Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].ON1C(=O)CCC1=O.C(N(CC)C(C)C)(C)C.[CH2:24]([O:26][CH:27]([O:30][CH2:31][CH3:32])[CH2:28][NH2:29])[CH3:25]>C(Cl)Cl>[CH2:24]([O:26][CH:27]([O:30][CH2:31][CH3:32])[CH2:28][NH:29][C:2](=[O:3])[O:4][CH2:5][CH3:6])[CH3:25]
Reactant: CCOC(=O)Cl
Reactant: CCOC(CN)OCC
Agent: O=C1CCC(=O)N1O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)NCC(OCC)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of ethyl chloroformate (3 g, 0.027 mol.) and N-hydroxysuccinimide (3.8 g, 0.033 mol.) in 10 mL of DCM at 0° C. under nitrogen atmosphere was added N,N-Diisopropylethylamine (7.0 mL, 0.04 mol). The progress of the reaction was monitored by thin layer chromatography (TLC). After stirring for 3 hrs at room temperature. DCM was evaporated and the residue was dissolved in 10 mL of acetonitrile, cooled in an ice-bath and then added dropwise a solution of aminoacetaldehyde diethyl acetal (4.7 mL, 1.2 eq). The resulting mixture was stirred at ice-bath temperature for 1 h and then overnight at room temperature. The progress of the reaction was monitored by thin layer chromatography (TLC). The reaction mixture was filtered, and the precipitate was washed with 2×10 mL DCM and dried over sodium sulfate. After removing the solvent under reduce pressure, the residue was purified by silica gel column chromatography to give ethyl (2,2-diethoxyethyl)carbamate as a colorless oil
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14](Cl)=[N:15][OH:16])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]([C:20]1[C:21]([NH2:27])=[N:22][C:23]([NH2:26])=[CH:24][CH:25]=1)#[CH:19].C(N(CC)CC)C>O1CCCC1>[CH:1]1([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]3[CH:19]=[C:18]([C:20]4[C:21]([NH2:27])=[N:22][C:23]([NH2:26])=[CH:24][CH:25]=4)[O:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ON=C(Cl)Cc1ccc(OC2CCCC2)cc1
Reactant: C#Cc1ccc(N)nc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(OC4CCCC4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 48.3 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-cyclopentyloxy-phenyl)-acetohydroximoyl chloride (150 mg, 0.592 mmol) described in Manufacturing Example 78-1-4 and 3-ethynyl-pyridin-2,6-diamine (50.3 mg, 0.378 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (206 μL, 1.48 mmol). This reaction mixture was stirred for 1.5 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1˜ethyl acetate) to obtain the title compound (64 mg, 31%).
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:31])[C:7]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])[C:8]([O:10]CC)=[O:9])C>O.C(O)C>[OH:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][CH2:24][CH2:23][CH2:22][C:7]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])([C:8]([OH:10])=[O:9])[C:6]([OH:31])=[O:5]
Reactant: CCOC(=O)C(CCCCC(C)(C)CO)(CCCCC(C)(C)CO)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(CO)CCCCC(CCCCC(C)(C)CO)(C(=O)O)C(=O)O
Yield: 60.1 %

