Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:15]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[C-:22]#[N:23].[K+]>O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:15]2([C:22]#[N:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCCC1
Reactant: [C-]#N
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: N#CC1(N2CCN(Cc3ccccc3)CC2)CCCCC1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
1 benzylpiperazine (Aldrich Chemical Co., Inc., supra) (6.12 g) was dissolved in 10 mL deionized water and cooled to 0° C. Concentrated hydrochloric acid (3.6 mL) was added to adjust the pH to 5. After warming to room temperature, 3.6 mL cyclohexanone was added, followed by potassium cyanide (2.4 g) in 6 mL deionized water. The solution slowly became cloudy. After 18 hours, the solid was filtered. The solid was dissolved in chloroform, dried over Na2SO4, filtered and the solvent was removed in vacuo to yield pure 1 benzyl-4-(1-cyanocyclohexyl) piperazine.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:23]=[CH:22][C:11]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:10][CH:9]=2)[CH2:3]1.[CH:24](=O)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].[BH4-].[Na+]>>[CH2:24]([N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:9]=[CH:10][C:11]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:22][CH:23]=2)[CH2:3]1)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: NC(=O)c1ccc(Oc2ccc(C3CCCNC3)cc2)nc1
Reactant: CCCCCC=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: CCCCCCN1CCCC(c2ccc(Oc3ccc(C(N)=O)cn3)cc2)C1
Yield: 30 %

Procedure:
Using a method similar to Example 324, 6-(4-piperidin-3-yl-phenoxy)-nicotinamide (free base of compound of example 322) (0.0260 g, 0.0874 mmol), hexanal (0.0195 mL, 0.162 mmol), and sodium borohydride (0.0076 g, 0.200 mmol) provide 0.0100 g (30%) of the title compound as an off-white foam: high resolution mass spectrum (electrospray): m/z calc for C13H32N3O2 382.2495, found 382.2513; 1H NMR (methanol-d4): 8.66 (d, 1H, J=2.0 Hz), 8.29 (dd, 1H, J=2.4, 8.8 Hz), 7.41-7.35 (m, 2H), 7.16-7.11 (m, 2H), 7.02 (d, 1H, J=8.3 Hz), 3.23-3.16 (m, 2H), 2.95 (tt, 1H, J=3.4, 11.7 Hz), 2.63-2.56 (m, 2H), 2.35-2.22 (m, 2H), 2.05-1.90 (m, 2H), 1.83 (tq, 1H, J=3.9, 13.7 Hz), 1.70-1.56 (m, 3H), 1.45-1.30 (m, 6H), 0.96 (t, 3H, J=6.3 Hz).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH:9]2[O:13][C:12](=[O:14])[CH:11]=[C:10]2[OH:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[F:24][C:25]1[CH:33]=[C:32]2[C:28]([C:29]([CH2:34][CH2:35][NH:36][C:37](=[O:39])[CH3:38])=[CH:30][NH:31]2)=[CH:27][CH:26]=1>>[CH:1]1([CH2:7][CH2:8][CH:9]2[O:13][C:12](=[O:14])[C:11]([CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:30]3[NH:31][C:32]4[C:28]([C:29]=3[CH2:34][CH2:35][NH:36][C:37](=[O:39])[CH3:38])=[CH:27][CH:26]=[C:25]([F:24])[CH:33]=4)=[C:10]2[OH:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccccc1
Reactant: O=C1C=C(O)C(CCC2CCCCC2)O1
Reactant: CC(=O)NCCc1c[nH]c2cc(F)ccc12
Product: CC(=O)NCCc1c(C(C2=C(O)C(CCC3CCCCC3)OC2=O)c2ccccc2)[nH]c2cc(F)ccc12

Procedure:
