Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NN.CC([CH2:7][N:8]([CH2:12][CH:13]([N:21]1C(=O)C2C(=CC=CC=2)C1=O)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9](=[O:11])[O-:10])(C)C>C1COCC1.CO>[NH2:21][CH:13]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:12][N:8]([CH3:7])[C:9](=[O:11])[O:10][C:15]([CH3:20])([CH3:16])[CH3:14]
Reactant: CC(C)(C)CN(CC(Cc1ccccc1)N1C(=O)c2ccccc2C1=O)C(=O)[O-]
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: CN(CC(N)Cc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 0.6 %

Procedure:
NH2NH2 (7 mL, 0.2 mol) was added to a THF/MeOH (100 mL/25 mL) solution of 1,1-dimethylethyl[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropyl]methylcarbamate (2.7 g, 6.8 mmol) and stirred overnight. After 12 hours, the solution was absorbed onto silica and purified by column chromatography using 5% MeOH in CHCl3 containing 0.5% NH4OH to give the title compound (5.8 mg, 88%) as a white solid: LC-MS (ES) m/z=265 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:17][CH2:16]2)=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc(N3CCNCC3)nc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2ccc(OCc3ccccc3)cn2)CC1
Reaction time: 3 h

Procedure:
A stirred solution of 1-[5-(benzyloxy)pyridin-2-yl]piperazine (104 g, 278 mmol) in CH2Cl2 (1.1L) at 0° C. was treated sequentially with triethylamine (94 mL, 672 mmol) and methanesulfonyl chloride (31 mL, 400 mmol). The reaction was brought to room temperature and stirred for 3 hour. The reaction was then diluted with DCM (3L) and washed with water (1L), HCl (0.5 M, 2×800 mL) and sat. NaHCO3 (800 mL), back-extracting with DCM (500 mL). The combined organic extracts were then dried (MgSO4), filtered and concentrated in vacuo to give 1-[5-(benzyloxy)pyridin-2-yl]-4-(methylsulfonyl)piperazine as a dark liquor (120 g, 278 mmol @ 81 wt %, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:20]=[C:21]([N+:24]([O-])=O)[C:22]=1[CH3:23])[O:8][CH:9]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]1)=[O:4]>CO.[Pd]>[NH2:24][C:21]1[CH:20]=[C:7]([CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:22]=1[CH3:23])[O:8][CH:9]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]1
Reactant: COC(=O)c1cc(OC2CN(C(=O)OC(C)(C)C)C2)cc([N+](=O)[O-])c1C
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(OC2CN(C(=O)OC(C)(C)C)C2)cc(N)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
To stirred solution of tert-butyl 3-(3-(methoxycarbonyl)-4-methyl-5-nitrophenoxy)azetidine-1-carboxylate (1.0 g, 2.7 mmol) in methanol (10 mL) was added a catalytic amount of 10% Pd/C. The mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 3 hours. On completion, the reaction mixture was filtered through a celite bed which was further washed with methanol. The combined filtrates were concentrated under reduced pressure to afford the title compound (0.90 g, 98%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([Li])CCC.Cl[Si:16]([CH3:19])([CH3:18])[CH3:17]>C(OCC)C>[CH3:17][Si:16]([CH3:19])([CH3:18])[N:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:1]
Reactant: CNCc1ccccc1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: CN(Cc1ccccc1)[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