Procedure:
To a stirred solution of KOH (4.83 g, 75 mmol) in water (4.2 mL) and ethanol (15 mL) was added 2,2-bis(6-hydroxy-5,5-dimethyl-hexyl)-malonic acid diethyl ester (15 g). The reaction mixture was heated to reflux for 14 h, then concentrated in vacuo, and extracted with chloroform. The aqueous layer was acidified with HCl until pH 1 and extracted with diethyl ether (3×50 mL). The ethereal solution was dried over anhydrous MgSO4 and concentrated in vacuo to afford get 2,2-bis-(6-hydroxy-5,5-dimethyl-hexyl)-malonic acid (7.8 g, 82.3%) as a yellow solid. 1H NMR (300 MHz, CD3OD/TMS): (ppm) 4.86 (s, 4H), 3.22 (s, 4H), 1.9-1.8 (m, 4H), 1.36-1.10 (m, 12H), 0.84 (s, 12H). 13C NMR (75 MHz, CD3OD/TMS): (ppm) 176.0, 72.0, 58.7, 39.8, 36.0, 34.1, 26.5, 25.5, 24.5. Mp.: 178-180 C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:13]3[N:14]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)=[CH:21][CH:20]=4)[C:16]([C:17]#[N:18])=[C:12]3[NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-:32].[Na+].OO>CS(C)=O.C(O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:13]3[N:14]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)=[CH:21][CH:20]=4)[C:16]([C:17]([NH2:18])=[O:32])=[C:12]3[NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1cccc(N)c1
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCO
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1cccc(N)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
To a solution of 7-(3-aminophenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrimidine-3-carbonitrile (130 mg, 0.32 mmol) in DMSO (2 mL) and ethanol (2 mL) was added a solution of 5 N NaOH aqueous solution (1 mL) and H2O2 (1 mL). The mixture was stirred at 60° C. for 30 minutes, concentrated and partitioned between EA (100 mL) and brine (100 mL). Organic layer was separated, washed with brine (3×100 mL), dried over Na2SO4 and purified by chromatography column on silica gel eluting with PE/EA to afford 35 mg (26%) of 7-(3-aminophenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.50 (d, J=8.4 Hz, 2H), 7.40-7.33 (m, 2H), 7.16 (t, J=7.6 Hz, 1H), 7.06 (d, J=8.0 Hz, 2H), 7.03 (d, J=8.4 Hz, 2H), 6.97 (t, J=7.6 Hz, 1H), 6.76 (s, 1H), 6.44 (d, J=8.4 Hz, 1H), 6.23-6.21 (m, 2H), 5.30-5.25 (m, 1H), 5.09 (s, 2H), 3.30-3.28 (m, 1H), 3.12-3.02 (m, 1H), 2.34-2.26 (m, 1H), 2.05-2.01 (m, 1H). MS (ESI) m/e [M+1]+ 426.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1/[C:15](/[CH3:19])=[CH:16]/[CH2:17]O>C(Cl)Cl>[Cl:3][CH2:17]/[CH:16]=[C:15](/[C:6]1[CH:7]=[CH:8][C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=1)\[CH3:19]
Reactant: O=S(Cl)Cl
Reactant: C/C(=C\CO)c1ccc2ccccc2c1
Solvent: ClCCl
Product: C/C(=C\CCl)c1ccc2ccccc2c1

Procedure:
Thionyl chloride (5.0 ml) was added to a solution of (E)-3-(2-naphthyl)-2-buten-1-ol (4.59 g) in CH2Cl2 (30 ml)at 0° C. and the mixture was refluxed for 4 hours. The mixture was washed with water, saturated NaHCO3 solution and brine, dried and concentrated. The residue was washed with hexane to give the titled compound (1.22 g) as a white solid.
Reaction SMILES: S1C=CC=[C:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[O:12]([S:20]([C:23](F)(F)F)(=O)=O)[S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14]>C(Cl)Cl>[F:17][C:16]([F:19])([F:18])[S:13]([O-:15])(=[O:14])=[O:12].[S:20]1[C:23]2=[NH+:7][CH:8]=[CH:9][CH:10]=[C:11]2[CH:6]=[CH:2]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: c1ccc(-c2cccs2)nc1
Solvent: ClCCl
Product: O=S(=O)([O-])C(F)(F)F
Product: c1c[nH+]c2sccc2c1
Reaction time: 0.08 h

