Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:6][C:7]1[O:11][C:10]([CH2:12]O)=[CH:9][CH:8]=1)[CH2:3][C:4]#[CH:5].Cl.[NH2:15][CH2:16][CH2:17][SH:18].[OH-].[Na+]>Cl.O>[CH3:1][N:2]([CH2:6][C:7]1[O:11][C:10]([CH2:12][S:18][CH2:17][CH2:16][NH2:15])=[CH:9][CH:8]=1)[CH2:3][C:4]#[CH:5]
Reactant: C#CCN(C)Cc1ccc(CO)o1
Reactant: NCCS
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C#CCN(C)Cc1ccc(CSCCN)o1
Temperature: 0 °C
Reaction time: 7 h
Yield: 791.4 %

Procedure:
A solution of 5-{[N-methyl-N-(2-propynyl)amino]methyl}-2-furanmethanol (40.0 g; 223 mmoles) [prepared in Step A] in 100 ml of ice-cold concentrated HCl was added to a cold (5°) stirred solution of cysteamine hydrochloride (27.9 g; 24.6 mmoles) in 125 ml of concentrated hydrochloric acid. The solution was allowed to stand at 0° for 21/2 days, and then at ambient temperature for 7 hours to complete the reaction. The reaction mixture was cooled in an ice-water bath, diluted with 200 ml of water, made strongly alkaline with 40% aqueous NaOH, and then extracted with three portions of methylene chloride. The combined organic phase was dried, filtered, and evaporated under reduced pressure to give the product as a thick oil (46.4 g). A rapid vacuum distillation of the oil yielded the title compound, bp 136°-140°/0.2 mm Hg.
Reaction SMILES: [CH:1]1([C:4]([NH:10][S@@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])([CH3:9])/[C:5](=[N:7]/[OH:8])/[NH2:6])[CH2:3][CH2:2]1.[CH2:17](OC(OCC)OCC)C>CC(O)=O>[CH:1]1([C:4]([NH:10][S@@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])([C:5]2[N:6]=[CH:17][O:8][N:7]=2)[CH3:9])[CH2:3][CH2:2]1
Reactant: CCOC(OCC)OCC
Reactant: CC(N[S@](=O)C(C)(C)C)(/C(N)=N/O)C1CC1
Solvent: CC(=O)O
Product: CC(N[S@](=O)C(C)(C)C)(c1ncon1)C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.8 %

Procedure:
(Z)-2-cyclopropyl-2-((R)-1,1-dimethylethylsulfinamido)-N′-hydroxypropanimidamide (321 mg, 1.30 mmol) in triethoxymethane (2.0 ml, 12 mmol) was treated with AcOH (2 ml) at rt. The reaction was allowed to stir at rt for 16 h. LCMS showed a major peak with the expected M+H. The reaction was concentrated to dryness azeotroping with toluene 2×. The resulting yellow oil was purified on silica gel (Biotage, EtOAc/hexanes gradient (Rf ˜0.2 in 70% EtOAc/Hex, visualized with permanganate stain), to give the expected product (first eluting diastereomer, 120 mg, 0.466 mmol, 36% yield) consistent by LCMS and NMR. LC-MS retention time: 1.21 min; m/z M+H: 258. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. 1H NMR (500 MHz, DMSO-d6) δ 9.53 (s, 1H), 5.29 (s, 1H), 1.53-1.49 (m, 1H), 1.47 (s, 3H), 1.10 (s, 9H), 0.49-0.40 (m, 4H).
Reaction SMILES: C([N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[C:6]([C:15]2[CH:32]=[CH:31][C:18]([O:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:17][CH:16]=2)=[N:5]1)(C)C.I[CH2:34][CH:35]([CH3:37])[CH3:36]>>[CH2:34]([N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[C:6]([C:15]2[CH:32]=[CH:31][C:18]([O:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:17][CH:16]=2)=[N:5]1)[CH:35]([CH3:37])[CH3:36]
Reactant: CC(C)CI
Reactant: CC(C)n1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Product: CC(C)Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Isopropyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting 1-Iodo-2-methyl-propane provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.44 (m, 2H), 8.18 (d, J=8.7 Hz, 1H), 8.06 (d, J=8.3 Hz, 1H), 7.83 (d, J=6.6 Hz, 1H), 7.73 (t, J=6.6 Hz, 1H), 7.54 (s, 1H), 7.52 (m, 1H), 7.38 (d, J=9.1 Hz, 2H), 7.15 (m, 2H), 7.00 (d, J=8.7 Hz, 2H), 5.38 (s, 2H) 3.93 (d, J=7.5 Hz, 2H), 4.29 (m, 1H), 0.95 (d, J=6.6 Hz, 6H); MS: (M+H m/z=435.2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:37])[C:14]([O:16][C@H:17]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[CH2:18][C:19]1[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=1[Cl:26])=[O:15])[CH:7]=[CH:6]2.CO>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@@H:13]([CH3:37])[C:14]([O:16][C@H:17]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[CH2:18][C:19]1[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=1[Cl:26])=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(C(C)C(=O)O[C@@H](Cc3c(Cl)cncc3Cl)c3ccc(OC)c(OC)c3)ccc2c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc2cc([C@@H](C)C(=O)O[C@@H](Cc3c(Cl)cncc3Cl)c3ccc(OC)c(OC)c3)ccc2c1
Reaction time: 2 h
Yield: 44.4 %