Using general procedure C, 5-(2-cyclohexyl-ethyl)-4-hydroxy-5H-furan-2-one (Example B2) was reacted with benzaldehyde and N-[2-(6-fluoro-1H-indol-3-yl)-ethyl]-acetamide (Example 18.1.) to give the title compound as pale green solid. MS: 517.2 ([M−H]−).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH2:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14])=[N+:2]=[N-:3].[OH:16][C@H:17]1[C:21]2[N:22]=[CH:23][N:24]=[C:25]([C:26]3[S:30][C:29]([C:31](O)=[O:32])=[CH:28][CH:27]=3)[C:20]=2[C@H:19]([CH3:34])[CH2:18]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[N:1]([CH2:4][C@@H:5]([NH:15][C:31]([C:29]1[S:30][C:26]([C:25]2[C:20]3[C@H:19]([CH3:34])[CH2:18][C@@H:17]([OH:16])[C:21]=3[N:22]=[CH:23][N:24]=2)=[CH:27][CH:28]=1)=[O:32])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14])=[N+:2]=[N-:3]
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(-c3ccc(C(=O)O)s3)c21
Reactant: [N-]=[N+]=NC[C@@H](N)Cc1ccc(Cl)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(-c3ccc(C(=O)N[C@H](CN=[N+]=[N-])Cc4ccc(Cl)cc4Cl)s3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
(S)-1-Azido-3-(2,4-dichlorophenyl)propan-2-amine (20 mg, 0.0724 mmol) was added to a solution of 5-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxylic acid (35 mg, 0.145 mmol) in DCM (0.5 mL). DMF (125 μL) was added to solubilize the starting material completely. DIPEA (126 μL, 0.724 mmol) was added, followed by the addition of HBTU (30 mg, 0.079 mmol). The reaction mixture was stirred at room temperature for 1 hour. LC-MS of the reaction mixture showed no more starting material. The solvent was removed, and the resulting residue was purified by reversed phase HPLC to yield N-((S)-1-azido-3-(2,4-dichlorophenyl)propan-2-yl)-5-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxamide product as a solid (4 mg, 10%). m/z 504 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[NH2:11][C:12]1[N:17]=[N:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])=[O:25])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[N:17]=[N:16][C:15]([N:18]2[CH2:19][CH2:20][N:21]([C:24](=[O:25])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])[CH2:22][CH2:23]2)=[CH:14][CH:13]=1)=[O:10]
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: O=C=Nc1ccccc1F
Product: O=C(Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1)Nc1ccccc1F

Procedure:
Following the procedure of Example 5, making variations only as required to use 2-fluorophenylisocyanate in place of (2-isocyanatocyclopropyl)benzene to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)-methanone, the title compound was obtained as a white solid (32% yield). 1H NMR (500 MHz, CDCl3) δ 7.90-8.30, 7.99, 7.75, 7.63, 7.57, 7.34, 7.10-7.17, 7.01-7.07, 3.94-4.01, 3.85-3.92, 3.56-3.66, 3.41-3.49, 3.24-3.29.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].[C:27](Cl)(=[O:30])[CH2:28][CH3:29].C(N(CC)CC)C>>[CH3:26][C:24]1[CH:23]=[C:4]([CH:3]=[C:2]([CH3:1])[CH:25]=1)[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][N:20]([C:27](=[O:30])[CH2:28][CH3:29])[CH2:19][CH2:18]1)(=[O:16])=[O:15]
Reactant: CCC(=O)Cl
Reactant: Cc1cc(C)cc(Oc2ccc(C#N)cc2S(=O)(=O)N2CCNCC2)c1
Solvent: CCN(CC)CC
Product: CCC(=O)N1CCN(S(=O)(=O)c2cc(C#N)ccc2Oc2cc(C)cc(C)c2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of compound 24 (0.102 g, 0.27 mmol) in CH2Cl, (2 mL) was added propionyl chloride (0.035 g, 0.38 mmol) and triethylamine (0.039 g, 0.38 mmol). The reaction mixture was stirred at room temperature for 20 hrs, whereupon the starting material was consumed (TLC, 1% MeOH in CH2Cl2). The reaction mixture was concentrated in vacuo, redissolved in a minimal amount of CH2Cl2, and chromatographed over normal phase silica (MeOH/CH2Cl2). The fractions containing the desired product were combined and concentrated in vacuo to yield a white powder, which was then triturated with CH2Cl2/diisopropyl ether and vacuum filtered to yield the desired product as a powder. The powder was redissolved in CH2Cl2 and chromatographed for a second time over normal phase silica (MeOH/CH2Cl2). The fractions containing the desired product were combined and concentrated in vacuo to yield a white powder. The powder was triturated with diisopropyl ether and vacuum filtered to yield compound 57 (0.061 g, 52.1% yield, 96.6% HPLC purity). 1H NMR (500 MHz, CDCl3): 8.27 (d, J=2 Hz, 1H), 7.67 (dd, J1=9 Hz, J2=2 Hz, 1H), 6.94 (s, 1H), 6.90 (d, J=9 Hz, 1H), 6.68 (s, 2H), 3.71 (m, 2H), 3.54 (m, 2H), 3.35 (m, 4H), 2.34 (s, 6H), 2.32 (m, 2H), 1.13 (t, J=7 Hz, 3H); MS (ESI, EI+): m/z=428 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:22]=[CH:21][C:8]([O:9][CH2:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1.[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(P(=CC#N)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34]([O:1][CH2:2][CH2:3][CH2:4][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]3[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=3[C:13]([O:15][CH3:16])=[O:14])=[CH:21][CH:22]=2)=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccccc1COc1ccc(CCCO)cc1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccccc1COc1ccc(CCCOc2ccc(OCc3ccccc3)cc2)cc1
Yield: 64.3 %

Procedure:
Methyl 2-{[4-(3-hydroxypropyl)phenoxy]methyl}benzoate (0.50 g, 1.66 mmol) and 4-(benzyloxy)phenol (0.33 g, 1.66 mmol) was added to a dry round bottomed flask fitted with a septum Dry toluene (10 ml) was added and N2 was flushed through the mixture for 5 minutes. (Tributylphosphoranylidene)acetonitrile (0.80 g, 3.33 mmol) was added dropwise and the reaction was performed in a single node microwave oven. After removing the solvent by evaporation the crude was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min)). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). Removing the solvent by evaporation gave 0.515 gram of methyl 2-[(4-{3-[4-(benzyloxy)phenoxy]-propyl}phenoxy)methyl]benzoate (yield 64.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[S:19][C:18]([CH2:20]Cl)=[CH:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([CH:34]([OH:38])[CH2:35][NH:36][CH3:37])=[CH:33][C:28]=2[O:27][CH2:26]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([CH:34]([OH:38])[CH2:35][N:36]([CH2:20][C:18]3[S:19][C:12]4[C:11](=[O:22])[C:10]([C:8]([NH:7][CH2:6][C:5]5[CH:23]=[CH:24][C:2]([Cl:1])=[CH:3][CH:4]=5)=[O:9])=[CH:15][N:14]([CH3:16])[C:13]=4[CH:17]=3)[CH3:37])=[CH:33][C:28]=2[O:27][CH2:26]1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CCl)cc21
Reactant: CNCC(O)c1ccc2c(c1)OCO2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN(Cc1cc2c(s1)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C)CC(O)c1ccc2c(c1)OCO2
Temperature: 60 °C
Reaction time: 5 h
