Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[CH2:14][C:13](=[O:30])[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:5]2=[CH:4][CH:3]=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42].N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][CH:24]4[CH2:29][CH2:28][N:27]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:26][CH2:25]4)[CH2:14][C:13](=[O:30])[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC2CCNCC2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC2CCN(S(C)(=O)=O)CC2)C12C(=O)Nc1cc(Cl)ccc12
Reaction time: 4 h
Yield: 6.2 %

Procedure:
To a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(4-piperidinyloxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (110 mg, 0.2 mmol), methanesulfonyl chloride (0.0185 mL, 0.24 mmol) in DCM (5 mL) was added pyridine (23 mg, 0.3 mmol) at r.t. The reaction mixture was stirred for 4 h, then concentrated and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated. The residue was purified with Prep-HPLC to give the title compound as a white solid (Yield: 8 mg).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[CH3:6][N:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)[CH3:8].O1CCCC1.ICCC>CCCCCC>[CH3:8][N:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1[CH2:1][CH2:2][CH3:3])[CH3:6]
Reactant: COc1cccc(CN(C)C)c1
Reactant: [Li]CCCC
Solvent: CCCI
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCc1c(CN(C)C)cccc1OC
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Under an argon atmosphere, 420 ml. of a 1.6 M solution of n-butyllithium in hexane were slowly added to a solution of 105.6 g. of N,N-dimethyl-3-methoxybenzylamine in 1000 ml. of tetrahydrofuran by means of an addition funnel, keeping the temperature below 0° C. with an external ice/ethanol bath. After the addition was completed, the reaction was stirred at 0° C. for four hours. At this time, 68.3 ml. of 1-iodopropane were added dropwise to the solution keeping the temperature below 10° C. The reaction was stirred for one hour. The cooling bath was removed and the reaction was stirred an additional two hours. The reaction was then heated to reflux for about 16 hours. The reaction solution was concentrated in vacuo and the residue was taken up in diethyl ether. The ether solution was first washed with an aqueous sodium hydroxide solution and then with water. The ether layer was dried over sodium sulfate and the solvent was removed in vacuo. The residue was vacuum distilled at 3 torr. The fraction collected between 105° and 115° C. provided 104.3 g. of the desired title intermediate. NMR, IR.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:2]1[O:4][CH2:3]1.[CH3:14][C:15]([NH2:26])([CH3:25])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>>[OH:4][CH:2]([CH2:1][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:3][NH:26][C:15]([CH3:25])([CH3:14])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1
Reactant: CCCCCCCCOCC1CO1
Reactant: COc1ccc(CC(C)(C)N)cc1
Product: CCCCCCCCOCC(O)CNC(C)(C)Cc1ccc(OC)cc1
Yield: 28.7 %

Procedure:
Using the method of Example 5, supra, 1-octyl glycidyl ether (187 mg, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1 mmol) were used to prepare 105 mg of the title compound as a clear, colorless oil: GC/EI-MS, m/z (rel. int.) 366 (M+1, 0.08), 350 (0.08), 244 (100), 222 (5.8), 163 (12), 121 (18): 1H-NMR (CDCl3) δ 7.08 (2H, d, J=8.6), 6.82 (2H, d, J=8.6), 3.79 (1H, m), 3.77 (3H, s), 3.45 (4H, m), 2.92 (1H, broad s), 2.79 (1H, dd, J=11.6 and 4.1), 2.65 (2H, m), 2.55 (2H, m), 1.27 (8H, m), 1.06 (3H, s), 1.04 (3H, s), 0.88 (3H, t, J=6.7); 13C-NMR (CDCl3) δ 158.0, 131.2, 129.9, 113.2, 73.4, 71.6, 68.9, 55.0, 53.3, 46.2, 44.6, 31.7, 29.5, 29.3, 29.1, 26.5, 26.4, 26.0, 22.5, 14.0; FT-IR (film) cm-1 3409 (broad), 1611, 1512, 1245, 1120.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[N:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH2:30][C:31](=[O:37])[NH:32]3)=[CH:24][CH:23]=1>>[CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=[C:30]1[C:29]2[C:33](=[CH:34][CH:35]=[CH:36][C:28]=2[C:25]2[CH:24]=[CH:23][N:22]=[CH:27][CH:26]=2)[NH:32][C:31]1=[O:37]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Product: Cc1c(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Yield: 73.1 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-pyridin-4-yl-1,3-dihydro-indol-2-one (prepared according to WO2002055517) as starting materials to give 3-methyl-2-(2-oxo-4-pyridin-4-yl-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (50 mg, 73.1%) as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([O:13]C)=[O:12])=[C:9]2[N:5]([CH2:6][CH2:7][CH2:8]2)[C:4](=[O:15])[CH:3]=1.C1COCC1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[N:5]([CH2:6][CH2:7][CH2:8]2)[C:4](=[O:15])[CH:3]=1
Reactant: COC(=O)c1c(Cl)cc(=O)n2c1CCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1c(Cl)cc(=O)n2c1CCC2
Yield: 84.7 %

