][CH:23]1[CH2:25][CH2:24]1>CN(C=O)C>[CH:25]1([CH2:24][O:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:22][CH:23]3[CH2:25][CH2:24]3)=[O:7])=[CH:4][C:3]=2[C:11]([F:12])([F:13])[F:14])[CH2:23][CH2:22]1
Reactant: O=C(O)c1ccc(O)c(C(F)(F)F)c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(OCC1CC1)c1ccc(OCC2CC2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 87.3 %

Procedure:
To a solution of 4-hydroxy-3-(trifluoromethyl)benzoic acid (0.483 g, 2.343 mmol) in DMF (10 mL) was added Cs2CO3 (2.29 g, 7.03 mmol), followed by (bromomethyl)cyclopropane (0.568 mL, 5.86 mmol). The reaction was stirred at 80° C. for 16 h. The mixture was filtered. The filtrate was concentrated under vacuum and taken up in EtOAc. The organic solution was washed with water (thrice), dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography to give the title compound as an oil (0.643 g). LCMS m/z=315.3 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 0.33-0.44 (m, 4H), 0.59-0.69 (m, 4H), 1.21-1.34 (m, 2H), 4.01 (d, J=6.57 Hz, 2H), 4.15 (d, J=7.20 Hz, 2H), 6.99 (d, J=8.84 Hz, 1H), 8.18 (dd, J=8.72, 2.15 Hz, 1H), 8.28 (d, J=2.02 Hz, 1H).
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:25]=[C:26]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:27]=[CH:28][C:29]=1[CH3:30].C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[CH3:30][C:29]1[CH:24]=[CH:25][C:26]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][C:28]=1[C:8]1[CH:9]=[CH:10][C:5]([O:4][C@@H:3]([CH3:14])[C@H:2]([OH:1])[CH2:15][CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:6][CH:7]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Reactant: Cc1ccc(S(N)(=O)=O)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(S(N)(=O)=O)cc1-c1ccc(O[C@@H](C)[C@H](O)CCc2cccnc2)cc1
Temperature: 90 °C
Yield: 89.4 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.15 g, Example 33), 3-bromo-4-methylphenylsulfonic acid amide (0.25 g, Example 69a)), ethanol (3 ml), 2M aqueous sodium carbonate (0.5 ml) and tetrakis(triphenylphosphine)palladium (0) (0.03 g) with heating at 90° C. for 3 hours. After work-up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give the title compound as a foam (0.19 g).
Reaction SMILES: [C:1](=[S:3])=[S:2].[C:4]1([C:18](=[O:20])[CH3:19])[C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[S:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.CC(C)([O-])C.[K+]>O1CCCC1>[O:20]=[C:18]([C:4]1[C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[S:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH2:19][C:1]([SH:3])=[S:2]
Reactant: S=C=S
Reactant: CC(=O)c1cccc2c1Sc1ccccc1S2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(CC(=S)S)c1cccc2c1Sc1ccccc1S2

Procedure:
A solution of CS2 (1.55 ml, 25.5 mmol) and 1-thianthren-1-yl-ethanone (6.59 g, 25.5 mmol) in dry tetrahydrofuran (20 ml) was added drop wise to a solution of potassium t-butoxide (5.73 g, 51 mmol) in dry tetrahydrofuran (50 ml) under N2 at 0° C. A red coloration and the formation of a precipitate were observed. The mixture was left under vigorous stirring over the weekend and was then poured onto water (200 ml) and extracted with ether (3×100 ml). The aqueous was acidified with 2N H2SO4 to pH 1 (Whatmann pH paper) and the extracted with ether (3×100 ml). The organic were dried over magnesium sulphate and the solvent was evaporated in vacuo to give the desired product as a dark orange resin (5.00 g, 59%). m/z (LC-MS, ESP), RT=5.11; (M−−1)=333
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[O:26][CH2:27][CH3:28])/[C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH2:18]O)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[NH:30]([CH2:34][CH2:35][N:36]1[C:40]([SH:41])=[N:39][N:38]=[N:37]1)[C:31]([NH2:33])=[NH:32]>CN(C=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[O:26][CH2:27][CH3:28])/[C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH2:18][S:41][C:40]4[N:36]([CH2:35][CH2:34][NH:30][C:31]([NH2:33])=[NH:32])[N:37]=[N:38][N:39]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CCO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CO)CS[C@H]12)c1csc(N)n1
Reactant: N=C(N)NCCn1nnnc1S
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCNC(=N)N)CS[C@H]12)c1csc(N)n1
Yield: 53.7 %

