Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][CH:6]([CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH2:13]1)[C:7]([F:10])([F:9])[F:8])C.[OH-].[Na+]>C(O)C>[F:10][C:7]([F:8])([F:9])[CH:6]([CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=2)[CH2:13]1)[CH2:5][C:4]([OH:28])=[O:3]
Reactant: CCOC(=O)CC(CN1CCCC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC(CN1CCCC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
In a 10 mL pear-shaped flask, 4,4,4-trifluoro-3-[3-(3-trifluoromethyl-phenyl)-piperidin-1-ylmethyl]-butyric acid ethyl ester (130 mg, 316 μmol) and NaOH (237 μl, 474 μmol) were combined with ethanol (6 ml) to give a colorless solution. The reaction mixture was heated at 90° C. and stirred for 30 min. The reaction mixture was concentrated and treated with a saturated solution of NaH2PO4 (20 ml) and extracted with ethyl acetate (2×30 ml). The combined organics were washed with brine and H2O, dried over MgSO4, filtered and concentrated to give 120 mg (99%) of 4,4,4-trifluoro-3-[3-(3-trifluoromethyl-phenyl)-piperidin-1-ylmethyl]-butyric acid as a waxy solid. MH+=384.
Reaction SMILES: CC(C)N=C=NC(C)C.[F:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([F:21])[C:19]=1[F:20])[C:14]([OH:16])=O.[CH2:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH2:22]([N:29]1[CH2:34][CH2:33][N:32]([C:14]([C:13]2[CH:17]=[C:18]([F:21])[C:19]([F:20])=[C:11]([F:10])[CH:12]=2)=[O:16])[CH2:31][CH2:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)c1cc(F)c(F)c(F)c1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: O=C(c1cc(F)c(F)c(F)c1)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 59.8 %

Procedure:
DIC (1.34 g, 10.2 mmol) was added drop wise to a stirred solution of 3,4,5-trifluoro benzoic acid (1.5 g, 8.5 mmol) in THF (10 mL) and the resulting mixture was maintained for 30 minutes at room temperature. Mono benzyl piperazine (1.64 g, 9.35 mmol) was then added and the mixture heated to reflux at 70° C. overnight, under an atmosphere of nitrogen. The resulting solid precipitate was filtered and the filtrate was washed with water and evaporated. The residue was purified by column chromatography using silica gel 60-120 mesh (12% ethyl acetate in hexane) to afford 1.7 g (60%) of (4-benzyl-piperazin-1-yl)-(3,4,5-trifluoro-phenyl)-methanone. 1H NMR: (CDCl3): δ 7.32 (m, 5H), 7.06 (t, 2H), 3.75 (bs, 2H), 3.54 (s, 2H), 3.44 (bs, 2H), 2.46 (bs, 4H).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:22]3[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=3)=[N:9][C:10]3[C:15]([CH:16]=2)=[C:14]([C:17]2[CH:18]=[N:19][NH:20][CH:21]=2)[N:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:30][CH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CN1C(=O)CCC1>[CH3:35][C:32]([CH3:36])([CH2:31][NH:30][CH2:26][C:25]1[CH:24]=[CH:23][C:22]([C:8]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[N:13][C:14]=3[C:17]3[CH:21]=[N:20][NH:19][CH:18]=3)[N:9]=2)=[CH:29][CH:28]=1)[CH2:33][OH:34]
Reactant: O=Cc1ccc(-c2nc3ccnc(-c4cn[nH]c4)c3cc2-c2ccccc2)cc1