Procedure:
Compound 1b (800 mg, 3.52 mmol) was stirred in a solution of THF (10 mL), MeOH (5 mL), and 1N NaOH (5 mL) at r.t. for 20 h. The solution was made acidic with 1N HCl and extracted (3×) with CHCl3. Organics were dried (MgSO4) and concentrated in vacuo to give 637 mg (85%) of compound 9a as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 13.17 (s, 1H), 6.43 (s, 1H), 3.99 (t, 2H, J=7.4 Hz), 3.32 (t, 2H, J=7.8 Hz), 1.95-2.21 (m, 2H). MS (ES) [m+H] calc'd for C9H8ClNO3, 214. found 214.
Reaction SMILES: [C:1]([O:8][CH2:9]Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:11]1[CH:12]=[CH:13][C:14]2[S:19][N:18]=[C:17]([N:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][C:28]4[CH:29]=[C:30]5[CH2:38][C:36](=[O:37])[NH:35][C:31]5=[CH:32][C:33]=4[Cl:34])[CH2:22][CH2:21]3)[C:15]=2[CH:16]=1.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1.C.[Cl-].[Cl-]>[C:1]([O:8][CH2:9][N:35]1[C:31]2[C:30](=[CH:29][C:28]([CH2:27][CH2:26][N:23]3[CH2:24][CH2:25][N:20]([C:17]4[C:15]5[CH:16]=[CH:11][CH:12]=[CH:13][C:14]=5[S:19][N:18]=4)[CH2:21][CH2:22]3)=[C:33]([Cl:34])[CH:32]=2)[CH2:38][C:36]1=[O:37])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C1Cc2cc(CCN3CCN(c4nsc5ccccc45)CC3)c(Cl)cc2N1
Reactant: CCCCCC(=O)OCCl
Agent: C
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCC(=O)OCN1C(=O)Cc2cc(CCN3CCN(c4nsc5ccccc45)CC3)c(Cl)cc21
Reaction time: 24 h
Yield: 27 %

Procedure:
Chloromethyl hexanoate (3.18 g, 19.0 mmol) in dichloromethane (6 mL) was added to a suspension of Ziprasidone free base (4.0 g, 9.6 mmol), triethyl amine (4.0 mL, 27 mmol) and 4-dimethylamino pyridine (DMAP, 0.708 g, 5 mmol) in dichloride methane (240 mL) at 25-30° C. The reaction solution was stirred for 24 h at same temperature. The crude mixture was washed with water (100 mL) followed by brine solution (100 mL), upon solvent evaporation under vacuum below 40° C. provided crude title product, Compound 322, which was further purified by silica gel column chromatography. (1.4 g, 27% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:6]([NH:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[OH:16])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1Cl.ClCCl>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]2[O:16][C:6]([C:5]3[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:8][C:9]=2[CH:14]=1
Reactant: COc1ccc(C(=O)Nc2cc(Cl)ccc2O)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc(-c2nc3cc(Cl)ccc3o2)cc1OC
Yield: 31.1 %