Procedure:
((S)-2-(3,5-dichloropyridin-4-yl)-1-(3,4-dimethoxyphenyl)ethyl) 2-(6-methoxynaphthalen-2-yl)propanoate (diastereoisomeric mixture prepared as described in Ex 1, Step 1, 79 g, 146 mmol) was dissolved in CHCl3 (100 ml), and MeOH (30 ml) was slowly added up to persistent opalescence and the mixture left at RT for 2 hours. The solid formed was collected by filtration and re-crystallized by CHCl3/MeOH (70 ml/20 ml) solvent system to obtain 35 g of the desired compound (yield 88%, ee 98%). Chiral HPLC analysis Rt=42.33 min; eluent:hexane:isopropanol 97:3; 1H NMR (600 MHz, CHLOROFORM-d) δ ppm 8.04 (s, 2H), 7.67 (d, J=8.79 Hz, 1H), 7.58 (d, J=8.52 Hz, 1H), 7.53 (m, 1H), 7.12-7.20 (m, 3H), 6.95 (dd, J=8.24, 1.92 Hz, 1H), 6.78-6.88 (m, 2H), 6.14 (dd, J=10.44, 4.12 Hz, 1H), 3.95 (s, 3H), 3.88 (s, 3H), 3.78-3.81 (m, 4H), 3.55 (dd, J=13.73, 10.44 Hz, 1H), 3.14 (dd, J=13.60, 4.26 Hz, 1H), 1.44 (d, J=7.14 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:19][CH3:20])[CH:13]=[C:12]([O:21][CH3:22])[C:11]=2[C@@H:23]1[CH2:28][CH2:27][NH:26][CH2:25][C@H:24]1[OH:29].[CH3:30][CH2:31][CH2:32]Br.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:19][CH3:20])[CH:13]=[C:12]([O:21][CH3:22])[C:11]=2[C@@H:23]1[CH2:28][CH2:27][N:26]([CH2:30][CH2:31][CH3:32])[CH2:25][C@H:24]1[OH:29]
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccccc3Cl)oc2c1[C@@H]1CCNC[C@H]1O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN1CC[C@@H](c2c(OC)cc(OC)c3c(=O)cc(-c4ccccc4Cl)oc23)[C@H](O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of compound of example 128 (0.871 g, 2.09 mmol), n-propyl bromide (0.335 g, 2.72 mmol) and anhydrous K2CO3 (1.15 g, 8.33 mmol) in dry DMF (20 mL) was stirred at 25° C. for 2 h. The reaction mixture was treated with water and extracted with EtOAc (2×100 mL). The organic extract was washed with water, dried (anhydrous Na2SO4) and concentrated. The crude obtained was purified on a silica gel column using a mixture of 1% MeOH+1% liquor NH3 in CHCl3 as eluant to get the title compound.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[C:22]([O:25][C:26]1[CH:27]=[C:28]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:29]=[CH:30][CH:31]=1)(=[O:24])[CH3:23]>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:35]2[CH2:34][CH2:33][N:32]([C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([O:25][C:22](=[O:24])[CH3:23])[CH:27]=3)[CH2:37][CH2:36]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: CC(=O)Oc1cccc(N2CCNCC2)c1
Product: CCc1cc(NC(=O)N2CCN(c3cccc(OC(C)=O)c3)CC2)c(OC)nc1C
Yield: 87 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3-acetoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[C:6]([N:14](S(C)(=O)=O)[S:15]([CH3:18])(=[O:17])=[O:16])[CH:5]=1.CC1C=CC(C(OC)=O)=C(NS(C)(=O)=O)C=1>CO>[CH3:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:5]=1
Reactant: COC(=O)c1ccc(C)cc1N(S(C)(=O)=O)S(C)(=O)=O
Agent: COC(=O)c1ccc(C)cc1NS(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C(=O)O)c(NS(C)(=O)=O)c1