Step 1—To a stirring solution of N-methylbenzylamine (100 ml, 93.9 g, 0.77 mol) in diethyl ether (500 ml) cooled at −78° C. was added n-butyl lithium (2.4 M in hexanes, 355 ml, 0.85 mol) keeping the temperature below −60° C. The resulting slurry was stirred for 1 hour then chlorotrimethylsilane (118 ml, 0.93 mol) was added while keeping the temperature below −70° C. The reaction was allowed to warm to room temperature overnight then filtered to remove the precipitated white solid. The filtrates were concentrated in vacuo then distilled under high-vacuum to yield the N-trimethylsilyl-N-methylbenzylamine (102 g, 94%) as a colorless liquid: b.p. 54° C./0.5 mmHg; 1H NMR (CDCl3) 0.19 (s, 9H), 2.37 (s, 3H), 3.90 (2, 2H) 7.22-7.39 (m, 5H)
Reaction SMILES: [CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=3)[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2].[N:22]([Si](C)(C)C)=[N+:23]=[N-:24]>CN(C=O)C>[CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([C:13]3[N:22]=[N:23][NH:24][C:14]=3[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=3)[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1cccc(C#Cc2ccc3nnc(C(C)C)n3c2)n1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: CN(C)C=O
Product: Cc1cccc(-c2[nH]nnc2-c2ccc3nnc(C(C)C)n3c2)n1
Yield: 39.1 %

Procedure:
To a 10 mL flask was added 100 mg (0.36 mmol) of 3-Isopropyl-6-(6-methylpyridin-2-ylethynyl)-[1,2,4]triazolo(4,3-a)pyridine, 1.5 mL of anhydrous DMF, and 168 μL (1.3 mmol) of azidotrimethylsilane. The reaction mixture was heated to reflux for 16 hours. After concentrating, the residue was suspended in 30 mL of water and was extracted with (2×30 mL) ethyl acetate. The organic extracts were combined, washed with 20 mL of water, 20 mL of brine, dried over magnesium sulfate, filtered, and concentrated. Product was purified by Shimodzu prep. HPLC using a 5 to 60% acetonitrile/buffer gradient (buffer is water with 0.1% formic acid, and the acetonitrile contains 0.1% formic acid as well) which yielded 45 milligrams (39%) of a light brown solid. HPLC tR=3.71 min (98%), LC-MS=320 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3](COCC[Si](C)(C)C)[N:4]=[C:5]2[C:10]=1[CH:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:7]=[C:6]2[CH:15]([O:17][CH2:18][C:19]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)[CH3:16].FC(F)(F)C(O)=O.C(Cl)Cl.C(=O)(OC(C)(C)C)OC(C)(C)C.C(N(CC)CC)C>ClCCl.N.CO>[CH3:1][C:2]1[C:10]2[C:5](=[C:6]([CH:15]([O:17][CH2:18][C:19]3([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])[CH2:21][CH2:20]3)[CH3:16])[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=2)[NH:4][N:3]=1
Reactant: Cc1c2cc(C(F)(F)F)cc(C(C)OCC3(c4ccccc4)CCN(C(=O)OC(C)(C)C)CC3)c2nn1COCC[Si](C)(C)C
Agent: CC(C)(C)OC(=O)OC(C)(C)C
Agent: N
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: Cc1n[nH]c2c(C(C)OCC3(c4ccccc4)CCN(C(=O)OC(C)(C)C)CC3)cc(C(F)(F)F)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(±)-tert-Butyl 4-((1-(3-methyl-5-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate (94 mg, 0.15 mmol) was treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvent was concentrated to afford a crude product which was dissolved in dichloromethane (3 mL), cooled to 0° C., and treated with di-tert-butyl carbonate (63 mg, 0.29 mmol) and triethylamine (30 μL, 0.22 mmol). After 1 h, the reaction was treated with a few drops of 2 M ammonia in methanol and concentrated. The residue was dissolved in ethyl acetate, washed with water (2×), brine (2×), dried over sodium sulfate, filtered and concentrated. Flash chromatography on silica gel (15% ethyl acetate/hexanes) afforded 62 mg (83%). 1H-NMR (CDCl3, 500 MHz) δ 7.81 (s, 1H), 7.38-7.41 (m, 2H), 7.30-7.35 (m, 3H), 7.19 (m, 1H), 4.56 (q, J=6.4 Hz, 1H), 3.76 (m, 2H), 3.40 (d, J=9.2 Hz, 1H), 3.29 (d, J=8.9 Hz, 1H), 2.99-3.06 (m, 2H), 2.54 (s, 3H), 2.11-2.31 (m, 2H), 1.75-1.87 (m, 2H), 1.42 (s, 9H), 1.40 (m, 3H). Mass spec.: 518.28 (MH)+.
