Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6](=O)[C@H:5](OS(C)(=O)=O)[CH2:4][C@H:3]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.[C-:21]#[N:22].[Na+]>CN(C=O)C.O>[C:21]([C@@H:5]1[CH2:6][N:2]([CH3:1])[C@H:3]([CH2:13][O:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:4]1)#[N:22]
Reactant: CN1C(=O)[C@H](OS(C)(=O)=O)C[C@H]1COc1cccnc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C[C@@H](C#N)C[C@H]1COc1cccnc1
Temperature: 100 °C
Yield: 35.1 %

Procedure:
To a solution of 300 mg (1.05 mmol) of 3-((trans-1-methyl-4-methanesulfonyloxy-5-oxo-2(S)-pyrrolidinyl)-methoxy)pyridine, prepared as in Example 88a above, dissolved in 7 mL of 6:1 DMF:H2O was added 0.51 g (10.5 mmol) of NaCN, and the reaction mixture was heated at 100° C. for 5 hours. The reaction mixture was cooled, diluted with water, and extracted with chloroform. The extract was dried over MgSO4 and concentrated. The residue was purified on a silica gel column, eluting with 100:2 chloroform:methanol, to give 80 mg of the title compound.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][C:11]1[CH:12]=[N:13][NH:14][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:10][C:11]1[CH:12]=[N:13][N:14]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH:15]=1
Reactant: Cc1cn[nH]c1
Reactant: O=Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cnn(-c2ccccc2C=O)c1
Temperature: 100 °C

Procedure:
2-Fluorobenzaldehyde (250 mg, 2.01 mmol), 4-methyl-1H-pyrazole (260 mg, 3.17 mmol) and potassium carbonate (820 mg, 5.93 mmol) are combined in DMSO (15 mL) and warmed to 100° C. for 18 hours. The reaction mixture is cooled to room temperature and the potassium carbonate is removed via filtration. The solids are washed with EtOAc and the combined filtrates are poured into water. Separate the layers and extract the aqueous phase with EtOAc (1×). The combined organics are washed with water and brine and dried (MgSO4), filtered, and concentrated. Purification via flash chromatography (12 g silica gel, 0-15% EtOAc/heptane) gives 2-(4-methyl-pyrazol-1-yl)-benzaldehyde.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](=O)[NH:13][C:12]([CH2:19][O:20][CH3:21])=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:24])=O.CN(C)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([Cl:24])=[N:13][C:12]([CH2:19][O:20][CH3:21])=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCc1nc2c(c(=O)[nH]1)CCN(Cc1ccccc1)C2
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)c1ccccc1
Solvent: ClCCCl
Product: COCc1nc(Cl)c2c(n1)CN(Cc1ccccc1)CC2
Temperature: 80 °C
Yield: 82.3 %