Procedure:
An aqueous solution of sodium hydroxide (11.0 g) was added to a solution of a mixture of methyl 4-methyl-2-(N,N-bis(methylsulphonyl)amino]benzoate and methyl 4-methyl-2-(N-methylsulphonylamino)benzoate (23.26 g) in methanol and the resulting suspension was heated at reflux for 1 hour. It was cooled and the methanol was removed by evaporations The aqueous solution was acidified and the resultant solid was filtered off to give 4-methyl-2-(N-methylsulphonylamino)benzoic acid (16.42 g) as a cream solid, m.p. 202-205° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1.[CH3:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:14])(=[O:13])[NH:22][C:21]2[CH:23]=[CH:24][C:18]([CH3:17])=[CH:19][CH:20]=2)[CH:7]=1
Reactant: Cc1ccc(N)cc1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C=Cc1cccc(S(=O)(=O)Nc2ccc(C)cc2)c1
Yield: 79.3 %

Procedure:
A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3) (2.0 g, 7.23 mmol) in dioxane (10 ml) was added to a mixture of 4-methylaniline (0.77 g, 7.23 mmol) in dioxane (20 ml) and NaHCO3 (1.2 g, 14.5 mmol) in water (20 ml), and the resultant solution was stirred at room temperature for one hour. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with dichloromethane-ethyl acetate (20:1, v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (1.9 g, 79%). 1H NMR (DMSO-d6, HMDSO), δ: 2.16 (3H, s); 3.69 (3H, s); 6.65 (1H, d, J=16.0 Hz); 7.00 (4H, s); 7.49–8.11 (5H, m); 10.14 (1H, br s).
Reaction SMILES: O[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH:5]3[N:12]3[C:16]4=[C:17]5[CH:23]=[CH:22][NH:21][C:18]5=[N:19][CH:20]=[C:15]4[NH:14][C:13]3=[O:24])[CH2:3]1)[CH2:9]2.C(S(F)(F)([F:31])(CC)N)C.C(=O)([O-])O.[Na+].C(OCC)(=O)C>ClCCl>[F:31][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH:5]3[N:12]3[C:16]4=[C:17]5[CH:23]=[CH:22][NH:21][C:18]5=[N:19][CH:20]=[C:15]4[NH:14][C:13]3=[O:24])[CH2:3]1)[CH2:9]2
Reactant: CCS(N)(F)(F)(F)CC
Reactant: O=c1[nH]c2cnc3[nH]ccc3c2n1C1C2CC3CC1CC(O)(C3)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=c1[nH]c2cnc3[nH]ccc3c2n1C1C2CC3CC1CC(F)(C3)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(5-Hydroxyadamantan-2-yl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2(1H)-one (92 mg) was suspended in dichloromethane, and diethyl aminosulfur trifluoride (DAST) was added. The mixture was stirred at ambient temperature for 1 hour. The saturated aqueous sodium hydrogencarbonate and ethyl acetate were added. The obtained solid was collected by filtration and washed with diisopropyl ethylether to obtain (5-fluoroadamantan-2-yl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2(1H)-one (34 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][C:21]1[C:25]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])=[CH:24][NH:23][C:22]=1[CH:34]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:34][C:22]4[NH:23][CH:24]=[C:25]([C:26]([N:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)=[O:27])[C:21]=4[CH3:20])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: Cc1c(C(=O)N2CCOCC2)c[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C(=O)N2CCOCC2)c[nH]c1C=C1C(=O)Nc2ncnc(Nc3ccc(F)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 96 h
