Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:14][O:15]CC3CCCCC3)[C:11]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)[CH:14]=[O:15])[C:11]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(COCC3CCCCC3)C3CCCCC3)c2cc1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: O=CC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To a solution of 200 mg (0.512 mmol) 2-[2-(4-chloro-phenyl)-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, intermediate c) in 2 ml dichloromethane was added 1.59 ml (2.17 g, 0.768 mmol) 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (Dess-Martin-periodinane; 15 wt % in dichloromethane). The reaction mixture was stirred for 2 h at room temperature and then poured onto 30 ml dichloromethane and 30 ml water. The aqueous layer were extracted again with 30 ml dichloromethane. The combined organic layers were washed with 30 ml brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by silica chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 60:40) to give the product as a colorless solid (74%). MS (Turbo Spray): m/z=389.2 [M+H].
Reaction SMILES: [CH3:1][N:2]1[CH2:11][C:10]2[C:12]3[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][C:17]=3[N:8]3[C:9]=2[C:4]([CH3:25])([CH2:5][CH:6]=[C:7]3[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:3]1.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:1][N:2]1[CH2:11][C:10]2[C:12]3[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][C:17]=3[N:8]3[C:9]=2[C:4]([CH3:25])([CH2:5][CH2:6][CH:7]3[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c3n2C(c2ccccc2)=CCC3(C)CN(C)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1ccc2c(c1)c1c3n2C(c2ccccc2)CCC3(C)CN(C)C1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 2,3a,10-trimethyl-6-phenyl-2,3,3a,4-tetrahydro-1H-indolo[3,2,1-ij][1,6]naphthyridine (100 mg, 0.304 mmol) in MeOH (5 mL) was added 10% Pd—C (100 mg) and ammonium formate (96 mg, 1.524 mmol). The reaction mixture was stirred at 80° C. for 4 h under N2. The reaction mixture was filtered on a Celite bed and washed with MeOH. The filtrate was concentrated under reduced pressure to obtain crude product which was purified by reverse phase HPLC to yield 2,3a,10-trimethyl-6-phenyl-2,3,3a,4,5,6-hexahydro-1H-indolo[3,2,1-ij][1,6]naphthyridine as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3](N1C=CN=C1)=[O:4].[CH3:12][C:13]1[N:14]=[C:15]([Si](C)(C)C)[O:16][CH:17]=1.O>C(OCC)C>[CH3:12][C:13]1[N:14]=[C:15]([C:3](=[O:4])[C:2]([F:11])([F:10])[F:1])[O:16][CH:17]=1
Reactant: O=C(n1ccnc1)C(F)(F)F
Reactant: Cc1coc([Si](C)(C)C)n1
Solvent: CCOCC
Solvent: O
Product: Cc1coc(C(=O)C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Trifluoroacetylimidazole (10 g) was added dropwise to 4-methyl-2-trimethylsilyloxazole (J. Chem. Soc., Chem. Commun., 1984, 258) (9.95 g) in diethyl ether (100 ml) at 0° C. under an atmosphere of dry nitrogen. The mixture was stirred overnight at room temperature. Water was added and the organic layer was separated, washed, dried and evaporated. Flash chromatography gave the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:9]([CH2:10]O)=[C:8]([CH3:12])[N:7]=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:5]=1.S(Cl)([Cl:25])=O>>[Cl:25][CH2:10][C:9]1[C:4]([CH2:3][O:2][CH3:1])=[N:5][C:6]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[N:7][C:8]=1[CH3:12]
Reactant: COCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C)c1CO
Reactant: O=S(Cl)Cl
Product: COCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C)c1CCl

Procedure:
In analogy to the procedure described in example 113H], [4-methoxymethyl-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-methanol and thionylchloride gave the title compound as a light red oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][N:6]([CH2:17][CH2:18][O:19][CH:20]([O:22][CH2:23][CH3:24])[CH3:21])[S:7]([C:10]1[S:11][CH:12]=[CH:13][C:14]=1[CH:15]=O)(=[O:9])=[O:8])[CH3:2].C1CCN2C(=NCCC2)CC1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:23]([O:22][CH:20]([O:19][CH2:18][CH2:17][N:6]1[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:25])=[CH:15][C:14]2[CH:13]=[CH:12][S:11][C:10]=2[S:7]1(=[O:9])=[O:8])[CH3:21])[CH3:24]
Reactant: CCOC(=O)CN(CCOC(C)OCC)S(=O)(=O)c1sccc1C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C1=Cc2ccsc2S(=O)(=O)N1CCOC(C)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a mixture of the product from Step B (10.2 g, 25.9 mmol) and molecular sieves (10 g) in ethyl acetate (150 mL) was added DBU (1 mL). The mixture was stirred overnight at ambient temperature, poured into a sainted solution of sodium bicarbonate (150 mL), and the organic layer was separated, dried and evaporated to give an oil (8.89 g, 91%).
