Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]I.N1C=CN=C1.[C:8]([O:12][C:13](=[O:22])[NH:14][C@H:15]([CH2:19][O:20][CH3:21])[CH2:16][CH2:17]O)([CH3:11])([CH3:10])[CH3:9]>ClCCl>[C:8]([O:12][C:13](=[O:22])[NH:14][C@H:15]([CH2:19][O:20][CH3:21])[CH2:16][CH2:17][I:1])([CH3:11])([CH3:10])[CH3:9]
Reactant: COC[C@H](CCO)NC(=O)OC(C)(C)C
Reactant: II
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC[C@H](CCI)NC(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
A suspension of polystyrene resin-bound triphenylphosphine (18.645 g, 3 mmol/g) in dry dichloromethane (250 ml) is treated with iodine (12.5 g, 49.22 mmol) and stirred for 15 minutes under argon. Imidazole (3.87 g, 55.94 mmol) is added and the reaction mixture stirred at room temperature for a further 15 minutes. The reaction mixture is then treated with a solution of ((S)-3-Hydroxy-1-methoxymethyl-propyl)-carbamic acid tert-butyl ester (4.9 g, 22.37 mmol) in dichloromethane (30 ml), and refluxed for 1.5 hours under argon. The resin is removed by filtration through a celite pad, washing with dichloromethane. The filtrate is washed with 5% aqueous sodium thiosulphate solution and water, dried over MgSO4 and evaporated to afford ((S)-3-Iodo-1-methoxymethyl-propyl)-carbamic acid tert-butyl ester as a crude oil. [M-BOC] 230.06.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:28]=[C:29]([OH:31])[CH:30]=1)[CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:11]1)[CH3:4].Cl[CH2:33][C:34]1[N:35]=[C:36]([C:39]2[S:40][CH:41]=[CH:42][CH:43]=2)[S:37][CH:38]=1.O>CN(C)C=O>[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:28]=[C:29]([O:31][CH2:33][C:34]2[N:35]=[C:36]([C:39]3[S:40][CH:41]=[CH:42][CH:43]=3)[S:37][CH:38]=2)[CH:30]=1)[CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:11]1)[CH3:4]
Reactant: ClCc1csc(-c2cccs2)n1
Reactant: CCOC(=O)CCc1cn(Cc2cc(O)cc(OCC)c2)cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2cc(OCC)cc(OCc3csc(-c4cccs4)n3)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.7 %

Procedure:
Sodium hydride (60%, oily, 50.0 mg) was added to a solution of ethyl 3-[1-(3-ethoxy-5-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (492 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2-(2-thienyl)thiazole (270 mg) was added to the mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[1-[3-ethoxy-5-[2-(2-thienyl)-4-thiazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (657 mg, yield: 92%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [NH2:1][C@H:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C@@H:14]([CH3:17])[CH2:15][CH3:16])=[CH:8][CH:7]=1)[C@H:3]([OH:5])[CH3:4].Cl.C(N([CH2:24][CH3:25])CC)C>ClCCl>[OH:5][C@H:3]([CH3:4])[C@H:2]([NH:1][C:3](=[O:5])[C@H:2]([C:25]1[CH:24]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:6])[C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][C@@H:14]([CH3:17])[CH2:15][CH3:16])=[CH:10][CH:11]=1
Reactant: CC[C@H](C)COc1ccc([C@@H](N)[C@@H](C)O)cc1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClCCl
Product: CC[C@H](C)COc1ccc([C@@H](NC(=O)[C@@H](C)c2ccccc2)[C@@H](C)O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 10 %