Procedure:
Under an inert atmosphere, 190 mg of the product of Step B, 5 ml of methylene chloride, and 0.126 g of thienyl pyridine were mixed together and stirred for 5 minutes. Then at -70° C., 0.140 ml of a solution of (CF3SO2)2O in methylene chloride was added dropwise followed by stirring for 50 minutes while allowing the temperature to rise to -50° C. After concentrating to dryness under a good vacuum, methylene chloride was added with stirring followed by washing with an N aqueous solution of hydrochloric acid, and again concentrating to dryness by distilling under reduced pressure. The residue was chromatographed over silica and eluted with a mixture of methylene chloride and methanol (9/1) to obtain 136 mg of syn isomer of trifluoromethane sulfonate of 1,1-dimethyl ethyl]-methyl]-thieno [2,3-b]pyridinium (6S, 7S ΔZ)l-[[7-((2-triphenylmethylamino)-4-thiazolyl [[2-bromo-2-propenyloxy)-imino]-acetamido]-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-carboxylate
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[C:5]([CH3:14])=[C:6]([CH2:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1.Br.CC(C)=O>C(O)(=O)C>[Br:1][CH2:12][C:11](=[O:13])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[C:5]=1[CH3:14]
Reactant: BrBr
Reactant: CC(=O)Cc1cccc(F)c1C
Agent: Br
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: Cc1c(F)cccc1CC(=O)CBr
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.5 %

Procedure:
Analogously to the procedure described in H. Y. Choi et al., Org. Lett. 5 (2003), 411, a solution of bromine (8.46 g, 52.95 mmol) in acetic acid (12 ml) was added at 0° C. to a solution of 1-(3-fluoro-2-methyl-phenyl)-propan-2-one (4.00 g, 24.07 mmol) in acetic acid (4 ml) and a 33% solution of hydrogen bromide in acetic acid (4 ml). The mixture was warmed to room temperature and stirred for 12 h. Then acetone was added and the mixture was stirred for 24 h. After evaporation under reduced pressure, the residue was extracted several times with DCM. The combined extracts were dried over sodium sulfate and evaporated to dryness. The residue was purified by preparative HPLC to give 4.10 g of the title compound as an oil.
Reaction SMILES: N([CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[C:12]1[N:16]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:15]=[N:14][N:13]=1)=[N+]=[N-].C1C(=O)N([Br:43])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:43][CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[C:12]1[N:16]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:15]=[N:14][N:13]=1
Reactant: [N-]=[N+]=NCc1cc(Cl)ccc1-c1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: Clc1ccc(-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CBr)c1
Temperature: 25 °C
Yield: 74.1 %

Procedure:
5-(2-Azidomethyl-4-chloro-phenyl)-1-trityl-1H-tetrazole: To 114A (4 g, 9.15 mmol) in chloroform (20 mL) was added NBS (1.711 g, 9.61 mmol) and benzoyl peroxide (30 mg, 0.124 mmol) and the reaction was heated at reflux overnight. Additional NBS and peroxide were added and the reaction was heated an addition 2 h. The reaction was cooled to rt, filtered, and purified by flash chromatography to give 5-(2-bromomethyl-4-chloro-phenyl)-1-trityl-1H-tetrazole (3.5 g, 74.1%). 1HNMR (400 MHz, CDCl3) δ: 4.78 (s, 2 H), 7.04-7.14 (m, 5 H), 7.24-7.35 (m, 11 H), 7.40 (d, J=2.02 Hz, 1 H), 8.06 (d, J=8.34 Hz, 1 H). This intermediate (1.57 g, 3.04 mmol) and sodium azide (0.198 g, 3.04 mmol) in DMF (8 mL) were stirred for two days. The reaction was partitioned with EtOAc/water/brine and extracted with EtOAc. The combined organic layers were washed with water and brine, dried (MgSO4), and purified by flash chromatography to give 114B. LCMS m/z 195.2 (M+H—N3)+; 152.1 (M+H—N6)+.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.Cl[CH:13]([O:15][CH3:16])[CH3:14]>CN(C=O)C>[CH3:16][O:15][CH:13]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)[CH3:14]
Reactant: c1ccc2[nH]ccc2c1
Reactant: COC(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(C)n1ccc2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58 %