Procedure:
A solution of N-(3,4-dimethoxybenzoyl)-2-hydroxy-5-chloroaniline (5.0 g, 0.015 mol) was heated under reflux for 11 hours in 30 ml o-dichlorobenzene and p-toluenesulfonic acid monohydrate (0.3 g, 15 mmol). The reaction mixture was diluted with dichloromethane and filtered through a pad of alumina (25 g). The solvent was evaporated under reduced pressure and the residue was triturated with petroleum ether and filtered to give 2.7 g of crudeproduct. The material was crystallized from methyl t-butyl ether with charcoal to give 1.35 g of material which was crystallized again from methyl t-butyl ether and sublimed at 130° C. (0.05 mm) to give pure title compound as tan crystals, mp 142-145° C.
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+].[NH:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1.[Cl:59][C:60]1[CH:65]=[C:64]([Cl:66])[CH:63]=[CH:62][C:61]=1Br>C1COCC1>[Cl:59][C:60]1[CH:65]=[C:64]([Cl:66])[CH:63]=[CH:62][C:61]=1[N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1
Reactant: C1CNCCN1
Reactant: Clc1ccc(Br)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1CCOC1
Product: Clc1ccc(N2CCNCC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
BINAP (219 mg), Pd(II)acetate (397 mg, 0.176 mmol), tBuONa (1.19 g, 12.3 mmol), piperazine (837 mg, 9.73 mmol) and THF (40 mL) were mixed together and stirred at room temperature for 30 min under nitrogen atmosphere. 2,4-dichlorobromobenzene (2 g, 8.84 mmol) in THF (10 mL) was added to the mixture drop wise and heated at 70° C. for 14 h. Excess THF was then evaporated and extracted with ethyl acetate. The crude product was obtained on concentration of the ethyl acetate layer after washing with brine and drying. Flash chromatography on silica gel eluting with 2% MeOH in CHCl3 gave 1-(2,4-Dichloro-phenyl)-piperazine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][NH:12][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[C:19]#[N:20].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH:14]([CH2:13][N:12]([C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[C:19]#[N:20])[CH2:11]2)[CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: N#Cc1ccccc1Br
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC2CN(c3ccccc3C#N)CC2C1
Temperature: 120 °C
Yield: 74 %

Procedure:
A mixture of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (464 mg, (2.19 mmol), 2-bromobenzonitrile (400 mg, 2.19 mmol), Pd2(dba)3 (100 mg, 0.11 mmol), xantphos (190 mg, 0.33 mmol), sodium t-butoxide (618 mg, 6.57 mmol) in degassed anhydrous dioxane (10 mL) was heated at 120° C. in a sealed tube for 1 h. The mixture was allowed to cool and filtered through celite. The filtrate was concentrated and purified by chromatography (EtOAc/hexanes) to yield the title compound (505 mg, 74%). m/z (M+1) 313.41.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3(O)[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.Cl>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C1CCC(O)(c2ccc3c(c2)OCO3)CC1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CC=C(c2ccc3c(c2)OCO3)CC1

Procedure:
A solution of 4-benzo[1,3]dioxol-5-yl-4-hydroxy-cyclohexanone (as prepared in the previous step, 3.5 g, 15 mmol) in THF (10 mL) was treated with 6N HCl (5 mL) overnight under argon at room temperature. The resulting solution was quenched with sufficient 1N NaOH to neutralize the reaction. The solvent was removed and the residue was partitioned between DCM and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow oil, which was then purified by silica gel column on a CombiFlash® system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)O)=[CH:3][CH:2]=1>C(O)(=O)C.[Zn]>[S:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: OC(c1ccncc1)c1cccs1
Agent: [Zn]
Solvent: CC(=O)O
Product: c1csc(Cc2ccncc2)c1
Yield: 87.2 %