Procedure:
A mixture of 7-benzyl-5,6,7,8-tetrahydro-2-(methoxymethyl)pyrido[3,4-d]pyrimidin-4(3H)-one (2.01 g, 7.04 mmol), phosphorus oxychloride (5.16 mL, 56.35 mmol) and N,N-dimethylaniline (0.89 mL, 7.04 mmol) in 1,2-dichloroethane was heated to 80° C. for two h. The mixture was allowed to cool to r.t. and poured over crushed ice (100 mL). The mixture was made basic (pH=˜8) by the addition of saturated aqueous sodium bicarbonate and extracted with ethyl acetate (200 mL). The organic layer was dried over magnesium sulfate and concentrated to leave a dark oil which was purified by silica gel chromatography (ethyl acetate/hexane gradient) to yield 1.76 g (82%) of the title compound as a brown oil.
Reaction SMILES: ClC1C=CC=C(C(OO)=O)C=1.S([O-])([O-])(=O)=O.[Mg+2].B(F)(F)F.CCOCC.[CH2:27]([O:29][C:30](=[O:44])[C:31]1[CH:36]=[CH:35][C:34]([CH:37]2[CH2:41][CH:40]([O:42]C)[O:39][CH2:38]2)=[CH:33][CH:32]=1)[CH3:28]>ClCCl.CCOCC>[CH2:27]([O:29][C:30](=[O:44])[C:31]1[CH:32]=[CH:33][C:34]([CH:37]2[CH2:41][C:40](=[O:42])[O:39][CH2:38]2)=[CH:35][CH:36]=1)[CH3:28]
Reactant: CCOC(=O)c1ccc(C2COC(OC)C2)cc1
Agent: FB(F)F
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S(=O)([O-])[O-]
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C2COC(=O)C2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 75% 3-chloroperbenzoic acid (2.7 g, 11.76 mmol) in dichloromethane (35 mL) is added magnesium sulfate (2.0 g, 16.6 mmol) and the mixture stirred for 30 min. Solids are removed by filtration and the filtrate treated with borontrifluoride etherate (0.5 mL, 3.92 mmol) and 4-(5-methoxy-tetrahydro-furan-3-yl)-benzoic acid ethyl ester (2.45 g, 9.8 mmol) in dichloromethane (5 mL). The mixture is stirred at room temperature 18 h, diluted with ether (200 mL) and washed with a 10% solution of sodium thiosulfite (150 mL), a saturated solution of sodium bicarbonate (150 mL) and brine. The mixture is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is chromatographed on SiO2 (elute with 20% ethyl acetate/hexanes) to yield the title compound, 2.2 g (96%), as an off-white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21](O)[CH2:22][OH:23].C(OCC)(OCC)OCC.C(=O)([O-])O.[Na+]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][C:10]1([CH2:12][O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[O:23][CH2:22][CH2:21][O:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCO
Reactant: O=C(COCc1ccccc1)COCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCOC(OCC)OCC
Product: c1ccc(COCC2(COCc3ccccc3)OCCO2)cc1
Temperature: 50 °C
Reaction time: 14 h
Yield: 81.6 %

Procedure:
The 1,3-bis(benzyloxy)acetone (30 g, 111 mmol) obtained in the step (4a) was mixed with ethylene glycol (64 ml, 1,148 mmol) and triethyl orthoformate (19 ml, 114 mmol), and p-toluenesulfonic acid monohydrate (591 mg, 3.11 mmol). The mixture was stirred at 50° C. for 14 hours. To the mixture, a saturated aqueous solution of sodium hydrogen carbonate and ethyl acetate were added. The organic layer was washed with water and a saline solution, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate=1/0-4/1 gradient) and desired fractions were concentrated to obtain the title compound (28.46 g, yield: 81.6%) as a colorless oil.
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[C:3]([C:15]([O:17]CC)=[O:16])=[C:4]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][N:5]12.[OH-].[Na+].Cl>>[CH:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[C:3]([C:15]([OH:17])=[O:16])=[C:4]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][N:5]12
Reactant: CCOC(=O)c1c2n(c3ccccc13)CCCCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1c2n(c3ccccc13)CCCCC2

Procedure:
The title compound (D5) was prepared from ethyl 7,8,9, 10-tetrahydro-6 H-azepino[1,2-a]indole-1 1-carboxylate by hydrolysis with sodium hydroxide as in the method of Description 3d. After 4 hours heating under reflux, the mixture was acidified with 5M HCl acid and the white solid formed filtered off and dried (82%).
Reaction SMILES: [CH2:1]([NH:9][C:10]([C@@H:12]1[CH2:14][C@H:13]1[C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:22]([OH:30])(=[O:29])[C:23]([CH2:25][C:26](O)=[O:27])=[CH2:24]>>[CH2:1]([NH:9][C:10]([C@@H:12]1[CH2:14][C@H:13]1[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:24][CH:23]([C:22]([OH:30])=[O:29])[CH2:25][C:26]2=[O:27])=[CH:17][CH:16]=1)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: CCCCCCCCNC(=O)[C@@H]1C[C@H]1c1ccc(N)cc1
Product: CCCCCCCCNC(=O)[C@@H]1C[C@H]1c1ccc(N2CC(C(=O)O)CC2=O)cc1