Procedure:
To a solution of (S)-(+)-2-phenylpropionic acid (0.067 g, 0.449 mmol) in dichloromethane (5 mL) in an ice-bath was added oxalyl chloride (0.39 mL, 4.49 mmol), then DMF (0.02 mL) under nitrogen. The reaction mixture was stirred for 30 minutes at 0° C. The excessive solvent was removed on ratovapor and dried under high vacuum for 2 hrs to give the corresponding acid chloride. A separate 50 mL round-bottom flask was charged with (1R,2R)-1-amino-1-[4-((S)-2-methyl-butoxy)phenyl]-propan-2-ol.HCl salt (0.37 mmol), dichloromethane (6 mL) and triethylamine (0.3 mL, 1.85 mmol) in an ice cold bath under nitrogen. The acid chloride mentioned above, in dichloromethane (2 mL) was added into the reaction mixture dropwise. The final reaction mixture was stirred for 1.5 hrs at room temperature. The finished reaction was quenched with water. The organic phase was washed with brine (3×10 mL), dried over MgSO4, filtrated, concentrated in vacuum and purified via column chromatography on silica gel with a gradient of 0%→100% of ethyl acetate in hexane to give a white solid (0.013 g, 10% yield). 1H NMR (400 MHz, CDCl3) δ 7.33 (m, 5H), 6.93 (d, J=8.8 Hz, 2H), 6.80 (m, 2H), 6.05 (d, J=8.3 Hz, 1H), 4.82 (dd, J=8.2, 3.7 Hz, 1H), 4.00 (br. s., 1H), 3.74 (m, 3H), 1.96 (d, J=3.0 Hz, 1H), 1.85 (d, J=6.6 Hz, 1H), 1.54 (m, 3H), 1.27 (m, 2H), 1.16 (d, J=6.3 Hz, 3H), 1.02 (m, 3H), 0.96 (t, J=7.5 Hz, 3H); LCMS (ESI) m/e 370.4 [(M+H), calcd. for C23H32NO3 370.5].
Reaction SMILES: [CH3:1]O.[C:3]1([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>OS(O)(=O)=O>[CH3:1][N:10]1[C:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:13][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:11]1
Reactant: CO
Reactant: c1ccc(-c2cc(-c3ccccc3)[nH]n2)cc1
Agent: O=S(=O)(O)O
Product: Cn1nc(-c2ccccc2)cc1-c1ccccc1
Yield: 95.7 %

Procedure:
308.5 g (9.64 mol) of methanol were vaporized dropwise at 155° C. in an electrically heated column with a diameter of 4 cm and equipped with a sintered disk at the lower end and fitted onto a 250 ml two-neck flask over the course of 6 hours and passed through a melt, at 200° C., of 10 g (0.0455 mol) of 3,5-diphenylpyrazole and 0.046 g (0.000455 mol) of concentrated H2SO4. The gaseous discharge from the reaction was condensed and concentrated under reduced pressure. 10.2 g (92.5%) of 1-methyl-3,5-diphenylpyrazole were obtained, boiling point 190° C./3 mbar, with a content of 96.6% (GC).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@H:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]([OH:32])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:33][C:34]([F:40])([F:39])[S:35]([NH2:38])(=[O:37])=[O:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@H:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30](=[O:32])[NH:38][S:35]([C:34]([F:40])([F:39])[F:33])(=[O:37])=[O:36])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)C(F)(F)F
Reactant: O=C(O)COc1ccc(Cl)cc1[C@@H]1c2ccccc2CCN1C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(COc1ccc(Cl)cc1[C@@H]1c2ccccc2CCN1C(=O)OCc1ccccc1)NS(=O)(=O)C(F)(F)F
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-1-(2-carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (138 mg, 0.30 mmol, 1.0 eq.) in DMF (1.2 mL), trifluoromethanesulfonamide (47 mg, 0.30 mmol, 1.0 eq.), HATU (125 mg, 0.33 mmol, 1.1 eq.), DIPEA (103 μL, 0.60 mmol, 2.0 eq.), and DMAP (spatula tip) were added. The resulting mixture was stirred at 50° C. for 18 hours. The mixture was then purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, basic conditions) and evaporated to give a white-off solid, contaminated with some DIPEA. The contaminated product was redissolved in AcOEt and washed with 1M aq. HCl soln. and sat. aq. NaCl soln. The org. phase was dried over MgSO4, filtered, and concentrated in vacuo to give the desired product as a white-off solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:15])([F:14])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20]Br.Cl>CS(C)=O.CS(C)=O.CCOCC.O>[F:3][C:4]([F:14])([F:15])[C:5]1[CH:6]=[CH:7][C:8]([C:11]2([C:12]#[N:13])[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:9][CH:10]=1
Reactant: BrCCCCBr
Reactant: N#CCc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CS(C)=O
Product: N#CC1(c2ccc(C(F)(F)F)cc2)CCCC1
Reaction time: 2 h
Yield: 65 %