Procedure:
To a stirred solution of pyridin-4-yl(thiophen-2-yl)methanol (G) (4 g, 20.94 mmol) in acetic acid (40 mL) was added Zn powder (11.69 g, 208.73 mmol) portion wise at 70° C. and the reaction mixture was allowed to reflux for 16 h. Then the reaction mixture was filtered through Celite® and the filtrate was rotary evaporated. The resultant residue was diluted with water (50 mL), basified with Na2CO3 solution to pH 9 at 0° C. and extracted with diethyl ether (2×100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was rotary evaporated under vacuum to get the desired compound as an oily liquid (3.2 g, 87%); 1H NMR (400 MHz, DMSO-d6) δ 8.48 (dd, J=1.5 Hz, 4.4 Hz, 2H), 7.37 (dd, J=1.5 Hz, 4.9 Hz, 1H), 7.26 (d, J=5.9 Hz, 2H), 6.99-6.93 (m, 2H), 4.19 (s, 2H).
Reaction SMILES: [OH:1][CH:2]([C:6]([O:19][CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[H-].[Na+].Cl[C:24]1[N:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=1>CN(C=O)C>[CH3:30][C:27]1[N:26]=[N:25][C:24]([O:1][CH:2]([C:6]([O:19][CH3:20])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]([OH:5])=[O:4])=[CH:29][CH:28]=1
Reactant: Cc1ccc(Cl)nn1
Reactant: COC(c1ccccc1)(c1ccccc1)C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(c1ccccc1)(c1ccccc1)C(Oc1ccc(C)nn1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11.4 %

Procedure:
1.3 g (4.8 mmol) of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid dissolved in DMF were added dropwise to a suspension of 0.43 g of NaH (14.3 mmol, 80% in white oil) in 10 ml of DMF. After stirring to room temperature for 30 minutes, the mixture was treated with 0.6 g (4.8 mmol) of 3-chloro-6-methylpyridazine in 10 ml of DMF and stirred overnight at room temperature. To complete the reaction, 0.6 g (4.8 mmol) of 3-chloro-6-methylpyridazine were then added again and the mixture was kept at 60° C. for 5 hours. It was poured onto ice water, extracted three times with ethyl acetate, the aqueous phase was brought to pH 2 with half-concentrated hydrochloric acid and the precipitate which was deposited was extracted with ethyl acetate. These ethyl acetate phases were dried with magnesium sulfate and then filtered and the solvent was stripped off under reduced pressure. 800 mg of the brown residue (1.19 g) were purified by means of MPLC, it being possible to isolate 199 mg of the desired product as a white solid.
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([N:41]1[N:45]=[N:44][C:43]([CH3:46])=[N:42]1)[CH2:20][O:21]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CC1N=NN(C(COC(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)CO)N=1.C(SCC(N1C(C)=NN=N1)CO)CCCCCCCCCCCCCCC>>[CH2:1]([S:17][CH2:18][CH:19]([N:41]1[N:45]=[N:44][C:43]([CH3:46])=[N:42]1)[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCSCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)n1nnc(C)n1
Agent: CCCCCCCCCCCCCCCCSCC(CO)n1nnnc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1nnn(C(CO)COC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O
Product: CCCCCCCCCCCCCCCCSCC(CO)n1nnc(C)n1