Procedure:
A mixture of 2.2 g. of trans-N-octyl-2-(4-aminophenyl)cyclopropanecarboxamide and 989 mg. of itaconic acid were heated as a melt at 140°-145° C. for 1 hour. The reaction mixture was cooled slightly and then it was triturated with 25 ml. of ethyl acetate. The white solid which formed was filtered off. It was recrystallized from ethanol containing a small amount of acetonitrile, and then from acetic acid, to give 1.09 g. of the title compound as a white solid, m.p. 213.5°-214.5° C. The infrared spectrum (KBr disc) showed absorptions at 3280, 3125, 1695 and 1625 cm1.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:23])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:26][N:27]1[CH2:31][CH2:30][CH2:29][C@:28]1([C:33]1[N:37]2[CH:38]=[C:39]([O:42][C@H:43]3[C:52]4[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=4)[C@@H:46]([NH2:53])[CH2:45][CH2:44]3)[CH:40]=[CH:41][C:36]2=[N:35][N:34]=1)[CH3:32]>>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:53][C@@H:46]2[C:47]3[C:52](=[CH:51][CH:50]=[CH:49][CH:48]=3)[C@H:43]([O:42][C:39]3[CH:40]=[CH:41][C:36]4[N:37]([C:33]([C@:28]5([CH3:32])[CH2:29][CH2:30][CH2:31][N:27]5[CH3:26])=[N:34][N:35]=4)[CH:38]=3)[CH2:44][CH2:45]2)=[O:23])[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:9]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CN1CCC[C@@]1(C)c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc([C@]5(C)CCCN5C)n4c3)c3ccccc32)cc1

Procedure:
The title compound was prepared as an off-white solid (80 mg, 53%) using (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 80 mg, 0.20 mmol) and Intermediate 47c (90 mg, 0.24 mmol) in a similar manner to Example 1, step d. LCMS (Method 5): Rt 3.83 min, m/z 633 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.51 (3H, s), 1.78-1.99 (5H, m), 2.02 (3H, s), 2.03-2.22 (3H, m), 2.36 (3H, s), 2.65 (1H, q, J 8.6), 3.11-3.17 (1H, m), 4.79-4.86 (1H, m), 5.32 (1H, t, J 4.2), 6.32 (1H, s), 7.11 (1H, d, J 8.6), 7.25-7.39 (9H, m), 7.75 (1H, d, J 9.8), 8.05 (1H, s), 8.43 (1H, d, J 2.2).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[CH2:23][OH:24])=[CH:17][CH:16]=2)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:25]([O:27][C@@H:28]([CH2:34][C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:26]>>[C:11]([C:9]1[CH:8]=[C:7]([C:15]2[CH:16]=[CH:17][C:18](/[CH:21]=[CH:22]/[CH2:23][O:24][C:38]3[CH:37]=[CH:36][C:35]([CH2:34][C@H:28]([O:27][CH2:25][CH3:26])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:40][CH:39]=3)=[CH:19][CH:20]=2)[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc(-c2ccc(/C=C/CO)cc2)cc(C(C)(C)C)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C/c2ccc(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3)cc2)cc1)OCC
Yield: 52 %

Procedure:
The title compound (110 mg, 51%) was prepared as a colourless gum from (E)-3-(3′,5′-di-tert-butyl-biphenyl-4-yl)-prop-2-en-1-ol (127 mg, 0.39 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (99 mg, 0.41 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:36])[NH:20][CH2:21][CH2:22][C:23]3[C:24]([CH:33]4[CH2:35][CH2:34]4)=[N:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:37]([OH:39])=[O:38].C[O-].[Na+:42]>CO>[Na+:42].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:36])[NH:20][CH2:21][CH2:22][C:23]3[C:24]([CH:33]4[CH2:34][CH2:35]4)=[N:25][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:27][CH:28]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:37]([O-:39])=[O:38]
Reactant: O=C(NCCc1ccc(C(F)(F)F)nc1C1CC1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(NCCc1ccc(C(F)(F)F)nc1C1CC1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Reaction time: 2 h
Yield: 100 %