Reactant: CC(C)(CN)CO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: CC(C)(CO)CNCc1ccc(-c2nc3ccnc(-c4cn[nH]c4)c3cc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[3-phenyl-5-(1H-pyrazol-4-yl)-1,6-naphthyridin-2-yl]benzaldehyde (1-3) (0.11 g, 0.29 mmol) in NMP (10 mL) was added 3-amino-2,2-dimethylpropan-1-ol (0.030 g, 0.29 mmol) and acetic acid (0.026 g, 0.43 mmol). After stirring at room temperature for 2 hours, sodium triacetoxyborohydride (0.092 g, 0.43 mmol) was added and the reaction was stirred at room temperature for 15 hours. The reaction was poured into saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. Purification by reverse phase chromatography (5-95% acetonitrile/water/0.1% TFA; Water Sunfire C18) gave 2,2-dimethyl-3-({4-[3-phenyl-5-(1H-pyrazol-4-yl)-1,6-naphthyridin-2-yl]benzyl}amino)propan-1-ol (1-4) as a off white solid. HRMS (M+H)+: calculated 464.2207; found 464.2194
Reaction SMILES: Cl[C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:17][S-:18].[Na+]>CN(C=O)C>[CH3:17][S:18][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: C[S-]
Reactant: CCOC(=O)c1ccc(C(F)(F)F)cc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C(F)(F)F)cc1SC
Yield: 94.6 %

Procedure:
Example 3 is repeated except that 2.53 g (10 mmol) of ethyl 2-chloro-4-(trifluoromethyl)benzoate are reacted with 0.77 g (11 mmol) of sodium thiomethoxide in 15 ml of DMF. 2.5 g of ethyl 2-methylmercapto-4-(trifluoromethyl)benzoate of high purity are obtained. It is therefore not necessary to purify by distillation.
Reaction SMILES: Br[CH2:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][S:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([C:21]([F:24])([F:23])[F:22])[CH:10]=2)=[CH:5][CH:4]=1.[C:27]([O:31][C:32](=[O:36])[CH2:33][CH2:34][NH2:35])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:36])[CH2:33][CH2:34][NH:35][CH2:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][S:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([C:21]([F:24])([F:23])[F:22])[CH:10]=2)=[CH:5][CH:4]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)CCN
Reactant: FC(F)(F)c1cc(SCc2ccc(CBr)cc2)ccc1-c1ccccc1
Product: CC(C)(C)OC(=O)CCNCc1ccc(CSc2ccc(-c3ccccc3)c(C(F)(F)F)c2)cc1

Procedure:
3-[4-(2-Trifluoromethyl-biphenyl-4-ylsulfanylmethyl)-benzylamino]-propionic acid tert-butyl ester is synthesized similarly as described above by reaction of 4-(4-bromomethyl-benzylsulfanyl)-2-trifluoromethyl-biphenyl with 3-amino-propionic acid tert-butyl ester.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:9])[C:6](Cl)=[O:7])#[N:2].[CH:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:12]([OH:19])[CH:11]=1.CN(C)C1C=CC=CC=1>C(Cl)Cl>[C:1]([CH2:3][NH:4][C:5](=[O:9])[C:6]([O:19][C:12]1[CH:11]=[CH:10][C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=1)=[O:7])#[N:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: N#CCNC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: N#CCNC(=O)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
50 mM of [(cyanomethyl)amino]oxoacetyl chloride dissolved in methylene chloride is added dropwise at 0° to a solution of 40 mM of p-nitrophenol and 40 mM of dimethylaniline in methylene chloride. After stirring for one hour, the reaction mixture is extracted once with dilute hydrochloric acid and twice with water. The dried methylene chloride phase is concentrated under vacuum and yields 4.2 g. of [(cyanomethyl)amino]-oxoacetic acid, 4-nitrophenyl ester as a brown oil which crystallizes upon trituration with ether. Recrystallization from toluene gives white crystals, m.p. 123-124°.