Yield: 65.3 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (80 mg, 0.21 mmol), 1-(1,3-benzodioxol-5-yl)-2-(methylamino)ethanol (Journal of Organometallic Chemistry, 1998, 339, 267-75) (62 mg, 0.32 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 5 hours at that temperature. After cooling to room temperature, the solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight in the refrigerator. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile/water (dissolved with warming 3 mL of acetonitrile, then cooled to 0° C. and then diluted with 2 mL of water, left overnight) gave the title compound (74 mg) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[N:18]=[C:17]([NH:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[C:16]2[C:15]([CH3:27])=[N:14][C:13]([NH2:28])=[N:12][C:11]=2[CH2:10]1.[CH3:29][O:30][C:31]1[N:36]=[C:35](B2OCCN(C3C=CC=CC=3)CCO2)[CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C.C(OCC)(=O)C>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C@@H:9]2[N:18]=[C:17]([NH:19][O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[C:16]3[C:15]([CH3:27])=[N:14][C:13]([NH2:28])=[N:12][C:11]=3[CH2:10]2)=[C:2]([C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([O:30][CH3:29])[N:36]=2)[CH:7]=1
Reactant: COc1cccc(B2OCCN(c3ccccc3)CCO2)n1
Reactant: Cc1nc(N)nc2c1C(NOC1CCCCO1)=N[C@@H](c1ccc(F)cc1Br)C2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3C(NOC3CCCCO3)=N2)n1
Temperature: 85 °C
Yield: 124.7 %

Procedure:
(7R)-7-(2-bromo-4-fluorophenyl)-4-methyl-5-(tetrahydro-2H-pyran-2-yloxyamino)-7,8-dihydropyrido[4,3-d]pyrimidin-2-amine (0.838 g, 1.86 mmol), 2-(6-methoxypyridin-2-yl)-6-phenyl-1,3,6,2-dioxazaborocane (1.33 g, 4.47 mmol), sodium carbonate 2M solution (3.72 mL, 7.44 mmol) were combined in N,N-Dimethylacetamide (12 mL) and then the mixture was purged with nitrogen for 5 minutes. 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(II) dichloromethane complex (0.136 g, 0.186 mmol) was then added and the reaction was heated in 85° C. oil bath overnight. Next day, the reaction was diluted with ethyl acetate 80 mL, washed with brine (80 mL), dried over sodium sulfate, and concentrated to a crude product which was then purified by flash column chromatography, SiO2, gradient 20-100% ethyl acetate/hexane to give a white solid, 1.11 g of product, contaminated with the impurity of mass 182 (byproduct from the boronic ester, compound 6). MS (ES) [M+H] calc'd for C25H27FN6O3, 479; found, 479.4.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][CH2:21][CH2:22][CH2:23][S:24](Cl)(=[O:26])=[O:25].C(Cl)(Cl)Cl>ClCCl>[C:2]1([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:14]2[CH2:19][CH2:18][N:17]([S:24]([CH2:23][CH2:22][CH2:21][Cl:20])(=[O:26])=[O:25])[CH2:16][CH2:15]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=S(=O)(CCCCl)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
39.2 g (155 mmol) benzhydrylpiperazine and 19.7 ml (141 mmol) TEA are present in 100 ml absolute dichloromethane and cooled to ca. 0° C. under moisture exclusion. 25 g (141 mmol) 3-chloropropanesulfonyl chloride are dissolved in 70 ml absolute dichloromethane and added dropwise. The mixture is stirred for two hours under cooling and subsequently mixed with chloroform and washed with saturated NaCl solution. The organic phase is dried over sodium sulfate and concentrated under vacuum until dry. The solid is further processed without further purification: yield 59.2 g.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH2:7][C:6]2[CH:17]=[C:18]([S:21][CH3:22])[CH:19]=[CH:20][C:5]=2[NH:4][C:3]1=[O:23].ClC1C=C(C=CC=1)C(OO)=[O:29]>C(Cl)Cl.C(OCC)(=O)C>[OH:1][C@H:2]1[C@@H:8]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[CH2:7][C:6]2[CH:17]=[C:18]([S:21]([CH3:22])=[O:29])[CH:19]=[CH:20][C:5]=2[NH:4][C:3]1=[O:23]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc([C@H]2Cc3cc(SC)ccc3NC(=O)[C@H]2O)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc([C@H]2Cc3cc(S(C)=O)ccc3NC(=O)[C@H]2O)cc1