Procedure:
To a solution of 467 mg of sodium 7β-[2-(2-aminothiazol-4-yl)-(Z)-2-ethoxyiminoacetamido]-3-hydroxymethyl -3-cephem-4-carboxylate and 374 mg of 1-(2-guanidinoethyl) -5-mercapto-1H-tetrazole in 10 ml of DMF was added 500 mg of ethyl o-phenylenephosphate at -20° C. under stirring. The reaction mixture was stirred at -20° C. to 0° C. for 60 minutes, and was subjected to a column chromatography on silica gel (100 g), being washed with acetonitrile and eluted with a (5:1) mixture of acetonitrile and water. The eluate was concentrated under reduced pressure, and then subjected to a column chromatography on XAD-II (150 ml), being washed with water and eluted with 20% aqueous ethanol. The eluate was concentrated under reduced pressure and then lyophilized to give 333 mg of the title compound as a colorless powder.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27](O)=[O:28])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:31]=[C:32]([NH2:36])[CH:33]([CH3:35])[CH3:34]>>[CH3:34][CH:33]([C:32]1[N:36]=[C:27]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:5][CH2:4][CH:3]([C:1]#[N:2])[CH2:8][CH2:7]3)=[O:10])[CH2:12]2)[O:28][N:31]=1)[CH3:35]
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Reactant: CC(C)C(N)=NO
Product: CC(C)c1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCC(C#N)CC3)C2)n1

Procedure:
100 mg (0.244 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 100A) and 27.4 mg (0.269 mmol) of N′-hydroxy-2-methylpropanimidamide were reacted according to the General Method 1. Yield: 78.9 mg (68% of theory).
Reaction SMILES: FC1C2C(C(=O)NC)=C(C3C=CC(F)=CC=3)OC=2C=CC=1C1C=C(C=CC=1C)C(O)=O.[NH:32]1[C:40]2[CH:39]=[CH:38][N:37]=[C:36]([C:41]3([NH2:44])CC3)[C:35]=2[CH:34]=[CH:33]1>>[NH:32]1[C:40]2[CH:39]=[CH:38][N:37]=[C:36]([C:41]#[N:44])[C:35]=2[CH:34]=[CH:33]1
Reactant: NC1(c2nccc3[nH]ccc23)CC1
Agent: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12
Product: N#Cc1nccc2[nH]ccc12

