Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=S)[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[NH2:23][NH2:24]>C(O)C>[NH:23]([C:12]1[N:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:6]=2)[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)[NH2:24]
Reactant: CC(C)Oc1cccc(-n2c(=S)[nH]c3ccccc3c2=O)c1
Reactant: NN
Solvent: CCO
Product: CC(C)Oc1cccc(-n2c(NN)nc3ccccc3c2=O)c1
Yield: 38.7 %

Procedure:
A mixture of 3-(3-isopropoxy-phenyl)-2-thioxo-2,3-dihydro-1H-quinazolin-4-one (Example 1) (3.12 g, 10 mmol) and anhydrous hydrazine (3.2 g, 100 mmol) in 100 mL of ethanol was refluxed for 18 hours The reaction mixture was then cooled and white solid was separated which was filtered to obtain 1.2 g (38%) of title compound as white solid. The filtrate was concentrated and an additional 1.6 g (50.4%) of title compound was isolated by crystallization from ethyl acetate, mp 158°-160° C.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][C:12](=[CH:14]OC)[CH2:11][CH2:10][N:9]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32]N)=[CH:28][CH:27]=1.C(O)(C(F)(F)F)=O.C(N(CC)CC)C.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>C(Cl)(Cl)Cl.CCOC(C)=O>[CH2:1]([CH:8]1[CH2:13][C:12]2([C:30]3[C:29](=[CH:28][CH:27]=[C:26]([Cl:25])[CH:31]=3)[N:32]=[CH:14]2)[CH2:11][CH2:10][N:9]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC=C1CCN(C(=O)OC(C)(C)C)C(Cc2ccccc2)C1
Reactant: NNc1ccc(Cl)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC2(C=Nc3ccc(Cl)cc32)CC1Cc1ccccc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Tert-butyl 2-benzyl-4-(methoxymethylene)piperidine-1-carboxylate (274 mg, 0.86 mmol) and (4-chlorophenyl)hydrazine hydrochloride (186 mg, 1.04 mmol) were dissolved in chloroform (10 mL) and then TFA (1.0 mL, 12.98 mmol) was added. The resulting mixture was heated to reflux for 8 h at which time it was cooled to ambient and then quenched by the slow addition of saturated sodium bicarbonate solution. The reaction mixture was dissolved in EtOAc and then washed twice with water and once with brine. The organic portion was dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in dichloromethane (10 mL) and cooled to 0° C. Triethylamine (0.24 mL, 1.73 mmol) was added followed by boc anhydride (189 mg, 0.86 mmol). The resulting solution was warmed ambient and stirred at this temperature for 12 h. At this time, it was taken up in EtOAc and washed twice with water and once with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue thus obtained was purified via silica gel chromatography to give tert-butyl 2′-benzyl-5-chlorospiro[indole-3,4′-piperidine]-1′-carboxylate as a mixture of diastereomers (220 mg, 62%). LCMS (APCI+) m/z 411.1 [M+H]+; Rt=4.56, 4.63 min
Reaction SMILES: [ClH:1].[OH:2][C@H:3]1[CH2:7][CH2:6][NH:5][C@@H:4]1[C:8]([OH:10])=[O:9].[CH3:11]O>>[ClH:1].[OH:2][C@H:3]1[CH2:7][CH2:6][NH:5][C@@H:4]1[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C(O)[C@H]1NCC[C@@H]1O
Reactant: CO
Agent: Cl
Product: COC(=O)[C@H]1NCC[C@@H]1O
Reaction time: 8 h
Yield: 94 %

Procedure:
Hydrogen chloride gas was bubbled through a suspension of trans-3-hydroxy-L-proline (1.5 g, 11.4 mmol) in 20 ml of freshly distilled MeOH at 0° C. for 30 min. The resulting clear solution was stirred overnight, then concentrated under reduced pressure to afford the title compound as a white solid (1.96 g). Yield 94%.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)=[CH:11][C:10]([CH2:25]Cl)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)=[CH:11][C:10]([CH2:25][N:27]2[CH2:33][CH2:32][CH2:31][N:30]([CH2:25][C:10]3[CH:11]=[C:12]([C:13]4[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=4)[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[N:9]=3)[CH2:29][CH2:28]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(-c2cc(CCl)nn2Cc2ccccc2)cc(OC)c1OC