Procedure:
To a suspension of NaH (8.18 g, 135.13 mmol, 60%) in dimethyl sulfoxide (100 mL) were added dropwise a mixture of (4-trifluoromethyl-phenyl)-acetonitrile (236) (25 g, 135.13 mmol) and 1,4-dibromobutane (16 mL, 135.13 mmol) dissolved in dimethyl sulfoxide:ether (1:1) (300 mL) at 0° C. and the reaction mixture was stirred at this temperature for 2 h. After completion of the reaction, water (100 mL) and 10% HCl solution (50 mL) were added to the mixture and extracted with ethyl acetate (2×400 ml). The organic layer was dried over Na2SO4, concentrated and purified by 100-200 silica column chromatography using hexane as the eluent to give 1-(4-trifluoromethyl-phenyl)-cyclopentanecarbonitrile (237) (21 g, 65%) as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=2)=[O:18])=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[C:7]([CH:11]=1)[C:8](O)=[O:9].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:51][CH2:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH3:1][O:2][C:3]1[C:4]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=2)=[O:18])=[CH:5][C:6]([C:12]([F:15])([F:13])[F:14])=[C:7]([CH:11]=1)[C:8]([NH:51][CH2:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=1)=[O:9]
Reactant: COc1cc(C(=O)O)c(C(F)(F)F)cc1NC(=O)Nc1cnc(C)cn1
Reactant: NCCc1ccccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1cc(C(=O)NCCc2ccccn2)c(C(F)(F)F)cc1NC(=O)Nc1cnc(C)cn1
Reaction time: 0.25 h
Yield: 67.4 %

Procedure:
To a stirred solution of 5-methoxy-4-[3-(5-methyl-pyrazin-2-yl)-ureido]-2-trifluoromethyl -benzoic acid (37 mg, 0.1 mmol) in 1 mL NMP at room temperature in a capped reaction vial was added HBTU (42 mg, 0.11 mmol) and the suspension stirred for 15 minutes. 2-aminoethylpyridine (13 μL, 0.11 mmol) was added followed by DIEA (35 μL, 0.2 mmol) and the reaction was stirred overnight. NMP was then removed by bulb to bulb transfer under high vacuum at 70° C. and the residue triturated and filtered with EtOAc to give the desired amide as a tan solid (32 mg, 68%). 1H-NMR (400 MHz, d6-DMSO) δ8.90 (br s, 1H), 8.66 (d, 1H, 8.61 (s, 1H), 8.52 (t, 1H), 8.23 (s, 1H), 8.10 (br m, 1H), 7.61 (br d, 1H), 7.57 (br m, 1H), 7.07 (s, 1H), 4.00 (s, 3H), 3.62 (m, 2H), 3.11 (m, 2H), 2.42 (s, 3H) LRMS (esi, positive) m/e 475.1 (M+1)
Reaction SMILES: Br[C:2]1[C:3]2[CH:12]=[CH:11][N:10](S(C3C=CC(C)=CC=3)(=O)=O)[C:4]=2[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[O:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[F-].[Cs+].C(=O)([O-])[O-].[K+].[K+]>COCCOC.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:8][N:6]1[CH:7]=[C:2]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[O:23][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:3]2[CH:12]=[CH:11][NH:10][C:4]=2[C:5]1=[O:9]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Br)cn(C)c(=O)c32)cc1
Reactant: OB(O)c1ccccc1Oc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: CO
Solvent: O
Product: Cn1cc(-c2ccccc2Oc2ccccc2)c2cc[nH]c2c1=O
Reaction time: 2 h
Yield: 59.3 %

Procedure:
A mixture of Example 1e (152 mg, 0.40 mmol), 2-phenoxyphenylboronic acid (0.111 g, 0.520 mmol, 1.3 equivalents), Pd(PPh3)4 (0.023 g, 5 mol %) and cesium fluoride (0.182 g, 1.2 mmol) in DME (3 mL) and methanol (1.5 mL) was heated under microwave condition (120° C., 30 minutes). To this mixture was added potassium carbonate (0.055 g, 0.40 mmol) and water (1 mL) and the reaction mixture was reheated in the microwave oven at 120° C. for another 2 hours. The organic layer was separated and purified by flash chromatography (silica gel, ethyl acetate). The resulting material was triturated with acetone and filtered to provide 0.075 g of the title compound (59%). 1H NMR (500 MHz, DMSO-d6) δ 3.50 (s, 3H), 6.21-6.23 (m, 1H), 6.88 (d, J=7.62 Hz, 2H), 6.99-7.04 (m, 2H), 7.24-7.30 (m, 5H), 7.36-7.40 (m, 1H), 7.50 (dd, J=7.48, 1.68 Hz, 1H), 11.98 (s, 1H). MS (ESI+) m/z 317 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[C:8]2[CH:7]=[C:6]([C:17]#[C:18][C:19]3[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][CH:20]=3)[CH:5]=[CH:4][C:3]1=2>C1COCC1.O>[CH3:1][C:2]1([CH3:30])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[C:8]2[CH:7]=[C:6]([C:17]#[C:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:28][CH:29]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2nccs2)=CCC3(C)C)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CC=C(c2nccs2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
A solution of 33.9 mg (0.08 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(2-thiazolyl)-2-naphthalenyl)ethynyl]benzoate (Compound 15a) and 8.5 mg (0.20 mmol) of LiOH--H2O in 3 ml of THF/water (3:1, v/v), was stirred overnight at room temperature. The reaction was quenched by the addition of sat. aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give the title compound as a colorless solid. PMR (d6 -DMSO): δ 1.29 (6H, s), 2.42 (2H, d, J=4.6 Hz), 6.68 (1H, t, J=4.6 Hz), 7.51 (2H, m), 7.62 (2H, d, J=8.2 Hz), 7.77 (1H, d, J=3.3 Hz), 7.93 (2H, d, J=8.2 Hz), 7.98 (1H, d, J=3.3 Hz).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[Cl:10][Si:11]([Cl:18])([Cl:17])[CH2:12][CH2:13][SiH:14]([Cl:16])[Cl:15]>>[Cl:10][Si:11]([Cl:18])([Cl:17])[CH2:12][CH2:13][Si:14]([Cl:16])([Cl:15])[CH2:3][CH2:2][CH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=CCc1ccccc1
Reactant: Cl[SiH](Cl)CC[Si](Cl)(Cl)Cl
Product: Cl[Si](Cl)(Cl)CC[Si](Cl)(Cl)CCCc1ccccc1
Temperature: 80 °C