Procedure:
Using 10.2 g of crude 1-hexadecylthio-2-(5-methyl-2H-tetrazol-2-yl)-3-triphenylmethoxypropane 5h and 500 mg (2.6 mM) of p-toluene sulfonic acid monohydrate in 200 ml of methanoltetrahydrofurane (1:1) mixture is converted to 3.17 g (49% from the compound 4h) of the title compound V h1 by the same procedure as described in (81).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:12]([CH:19]1[CH2:24][CH2:23][N:22]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(Br)cc1)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
4-Bromobenzene-1-sulfonyl chloride (100 mg, 0.391 mmol) dissolved in DCM (2.0 mL) at ambient temperature. 4-Benzylpiperidine (89 mg, 0.51 mmol) were diluted in DCM (2.0 mL) and treated with DIPEA (0.205 mL, 1.174 mmol) at ambient temperature. To this mixture a solution of 4-bromobenzene-1-sulfonyl chloride (100 mg, 0.391 mmol) dissolved in DCM (2.0 mL) was added and the reaction stirred at ambient temperature for 17 hours. The reaction was then concentrated in vacuo to afford the title compound, which was used without further purification. LRMS (ESI) calc'd for C18H20BrNO2S [M+H}+: 394. found 394
Reaction SMILES: [NH2:1][C:2]1([C:15]([OH:17])=[O:16])[CH2:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH2:4][CH2:3]1.C1C(=O)N([O:25][C:26]([O:28][CH2:29][CH:30]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36]3[C:31]2=[CH:32][CH:33]=[CH:34][CH:35]=3)=O)C(=O)C1.CCN(CC)CC>[OH-].[Na+].C(#N)C.C(#N)C.O>[CH:41]1[C:42]2[CH:30]([CH2:29][O:28][C:26]([NH:1][C:2]3([C:15]([OH:17])=[O:16])[CH2:14][C:13]4[C:12]5[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=5)[NH:6][C:5]=4[CH2:4][CH2:3]3)=[O:25])[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:37]=2[CH:38]=[CH:39][CH:40]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: NC1(C(=O)O)CCc2[nH]c3ccccc3c2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(NC1(C(=O)O)CCc2[nH]c3ccccc3c2C1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
26 mmol (5.8 g) of 3-amino-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid in 26 ml of 1N NaOH and 26 mmol (8.76 g) of Fmoc-ONSu in 28 ml of acetonitrile are combined at room temperature and diluted with 130 ml of acetonitrile/H2O 1:1. After two hours, the pH is readjusted to 9 (1.5 ml) with NEt3 and stirred overnight at room temperature. Then, another 6.3 g (18.7 mmol) of Fmoc-ONSu, dissolved in 19 ml of acetonitrile, is added and stirred for another two hours while the pH is monitored. After distillative removal of the acetonitrile, it is acidified with 0.01 M HCl and extracted with ethyl acetate. The extract is washed neutral, dried with Na2SO4 and spun in until a dry state is reached. Recrystallization is carried out from ether/hexane. Yield: 10.7 g.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>>[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:7]([C:6]2[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)=[NH:8])=[CH:14][CH:13]=1
Reactant: CSc1ccc(C#N)cc1
Reactant: Nc1ccc(Br)cc1
Product: CSc1ccc(C(=N)Nc2ccc(Br)cc2)cc1
Yield: 77.7 %

Procedure:
The title compound was prepared from 4-methylthiobenzonitrile (17.3 g, 116 mmol) and 4-bromoaniline (20 g, 116 mmol) by following the procedure described in preparation 10 (29 g, yield 77.7%, purity 99.8% by HPLC). MS m/z:321.1/323.2 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.Cl.[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:27]3[CH:23]([CH2:24][NH:25][CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[C:29]1([C:19]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:27]3[CH:23]([CH2:24][N:25]([C:9](=[O:11])[CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: O=C(O)Cc1ccccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccccc3Cl)CC12
Reaction time: 0.25 h
Yield: 61.5 %

Procedure:
N,N'-Carbonyldiimidazole (1.13 g) is added to a solution of 2-chlorophenylacetic acid (1.19 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 15 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.28 g) and triethylamine (1.96 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 2.5 hours, then washed with water (2×150 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from a mixture of acetonitrile (25 cc) and isopropyl ether (25 cc). The crystals are drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-diphenyl-2-[(2-chlorophenyl)acetyl]-4-perhydroisoindolone (1.9 g) is obtained in the form of white crystals melting at 206° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([O:14][CH3:15])[N:11]=[C:10]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH2:31]([O:30][C:28](=[O:29])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:9]=[C:10]([NH:16][CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[N:11]=[C:12]([O:14][CH3:15])[N:13]=2)[CH:3]=1)[CH3:32]
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(CCNc2cc(-c3cccc(N)c3)nc(OC)n2)cc1
Product: CCOC(=O)Nc1cccc(-c2cc(NCCc3ccc(OC)cc3)nc(OC)n2)c1

Procedure:
By proceeding in a similar manner to Example 6(b) but using [6-(3-amino-phenyl)-2-methoxy-pyrimidin-4-yl]-[2-(4-methoxy-phenyl)-ethyl]-amine [169 mg, Example 2] and ethyl chloroformate (47 μL), and subjected the reaction product to flash column chromatography on silica gel (10 g) eluting with 20 to 40% EtOAc in heptane) there is prepared (3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-carbamic acid ethyl ester [40.1 mg, 23%, Example 6(c)]. LCMS: RT=2.84 minutes, MS: 423 (M+H).