Procedure:
This example was prepared from the coupling of 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid with 1-(1H-pyrrolo[3,2-c]pyridin-4-yl)cyclopropanamine (obtained from 1H-pyrrolo[3,2-c]pyridine-4-carbonitrile by the reaction using Ti(OiPr)4/EtMgBr/BF3OEt2). Purification was performed by Shimadzu-VP preparative reverse phase HPLC using the separation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=10, Final % B=100, Gradient time=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column: Sunfire Prep C18 19×100 5 um, Fraction Collection: 7.86-8.40 min. (UV detection at 220 nm). The material obtained was further purified by preparative TLC (500 um×20×20 cm plate, 10% MeOH/CH2Cl2). Analytical TLC Rf=0.30 (10% MeOH/CH2Cl2). 1H NMR (500 MHz, CD3OD) δ 8.05 (d, J=5.80, 1H), 7.94 (m, 2H), 7.86 (d, J=7.93, 1H), 7.80 (s, 1H), 7.53 (d, J=8.55, 1H), 7.46 (d, J=8.24, 1H), 7.37 (d, J=3.36, 2H), 7.31-7.27 (overlapping m, 3H), 6.93 (d, J=3.05, 1H), 2.95 (s, 3H), 2.28 (s, 3H), 1.77 (m, 2H), 1.47 (m, 2H). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)+=577.25, HPLC Rt=1.427 min. Analytical HPLC were performed by using Shimadzu-VP instrument with UV detection at 220 nm and 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H2O-0.1% TFA, Solvent B=95% MeCN-5% H2O-0.1% TFA, Start % B=20, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150 mm, Rt=8.06 min; Column: Xbridge Phenyl 3.5 um, 4.6×150 mm, Rt=8.78 min. Analytical HPLC method: Solvent A=5% MeOH-95% H2O-10 mM NH4HCO3, Solvent B=95% MeOH-5% H2O-10 mM NH4HCO3, Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: Xbridge Phenyl 3.5 um, 4.6×150 mm, Rt=10.20 min.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:9]1)=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:11]2([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:35])([CH3:33])[CH3:34])[NH:9][CH:8]([C:6]([OH:7])=[O:5])[CH:12]2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)=[C:24]([F:30])[CH:25]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2ccc(Cl)c(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)O)C(c2ccc(Cl)c(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 96 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-3-(3,4-dichloro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 68b (1.7 g, 3.1 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-3-(3,4-dichloro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.8 g, 96%).
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]2=3)(=O)=O)=CC=1.[OH-].[Na+]>>[NH:10]1[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[C:12]2[CH:18]=[CH:19][CH:20]=[CH:21][C:11]1=2
Reactant: Cc1ccc(S(=O)(=O)N2CCCC(=O)c3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C1CCCNc2ccccc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
To preheated polyphosphoric acid (PPA, 220 g) at 70-80° C. was added 1-(Toluene-4-sulfonyl)-1,2,3,4-tetrahydro-benzo[b]azepin-5-one (50.0 g, 0.16 mol). The mixture was stirred for 3.0 h at the same temperature and then poured into ice water. After the pH was adjusted to about 8-9 by adding aq NaOH, the mixture was extracted with ethyl acetate. The organic layer was separated, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography (eluent, 3:1 n-hexanes:ethyl acetate) to give 1,2,3,4-Tetrahydro-benzo[b]azepin-5-one (22 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:20]3[C:11](=[CH:12][C:13]4[CH:14]=[CH:15][CH:16]=[N:17][C:18]=4[CH:19]=3)[O:10][CH2:9][CH2:8]2)[CH2:4][CH2:3]1>C(O)C.C(O)(=O)C.O=[Pt]=O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:20]3[C:11](=[CH:12][C:13]4[CH2:14][CH2:15][CH2:16][NH:17][C:18]=4[CH:19]=3)[O:10][CH2:9][CH2:8]2)[CH2:4][CH2:3]1
Reactant: CN1CCC2(CCOc3cc4cccnc4cc32)CC1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CC(=O)O
Product: CN1CCC2(CCOc3cc4c(cc32)NCCC4)CC1
Yield: 91.8 %