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
A solution of (cis)-1,3,4,5-Tetrahydro-3-hydroxy-7-methylthio-4-(4-methoxyphenyl)-2H-1-benzazepin-2-one (1.0 g, 3.04 mmol) in dry methylene chloride (30 ml) at 5° C. was treated with m-chloroperoxybenzoic acid (0.615 g, 3.04 mmol). After 30 minutes, the reaction was complete and the reaction mixture was diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate, water, and brine. The organic layer was filtered and concentrated in vacuo to give a solid residue (1.02×g). Trituration with hot ethyl acetate, cooling and filtration afforded the product (600 mg), m.p. 214°14 216° C. The mother liquors were concentrated in vacuo and chromatographed on LPS-1 silica (methylene chloride/methanol). The product fractions were combined and concentrated in vacuo, and the residue crystallized from ethyl acetate to give an additional 200 mg of product.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O.[Br-].[CH3:24][C:25]1[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:26]=1[CH2:27][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1C>>[CH3:24][C:25]1[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:26]=1/[CH:27]=[CH:18]/[C:17]1[CH:16]=[C:15]([CH2:14][CH2:13][CH2:12][N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])[CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Reactant: Cc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2C)c(C)c1
Agent: [Br-]
Product: Cc1ccc(/C=C/c2cccc(CCCN3C(=O)c4ccccc4C3=O)c2)c(C)c1

Procedure:
Phthalimide 29 was coupled with 2,4-dimethylmethylbenzyltriphenylphosphonium bromide and purified by flash chromatography (20 to 50% EtOAc-hexanes gradient) to give (E)-2-(3-(3-(2,4-dimethylstyryl)phenyl)propyl)isoindoline-1,3-dione as an oil. Yield (0.3974 g, 92%), trans-/cis-isomer ratio 1.2:1. Cis-isomer: 1H NMR (400 MHz, CDCl3) δ 7.80-7.88 (m, 4H), 6.80-7.55 (m, 7H), 6.62 (d, J=12.0 Hz, 1H), 6.57 (d, J=12.0 Hz, 1H), 3.63 (t, J=7.2 Hz, 2H), 2.65 (t, J=7.2 Hz, 2H), 2.37 (s, 3H), 2.27 (s, 3H), 1.95 (quint, J=7.2 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N:19]4[CH2:24][CH2:23][N:22]([CH:25]5[CH2:28][O:27][CH2:26]5)[CH2:21][CH2:20]4)[CH:17]=3)[O:12][CH2:11][C@@H:10]2[OH:29])=[O:7])=[CH:4][CH:3]=1.[CH3:32][NH2:33].[OH-].[Na+].C1[CH2:40][O:39]CC1>>[F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N:19]4[CH2:20][CH2:21][N:22]([CH:25]5[CH2:28][O:27][CH2:26]5)[CH2:23][CH2:24]4)[CH:17]=3)[O:12][CH2:11][C@@H:10]2[O:29][C:40](=[O:39])[NH:33][CH3:32])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(N[C@H]1c2cc(N3CCN(C4COC4)CC3)ccc2OC[C@@H]1O)c1ccc(F)cc1
Reactant: C1CCOC1
Reactant: CN
Agent: [Na+]
Agent: [OH-]
Product: CNC(=O)O[C@H]1COc2ccc(N3CCN(C4COC4)CC3)cc2[C@@H]1NC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Suspend 4-fluoro-N-[(3R,4S)-3-hydroxy-6-[4-(oxetan-3-yl)piperazin-1-yl]chroman-4 yl]benzamide (10.0 g, 23.4 mmol) in THF (200 mL) and add 1,1 carbonyldiimidazole (4.9 g, 30.4 mmol). Stir at ambient temperature for 3 hr. Cool the reaction mixture to −5° C. and add 2 M methyl amine (in THF, 21 mL, 42.1 mmol) over 15 min. Stir the resulting mixture at −5-0° C. for 3 hr. Add 2 N NaOH (100 mL) and stir the mixture