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][C:10]#[N:11])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.C(O)(=O)C.N1CCCCC1>CC(O)C>[C:3]([C:2](=[CH:16][C:15]1[CH:18]=[CH:19][CH:20]=[C:13]([Cl:12])[CH:14]=1)[C:1]([O:7][CH2:8][CH2:9][C:10]#[N:11])=[O:6])(=[O:4])[CH3:5]
Reactant: O=Cc1cccc(Cl)c1
Reactant: CC(=O)CC(=O)OCCC#N
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC(=O)C(=Cc1cccc(Cl)c1)C(=O)OCCC#N

Procedure:
1.00 g (6.45 mmol) of 2-cyanoethyl acetoacetate and 730 μl (6.44 mmol) of 3-chlorobenzaldehyde were stirred in the presence of a catalytic amount of acetic acid and piperidine in 100 ml of 2-propanol at room temperature overnight. The solvent was evaporated under reduced pressure to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:22])[C:8]4[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:22])[C:8]4[CH:20]=[CH:19][C:18]([O:21][CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: CCN(CC)CCCl
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(Cl)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCOc1ccc2c(c1)C(C)(C)c1[nH]c3cc(Cl)ccc3c1C2=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
3-Chloro-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound S2-1, 10 mg, 0.03207 mmol) was dissolved in DMF (0.1 mL), added with (2-chloroethyl)diethylamine (5.5 mg, 0.03207 mmol) and cesium carbonate (20.9 mg, 0.06414 mmol), and stirred at 80° C. for 2 hr. The reaction solution was added to water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. The residues obtained after concentration under reduced pressure were purified by NH silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (11.6 mg, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19]C)=[CH:16][CH:17]=3)[CH2:12][N:11]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N+:30]([O-:32])=[O:31])(=[O:23])=[O:22])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=3)[CH2:12][N:11]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N+:30]([O-:32])=[O:31])(=[O:23])=[O:22])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc2c(c1)CN(S(=O)(=O)c1ccccc1[N+](=O)[O-])CC2c1ccc(Cl)c(Cl)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N1Cc2cc(O)ccc2C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 98.6 %

Procedure:
To a −78° C. solution of 4-(3,4-dichlorophenyl)-7-methoxy-2-(2-nitrophenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (3.39 g, 6.88 mmol) in dichloromethane (70 mL) was added boron tribromide (3.25 mL, 34.4 mmol) drop wise. The mixture was stirred for 5 minutes and then warmed to 0° C. for 1 hour. The mixture was quenched with water slowly and then the aqueous layer was extracted with dichlormethane (2×). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give 4-(3,4-dichlorophenyl)-2-(2-nitrophenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-ol (3.25 g, 98%) as a yellow solid: 1H NMR (CDCl3, 500 MHz) δ 7.80 (dd, J=8.0, 1.2 Hz, 1H), 7.67-7.63 (m, 1H), 7.58 (dd, J=7.9, 1.2 Hz, 1H), 7.54-7.50 (m, 1H), 7.16 (d, J=8.3 Hz, 1H), 7.02 (d, J=2 Hz, 1H), 6.86 (dd, J=8.3, 2 Hz, 1H), 6.77 (d, J=8.2 Hz, 1H), 6.68-6.65 (m, 2H), 4.88 (s, 1H), 4.74 (d, J=16.2 Hz, 1H), 4.53 (d, J=16.1 Hz, 1H), 4.16 (dd, J=4.9, 4.9 Hz, 1H), 3.83 (dd, J=13.2, 4.5 Hz, 1H), 3.62 (dd, J=13.1, 5.5 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[O:11][CH2:10][CH:9]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[O:8][C:5]2=[N:6][CH:7]=1.[Li][CH2:22]CCC.IC.[NH4+].[Cl-]>C1COCC1>[CH3:18][C:17]([Si:14]([CH3:16])([CH3:15])[O:13][CH2:12][CH:9]1[O:8][C:5]2=[N:6][CH:7]=[C:2]([CH3:22])[CH:3]=[C:4]2[O:11][CH2:10]1)([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OCC1COc2cc(Br)cnc2O1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cnc2c(c1)OCC(CO[Si](C)(C)C(C)(C)C)O2