Procedure:
To a suspension of NaH (1.92 gm of a 60% dispersion in oil) in 75 mL of DMF was added indole (4.68 gm, 40 mmol) (Aldrich). The mixture was stirred for 15 minutes at 0° C., and 1-chloroethyl methylether (4 mL) was added dropwise. The resulting mixture was stirred at 0° C. for 1 hour and poured over ice/water, and extracted with toluene. The organic layer was dried over magnesium sulfate, and evaporated. The residue was purified by flash chromatography using EtOAc/hexanes to give 4 gm of 1-[1-methoxyethyl]indole. (Yield 58%).
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[CH3:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[CH2:18][Mg]Br>>[CH3:14][C:15]1[CH:23]=[C:22]([CH:21]=[C:17]([CH3:18])[CH:16]=1)[CH2:24][CH:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[CH3:14][C:15]1[CH:23]=[C:22]([CH:21]=[C:17]([CH3:18])[CH:16]=1)/[CH:24]=[C:2]1\[CH2:3][CH2:4][C:5]2[NH:6][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:9]\1=2
Reactant: Cc1cc(C)cc(C[Mg]Br)c1
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Product: COC(=O)c1cc2c([nH]1)CC/C2=C\c1cc(C)cc(C)c1
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1cc(C)cc(C)c1

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.5 g, 2.79 mmol) was reacted with 3,5-dimethylbenzylmagnesium bromide (28 mL, 6.97 mmol, 0.25 M in THF, 2.5 equiv) according to General Procedure 3 to give (E)-methyl 4-(3,5-dimethylbenzylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate, followed by hydrogenation according to General Procedure 6. The title compound was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-100% EtOAc/heptane. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.07-2.18 (m, 1H) 2.33 (s, 6H) 2.50-2.77 (m, 4H) 2.77-2.84 (m, 1H) 3.30 (quin, J=7.08 Hz, 1H) 3.83 (s, 3H) 6.46 (d, J=1.46 Hz, 1H) 6.85 (s, 2H) 6.88 (s, 1H) 9.00 (br. s, 1H).
Reaction SMILES: [CH3:1][N:2]1CCN(C2C=CC3C(C=2)=CC=C2C=3OC(C(NC3C=CC(N4CCOCC4)=CC=3)=O)=CC2=O)CC1.C(O[C:41]1[CH:46]=[C:45]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)[C:44](OCC)=[CH:43][C:42]=1[NH:56][C:57]([C:59]1[O:60][C:61]2[C:66]([C:67](=[O:69])[CH:68]=1)=[CH:65][CH:64]=[CH:63][C:62]=2[N:70]1[CH2:75][CH2:74][N:73]([CH3:76])[CH2:72][CH2:71]1)=[O:58])C>>[C:1]([C:44]1[CH:43]=[C:42]([NH:56][C:57]([C:59]2[O:60][C:61]3[C:66]([C:67](=[O:69])[CH:68]=2)=[CH:65][CH:64]=[CH:63][C:62]=3[N:70]2[CH2:75][CH2:74][N:73]([CH3:76])[CH2:72][CH2:71]2)=[O:58])[CH:41]=[CH:46][C:45]=1[N:47]1[CH2:48][CH2:49][O:50][CH2:51][CH2:52]1)#[N:2]
Reactant: CCOc1cc(N2CCOCC2)c(OCC)cc1NC(=O)c1cc(=O)c2cccc(N3CCN(C)CC3)c2o1
Reactant: CN1CCN(c2ccc3c(ccc4c(=O)cc(C(=O)Nc5ccc(N6CCOCC6)cc5)oc43)c2)CC1
Product: CN1CCN(c2cccc3c(=O)cc(C(=O)Nc4ccc(N5CCOCC5)c(C#N)c4)oc23)CC1

Procedure:
This compound was prepared from 8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 1) and 5-amino-2-morpholin-4-yl-benzonitrile (Reference Example 15) as prepared in Example 12, yielding a yellow solid. (120 mg=82%), LCMS−m/z=474.5
Reaction SMILES: [CH3:1][C:2]1[CH:3]=C(C#N)[C:5]2[CH:10]=[N:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[N:7]=1.[OH-:20].[Na+].[CH2:22]([OH:24])[CH3:23]>O>[CH3:1][C:2]1[CH:3]=[C:23]([C:22]([OH:20])=[O:24])[C:5]2[CH:10]=[N:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[N:7]=1
Reactant: [OH-]
Reactant: CCO
Reactant: Cc1cc(C#N)c2cnn(Cc3ccccc3)c2n1
Agent: [Na+]
Solvent: O
Product: Cc1cc(C(=O)O)c2cnn(Cc3ccccc3)c2n1
Temperature: 25 °C