Yield: 32.3 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 3-methyl-4-(morpholine-4-carbonyl)-1H-pyrrole-2-carbaldehyde (66.7 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for 4 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 39 mg (32%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.30 (br s, 1H, NH), 11.69 (br s, 1H, NH), 9.16 (br s, 1H), 8.31 (s, 1H), 7.72 (dd, J=2.8 & 6.7 Hz, 1H), 7.46 (d, J=2.8 Hz, 1H), 7.43 (m, 1H), 7.41 (s, 1H), 7.35 (t, J=9 Hz, 1H), 3.59 (m, 4H, 2×CH2), 3.51 (m, 4H, 2×CH2), 2.21 (s, 3H, CH2). MS 483 [M++1].
Reaction SMILES: [C:1]1([C:7]2[CH:19]=[CH:18][C:10]([C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]1COCC1.C[Mg]I.[NH4+].[Cl-]>CCOCC>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:19]=[CH:18][C:10]([C:11]([OH:12])([CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(=O)c1ccc(-c2ccccc2)cc1
Reactant: C1CCOC1
Agent: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCOC(=O)C(C)(O)c1ccc(-c2ccccc2)cc1
Temperature: -25 °C

Procedure:
To a flame dried 500 mL flask flushed with N2, was added 24 g (100 mmol) of ethyl 4-phenylbenzoylformate and 300 mL of anhydrous THF. The solution was cooled with stirring to -25° C. and 37 mL (110 mmol) of a 3.0 M solution of methylmagnesium iodide was added at a rate to maintain the reaction temperature below -10° C. The reaction progress was monitored by TLC and upon disappearance of starting material, 100 mL of saturated NH4Cl solution and 200 mL of ether were added. The organic layer was separated and washed with 2×50 mL of brine, dried (MgSO4) and concentrated leaving racemic ethyl 2-[(1,1'-biphenyl)-4-yl]-2-hydroxypropionate as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([CH:15]2[CH2:17][CH2:16]2)[OH:14])[CH2:9]1)=O)(C)(C)C.CN(C=O)C.[H-].[Na+].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](F)[C:27]=1[CH3:33].Cl.CCO>>[Cl:25][C:26]1[C:27]([CH3:33])=[C:28]([CH:29]=[CH:30][CH:31]=1)[O:14][C@H:13]([CH:15]1[CH2:16][CH2:17]1)[C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@H](O)C2CC2)C1
Reactant: Cc1c(F)cccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1c(Cl)cccc1O[C@H](C1CC1)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((R)-Cyclopropylhydroxymethyl)pyrrolidine-1-carboxylic acid t-butyl ester (1.0 g, 4.1 mmol) was dissolved in DMF (15 mL, 200 mmol). Washed and dried sodium hydride (298 mg, 12.4 mmol) was added carefully in three separate portions and the resulting mixture was stirred at room temperature for 15 minutes. 2-Chloro-6-fluorotoluene (749 μL, 6.2 mmol) was added, and the mixture was stirred overnight at 70° C. The mixture was concentrated and the BOC-protected intermediate was purified by silica gel chromatography (0-10% EtOAc in hexanes for 10 minutes, 10-50% in 10 minutes) and the desired fractions were isolated and concentrated. The crude material was then treated with 1.25M HCl in EtOH (23.2 mL, 29.0 mmol) and stirred overnight at room temperature. The product was concentrated under vacuum and purified by preparative HPLC to yield the title compound as a mono-TFA salt (240 mg, 99.4% purity). MS m/z: [M+H]+ calcd for C15H20ClNO, 266.12; found 266.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8]2.[S:17]1[C:21]([CH2:22][C:23](O)=O)=[CH:20][C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]1=2>>[S:17]1[C:21]([CH2:22][CH2:23][N:13]([CH:10]2[CH2:9][CH2:8][C:7]3[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=3)[CH2:11]2)[CH2:14][CH2:15][CH3:16])=[CH:20][C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]1=2
Reactant: CCCNC1CCc2cccc(OC)c2C1
Reactant: O=C(O)Cc1cc2ccccc2s1
Product: CCCN(CCc1cc2ccccc2s1)C1CCc2cccc(OC)c2C1