Reaction SMILES: [N:1](OCCC(C)C)=[O:2].[F:9][C:10]1[CH:11]=[CH:12][C:13]2[O:18][CH2:17][CH2:16][NH:15][C:14]=2[CH:19]=1>C(Cl)Cl>[F:9][C:10]1[CH:11]=[CH:12][C:13]2[O:18][CH2:17][CH2:16][N:15]([N:1]=[O:2])[C:14]=2[CH:19]=1
Reactant: Fc1ccc2c(c1)NCCO2
Reactant: CC(C)CCON=O
Solvent: ClCCl
Product: O=NN1CCOc2ccc(F)cc21

Procedure:
Isoamyl nitrite is added to a solution of 6-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine (1 g) in DCM (15 mL) and heated to reflux overnight. The reaction mixture is concentrated in vacuo and the residue is purified by silica gel chromatography eluting with 10% EtOAc in heptane to give 6-Fluoro-4-nitroso-3,4-dihydro-2H-benzo[1,4]oxazine (0.83 g).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@H:23]5[CH2:28][CH2:27][NH:26][CH2:25][C@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.[CH:37](=O)[CH3:38]>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@H:23]5[CH2:28][CH2:27][N:26]([CH2:37][CH3:38])[CH2:25][C@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@H]1CCNC[C@H]1F
Reactant: CC=O
Product: CCN1CC[C@H](N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)[C@H](F)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(cis)-1-ethyl-3-fluoropiperidin-4-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(cis)-3-fluoropiperidin-4-yl]-1,3-thiazolidine-2,4-dione (Example 201) and acetaldehyde (in place of formaldehyde) following General Procedure R2.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.CS(O[CH:25]1[CH2:28][N:27]([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26]1)(=O)=O>C(#N)C.O1CCCC1>[C:30]1([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:27]2[CH2:28][CH:25]([N:10]3[CH2:11][CH2:12][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:9]3)[CH2:26]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
Potassium carbonate (26 g) was added to a solution of tert-butyl piperazine-1-carboxylate (7.7 g) in acetonitrile (100 ML), to which a suspension of 1-(diphenylmethyl)azetidin-3-yl methanesulfonate (12.05 g) in tetrahydrofuran (30 mL) was added at room temperature, and the mixture was stirred for 4 hours at 100° C., and then concentrated. To the resulting residue was added water, and the mixture was extracted with ethyl acetate twice. The extract was dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to column chromatography on silica gel (hexane:ethyl acetate=3:1→1:2), and the product was washed with tert-butyl methyl ether and collected by filtration to give the title compound (10.68 g) having the following physical data.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:6][NH:5][CH2:4]1.Cl.Cl[C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]2[C:19](=[O:20])[C:18]([N:21]3[CH:25]=[CH:24][N:23]=[CH:22]3)=[CH:17][NH:16]2)[CH:10]=1.C(N(C(C)C)C(C)C)C>O1CCCC1>[N:21]1([C:18]2[C:19](=[O:20])[N:15]([C:11]3[CH:10]=[C:9]([N:5]4[CH2:6][CH:3]([CH3:2])[CH2:4]4)[N:14]=[CH:13][N:12]=3)[NH:16][CH:17]=2)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: CC1CNC1
Reactant: O=c1c(-n2ccnc2)c[nH]n1-c1cc(Cl)ncn1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1CN(c2cc(-n3[nH]cc(-n4ccnc4)c3=O)ncn2)C1

Procedure:
43 mg (0.4 mmol) of 3-methylazetidine hydrochloride, 100 mg (0.3 mmol) of the compound from Example 13A and 174 μl (130 mg, 1.0 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine are suspended in 2 ml of tetrahydrofuran and reacted in a single mode microwave (Emrys Optimizer) at 120° C. for 4.5 h. The reaction mixture is concentrated under reduced pressure, taken up in water with addition of aqueous 1 N sodium hydroxide solution (pH=9-10) and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). Yield: 30 mg (30% of theory)