Procedure:
6-Chloro-7-(4-(2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylic acid (15 mg, 0.027 mmol) was diluted with methanol (1 mL) followed by the addition of NaOMe in methanol (53 μL, 0.027 mmol). After stirring for 2 hours, the reaction was concentrated and dried under high vacuum pressure for 2 hours. The material was diluted with hexanes, sonicated and concentrated to afford 6-chloro-7-(4-(2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylic acid sodium salt (15 mg, 0.027 mmol, 100% yield) as a white solid. MS (es+apci, positive) m/z=561.1. 1H NMR (400 MHz, D6 DMSO) δ 8.59 (br s, 1H), 7.81 (d, 2H), 7.75 (d, 1H), 7.54 (d, 1H), 7.49 (s, 1H), 6.95 (d, 2H), 6.57 (s, 1H), 4.17 (br s, 2H), 3.55-3.53 (m, 3H), 3.35-3.31 (m, 4H), 3.11-3.09 (m, 2H), 2.47-2.43 (m, 1H), 2.21-2.17 (m, 1H), 1.92-1.87 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:6][N:7]([CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=1[C:30]1[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[CH:33]=[CH:32][C:31]=1[O:39][CH3:40])[C:8]1[N:9]=[N:10][N:11]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[N:12]=1.[OH-].[Na+:51]>C(O)C>[Na+:51].[F:47][C:44]([F:45])([F:46])[C:42]1[CH:41]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:48])[F:49])[CH:43]=1)[CH2:6][N:7]([CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=1[C:30]1[CH:35]=[C:34]([CH:36]([CH3:37])[CH3:38])[CH:33]=[CH:32][C:31]=1[O:39][CH3:40])[C:8]1[N:9]=[N:10][N:11]([CH2:13][CH2:14][CH2:15][C:16]([O-:18])=[O:17])[N:12]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCCC(=O)O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCCC(=O)[O-])n1