Procedure:
Synthesis works according to the preparation of A4-1 or A4-4 when using N-(8-methoxytetralin-2-yl)-N-propylamine (A2-1: R=OMe) and 2-benzo[b]thienyl acetic acid (A3-10: R=OMe, Cy=2-benzo[b]thienyl) (purchasable from Rare Chemicals, Kiel (Germany); order number: GT HW 0344) and subsequent reaction according to the synthesis of A5-1.
Reaction SMILES: [C:1]([CH:4]1[NH:9][CH2:8][CH2:7][N:6]([S:10]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)(=[O:12])=[O:11])[CH2:5]1)#[C:2][CH3:3].Cl[C:19]1[N:24]=[CH:23][C:22]([C:25]([OH:31])([CH3:30])[C:26]([F:29])([F:28])[F:27])=[CH:21][N:20]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[F:29][C:26]([F:27])([F:28])[C:25]([C:22]1[CH:23]=[N:24][C:19]([N:9]2[CH2:8][CH2:7][N:6]([S:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)(=[O:12])=[O:11])[CH2:5][CH:4]2[C:1]#[C:2][CH3:3])=[N:20][CH:21]=1)([OH:31])[CH3:30]
Reactant: CC(O)(c1cnc(Cl)nc1)C(F)(F)F
Reactant: CC#CC1CN(S(=O)(=O)c2cccs2)CCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC#CC1CN(S(=O)(=O)c2cccs2)CCN1c1ncc(C(C)(O)C(F)(F)F)cn1
Temperature: 140 °C
Reaction time: 3 h
Yield: 19.3 %

Procedure:
A mixture of 3-(1-propyn-1-yl)-1-(2-thiophenylsulfonyl)piperazine (55 mg, 0.203 mmol), 2-(2-chloro-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (100 mg, 0.441 mmol, Intermediate E), Hünig's base (100 μL, 0.573 mmol), and dioxane (2 mL) was heated in an Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 140° C. for 1 h and then at 160° C. for 3 h. The resulting red mixture was purified via silica gel chromatography (10-50% EtOAc in hexanes) to give 1,1,1-trifluoro-2-(2-(2-(1-propyn-1-yl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol (18 mg) as a mixture of 4 isomers.
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:19][O:20][N:21]1[C:29]2[C:24](=[N:25][C:26]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:28]=2)[CH:23]=[CH:22]1.[Cl:40]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:19][O:20][N:21]1[C:29]2[C:24](=[N:25][C:26]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:28]=2)[C:23]([Cl:40])=[CH:22]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1cc2c(ccn2OC)nc1C(=O)OCC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cc2c(nc1C(=O)OCC)c(Cl)cn2OC
Temperature: 60 °C
Yield: 51 %