Reaction SMILES: [O:1]1C=CC=[C:2]1[C:6]1[N:10]([C:11]2[S:15][C:14]([CH2:16][NH:17][C:18](=[O:29])[C@@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:20])=[CH:13][CH:12]=2)[N:9]=[C:8]([C:30]([F:33])([F:32])[F:31])[CH:7]=1.P([O-])(O)(O)=[O:35].[Na+].Cl([O-])=O.[Na+]>C(#N)C.O>[C:24]([O:23][C:22]([NH:21][C@@H:19]([CH3:20])[C:18]([NH:17][CH2:16][C:14]1[S:15][C:11]([N:10]2[C:6]([C:2]([OH:35])=[O:1])=[CH:7][C:8]([C:30]([F:32])([F:31])[F:33])=[N:9]2)=[CH:12][CH:13]=1)=[O:29])=[O:28])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=P([O-])(O)O
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1ccc(-n2nc(C(F)(F)F)cc2-c2ccco2)s1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1ccc(-n2nc(C(F)(F)F)cc2C(=O)O)s1
Temperature: 21 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
To a stirred solution of 24 (70 mg, 0.144 mmol) in acetonitrile (0.42 mL) at 0° C. was added a solution of sodium dihydrogen phosphate (87 mg, 0.722 mmol) in water (0.17 mL). Then a solution of sodium chlorite (131 mg, 1.44 mmol) in water (0.59 mL) was added drop wise. The mixture was allowed to reach 21° C., stirring for 3 h at 21° C. The mixture was quenched with 1N NaOH, washed with CH2Cl2 (2×), and the combined organic phase was extracted with 1N NaOH. The combined aqueous phase was acidified to pH 1 with 1N HCl, extracted with AcOEt, dried (MgSO4) filtered and concentrated to afford 25 (59 mg, 88%) as a yellow solid. LRMS (ESI): calc. 462.1; found 485.2 (MNa)+.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:34])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26]C(OC(C)(C)C)=O)[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1.ClCCl>[ClH:1].[ClH:1].[NH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C:15]([N:12]1[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1)=[O:34]
Reactant: CC(C)(C)OC(=O)NCCCCCCCCCCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCCCCCCCCCCC(=O)N1CCNCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 4.0 M hydrochloric acid in dioxane (1 mL) was added dropwise to a solution of amide 7 (204 mg, 0.43 mmol) in dichloromethane (3 mL) which had been pre-cooled to 0° C. The reaction was allowed to warm to ambient temperature, stirred for 2 hours, and the solvent then removed under vacuum. Recrystallization from methanol and diethyl ether produced salt 8 (123 mg, 84%) as a white solid: 1H NMR (300 MHz, CD3OD) δ 1.34 (s, 12H), 1.58-1.66 (m, 4H), 2.43 (t, 2H, J=7.4 Hz), 2.90 (t, 2H, J=7.5 Hz), 3.20-3.28 (m, 4H), 3.78-3.83 (m, 4H); m/z (ESI) 270 [C15H31N3O+H]+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18]CC2C=CC(OC)=CC=2)=[CH:14][CH:13]=1)=[O:11].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>ClCCl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:11]
Reactant: COc1ccc(COc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a slurry of compound (1H-benzo[d]imidazol-2-yl)(4-(4-methoxybenzyloxy)phenyl)methanone (268 g, 0.75 mol) in dichloromethane (2.7 L) at ambient temperature was added TFA (289 mL, 3.75 mol, 5.0 eq.) slowly using an addition funnel. The reaction was stirred at ambient temp for 16 h. LCMS analysis of the reaction mixture revealed that the reaction was complete. The reaction mixture was neutralized with satd. aqueous NaHCO3 to pH=7-8, and stirred for 20 minutes. The resulting solid was filtered and washed with water and dried under vacuum oven at 45° C. to give product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:31]=CC=C[CH:27]=1.C(O)(C)C.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([O:25][CH:26]([CH3:31])[CH3:27])[CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1ccc(O)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(C)C)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 81.7 %

Procedure:
To a solution of methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-hydroxy-benzoate (0.735 g, 2.1 mmol), triphenylphosphine (0.551 g, 2.1 mmol), and isopropanol (0.158 mL, 2 mmol) in tetrahydrofuran was added diisopropyl azodicarboxylate (0.433 mL, 2.2 mmol) dropwise. The solution was sonicated for 30 minutes. The reaction mixture was purified without workup by RPLC (EtOAc/Hexane 3:7) to give 0.675 g (86%) of pure product.