Temperature: -78 °C
Reaction time: 1.25 h
Yield: 41.9 %

Procedure:
Reaction under nitrogen atmosphere. A solution of intermediate (37) (0.00194 mol) in THF was cooled to −78° C. BuLi (0.00214 mol, 2.5M) was added dropwise and the mixture was stirred for 75 minutes at −78° C. Then, iodomethane (00214 mol) was added and the reaction mixture was stirred for 45 minutes. A saturated aqueous NH4Cl solution was added and the mixture was allowed to warm to room temperature. This mixture was extracted with ethyl acetate. The separated organic layer was dried, filtered and the solvent evaporated. The residue was purified by flash column chromatography over silica gel (eluent: hexane/ethyl acetate 80/20). The desired fractions were collected and the solvent was evaporated, yielding 0.24 g of 3-[[[(1,1-dimethylethyl)dimethyl-silyl]oxy]methyl]-2,3-dihydro-7-methyl-[1,4]dioxino[2,3-b]pyridine (intermediate 38).
Reaction SMILES: CON(C)[C:4]([C@H:6]1[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][C@@:8]2([C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:26])[CH2:7]1)=[O:5].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([Mg]Br)=[CH:31][CH:30]=1>C1COCC1>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:4]([C@H:6]2[N:10]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:9][C@@:8]3([C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][C:18]3=[O:26])[CH2:7]2)=[O:5])=[CH:31][CH:30]=1
Reactant: CON(C)C(=O)[C@@H]1C[C@]2(CN1C(=O)OC(C)(C)C)C(=O)Nc1ccccc12
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@]2(C[C@H]1C(=O)c1ccc(Cl)cc1)C(=O)Nc1ccccc12
Reaction time: 8 h
Yield: 68.1 %

Procedure:
To a stirred solution of (3S,5′S)-tert-butyl 5′-(methoxy(methyl)carbamoyl)-2-oxospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate (310 mg, 0.826 mmol) in THF (4 mL) was added 4-chloro phenylmagnesium bromide (1.0 N in THF, 2.89 mL, 2.89 mmol) at about 0° C. The reaction mixture was warmed to about room temperature and stirred overnight. The reaction was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The crude product was purified by column chromatography (hexanes:EtOAc, 1:1) to give (3S,5′S)-tert-butyl 5′-(4-chlorobenzoyl)-2-oxospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate (0.240 g, 68%). LCMS (APCI+) m/z 427, 429 [M+H]+; Rt=3.94 min.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[NH:14][CH:13]=[C:12]([C:15]2[CH:38]=[CH:37][C:18]3[N:19]([C:22]4[CH:23]=[C:24]([NH2:36])[CH:25]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=5[F:35])[CH:27]=4)[CH:20]=[N:21][C:17]=3[CH:16]=2)[CH:11]=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:39]([N:45]=[C:46]=[O:47])[C:40]1[O:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:38]=[CH:37][C:18]3[N:19]([C:22]4[CH:23]=[C:24]([NH:36][C:46]([NH:45][CH2:39][C:40]5[O:44][CH:43]=[CH:42][CH:41]=5)=[O:47])[CH:25]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=5[F:35])[CH:27]=4)[CH:20]=[N:21][C:17]=3[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(C4=CNC(OCc5ccccc5)C=C4)ccc32)c1
Reactant: O=C=NCc1ccco1
Solvent: ClCCl
Product: O=C(NCc1ccco1)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4ccc(OCc5ccccc5)nc4)ccc32)c1
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of 5-(5-(6-(benzyloxy)-1,6-dihydropyridin-3-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-amine (75 mg, 0.148 mmol) in DCM was added furfuryl isocyanate (19 mg, 0.163 mmol, 1.1 eq.). The mixture was stirred overnight and quenched and extracted as in Example 2(b). The solvent was distilled off to afford the crude residue which was recrystallized in ether to afford the title compound in 86% yield (80 mg).