Reaction SMILES: [CH2:1]([P:5]([CH2:8][CH:9]([C:22]([O:24]CC1C=CC=CC=1)=[O:23])[CH2:10][CH2:11][C:12]([O:14]CC1C=CC=CC=1)=[O:13])(=[O:7])[OH:6])[CH2:2][CH2:3][CH3:4]>O>[CH2:1]([P:5]([CH2:8][CH:9]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:22]([OH:24])=[O:23])([OH:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCP(=O)(O)CC(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Solvent: O
Product: CCCCP(=O)(O)CC(CCC(=O)O)C(=O)O
Yield: 43.3 %

Procedure:
Butyl[2,4-di(benzyloxycarbonyl)butyl]phosphinic acid (2.9 g, 6.5 mmol) in 30 mL of water containing 0.32 g 10% Pd/C was hydrogenated at 40 psi for 4.5 hours. The mixture was filtered through a pad of Celite and evaporated under high vacuum to give 2-[(butylhydroxyphosphinyl)methyl]-pentanedioic acid (4, R=n-butyl,) (0.75 g, 43%) as a clear and colorless viscous oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:26]2=[CH:27][CH:28]=[N:29][CH:30]=[C:25]2[C:5]2[C:6]([OH:24])=[CH:7][C:8]([CH:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:11])=[CH:9][C:4]=2[O:3]1.[ClH:32].[N:33]1([CH2:39][CH2:40][CH2:41][C:42](O)=[O:43])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:32].[CH3:31][C:2]1([CH3:1])[C:26]2=[CH:27][CH:28]=[N:29][CH:30]=[C:25]2[C:5]2[C:6]([O:24][C:42](=[O:43])[CH2:41][CH2:40][CH2:39][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:7][C:8]([CH:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: O=C(O)CCCN1CCCCC1
Reactant: CCCCCCCCCCCCC(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CCCCCCCCCCCCC(C)c1cc(OC(=O)CCCN2CCCCC2)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
5,5-Dimethyl-8-(2-tetradecyl)-10-[4-(piperidino)butyryloxy]-5H-[1]benzopyrano[3,4-d]pyridine hydrochloride is prepared according to the method of Example 29 by reacting equimolar quantities of 5,5-dimethyl-10-hydroxy-8-(2-tetradecyl)-5H-[1]benzopyrano[3,4-d]pyridine and γ-piperidinobutyric acid hydrochloride in the presence of dicyclohexyl carbodiimide.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:47])[CH2:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[C:37]([CH2:38][O:39]C3CCCCO3)=[CH:36][N:35]=[N:34]2)[CH:28]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:39][CH2:38][C:37]1[N:33]([C:29]2[CH:28]=[C:27]([C:26]3[CH2:25][C:24](=[O:47])[NH:23][C:9]4[CH:10]=[C:11]([C:19]([F:22])([F:20])[F:21])[C:12]([N:14]5[CH2:18][CH2:17][CH2:16][CH2:15]5)=[CH:13][C:8]=4[N:7]=3)[CH:32]=[CH:31][CH:30]=2)[N:34]=[N:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3nncc3CO)c2)=Nc2cc(N3CCCC3)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from (RS)-[2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-5-pyrrolidin-1-yl-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example M37) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (33 mg).