Procedure:
Benzoyl peroxide (0.91 g, 0.037 mol) is added to diethyl 1-methoxypyrrolo[3,2-b]pyridine-5,6-dicarboxylate (1.0 g, 0.003 mol) dissolved in (40 mL) carbon tetrachloride under a nitrogen atmosphere and the suspension stirred for ten minutes. N-Chlorosuccinimide (0.84 g, 0.0063 mol) is then added and the reaction heated at 60° C. for four hours. The mixtue is cooled to room temperature and the inorganics are removed by filtration. The organic mother liquors are washed with water and sodium bisulfate and concentrated in vacuo to an orange oil. The oil is flash chromatographed using hexanes and then 4:1 hexanes/ethyl acetate, giving the title product as an off-white solid in 51% yield, having a melting point 146°-148° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][S:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.[CH3:15][N:16]=[C:17]=[O:18].CCOCC>C1C=CC=CC=1.CN(C)C>[CH3:15][NH:16][C:17](=[O:18])[O:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([S:5][CH2:4][CH:3]([O:2][CH3:1])[O:13][CH3:14])[CH:7]=1
Reactant: COC(CSc1cccc(O)c1)OC
Reactant: CN=C=O
Agent: CN(C)C
Solvent: c1ccccc1
Solvent: CCOCC
Product: CNC(=O)Oc1cccc(SCC(OC)OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(2,2-Dimethoxyethylthio)phenol (1.80 grams) dissolved in benzene (5 ml) was charged into a glass reaction vessel equipped with a mechanical stirrer. Methyl isocyanate (12 ml) and trimethylamine (2 drops) were then added, and the resulting mixture was stirred at room temperature for a period of about 51/2 hours. The mixture was then allowed to stand overnight and was then stripped of excess methyl isocyanate and a portion of the benzene. The concentrated solution was then added to ether and cooled to -60° C., resulting in a precipitate. The precipitate was recrystallized from ether to yield the desired product O-[3-(2,2-dimethoxyethylthio)phenyl]-0 N-methylcarbamate having a melt point of 46° to 48° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(OC(=O)C)(=O)C.[Br:12][C:13]1[CH:17]=[CH:16][S:15][CH:14]=1>C(O)(=O)C>[Br:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Brc1ccsc1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1sccc1Br
Reaction time: 0.17 h

Procedure:
7.4 ml of fuming nitric acid was slowly added to 92.1 ml of acetic acid under ice-cooling, followed by stirring for 10 minutes, and a solution of 52.1 ml of acetic anhydride containing 25 g of 3-bromothiophene was slowly added in such a manner that the bulk temperature did not exceed 10° C., followed by stirring at 10 ° C. for 2 hours. Ice was added to the reaction solution, and the resulting crystals were collected by filtration, and washed with water and diethyl ether/n-hexane=1/5 successively, to give 17.4 g of the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:14]1([C:20]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:28]3[CH:24]([CH2:25][NH:26][CH2:27]3)[C:23](=[O:29])[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[C:30]1([C:20]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:28]3[CH:24]([CH2:25][N:26]([C:10](=[O:12])[CH2:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[S:2][CH3:1])[CH2:27]3)[C:23](=[O:29])[CH2:22][CH2:21]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: CSc1ccccc1CC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1ccccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 0.25 h
Yield: 59.5 %

Procedure:
N,N'-Carbonyldiimidazole (0.77 g) is added to a solution of 2-methylthiophenylacetic acid (0.87 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 (1.56 g) and triethylamine (1.34 cc) in dichloromethane (30 cc) is then added. The reaction mixture is stirred at 20° C. for 3.5 hours, then washed with water (3×100 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.04-0.063 mm, diameter 5 cm, height 50 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (60/40 by volume) and collecting 50 cc fractions. Fractions 1 to 14 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is recrystallized from acetonitrile (5 cc) and the crystals are drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-diphenyl-2-[(2-methylthiophenyl)acetyl]-4-perhydroisoindolone (1.29 g) is obtained in the form of pale yellow crystals melting at 188° C.