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27]>>[CH2:27]([P:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=[CH2:14]
Reactant: C=CCCCCCCCCCCC=C
Reactant: c1ccc(Pc2ccccc2)cc1
Product: C=CCCCCCCCCCCCCP(c1ccccc1)c1ccccc1
Yield: 36.8 %

Procedure:
A magnetically stirred solution of an equimolar mixture of 93 grams (0.5 moles) of diphenyl phosphine and 97 g (0.5 moles) of 1,13-tetradecadiene in a closed cylindrical quartz tube was irradiated from about 3 cm distance with two 75 Watt Hanau tube immersion lamps with a wide spectrum of ultraviolet radiation, in a 15° C. water bath for 28 hours. A subsequent nmr analysis indicated a partial disappearance of the double bond due to the diphenyl phosphine addition. The resulting reaction mixture was fractionally distilled to recover the unreacted tetradecadiene and diphenyl phosphine and to obtain 70 g (35%) of 13-tetradecenyl diphenyl phosphine monoadduct as a clear colorless liquid distillate of bp. 185°-190° C. at 0.05 mm. The terminal olefinic unsaturation was clearly indicated by the nmr pattern of the vinylic portions of the distillate product. Anal. Calcd. for C26H37P; C, 82.06; H, 9.80; P, 8.14 Found: C, 82.02, H, 9.60; P, 8.32.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O[C:12](=[O:15])[CH2:13][Cl:14])C.Cl>CCOCC>[Cl:14][CH2:13][C:12]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[OH:15]
Reactant: Brc1ccccc1
Reactant: CCOC(=O)CCl
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: OC(CCl)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
15 g of magnesium chips are reacted with 94.2 g of bromobenzene in 250 ml of absolute ether at 30° to 35° C., followed by the dropwise addition over a period of 30 minutes at 0° to 10° C. of 24.5 g of chloroacetic acid ethyl ester. After stirring for 1 hour, the reaction mixture is poured onto ice, acidified with dilute hydrochloric acid and extracted by shaking with methylene chloride. The organic phase is washed twice with water, subsequently dried over sodium sulphate and concentrated in vacuo. The oily residue is distilled in a high vacuum at 135°-140° C./0.03 Torr. 2-Chloro-1,1-diphenyl-ethan-1-ol melting at 64° to 66° C. is obtained in a yield of 32.8 g.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]2[NH:19][C:20](=[O:29])[N:21]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:7]=2[CH:6]=1)=O.[CH:30]1([CH2:33][NH2:34])[CH2:32][CH2:31]1>>[CH:30]1([CH2:33][NH:34][C:3]([C:5]2[N:10]=[C:9]([NH:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:8]3[NH:19][C:20](=[O:29])[N:21]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:7]=3[CH:6]=2)=[O:2])[CH2:32][CH2:31]1
Reactant: NCC1CC1
Reactant: COC(=O)c1cc2c([nH]c(=O)n2Cc2ccccc2)c(NCc2ccccc2)n1
Product: O=C(NCC1CC1)c1cc2c([nH]c(=O)n2Cc2ccccc2)c(NCc2ccccc2)n1
Temperature: 80 °C

Procedure:
1-Benzyl-4-benzylamino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid methyl ester (0.05 g) Was taken up in cyclopropylmethylamine (1 mL) and heated in a ReactiVial at 80° C. for 3 h. The solvent was removed in vacuo and diethyl ether was added which caused a solid to precipitate out. This solid was filtered off and dried in vacuo to give 40 mg of a white solid. This solid was purified by preparative HPLC using mixtures of acetonitrile, water and diethylamine as the eluant to give the title compound as a white solid (18 mg).