Procedure:
A solution of 2,3-dihydro-1'-methylspiro[4H-pyrano[2,3-g]quinoline-4,4' piperidine] (D106, 150 mg, 0.0006 mole) in ethanol (50 ml) and glacial acetic acid (2 ml) was hydrogenated over PtO2 (35 mg) at 50 psi for 2 days. The catalyst was removed by filtration through kieselguhr and the filtrate concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 30% MeOH/dichloromethane with 1% ammonia solution to afford the title compound (150 mg, 99%).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[N:8][C:9]([NH2:10])=[C:4]2[CH:3]=[N:2]1.[H-].[Na+].CS(O[CH:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]1)(=O)=O>CN(C=O)C>[NH2:10][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:1]([CH:22]3[CH2:23][CH2:18][CH2:19][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21]3)[N:2]=[CH:3][C:4]=12
Reactant: CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1
Reactant: Nc1ncnc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(n2ncc3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a solution of 1H-pyrazolo[3,4-d]pyrimidin-4-amine (675 mg, 5 mmol) in DMF (12 mL) was added NaH (60% wt in mineral oil, 240 mg, 6.0 mmol, 1.2 eq) and the mixture was stirred at rt for 0.5 h. The tert-butyl 3-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.67 g, 6 mmol, 1.2 eq) was added and the mixture was heated to 100° C. for 16 h. The solution was cooled to rt and the reaction was quenched with brine (50 mL) and extracted with EtOAc (80 mL×4). The organic layers were dried over Na2SO4, concentrated in vacuo to afford a residue which was purified by column chromatography (silica gel, pure EtOAc) to give the title product (700 mg, yield: 50%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 9.24 (br s, 1H), 8.72 (br s, 1H), 8.41 (s, 1H), 8.33 (s, 1H), 4.67-4.62 (m, 1H), 4.05-3.58 (m, 3H), 3.40-3.33 (m, 1H), 2.98-2.95 (m 1H), 2.16-2.04 (m, 1H), 1.61-1.24 (m, 11H). ESI-MS (M+H+): 319.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:17][C:10]3[C:11](=[O:16])[NH:12][CH2:13][CH2:14][S:15][C:9]=3[C:7]=2[CH:8]=1.CC(O)=[O:20]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:17][C:10]3[C:11](=[O:16])[NH:12][CH2:13][CH2:14][S:15](=[O:20])[C:9]=3[C:7]=2[CH:8]=1
Reactant: COc1ccc2sc3c(c2c1)SCCNC3=O
Reactant: CC(=O)O
Product: COc1ccc2sc3c(c2c1)S(=O)CCNC3=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
A mixture of 2,3 -dihydro-9 -methoxy-[1]benzothieno [2,3-f]-1,4-thiazepin-5 (4H) -one (200 mg, 0.75 mmol) and NaBO3 -4H2O (116 mg, 0.75 mmol) in 18 mL of AcOH is stirred at room temperature overnight. The reaction mixture is filtered and 60 mL of water is added to the filtrate. Filtration provides 2,3-dihydro-9-methoxy-[1]benzothieno[2,3-f]-1,4-thiazepin-5 (4H) -one-1-oxide in 69% yield, mp 215°-216° C. (dec).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].Br[CH2:15][CH:16]1[CH2:21][CH2:20][Si:19]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])(C2C=CC=CC=2)[CH2:18][CH2:17]1>>[F:1][C:2]1[CH:3]=[C:4]([O:13][CH2:15][C@H:16]2[CH2:21][CH2:20][Si@H:19]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:18][CH2:17]2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:11])([F:12])[F:10]
Reactant: Oc1ccc(OC(F)(F)F)c(F)c1
Reactant: CCCCCCC[Si]1(c2ccccc2)CCC(CBr)CC1
Product: CCCCCCC[Si@H]1CC[C@H](COc2ccc(OC(F)(F)F)c(F)c2)CC1

Procedure:
The general procedure of Example 9 was repeated using 3-fluoro-4-trifluoromethoxyphenol and 4-bromomethyl-1-n-heptyl-1-phenyl-1-silacyclohexane, thereby obtaining the intended compound.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:22])[N:4]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:5]([CH3:16])=[CH:6][C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>>[F:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:7]2[CH:6]=[C:5]([CH3:16])[N:4]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:3](=[O:22])[C:2]=2[NH:1][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[CH:10][CH:11]=1
Reactant: COC(=O)Cn1c(C)cc(Cc2ccc(F)cc2)c(N)c1=O
Reactant: O=C(Cl)OCc1ccccc1
Product: COC(=O)Cn1c(C)cc(Cc2ccc(F)cc2)c(NC(=O)OCc2ccccc2)c1=O
Yield: 83 %