Reactant: C1CNCCNC1
Product: COc1cc(-c2cc(CN3CCCN(Cc4cc(-c5cc(OC)c(OC)c(OC)c5)n(Cc5ccccc5)n4)CC3)nn2Cc2ccccc2)cc(OC)c1OC

Procedure:
1-Benzyl-3-chloromethyl-5-(3,4,5-trimethoxy-phenyl)pyrazole (559 mg) and homopiperazine (68 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].O=[C:8]1[CH:17]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9]1>C1COCC1>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][CH:17]([NH:18][S:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)(=[O:20])=[O:21])[CH2:8]1
Reactant: O=C1Nc2ccccc2CC1NS(=O)(=O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(NC1CNc2ccccc2C1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.8 %

Procedure:
To a solution of LAH (1.0 mL, 1.0 M solution in Et2O) cooled at 0° C. was added dropwise a solution of 162A (120 mg, 0.4 mmol) in THF (5 mL) in 5 min. After addition, the reaction mixture was stirred at RT for 4 h, then quenched by slow addition of EtOAc (2.0 mL), followed by water (15 mL). The mixture was extracted with EtOAc (2×20 mL). The combined EtOAc extracts were washed with water, brine, dried (MgSO4) and concentrated. The residue was chromatographed (silica gel) eluting with EtOAc (30-60%) in hexane to give the title compound (84 mg, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]([C:35]2[CH:49]=[CH:48][C:38]([O:39][CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[CH:37][CH:36]=2)[CH:10]([S:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:11](=[O:24])N2[C@@H](C3C=CC=CC=3)COC2=O)=[CH:4][CH:3]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:24])[C@H:10]([S:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C@H:9]2[C:35]2[CH:36]=[CH:37][C:38]([O:39][CH2:40][C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])=[CH:48][CH:49]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CSC(C(=O)N2C(=O)OC[C@@H]2c2ccccc2)[C@H](Nc2ccc(Cl)cc2)c2ccc(OCC(=O)OC(C)(C)C)cc2)cc1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: Cc1ccccc1
Product: COc1ccc(CS[C@H]2C(=O)N(c3ccc(Cl)cc3)[C@@H]2c2ccc(OCC(=O)OC(C)(C)C)cc2)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
tert-Butyl (4-{(1R)-1-[(4-chlorophenyl)amino]-2-[(4-methoxybenzyl)thio]-3-oxo-3-[(4S)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]propyl}phenoxy)acetate (Method 25) (2.3 g, 3.3 mmol) was dissolved in dry toluene (250 mL) and heated to 90° C. under inert atmosphere. N,O-Bis(trimethylsilyl)acetamide (BSA, 2.4 mL, 9.8 mmol) was added and the mixture was stirred at 90° C. for one hour. The mixture was then given 45° C. and tetrabutylammonium fluoride (TBAF, 0.2 g) was added. The mixture was stirred at 45° C. for 2 hours. After cooling, the mixture was concentrated under reduced pressure and purified by flash-chromatography (Heptane:EtOAc 4:1). This afforded the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:16]=[C:15]([CH2:17][CH3:18])[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:19])[C:5]=2[CH:4]=1)[CH3:2].[BH4-].[Na+].O>CO>[CH2:1]([C:3]1[CH:16]=[C:15]([CH2:17][CH3:18])[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]([OH:19])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc(CC)c2sc3ccccc3c(=O)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCc1cc(CC)c2c(c1)C(O)c1ccccc1S2