Reaction SMILES: C(O[CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:7][CH:6]=1)C.[O-]S([O-])(=O)=O.[Na+].[Na+].Cl.[NH2:32][OH:33]>CC1OCCC1.CC(OC)(C)C>[OH:33][N:32]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:7][CH:6]=1
Reactant: NO
Reactant: CCOC(OCC)c1ccc(CN(C)C(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CC1CCCO1
Product: CN(Cc1ccc(C=NO)cc1)C(=O)OC(C)(C)C
Temperature: 30 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
A biphasic solution of tert-butyl N-[[4-(diethoxymethyl)phenyl]methyl]-N-methyl-carbamate (50.0 g, 154.6 mmol) in 2-MeTHF (400.0 mL) and Na2SO4 (100.0 mL of 10% w/v, 70.40 mmol) was stirred at 8-10° C. in a 1-L, glass-jacketed reactor. Hydroxylamine hydrochloride (46.38 mL of 5.0 M, 231.9 mmol) was added and the biphasic solution was stirred at 30° C. for 16 hours. The reaction was diluted with MTBE (200.0 mL) and the layers separated. The organic phase was washed with water (200.0 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was diluted with heptane (200.0 mL) and the resultant suspension was stirred at ambient temperature for 30 minutes. The solid was collected by filtration to give the title compound as a white solid (36.5 g, 89% Yield); 1H NMR (400 MHz, CDCl3) δ 1.50 (s, 9H), 2.88 (br s, 3H), 4.60 (s, 2H), 7.26 (d, 2H), 7.52 (d, 2H) and 8.15 (s, 1H) ppm.
Reaction SMILES: [CH3:1][CH:2]([C:5]1[N:6]([CH2:17][C:18]2[N:23]=[C:22]([C:24]([OH:26])=O)[CH:21]=[CH:20][CH:19]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[C:9]([Cl:16])[CH:8]=2)[CH2:3][CH3:4].[CH3:27][S:28]([NH2:31])(=[O:30])=[O:29].Cl.C(N=C=NCCCN(C)C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][CH:2]([C:5]1[N:6]([CH2:17][C:18]2[N:23]=[C:22]([C:24]([NH:31][S:28]([CH3:27])(=[O:30])=[O:29])=[O:26])[CH:21]=[CH:20][CH:19]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[C:9]([Cl:16])[CH:8]=2)[CH2:3][CH3:4]
Reactant: CCC(C)c1cc2cc(OC)c(Cl)cc2n1Cc1cccc(C(=O)O)n1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCC(C)c1cc2cc(OC)c(Cl)cc2n1Cc1cccc(C(=O)NS(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 62 h
Yield: 75.6 %

Procedure:
To a solution of 6-[2-(butan-2-yl)-6-chloro-5-methoxyindol-1-ylmethyl]pyridine-2-carboxylic acid (68 mg) in dichloromethane (1.8 mL) were successively added methanesulfonamide (19 mg), 4-dimethylaminopyridine (49 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (77 mg). This mixture was stirred for 62 hours at room temperature. To the reaction mixture was added 1 mol/L hydrochloric acid, followed by extraction with dichloromethane. The organic layer was washed with 1 mol/L hydrochloric acid and saturated brine successively, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-methanol) to obtain the title compound (62 mg). 1H-NMR (DMSO-d6) δ ppm: 0.79 (3H, t, J=7.3 Hz), 1.19 (3H, d, J=6.9 Hz), 1.45-1.75 (2H, m), 2.80-2.95 (1H, m), 3.34 (3H, s), 3.83 (3H, s), 5.58 (2H, s), 6.32 (1H, s), 6.65-6.80 (1H, m), 7.20 (1H, s), 7.53 (1H, s), 7.85-7.95 (2H, m), 11.41 (1H, br s). ESI-MS (m/z): 450, 452 (M+H)+