Procedure:
18.77 g (0.159 mol) allylbenzene and 50 μl H2PtCl6/IPA solution were added to a 100 ml vessel. Solution was heated up to 80° C. and 41.85 g (0.159 mol) 1,1,1,4,4-pentachloro-1,4-disilabutane was added slowly during 30 min. Heat was switched off when exothermic reaction was observed. Temperature during the addition was kept below 130° C. After addition heat was again switched on and solution was stirred for an hour at 110° C. After that product was purified by distillation. B.p. 137° C./0.8 mbar. Yield 35.10 g (58%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH2:16][CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CC#N>[Si:19]([O:18][CH2:17][CH2:16][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)OB(c2cnn(CCO[Si](C)(C)C(C)(C)C)c2)OC1(C)C
Temperature: 70 °C
Yield: 63.1 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.500 g, 2.58 mmol), (2-bromoethoxy)-t-butyldimethylsilane (2.211 mL, 10.31 mmol), K2CO3 (1.425 g, 10.31 mmol) and NaI (0.039 g, 0.258 mmol) in MeCN (8 mL) was heated to 70° C. for 2 days. The mixture was cooled to RT, the solid removed via filtration, rinsed with EtOAc and the filtrate washed with 50% satd. NaCl (1×). The organic layer was dried over MgSO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (574 mg, 63%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6): δ 7.79 (s, 1H), 7.51 (s, 1H), 4.12 (t, J=5.4 Hz, 2H), 3.79 (t, J=5.4 Hz, 2H), 1.17 (s, 12H), 0.71 (s, 9H), −0.17 (s, 6H); MS (ESI) m/z: 353.2 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][C@H:11]([NH:16][S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[CH2:10]2.[CH3:30][NH:31][CH3:32]>CN(C=O)C>[CH3:30][N:31]([CH2:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][C@H:11]([NH:16][S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[CH2:10]2)[CH3:32]
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(Cc3cc(CCl)cc(C(F)(F)F)c3)cc2C1
Reactant: CNC
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(Cc3cc(CN(C)C)cc(C(F)(F)F)c3)cc2C1
Temperature: 60 °C

Procedure:
To a solution of (S)-N-(5-(3-(chloromethyl)-5-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (0.090 mmol, 40 mg) in DMF (1 mL) was added dimethylamine (2M solution, 0.224 mmol, 0.112 mL). The whole was heated to 60° C. for 2 h before the reaction mixture was purified directly by prep HPLC to give the title compound. (21.2 mg, 52%). MS (ESI): m/z [M+H]+ 455.2
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:10][SH:11])[C:5]([F:16])=[CH:4][N:3]=1.[C:17]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:10][S:11][CH3:17])[C:5]([F:16])=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)[C@@H](CS)Nc1nc(Cl)ncc1F
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CSC[C@@H](Nc1nc(Cl)ncc1F)C(C)(C)C
Temperature: 70 °C