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a stirred solution of 2,4-diethyl-9H-thioxanthen-9-one (20 g, 74.5 mmol) in methanol (400 ml) cooled in an ice bath was added sodium borohydride (8 g, 0.2 mole) portionwise. After 1 hour at room temperature, water (100 ml) was added to the reaction mixture and the precipitate collected and washed with water to give the title compound as a white solid (20 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[NH2:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][C:32]=1[CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]([CH3:29])[CH3:28])[CH:22]=1)=[O:19]>>[CH3:29][N:27]([CH3:28])[C:23]1[CH:22]=[C:21]([NH:20][C:18](=[O:19])[C:17]2[CH:30]=[CH:31][C:32]([CH3:33])=[C:15]([NH:14][C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[O:12])[CH:16]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: Cc1ccc(C(=O)Nc2cccc(N(C)C)c2)cc1N
Product: Cc1ccc(C(=O)Nc2cccc(N(C)C)c2)cc1NC(=O)c1ccc2ccccc2c1

Procedure:
Using an analogous procedure to that described in Example 1, 2-naphthoyl chloride was reacted with 3-amino-N-(3-dimethylaminophenyl)-4-methylbenzamide to give the title compound; Mass Spectrum: M+H+ 424.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C(N(CC)C(C)C)(C)C.[CH:22]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C)C=O.C(OCC)(=O)C>[CH:22]1([NH:28][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=[N+]([O-])c1cc(CO)ccc1F
Reactant: NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(CO)ccc1NC1CCCCC1

Procedure:
A mixture of (4-Fluoro-3-nitrophenyl)methanol (1.00 g, 0.0058 mol), N,N-diisopropylethylamine (2.036 mL, 0.0117) and cyclohexanamine (2.005 mL, 0.0175 mol) in N,N-Dimethylformamide (2.46 mL) was placed in a microwave vial, the contents were mixed thoroughly then microwaved at 130° C. for 7 minutes. The resultant gel was dissolved in ethyl acetate then washed with 5% citric acid, brine, dried and concentrated to give the title compound.
Reaction SMILES: [Si]([O:8][CH:9]([C:28]([F:31])([F:30])[F:29])[CH2:10][C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([N:23]=[CH:24][N:25]([CH3:27])[CH3:26])(=[O:22])=[O:21])([CH3:13])[CH3:12])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:27][N:25]([CH3:26])[CH:24]=[N:23][S:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]([CH3:12])([CH3:13])[CH2:10][CH:9]([OH:8])[C:28]([F:29])([F:30])[F:31])(=[O:22])=[O:21]
Reactant: CN(C)C=NS(=O)(=O)c1ccccc1C(C)(C)CC(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN(C)C=NS(=O)(=O)c1ccccc1C(C)(C)CC(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.1 %

Procedure:
To a round bottom flask was added 2-[3-(tert-butyldimethylsilanyloxy)-4,4,4-trifluoro-1,1-dimethylbutyl]-N-[1-dimethylaminomethylidene]benzenesulfonamide (820 mg, 1.76 mmol) in 15 mL of dry THF, followed by the addition of a solution of 1M TBAF in THF (1.76 mL, 1.76 mmol). The reaction mixture was stirred at room temperature for 10 minutes, quenched with 100 mL of saturated aqueous sodium bicarbonate solution, and extracted with 250 mL of ethyl acetate. The organic layer was separated, washed with 100 mL of water and 100 mL of brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude mixture was purified by flash chromatography. The column was eluted with 0-40% EtOAc/hexanes to afford 381 mg (59%) of N-[1-dimethylaminomethylidene]-2-(4,4,4-trifluoro-3-hydroxy-1,1-dimethylbutyl)benzenesulfonamide. MS (ES+) m/z 367 [M+H]+.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([CH2:39][NH:40][C:41](=[O:45])[CH2:42][NH:43][CH3:44])[CH2:4][CH2:3]2.C=O.[C:48](O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:44][N:43]([CH3:48])[CH2:42][C:41]([NH:40][CH2:39][C@:5]12[CH2:35][CH2:34][C@@H:33]([C:36]([CH3:38])=[CH2:37])[C@@H:6]1[C@@H:7]1[C@@:2]([CH3:1])([CH2:3][CH2:4]2)[C@@:19]2([CH3:20])[C@@H:10]([C@:11]3([CH3:32])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1)=[O:45]