Reaction SMILES: [Li+].[OH-].[Br:3][C:4]1[CH:40]=[CH:39][C:7]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH2:19][C:20]4[CH:29]=[CH:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]=4)=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:30][C:31]([CH3:38])([CH3:37])[C:32]([O:34]CC)=[O:33])=[CH:6][CH:5]=1.C1COCC1.CO>O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH2:19][C:20]4[CH:29]=[CH:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]=4)=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:30][C:31]([CH3:37])([CH3:38])[C:32]([OH:34])=[O:33])=[CH:39][CH:40]=1
Reactant: CCOC(=O)C(C)(C)Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Br)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Br)cc1)C(=O)O
Temperature: 80 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
A solution of LiOH (39 mg, 0.9 mmol) in water (2 mL) was added to a 20 mL round-bottomed flask containing ethyl 3-(1-(4-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)-2,2-dimethylpropanoate (106 mg, 0.19 mmol), THF (3 mL), MeOH (3 mL), and water (3 mL). The resulting solution was heated to 80° C. After 2 h, the solution was concentrated to dryness and the residue was treated with sat. ammonium chloride (20 mL) and EtOAc (20 mL). The organic layer was separated and the aqueous layer was further extracted with EtOAc (2×20 mL). The combined organic layers were dried with sodium sulfate, filtered, and concentrated to dryness. The residue was subjected to FCC to give the title compound (84 mg, 83%). MS (ESI): mass calcd. for C29H26BrN3O3, 543.12; m/z found, 544.2 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 9.00 (d, J=8.7, 1H), 8.32 (d, J=8.5, 1H), 8.26 (d, J=8.4, 1H), 8.15-8.08 (m, 2H), 7.94-7.88 (m, 1H), 7.59 (d, J=8.8, 1H), 7.57-7.51 (m, 3H), 7.41 (dd, J=9.1, 2.4, 1H), 7.19 (d, J=8.6, 2H), 5.82 (s, 2H), 5.76 (s, 2H), 3.53 (s, 2H), 1.42 (s, 6H).
Reaction SMILES: Cl.CO.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:26]=[CH:27][C:28]=1[O:29]C1CCCCO1)[CH:9]=[CH:10][C:11]([CH:13]1[CH2:18][CH2:17][C:16]([CH3:25])([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[CH2:15][CH2:14]1)=[O:12].[Cl-].[Na+]>CO>[OH:29][C:28]1[CH:27]=[CH:26][C:8]([CH:9]=[CH:10][C:11]([CH:13]2[CH2:14][CH2:15][C:16]([CH3:25])([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[CH2:17][CH2:18]2)=[O:12])=[CH:7][C:6]=1[O:5][CH3:4]
Reactant: C=CCOC(=O)C1(C)CCC(C(=O)C=Cc2ccc(OC3CCCCO3)c(OC)c2)CC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: C=CCOC(=O)C1(C)CCC(C(=O)C=Cc2ccc(O)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
10 ml of 2N hydrochloric acid - methanol was added to a solution of 1.1 g of allyl 4-[3-methoxy-4-(2-tetrahydropyranyloxy)cinnamoyl]-1-methyl-1-cyclohexanecarboxylate (Example 38) in 30 ml of methanol. The solution was stirred for 0.5 hours at room temperature. After reaction, 100 ml of an aqueous sodium chloride solution was added to the reaction solution. The solution was extracted three times with 50 ml of ethyl acetate. The organic layer obtained was washed twice with an aqueous sodium chloride solution and dried over magnesium sulfate. Thereafter, the solvent was removed in vacuo, yielding 0.85 g of allyl 4-(4-hydroxy3-methoxycinnamoyl)-1-methyl-1-cyclohexanecarboxylate (a compound of the present invention) as a pale yellow oil, which had the following physiochemical properties:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[I:9]([O-])(=O)(=O)=O.[Na+].II.FC(F)(F)C(O)=O.S([O-])([O-])=O.[Na+].[Na+]>C(#N)C.O>[NH2:1][C:2]1[C:7]([I:9])=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1