Procedure:
4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-tetrazol-2-yl}-butyric acid (154 mg) is dissolved in ethanol (3 ml), and thereto is added 1M-aqueous sodium hydroxide solution (225 μl), and concentrated under reduced pressure to give 4-{5-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-tetrazol-2-yl}-butyric acid sodium salt (153 mg). MS (m/z): 702 [M−Na]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:35])[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1.[C:36]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)(=[O:38])[CH3:37]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:35])[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:42]3[CH2:43][CH2:44][N:39]([C:36](=[O:38])[CH3:37])[CH2:40][CH2:41]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:33])[CH3:34])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(=O)N1CCNCC1
Reactant: COc1ccc(C2=NC(C)(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Product: COc1ccc(C2=N[C@@](C)(c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCN(C(C)=O)CC2)c(OC(C)C)c1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-acetyl-piperazine (Aldrich) to give the title compound. LC-MS: 623.2 [(M+H)+]
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.[Cl:26][CH2:27][CH2:28][NH:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[C:35](=O)[O:34][CH2:33]2.Cl.[OH-].[Na+]>C(COC)OC>[Cl:26][CH2:27][CH2:28][NH:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[C:35](=[C:3]1[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]1=[O:10])[O:34][CH2:33]2
Reactant: O=C1OCc2cc(NCCCl)ccc21
Reactant: O=C1Cc2ccccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1=C1OCc2cc(NCCCl)ccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of oxindole (707 mg, 5.3 mmol) in anhydrous dimethoxyethane (20 ml) under nitrogen was added 1M LiHMDS/THF solution (18.5 ml, 18.5 mmol). The mixture was stirred at room temperature for 10 minutes, and 5-(2-chloro-ethylamino)-3H-isobenzofuran-1-one (900 mg, 4.25 mmol) was added. The mixture was stirred at room temperature for 2.5 hours and poured into 0.1M HCl solution (400 ml). The mixture was stirred for 30 min, then basified with aqueous NaOH solution. The precipitants were filtered, washed with water, and dried under vacuum to result in a crude product mixture. The crude product mixture was purified by silica gel column chromatography, eluted with a gradient of MeOH in CHCl3. The major product, 3-[5-(2-chloro-ethylamino)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one (Example 45), was obtained as a yellow solid (560 mg, 40%) and so was the minor product, 3-[5-(2-hydroxy-ethylamino)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one (Example 93), as a yellow solid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([S:19][CH2:20][CH3:21])[CH:18]=[C:13]3[CH:12]=[C:11]2[CH:22]([OH:29])[CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:32]>ClCCl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([S:19]([CH2:20][CH3:21])=[O:32])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:22](=[O:29])[CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCSc1cnc2c(c1)cc(C(O)CC1CCCC1)n2S(=O)(=O)c1ccccc1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCS(=O)c1cnc2c(c1)cc(C(=O)CC1CCCC1)n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
To a solution of 1-(1-benzenesulfonyl-5-ethylsulfanyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-ethanol (3.0 g, 7.0 mmol) in dichloromethane (150 mL) was added Dess-Martin periodinane (7.4 g, 17.4 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 1 h and then quenched with a saturated aqueous sodium bicarbonate solution (60 mL). The mixture was extracted with ethyl acetate (250 mL), washed with a saturated aqueous sodium bicarbonate solution (3×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by flash column chromatography (silica gel from QingDao, 200-300 mesh, 20% ethyl acetate/hexanes) to afford 1-(1-benzenesulfonyl-5-ethanesulfinyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-ethanone (1.5 g, 48%) as a light yellow solid: LC/MS m/e calcd for C22H24N2O4S2 [M+H]+ 445.58, observed 444.9.
Reaction SMILES: [C:1]([CH:5]([NH:12][NH:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:16]=1[CH3:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([CH3:35])[CH:34]=1)[C:29](Cl)=[O:30].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:1]([CH:5]([N:12]([C:29](=[O:30])[C:28]1[CH:32]=[C:33]([CH3:35])[CH:34]=[C:26]([CH3:25])[CH:27]=1)[NH:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:16]=1[CH3:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCCC(NNC(=O)c1cccc(OC)c1C)C(C)(C)C
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCCCCCC(N(NC(=O)c1cccc(OC)c1C)C(=O)c1cc(C)cc(C)c1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
164 mg (0.49 mmol) of 3-methoxy-2-methyl-benzoic acid N′-(1-tert-butyl-heptyl)-hydrazide and 82 mg 3,5-dimethylbenzoyl chloride were dissolved in 10 mL CH2Cl2. 7 mL of 25% K2CO3 were added, and the reaction mixture was stirred at room temperature overnight. The reaction was monitored by TLC. The phases were separated, adding additional CH2Cl2 and/or water as needed to aid manipulation. The CH2Cl2 layer was dried and solvent was removed in vacuo to provide 240 mg of crude product. This material was purified by silica gel column chromatography, eluting with a step gradient of 5–20% ethyl acetate in hexane. The desired product eluted in the 15% ethyl acetate fraction, TLC Rf=0.62 (1:1 ethyl acetate:hexane), to yield 195 mg 3,5-dimethyl-benzoic acid N-(1-tert-butyl-heptyl)-N′-(3-methoxy-2-methyl-benzoyl)-hydrazide. 1H NMR (500 MHz, CDCl3) δ (ppm): 7.2 (s, NH), 7.05 (s, 2H), 7.03 (m, 1H), 7.01 (s, 1H), 6.83 (d, 1H), 6.25 (d, 1H), 4.67 (d, 1H), 3.81 (s, 3H), 2.28 (s, 6H), 1.79 (s, 3H), 1.55 (br m, 2H), 1.3 (br, 8H), 1.34+1.07 (s+s, 9H), 0.089 (br s, 3H).
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][F:15])[O:7][C@H:6]1[N:16]1[C:31]2[N:30]=[C:29]([Cl:32])[N:28]=[C:20]([NH:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:19]=2[N:18]=[CH:17]1)(=O)C>N>[Cl:32][C:29]1[N:28]=[C:20]([NH:21][N:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[C:19]2[N:18]=[CH:17][N:16]([C:31]=2[N:30]=1)[C@@H:6]1[O:7][C@H:8]([CH2:14][F:15])[C@@H:9]([OH:10])[C@H:5]1[OH:4]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](CF)O[C@H]1n1cnc2c(NN3CCCCC3)nc(Cl)nc21
Agent: N
Product: O[C@@H]1[C@H](O)[C@@H](CF)O[C@H]1n1cnc2c(NN3CCCCC3)nc(Cl)nc21
Reaction time: 1 h
Yield: 581.7 %