Reactant: C=C(C)[C@@H]1CC[C@]2(CNC(=O)CNC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(CNC(=O)CN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(methylamino)acetamido)methyl)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, example 139, (10 mg, 0.016 mmol) and formaldehyde (0.488 mg, 0.016 mmol) in MeOH (1 ml) was added acetic acid (1.860 mL, 0.033 mmol) and sodium cyanoborohydride (1.022 mg, 0.016 mmol). A clear solution was formed soon after mixing. The mixture was stirred at rt for 2 h, LC/MS showed the mass of the expected product. The mixture was diluted with 7 ml of sat. NaHCO3 and was extracted with dichloromethane (3×7 ml). The combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to afford the title compound as a white solid (2 mg, 18.6%). LCMS: m/e 629.4 (MH+), 2.72 min (method 3). 1H NMR (400 MHz, MeOD) δ ppm 7.90 (d, J=8.6 Hz, 2H), 7.20 (d, J=8.3 Hz, 2H), 5.19-5.42 (m, 1H), 4.72 (d, J=1.8 Hz, 1H), 4.59 (s, 1H), 3.93 (s, 2H), 3.58 (br. s., 1H), 3.04-3.17 (m, 1H), 2.89 (s, 6H), 2.46-2.60 (m, 1H), 2.10-2.18 (m, 2H), 1.80 (br. s., 2H), 1.65-1.77 (m, 7H), 1.63 (s, 1H), 1.58 (br. s., 2H), 1.38-1.55 (m, 4H), 1.19-1.34 (m, 4H), 1.13-1.19 (m, 4H), 1.06-1.13 (m, 2H), 1.04 (s, 3H), 1.02 (s, 3H), 0.95 (s, 3H), 0.93 (s, 3H).
Reaction SMILES: CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4:17].[CH3:18][C:19](=[O:24])[CH2:20][C:21](=[O:23])[CH3:22]>C(O)C>[C:21]([CH2:20][C:19](=[O:24])[CH3:18])(=[O:23])[CH3:22].[C:21]([CH2:20][C:19](=[O:24])[CH3:18])(=[O:23])[CH3:22].[Ti:17]
Reactant: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCO
Solvent: CC(=O)CC(C)=O
Product: [Ti]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a dried vial fitted with a stir bar and septum cap was added titanium tetraisopropoxide (2.8573 g, 1.005 mmol) then 2,4-pentanedione (1.0257 g, 1.0245 mmol), and quickly cooled in an ice water bath. The dark yellow liquid was stirred overnight at room temperature. The solution was then diluted with 32.4 ml ethanol (200 proof).
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.B([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37]([OH:39])=[O:38])(O)O>>[C:27]([O:26][C:24]([N:19]1[C:18]([C:34]2[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=2)[C:37]([OH:39])=[O:38])=[CH:23][O:22][CH2:21][CH2:20]1)=[O:25])([CH3:28])([CH3:29])[CH3:30]
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOC=C1c1cccc(C(=O)O)c1
Yield: 26 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and 3-boronobenzoic acid using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as an off-white solid (26% yield); 1H-NMR (d6-DMSO) 1.01 (9H, s), 3.71 (2H, t), 4.12 (2H, t), 6.50 (1H, s), 7.40-7.46 (2H, m), 7.74-7.77 (2H, m), 12.94 (1H, brs); 13C-NMR (d6-DMSO) 27.7, 41.5, 66.8, 126.8, 128.0, 128.2, 130.1, 133.0; MS ES(+) 249.9 (M+-tBu). IR λmax=1694 cm−1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N:12]1([CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]2[C:27]([CH:28]([CH3:30])[CH3:29])=[C:26]([CH:31]=O)[NH:25][C:24]=2[CH:33]([CH3:35])[CH3:34])=[O:22])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[N:12]1([CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]2[C:27]([CH:28]([CH3:30])[CH3:29])=[C:26]([CH:31]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[NH:25][C:24]=2[CH:33]([CH3:35])[CH3:34])=[O:22])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CC(C)c1[nH]c(C=O)c(C(C)C)c1C(=O)NCCCN1CCCC1
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: CC(C)c1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(C(C)C)c1C(=O)NCCCN1CCCC1
Yield: 15.2 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (130 mg, 0.6 mmol) was condensed with 5-formyl-2,4-diisopropyl-1H-pyrrole-3-carboxylic acid (3-pyrrolidin-1-ylpropyl)amide (150 mg, 0.45 mmol) to give 36 mg (15%) of the title compound as a tan-orange solid.