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11](=[O:18])[C:12]2[CH2:17][CH2:16][CH2:15][NH:14][CH:13]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl>[CH3:1][C:2]1[C:10]([C:11](=[O:18])[C:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:27](=[O:28])[NH:26][C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)[CH:13]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Cc1nn2ccccc2c1C(=O)C1=CNCCC1
Solvent: ClCCl
Product: Cc1nn2ccccc2c1C(=O)C1=CN(C(=O)Nc2ccc(Cl)cc2)CCC1

Procedure:
One g of 2-methyl-3-(1,4,5,6-tetrahydronicotinoyl)-pyrazolo[1,5-a]pyridine was dissolved in 20 ml of methylene chloride and 1 g of p-chlorophenyl isocyanate was added dropwise whilst stirring to the solution. The mixture was stirred at room temperature for 2 hours, and after removal of solvent in vacuo, the residue was recrystallized from ethyl acetate to afford the title compound in yield of 1.2 g (73%), mp 198°-200° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:12](=[O:18])[NH:13][CH:14]=[CH:15][C:16]=1[I:17])=O.O=P(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[NH:1]1[C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]=[C:9]1[C:11]1[C:12](=[O:18])[NH:13][CH:14]=[CH:15][C:16]=1[I:17]
Reactant: Nc1ccncc1NC(=O)c1c(I)cc[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: O=c1[nH]ccc(I)c1-c1nc2cnccc2[nH]1
Reaction time: 2 h

Procedure:
To a solution of 4-iodo-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (4-amino-pyridin-3-yl)-amide (281 mg, 0.79 mmol) in 9 mL pyridine at 0 C was added (slowly) 0.5 mL POCl3 (5.3 mmol). The mixture was stirred at 0 C for 2 hours, then poured on a mixture of ice and saturated aqueous sodium bicarbonate solution. The product precipitates as a colloid. All attempts to filter or extract the product failed. The mixture was concentrated in vacuum, water removed by aceotropic destillation with n-propanol and the crude mixture used as it is. LCMS [M+H]+339, T=0.54 min product and [M+H]+357, T=0.29 min unreacted starting material [YMC ODS-A C18 S7 3.0×50 mm column; 0–100% gradient over 2 min*; 5 mL/min flow rate].* Gradient begins with 10% methanol/90% water (0.1% TFA) and end with 90% methanol/10% water (0.1% TFA)
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([N+]([O-])=O)[CH:11]=[C:12]([S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:5]=2[CH2:4][CH2:3]1.S(S([O-])=O)([O-])=[O:24].[Na+].[Na+]>>[OH:24][C:10]1[CH:11]=[C:12]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:8][CH2:7][C:6]=2[CH:9]=1
Reactant: CN1CCc2cc([N+](=O)[O-])cc(Sc3ccccc3)c2CC1
Reactant: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: CN1CCc2cc(O)cc(Sc3ccccc3)c2CC1

Procedure:
Following the procedures outlined in Examples 9 and 10, the 3-methyl-8-nitro-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine is reduced with sodium hydrosulfite and the corresponding 8-amino derivative is diazotized and then heated with cuprous sulfate/sulfuric acid to yield 8-hydroxy-3-methyl-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][CH:10]1[C:40]1[C:48]2[O:47][CH2:46][CH2:45][C:44]=2[C:43]([Cl:49])=[C:42]([CH2:50]Br)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:58][O:59][C:60]1[CH:65]=[CH:64][C:63](B(O)O)=[CH:62][CH:61]=1>CC(C)=O.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:49][C:43]1[C:44]2[CH2:45][CH2:46][O:47][C:48]=2[C:40]([CH:10]2[C@H:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:13]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[O:11]2)=[CH:41][C:42]=1[CH2:50][C:63]1[CH:64]=[CH:65][C:60]([O:59][CH3:58])=[CH:61][CH:62]=1
Reactant: Clc1c(CBr)cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c2c1CCO2
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)CCO3)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a mixture of compound 49 (623 mg, 0.81 mmol), K2CO3 (447 mg, 3.24 mmol) and 4-methoxyphenyl boronic acid (306 mg, 2.02 mmol) in acetone (7.5 mL) and H2O (2.5 mL) was added bis(triphenylphosphine)palladium chloride (56 mg, 0.08 mmol) at 0° C. under atmosphere of nitrogen. The mixture was stirred at 0° C. for 30 min and then, stirred at room temperature for 16 hours. The mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the product 50 (407 mg, 62%) as colorless oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[C:13]([O:15]C)=[O:14].O.[OH-].[Li+]>CO.O1CCCC1>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[C:13]([OH:15])=[O:14]