Procedure:
The above 2',3'-di-O-acetyl-2-chloro-5'-deoxy-5'-fluoro-N-(1-piperidinyl)adenosine (0.38 g, 0.8 mmol) was dissolved in methanolic ammonia (15 ml) and stirred for 1 h. The reaction mixture was evaporated in vacuo and the resultant residue was purified by flash chromatography eluting with dichloromethane and 10% ammonia in ethanol (95:5) to afford 2-chloro-5'-deoxy-5'-fluoro-N-(1-piperidinyl)adenosine (1.8 g, 86%) as a white solid, m.p. 199°-201° C. 1H-NMR (400 MHz, DMSO-d6) δ1.35 (2H, br, piperidine C--H), 1.52 (4H, br, piperidine C--H), 2.80 (4H, br, piperidine C--H), 4.10 (1H, ddd, H-4'), 4.20 (1H, br, H-3'), 4.51 (1H, br, H-2'), 4.65 (2H, dd, H-5'a and H-5'b), 5.88 (1H, d, H-1'), 8.28 (1H, s, H-8). HPLC retention time 7.15 min. (gradient elution over 30 min.; 20-80% acetonitrile/0.1% TFA in water). C15H20ClFN6O3, 0.75H2O requires C, 45.2; H, 5.4; N, 21.1. Found: C, 45.2; H, 5.2; N, 20.8%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6]Br.[C-:11]#[N:12].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][C:11]#[N:12]
Reactant: [C-]#N
Reactant: Fc1cccc(CCBr)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCCc1cccc(F)c1
Temperature: 60 °C
Yield: 34.8 %

Procedure:
3-Fluorophenethyl bromide (23, 1.00 g, 12.3 mmol) was diluted in dry DMF (25 mL). Sodium cyanide (1.06 g, 61.6 mmol) was added in one portion, and the mixture was heated to 60° C. under argon for 16 h. The mixture was cooled and concentrated, and the residue was partitioned between EtOAc and H2O (50 mL each). The layers were separated, and the aqueous phase was extracted with EtOAc (2×20 mL). The organic layers were washed with H2O and sat. aq. NaCl (50 mL each), dried over anhydrous sodium sulfate, and concentrated. The resulting oil was purified by flash column chromatography (SiO2), eluting with a gradient of 5% EtOAc in hexanes to 30% EtOAc in hexanes to yield the desired product as a colorless oil (0.638 g, 87%). 1H-NMR (500 MHz; CDCl3): δ 7.31 (td, J=7.9, 6.0 Hz, 1 H), 7.03-6.93 (m, 3 H), 2.96 (t, J=7.4 Hz, 2 H), 2.63 (t, J=7.4 Hz, 2 H).