Reaction SMILES: O.O[N:3]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:24]([O:28][C:29]([NH:31][C@H:32]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:33][C:34](O)=[O:35])=[O:30])([CH3:27])([CH3:26])[CH3:25].N>ClCCl>[NH2:3][C:34](=[O:35])[CH2:33][C@H:32]([NH:31][C:29](=[O:30])[O:28][C:24]([CH3:27])([CH3:26])[CH3:25])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-hydroxybenzotriazole hydrate (3.46 g, 25.6 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.91 g, 25.6 mmol), and (S)-N-tert-butoxycarbonyl-3-amino-3-phenylpropanoic acid (6.80 g, 25.6 mmol) in dichloromethane (250 ml) was stirred at room temperature for 1 hour. 0.88 Ammonia (20 ml) was added and the mixture stirred at room temperature for a further 18 hours. The resulting solid was filtered off and washed with sodium bicarbonate solution, then water and dried under vacuum at 50° C. to afford the title compound, 6.78 g.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[N:6][C:7]([OH:10])=[N:8][CH:9]=1.[C:11]([O:15][C:16](=[O:19])[CH2:17]Br)([CH3:14])([CH3:13])[CH3:12].O>CN(C=O)C>[C:11]([O:15][C:16](=[O:19])[CH2:17][O:10][C:7]1[N:8]=[CH:9][C:4]([Br:3])=[CH:5][N:6]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: Oc1ncc(Br)cn1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)COc1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
137 mg of sodium hydride (55% in mineral oil) were added to 500 mg (2.86 mmol) of 5-bromo-pyrimidin-2-ol in 20 ml of DMF, and the mixture was stirred at room temperature for 15 min. Then 613 mg (3.14 mmol) of bromoacetic acid tert-butyl ester were added and the reaction mixture was stirred for 1 h. After addition of water, the mixture was extracted with ethyl acetate. The combined extracts were dried and evaporated to give the crude product. Yield: 868 mg.
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[N:21]#[C:22][NH2:23].[Na].C>C1COCC1>[C:1]([NH:23][C:22]#[N:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: N#CN
Agent: [Na]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCC(=O)NC#N
Reaction time: 63 h
Yield: 92.4 %

Procedure:
Stearoyl chloride (3.03 g, 0.010 mol) in 50 ml of freshly distilled dry THF was added drop-wise to a suspension of sodium cyanamide (1.92 g, 0.030 mol) in 100 ml of freshly distilled dry THF with vigorous stirring. The reaction was allowed to proceed at 25° C. for 63 hours. The solids which formed were collected by filtration and the solid cake was suspended in 200 ml of distilled water. The resulting soapy suspension (pH 10.5) was acidified to pH 1.5 with 10% HCl, filtered, and air-dried to give 2.85 g (92.4% yield) of crude 7. This was dissolved in THF and the solution decolorized with activated charcoal. The filtrate was concentrated until the solution became turbid. Addition of petroleum ether gave 2.29 g (crop 1) of white waxy 7. The filtrate was concentrated and petroleum ether added to give 0.28 g (crop 2) of additional product giving a total yield of 83.3%, mp 74°- 75° C. TLC: Rf =0.69 in EtOAc/petroleum ether/AcOH (50:100:1), detected by UV quenching (weak) and no color reaction with ferricyanide spray reagent; IR (Nujol, cm-1) 3210 (NH), 2250 (C≡N), 1735 (C=O); NMR (Silanor C, δ from TMS) 2.3-2.6 (t, --CH2 --CH2 --C=O), 1.0-1.8 (fused s, (CH2)14), 0.8-0.9 (t, CH3 --CH2 --); Anal. Calcd for C19H36N2O: C, 73.97; H, 11.76; N, 9.08. Found: C, 73.88; H, 11.50; N, 9.09.