Reactant: Nc1ccc(Br)cn1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: II
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1ncc(Br)cc1I
Temperature: 80 °C
Yield: 75 %

Procedure:
To a solution of 2-amino-5-bromopyridine (2) in acetonitrile was added sodiumperiodate (0.4 equiv) and iodine (0.65 equiv). Trifluoroacetic acid (0.65 equiv) was added over 15 min and the reaction mixture was heated at 80° C. overnight. HPLC indicated 96% conversion at this point. An aqueous solution of sodium sulfite was added, followed by more water to precipitate the product which was filtered off and washed with water. The title compound (11) was isolated as a brown crystalline solid in 75% yield. MS (Turbo Spray): 298 (M+H+, 100%)
Reaction SMILES: [C:1]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.Br[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1>C1COCC1>[CH3:27][O:26][C:24](=[O:25])[C:23]1[CH:28]=[CH:29][C:20]([CH2:19][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:1]2=[O:9])=[CH:21][CH:22]=1
Reactant: O=C1CCCCCCC1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC2CCCCCCC2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a stirring solution of cyclooctanone (1.76 g, 14.0 mmol) in THF (30 mL) at −78° C. was added LDA (8.54 mL, 15.4 mmol, 1.8 M in heptane/THF/ethylbenzene). After 1 h, a solution of methyl 4-bromomethylbenzoate (3.53 g, 15.4 mmol) in THF (10 mL) was added and the reaction mixture was allowed to warm to rt. After 30 min, the reaction was quenched with H2O (10 mL) and the THF was removed on a rotary evaporator. The residue was diluted with EtOAc (100 mL), washed with H2O (3×100 mL) and brine (1×50 mL), and dried over MgSO4. Chromatography of the crude product (50:1 to 9:1 hexanes/EtOAc) yielded the desired product as a colorless oil (3.08 g, 80%, Rf=0.30, 9:1 hexanes/EtOAc). IR: 3426, 2929, 2856, 1721, 1700, 1657, 1611 cm−1. 1H NMR (CDCl3, 300 MHz): δ 1.10-1.28 (m, 1H), 1.28-1.42 (m, 1H), 1.42-1.80 (m, 6H), 1.80-1.90 (m, 1H), 1.90-2.08 (m, 1H), 2.08-2.18 (m, 1H), 2.22-2.35 (m, 1H), 2.64 (dd, 1H, J=12.6, 6.0 Hz), 3.01 (m, 2H), 3.89 (s, 3H), 7.20 (d, 2H, J=8.1 Hz), 7.93 (d, 2H, J=8.4 Hz). 13C NMR (CDCl3, 75 MHz): δ 24.5, 24.6, 25.1, 27.7, 32.9, 38.1, 43.2, 51.5, 52.0, 128.1, 129.0, 129.7, 145.6, 167.0, 218.9. FAB—HRMS: Calcd. for C17H23O3+ [M+H]+: 275.1647, found: 275.1648.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[O:1]=[CH:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: ClCc1ccccc1
Reactant: O=C(O)CCOCCOCCOCCO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=CCOCCOCCOCCC(=O)OCc1ccccc1

Procedure:
The title compound was prepared from 6 g (21.55 mmol) of commercially available 3-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}propanoic acid under standard conditions, first by esterification with benzyl chloride and caesium carbonate and subsequent oxidation with sulphur trioxide-pyridine complex.