Reactant: COC[C@@H]1CCCN1Cc1cc(C)cc(C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COC[C@@H]1CCCN1Cc1cc(C)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 3-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]methyl}-5-methylbenzoate (170 mg, 0.50 mmol) in methanol (2 mL), tetrahydrofuran (1 mL), and water (1 mL) is added lithium hydroxide (211 mg, 5.0 mmol), and the reaction mixture stirred at room temperature for 2 h. The reaction mixture is concentrated under reduced pressure, dissolved in methylene chloride, filtered, and the filtrate concentrated under reduced pressure to provide the title compound. ESI MS m/z 264 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH2:9][C:10]([O:12][CH3:13])=[O:11].[CH:14](OC)=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:15][CH:14]=[C:9]([C:5]1[N:4]([CH3:3])[CH:8]=[CH:7][CH:6]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC=O
Reactant: COC(=O)Cc1cccn1C
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(=CO)c1cccn1C
Reaction time: 3 h
Yield: 93.1 %

Procedure:
Sodium hydride (3.05 g, 50% dispersion in oil, 64 mmol) was washed with 40°-60° C. petroleum ether and then suspended in dry DMF (30 ml) under an atmosphere of nitrogen. A solution of methyl (1-methylpyrrol-2-yl)acetate (5 g, 32 mmol) and methyl formate (39.5 ml, 64 mmol) in DMF (10 ml) was then added dropwise at room temperature with vigorous stirring. After 3 hours, the reaction mixture was poured into 10% aqueous potassium carbonate (100 ml) and extracted with ether (2×100 ml). The aqueous layer was treated with concentrated hydrochloric acid and re-extracted with ether (2×100 ml). The combined ether layers were dried and evaporated to give methyl 3-hydroxy-2-(1-methylpyrrol-2-yl)propenoate (5.4 g) as an orange oil which was used without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[CH3:6][C:7]([C:9]1[CH:17]=[CH:16][C:14]([OH:15])=[C:11]([O:12][CH3:13])[CH:10]=1)=[O:8].[OH-].[Na+]>O>[Cl:5][CH2:4][CH2:3][CH2:2][O:15][C:14]1[CH:16]=[CH:17][C:9]([C:7](=[O:8])[CH3:6])=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1cc(C(C)=O)ccc1O
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCCCCl
Temperature: 86 °C

Procedure:
To a mixture of 15.15 kg (96.26 mole) of 1-bromo-3-chloropropane and 25 liter of water heated to 86° C. was added a solution of 8 kg (48.13 mole) of acetovanillone in 3.93 kg (48.6 mole) of 50% aqueous sodium hydroxide and 89 liter of water over a 2.5 hr period. The mixture was heated at 80°-85° C. for 2.5 hr after addition was complete. The mixture was cooled and extracted twice with 49 kg portions of toluene. The combined extracts were washed once with 1.9 kg of 50% sodium hydroxide diluted to 5 gal and once with 5 gal of water. The toluene layer was dried over 3 lb of anhydrous sodium sulfate and concentrated under reduced pressure. The residue was heated to reflux in 15 gal of isopropylether, filtered, and the filtrate cooled. The crystallized title compound obtained by filtration together with additional compound obtained by concentrating the filtrate to 25% of its original volume amounted to 4.2 kg (36%). Acetovanillone recovered was 3.4 kg. The product was recrystallized twice from cyclohexane and twice from ligroin, m.p. 57.8°-58.5° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[S:13][C:14]([C:17]#[N:18])=[CH:15][N:16]=2)[CH2:8][CH2:7]1.CCN(CC)CC.[SH2:32].CC[O-].[Na+].C(O)C>O1CCOCC1>[F:24][C:2]([F:23])([F:1])[C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[S:13][C:14]([C:17](=[S:32])[NH2:18])=[CH:15][N:16]=2)[CH2:8][CH2:7]1
Reactant: N#Cc1cnc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)s1
Reactant: S