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.C([O-])=O.[NH4+]>[Pd].CCO>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ccc([N+](=O)[O-])cn3)cc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)CC1CCC(c2ccc(-c3ccc(N)cn3)cc2)CC1
Temperature: 25 °C

Procedure:
To a solution of {4-[4-(5-Nitro-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (1.4 g, 4.0 mmol) in 20 Ml EtOH was added Pd/C (0.4 g) followed by ammonium formate (2 g). The reaction mixture was heated to reflux for 4 h, then cooled to room temperature and filtered through Celite. Removal of solvent in vacuo afforded the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08-1.20 (m, 2 H) 1.43-1.54 (m, 1 H) 1.48 (dd, J=12.57, 2.46 Hz, 2H) 1.81 (d, J=11.75 Hz, 6 H) 2.26 (d, J=6.69 Hz, 2 H) 3.61 (s, 3 H) 6.98 (dd, J=8.59, 2.78 Hz, 1 H) 7.24 (d, J=8.34 Hz, 2 H) 7.57 (d, J=8.59 Hz, 1 H) 7.81 (d, J=8.34 Hz, 2 H) 8.00 (d, J=2.65 Hz, 1 H); (M+H)+ 325.2.
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([O:10][CH2:11][C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]#[N:24])[CH2:19][CH2:18]4)[S:15][CH:16]=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[OH:27][NH:28][C:29](=N)[CH:30]([CH3:32])[CH3:31]>C1COCC1.[Cl-].[Zn+2].[Cl-]>[CH:30]([C:29]1[N:24]=[C:23]([N:20]2[CH2:21][CH2:22][CH:17]([C:14]3[S:15][CH:16]=[C:12]([CH2:11][O:10][C:9]4[CH:8]=[CH:7][C:6]([N:1]5[CH:5]=[N:4][N:3]=[N:2]5)=[CH:26][CH:25]=4)[N:13]=3)[CH2:18][CH2:19]2)[O:27][N:28]=1)([CH3:32])[CH3:31]
Reactant: CC(C)C(=N)NO
Reactant: N#CN1CCC(c2nc(COc3ccc(-n4cnnn4)cc3)cs2)CC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CC(C)c1noc(N2CCC(c3nc(COc4ccc(-n5cnnn5)cc4)cs3)CC2)n1
Reaction time: 0.25 h

Procedure:
To a solution of 4-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carbonitrile (0.450, 1.22 mmol) and N-hydroxy-isobutyramidine (0.150 g, 1.47 mmol) in dry THF (10 mL) was added a 1 M solution of zinc chloride in THF (1.47 mL, 1.47 mmol) over 15 min. The suspension was left to settle for 15 minutes and the white precipitate was collected by filtration and dissolved in 4N HCl in ethanol and water (1:1). The solution was refluxed for 1 hour, cooled and the solid precipitate was filtered off. The filtrate was neutralized by the addition of excess sodium carbonate. The excess was filtered off and the filtrate was diluted with EtOAc. The solution was washed with water, separated, dried (Na2SO4), filtered and concentrated. The residual oil was chromatographed on silica gel (1:1 Hex/EtOAc) to afford the desired compound. 1H NMR (CDCl3): δ 8.92 (1H, s), 7.62 (2H, d), 7.28 (1H, s), 7.19 (2H, d), 5.24 (2H, s), 4.26 (2H, m), 3.20 (3H, m), 2.89 (1H, m), 2.26 (2H, m), 1.92 (2H, m), 1.30 (6H, d).