Procedure:
6-Methyl-1-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-4-carbonitrile (1 g), sodium hydroxide (0.805 g, 20.14 mmol), ethanol (25 mL) and water (10 mL) were heated at reflux for 2 hours. After cooling to room temperature, the solvent was removed under reduced pressure. The crude product was suspended in water (50 mL) and acidified by dropwise addition of 6N HCl. The solid product was filtered off and dissolved in 100 ml of EtOAc. The solution dried over MgSO4, filtered, and concentrated in vacuo. The final product was obtained as 0.730 g. LCMS E-S (M+H)=267.9. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.71 (s, 3H), 5.70 (s, 2H), 7.15-7.37 (m, 5H), 7.63 (s, 1H), 8.33 (s, 1H), 13.86 (s, 1H).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].[CH2:17]1COCC1>>[C:2]1([C:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([OH:8])[CH3:17])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Product: CC(O)(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
To this reaction mixture was added dropwise a liquid mixture of 182.22 g (1.1 mol) of benzophenone (3a; R1,R2 =H) and 364 ml of dry THF at 35° to 40° C. over a period of 30 minutes. This mixture was stirred first at that temperature for 2 hours and then at that temperature for 13 hours to complete the reaction. The resulting solution was added to 1,400 g of cooled 10% aqueous ammonium chloride solution with cooling with ice. The mixture was stirred for 30 minutes, allowed to stand, and then subjected to liquid separation, followed by washing with aqueous common salt solution, drying with magnesium sulfate, and concentration to obtain 200.23 g of crude 1,1-diphenylethanol (theoretical yield based on the benzophenone, 98.6%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[Cl:17][C:18]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1>C1COCC1.C(O)C>[Cl:17][C:18]1[N:23]=[C:22]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=2)[CH:21]=[CH:20][N:19]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(=O)Nc1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Nc2ccnc(Cl)n2)cc1
Temperature: 85 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
To a stirred solution of N-(4-aminophenyl)acetamide (5 g, 0.033 mol) and NaHCO3 (5.6 g, 0.067 mol) in THF (20 mL) and ethanol (80 mL) was added 2,4-dichloropyrimidine (5.95 g, 0.04 mol) at room temperature. The reaction was gradually heated to 85° C. After the reaction was stirred for four hours at 85° C. under N2, the suspension was filtered and washed thoroughly with ethanol. The filtrate was concentrated under reduced pressure, and the resulting solid was washed with EtOAc to remove excess 2,4-dichloropyrimidine to yield 8.35 g (95.5% yield) of N-{4-[(2-chloropyrimidin-4-yl)amino]phenyl}acetamide as an off-white solid.
Reaction SMILES: Cl[S:2]([C:5]1[CH:21]=[CH:20][C:8]([O:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Na].[CH3:23][O:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([CH2:35][S:36]([C:38]2[NH:42][C:41]3[CH:43]=[CH:44][CH:45]=[CH:46][C:40]=3[N:39]=2)=[O:37])[C:30]=1[CH3:47]>ClCCl.C(N(CC)CC)C>[CH3:23][O:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([CH2:35][S:36]([C:38]2[N:39]([S:2]([C:5]3[CH:21]=[CH:20][C:8]([O:9][CH2:10][C:11]([NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)=[O:12])=[CH:7][CH:6]=3)(=[O:4])=[O:3])[C:40]3[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=3[N:42]=2)=[O:37])[C:30]=1[CH3:47]
Reactant: COCCCOc1ccnc(CS(=O)c2nc3ccccc3[nH]2)c1C
Reactant: O=C(COc1ccc(S(=O)(=O)Cl)cc1)Nc1ccccn1
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCOc1ccnc(CS(=O)c2nc3ccccc3n2S(=O)(=O)c2ccc(OCC(=O)Nc3ccccn3)cc2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
170 mg of 2-[p-(chlorosulfonyl)phenoxy]-N-(2-pyridyl)acetamide was added to 191 mg of 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole sodium salt in dichloromethane (15 ml) and triethylamine (0.1 ml). The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water. Organic layer was dried over anhydrous magnesium sulfate, and evaporated. Residual material was lyophilized in vacuo to give 244 mg of the titled product.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11]C)=[C:9]([O:13]C)[CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][NH2:6].[F:15][C:16]([F:29])([F:28])[C:17]1[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=1)[CH2:20][CH:21]([Br:24])OC>>[BrH:24].[Cl:1][C:2]1[C:3]2[CH2:4][CH2:5][NH:6][CH2:21][CH:20]([C:19]3[CH:25]=[CH:26][CH:27]=[C:17]([C:16]([F:15])([F:28])[F:29])[CH:18]=3)[C:7]=2[CH:8]=[C:9]([OH:13])[C:10]=1[OH:11]
Reactant: COc1ccc(CCN)c(Cl)c1OC
Reactant: COC(Br)Cc1cccc(C(F)(F)F)c1
Product: Br
Product: Oc1cc2c(c(Cl)c1O)CCNCC2c1cccc(C(F)(F)F)c1