Agent: CC[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: C1COCCO1
Product: NC(=S)c1cnc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,3-thiazole-5-carbonitrile (354 mg, 1.0 mmol) in dioxane was added Et3N (20 μL, 0.14 mmol) and H2S (gas) was bubbled through the solution for about 1 min. After stirring at room temperature for 3 h, ethanol was added, followed by 21 wt. % NaOEt in ethanol (238 μL, 0.6 mmol). More H2S (gas) was bubbled through the solution for another minute. The mixture was then stirred at room temperature for 3 days. Volatile materials were removed in vacuo. The residue was dissolved in EtOAc, washed twice with water, dried (Na2SO4) and concentrated. Trituration with Et2O gave the title compound as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][C:18](=[O:20])[N:17](CC[Si](C)(C)C)[S:16]2(=[O:28])=[O:27])=[C:11]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:10]=1)=[O:5])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][C:18](=[O:20])[NH:17][S:16]2(=[O:27])=[O:28])=[C:11]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CC1c1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CC1c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To 2-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-cyclopropanecarboxylic acid ethyl ester (75 mg, 0.14 mmol) in THF (3 mL) is added 1M TBAF in THF (0.21 mL) and the solution is stirred at 60° C. for 2 h. The reaction is cooled to RT and diluted with EtOAc and washed with 1N HCl and brine. The organic layer is dried over MgSO4 and concentrated under reduced pressure to afford the title compound as a yellow oil, which is used in the next step without further purification: (M+H)+=448.
Reaction SMILES: O.NN.[OH-].[Na+].[Cl:6][C:7]1[N:12]=[C:11]([Cl:13])[C:10]([Cl:14])=[C:9](Cl)[C:8]=1Cl>O>[Cl:13][C:11]1[C:10]([Cl:14])=[CH:9][CH:8]=[C:7]([Cl:6])[N:12]=1
Reactant: Clc1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Clc1ccc(Cl)c(Cl)n1

Procedure:
Collins et al., J. Chem. Soc., (c); pages 167-174 (1971) teach that halogens ortho and para to the ring nitrogen in pentachloropyridine are reactive with hydrazine hydrate. This reference further teaches the formation of tetrahalo-4-hydroxy pyridine from the action of aqueous sodium hydroxide on tetrahalo-4-hydrazino pyridines. From this same starting material, 2,3,6-trichloropyridine is formed from the reaction with cuprous oxide in hot water.
Reaction SMILES: [N:1]1[P:6](Cl)(Cl)=[N:5][P:4](Cl)(Cl)=[N:3][P:2]=1(Cl)Cl.[CH2:13]([OH:17])[CH2:14][CH2:15][CH3:16]>N1C=CC=CC=1>[CH2:13]([O:17][P:2]1([O:17][CH2:13][CH2:14][CH2:15][CH3:16])[N:3]=[P:4]([O:17][CH2:13][CH2:14][CH2:15][CH3:16])([O:17][CH2:13][CH2:14][CH2:15][CH3:16])[N:5]=[P:6]([O:17][CH2:13][CH2:14][CH2:15][CH3:16])([O:17][CH2:13][CH2:14][CH2:15][CH3:16])[N:1]=1)[CH2:14][CH2:15][CH3:16]
Reactant: ClP1(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=N1
Reactant: CCCCO
Solvent: c1ccncc1
Product: CCCCOP1(OCCCC)=NP(OCCCC)(OCCCC)=NP(OCCCC)(OCCCC)=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a chilled solution (0°-5° C.) of triphosphonitrilic chloride (0.018 mole) in 26 ml of pyridine, butanol (0.34 mole) was added. The mixture was stirred at room temperature overnight, diluted with petroleum ether and washed with dilute HCl, NaHCO3, and water successively. After removal of solvent, the product IIa was obtained in a yield of 90%. Found (and calcd. for C24H54N3O6P3 /M.W. 574): C 47.32 (50.25); H 9.00 (9.49); and N 7.71 (7.33).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH:32]1[CH2:36][CH2:35][CH2:34][NH:33]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:33]1[CH2:34][CH2:35][CH2:36][CH:32]1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=1)=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: c1ccc(C2CCCN2)nc1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCCC2c2ccccn2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-2-(pyridin-2-yl)pyrrolidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.98 minutes; C26H23Cl2N5O2 (508.41); mass spectrum: (M−H)−=507/509/511 (chlorine isotope).