for 1 hr. at 10-30° C. Separate the layers and wash the organics with 2 N NaOH (4×100 mL). Add water (200 mL) and concentrate the mixture under reduced pressure to approximately twenty volumes (based on starting material). Add THF (200 mL) and stir at ambient temperature for 1 hr. Filter the mixture and transfer the product wetcake back to a clean reaction vessel. Add THF (200 mL) and water (200 mL) and stir at ambient temperature for 1 hr. Isolate the technical grade title compound by filtration and vacuum dry at 80° C. (9.0 g, 80%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[N:22]=[C:21]([N:24]2[C:28]4[CH:29]=[CH:30][C:31]([OH:33])=[CH:32][C:27]=4[N:26]=[CH:25]2)[CH:20]=[CH:19]3)[CH2:10][CH2:9]1)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].[Br-].[CH:42]1([CH3:45])[CH2:44][CH2:43]1>CN(C=O)C.C(O)(C(F)(F)F)=O>[CH:42]1([CH2:45][O:33][C:31]2[CH:30]=[CH:29][C:28]3[N:24]([C:21]4[CH:20]=[CH:19][C:18]5[C:23](=[C:14]([N:11]6[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]6)[CH:15]=[CH:16][CH:17]=5)[N:22]=4)[CH:25]=[N:26][C:27]=3[CH:32]=2)[CH2:44][CH2:43]1
Reactant: CC1CC1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cccc3ccc(-n4cnc5cc(O)ccc54)nc23)CC1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(c2cccc3ccc(-n4cnc5cc(OCC6CC6)ccc54)nc23)CC1
Temperature: 65 °C
Reaction time: 4 h
Yield: 65.6 %

Procedure:
{1-[2-(5-Hydroxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester 3A (200 mg, 0.435 mMol) was dissolved in 1.5 mL of anhydrous DMF under an atmosphere of dry N2. To this solution was added Cs2CO3 (170 mg, 0.520 mMol) followed by cyclopropyl methane bromide (46 μL, 0.48 mMol). The reaction mixture was subsequently heated to 65° C. and stirred at this temperature for 4 hours. The reaction mixture was then cooled to ambient temperature and partitioned between EtOAc and water. The EtOAc layer was washed 4 more times with water and then with brine. The EtOAc was then dried over Na2SO4, filtered and concentrated under vacuum and the resulting green oil was chromatographed on flash silica gel eluting with MeOH/DCM (2:98) to give the a green oil. The oil was dissolved in 1.5 mL of TFA under an atmosphere of dry N2. The reaction mixture was stirred at ambient temperature for 10 minutes after which time it was concentrated under vacuum and the resulting residue was partitioned between DCM and aqueous 0.1 N NaOH. The DCM layer was then washed with basic brine (pH 10), dried over Na2SO4, filtered and concentrated under vacuum to give 118 mg of the title compound as a yellow solid 32.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]3[CH2:14][O:13]3)=[CH:8][CH:7]=2)[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[CH2:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][NH:22]1>C(O)C>[S:1]1[CH:5]=[C:4]([C:6]2[CH:16]=[CH:15][C:9]([O:10][CH2:11][C@H:12]([OH:13])[CH2:14][N:22]3[CH2:23][CH2:24][C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:21]3)=[CH:8][CH:7]=2)[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: c1ccc2c(-c3ccc(OCC4CO4)cc3)csc2c1
Reactant: c1ccc2c(c1)CCNC2
Solvent: CCO
Product: O[C@@H](COc1ccc(-c2csc3ccccc23)cc1)CN1CCc2ccccc2C1

Procedure:
The title compound is prepared from a mixture of 2-(4-benzo[b]thiophen-3-yl-phenoxymethyl)-oxirane, 1,2,3,4-tetrahydroisoquinoline and ethanol essentially as described above in Example 94. Purity by LC/MS=100%, [M+H]+=416.