Procedure:
A mixture of 8.0 g of 2-chloro-3,4-dimethoxy-phenethylamine and 5.25 g of m-trifluoromethyl-α-methoxyphenethylbromide is heated at 100°-105° for 21/2 hours. The product was partitioned betwen ethyl acetate and 5% sodium bicarbonate solution. The organic layer was removed, washed with brine, dried and concentrated. The residue was passed over 350 g of silica gel with 1 to 2 % methanol/chloroform. The resulting product was an oil whose hydrochloride melted at 200°-202° . The oily base (2.5 g.) was heated with 50 ml of 48% hydrogen bromide and worked up as above to give the desired 6-chloro-7,8-dihydroxy-1-(m-trifluoromethylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide, m.p. ~250°.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(C)(C)C.Br[CH:16]([F:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+].Cl.O1CCOCC1>C(#N)C.C(OCC)(=O)C>[F:18][CH2:16][CH2:17][N:11]1[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CC(F)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: C1COCCO1
Product: NC1CCN(CCF)CC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A mixture of piperidin-4-yl-carbamic acid tert-butyl ester (2.00 g, 10.00 mmol), bromofluoroethane (1.5 g, 12.00 mmol) and potassium carbonate (2.80 g, 20.00 mmol) in acetonitrile (50 mL) was heated at 80° C. for 20 h. Cooled, diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate and concentrated. The residue was dissolved in DCM (10 mL) and 4N HCl/dioxane (12 mL, 50.00 mmol) was added and the suspension was stirred for 20 h at ambient temperature. The solid was collected by filtration, washed well with ethyl acetate and dried in a vacuum oven to afford 1-(2-fluoro-ethyl)-piperidin-4-ylamine.HCl salt (1.70 g, 93%): 1H NMR (400 MHz, DMSO) δ 8.43 (s, 3H), 5.02-4.90 (m, 1H), 4.89-4.77 (m, 1H), 3.56-3.50 (m, 2H), 3.46 (d, J=3.7 Hz, 1H), 3.38 (d, J=3.8 Hz, 1H), 3.26 (d, J=4.9 Hz, 1H), 3.18-3.02 (m, 2H), 2.20-2.09 (m, 2H), 2.07-1.89 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:20]([OH:22])=[O:21])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[C:25](=O)([O-])O.[Na+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:20]([O:22][CH3:25])=[O:21])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2)CC1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 3 h
Yield: 82 %

Procedure:
To a solution of 1-tert-butoxycarbonyl-4-carboxy-4-phenylpiperidine (1.53 g) in tetrahydrofuran (2 mL)-methanol (2 mL) was added dropwise 2N (trimethylsilyl)diazomehane-diethyl ether solution (8.8 mL) at room temperature and the mixture was stirred at the same temperature for 3 hours. To the reaction mixture was added an aqueous saturated sodium hydrogencarbonate solution and the mixture was stirred and extracted with chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=90/10 to 85/15) to obtain 1-tert-butoxycarbonyl-4-methoxycarbonyl-4-phenylpiperidine (1.31 g, yield: 82%) as a colorless solid.