Procedure:
1.8 g (5.91 mmol) of methyl 3-amino-4-[(4-fluorophenyl)methyl]-6-methyl-2-oxo-1,2-dihydro-pyridine-1-acetate are treated with 1 ml (7.09 mmol) of phenylmethyl chloroformate according to the method described in Example 3. The residue is purified by chromatography on a silica gel column, eluting with a dichloromethane:methanol (98:2) mixture. 2.15 g of product are obtained.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(O)C.[OH-].[Na+].[ClH:36]>O1CCCC1>[ClH:36].[CH2:1]([O:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:15][CH2:16][N:17]([C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)[CH2:18][CH2:19]2)=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc(N2CCN(c3ccc(C(=O)OCC)cc3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCOc1ccc(N2CCN(c3ccc(C(=O)O)cc3)CC2)cc1

Procedure:
To a solution of ethyl 4-[4-(4-hexyloxyphenyl)piperazin-1-yl]benzoate (2.19 g) in the mixture of ethanol (22 ml) and tetrahydrofuran (22 ml) was added 2N NaOH aq. and refluxed for 5 hours. The reaction mixture was adjusted to pH 1-1.5 with 1N HCl and the resulting precipitate was collected by filtration to give 4-[4-(4-hexyloxyphenyl)piperazin-1-yl]benzoic acid hydrochloride (1.99 g).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[O:6][C:7]=1[CH3:8].[O:17]=[CH:18][C:19]1[CH:27]=[CH:26][C:24]([OH:25])=[C:21]([O:22][CH3:23])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:18]([C:19]1[CH:27]=[CH:26][C:24]([O:25][CH2:2][C:3]2[N:4]=[C:5]([C:9]3[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=3)[C:12]#[N:13])[O:6][C:7]=2[CH3:8])=[C:21]([O:22][CH3:23])[CH:20]=1)=[O:17]
Reactant: Cc1oc(-c2cccc(C#N)c2)nc1CCl
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCc1nc(-c2cccc(C#N)c2)oc1C
Temperature: 90 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
A mixture of 3-(4-chloromethyl-5-methyl-1,3-oxazol-2-yl)benzonitrile (26.3 g), vanillin (17.19 g), anhydrous potassium carbonate (15.62 g) and N,N-dimethylformamide (300 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give 3-{4-[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzonitrile as colorless crystals (33.9 g, yield 86%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 166-167° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@@H:7]([OH:8])[C@H:6]([NH2:9])[C:5]2[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:4]=2[O:3]1.[C:18]([C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O)(OC)=[O:19].C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[CH3:1][C:2]1([CH3:17])[C@@H:7]([OH:8])[C@H:6]([N:9]2[CH2:24][C:23]3[C:22](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:18]2=[O:19])[C:5]2[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:4]=2[O:3]1
Reactant: COC(=O)c1ccccc1C=O
Reactant: CC1(C)Oc2cc([N+](=O)[O-])ccc2[C@@H](N)[C@@H]1O
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)Oc2cc([N+](=O)[O-])ccc2[C@@H](N2Cc3ccccc3C2=O)[C@@H]1O
Temperature: 50 °C
Reaction time: 48 h
Yield: 74.4 %

Procedure:
To 351 mg (1.48 mmol) of trans-3,4-dihydro-2,2-dimethyl-3-hydroxy-7-nitro-2H-1-benzopyran-4-amine in methanol (3 mL) containing 290 mg (1.77 mmol) of 2-carbomethoxybenzaldehyde was added 1.5 mL (0.75 mmol) of 0.5M zinc chloride-modified sodium cyanoborohydride in methanol, prepared according to the method of Kim et al. J. Org. Chem. 50 (11), 1927 (1985). After stirring at 50° C. for two days, the reaction mixture was quenched with saturated NaHCO3 solution, extracted into CH2Cl2, dried (K2CO3) and concentrated. The residue was dissolved in a minimal amount of THF and silica gel was added. The solvent was removed in vacuo and the silica gel was applied onto the head of a flash column. Eluting with 20%→50% ether/CH2Cl2 gave 390 mg of the title compound as a pale yellow powder, m.p. 249°-250° C.