Procedure:
To a suspension of (S)-2-(2-chloro-5-fluoropyrimidin-4-ylamino)-3,3-dimethylbutane-1-thiol, 77a, (0.85 g, 3.60 mmol) and K2CO3 (2.26 g, 16.35 mmol) in acetone was added iodomethane (0.82 mL, 13.08 mmol). The suspension was heated at 70° C. for 1.30 hours and then cooled to room temperature. The solid was filtered and the solution was concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-10% EtOAc/Hexanes gradient) to afford 310 mg of the desired product as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 5.12 (m, 1H), 4.21 (t, J=9.1 Hz, 1H), 3.15-2.90 (m, 2H), 2.23 (s, 3H), 0.95 (m, 9H); LC/MS (60-90% ACN/water 5 min with 0.9% FA) m/z 278.29 (M+H) RT =1.35 minutes.
Reaction SMILES: C([Si](C)(C)[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=2)[CH:8]=[CH:7]1)(C)(C)C.Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH:29]2[CH2:34][C:33]([CH3:36])([CH3:35])[NH:32][C:31]([CH3:38])([CH3:37])[CH2:30]2)[N:23]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH3:35][C:33]1([CH3:36])[CH2:34][CH:29]([NH:28][C:24]2[N:23]=[C:22]([C:8]3[C:9]4[C:14](=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=4)[NH:6][CH:7]=3)[CH:27]=[CH:26][N:25]=2)[CH2:30][C:31]([CH3:38])([CH3:37])[NH:32]1
Reactant: CC(C)(C)[Si](C)(C)n1ccc2ccc(C(F)(F)F)cc21
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)CC(Nc2nccc(-c3c[nH]c4cc(C(F)(F)F)ccc34)n2)CC(C)(C)N1

Procedure:
The title compound was prepared as described in Example 215, starting from 1-(tert-butyl-dimethyl-silanyl)-6-trifluoromethyl-1H-indole (prepared by TBDMS protection of 6-trifluoromethyl-1H-indole) and (4-chloro-pyrimidin-2-yl)(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by in situ cleavage of the TBDMS protecting group with catalytic amounts of TBAF. Yield: 640 mg (77%).
Reaction SMILES: Br.[CH2:2]([O:9][CH2:10][CH:11]1[O:16][C:15](=[O:17])[CH:14]([C:18](=[O:29])[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[N+:26]([O-:28])=[O:27])[C:13](=[O:30])[CH2:12]1)[C:3]1C=CC=CC=1.C(O)(=[O:33])C>>[C:2]([O:9][CH2:10][CH:11]1[O:16][C:15](=[O:17])[CH:14]([C:18](=[O:29])[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[N+:26]([O-:28])=[O:27])[C:13](=[O:30])[CH2:12]1)(=[O:33])[CH3:3]
Reactant: O=C1CC(COCc2ccccc2)OC(=O)C1C(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CC(=O)O
Agent: Br
Product: CC(=O)OCC1CC(=O)C(C(=O)c2ccc(Cl)cc2[N+](=O)[O-])C(=O)O1
Temperature: 0 °C

Procedure:
To 7.7 ml of 25% acetic acid solution of hydrobromic acid was dissolved 2.40 g (5.7 mmole) of 6-benzyloxymethyl-3-(4-chloro-2-nitrobenzoyl)tetrahydropyran-2,4-dione, then this solution was reacted at room temperature for 5 hours. After the completion of the reaction, the mixture was poured into ice water, then extracted with chloroform. The organic solvent layer extracted was washed with water and saturated brine in turn, dried with magnesium sulfate, then the solvent was distilled therefrom. The residue obtained was purified by silica gel column chromatography to obtain 1.50 g of the objective product in a state of orange-coloured sticky oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>CN(C=O)C.C(Cl)Cl.O>[Cl:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]([CH3:11])=[C:6]([C:7]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[O:9])[CH:10]=1
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1C(=O)O
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc([N+](=O)[O-])c(Cl)cc1C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.2 %

Procedure:
To 5-chloro-2-methyl-4-nitrobenzoic acid (197 mg, 0.91 mmol) in DMF (5 mL) was added triethylamine (0.13 mL, 0.91 mmol) and HATU (345 mg, 0.91 mmol) followed by morpholine (0.08 mL, 0.91 mmol). The mixture was allowed to stir at RT for 18 h and then water (10 mL) and DCM were added. The organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification of the residue via silica gel column chromatography (0-100% EtOAc in iso-hexane) gave (5-chloro-2-methyl-4-nitrophenyl)(morpholino)methanone (244 mg, 95%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M+H]+=285 at 3.05 min. 1H NMR (400 MHz, CDCl3): δ 7.76 (s, 1H), 7.36 (s, 1H), 3.83-3.76 (m, 4H), 3.66-3.58 (m, 2H), 3.28-3.20 (m, 2H), 2.37 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]#[N:28])=[CH:17][CH:16]=2)=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:29](=S)(OCC)[S-:30].[Na+]>C(O)C>[C:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:13]2[C:3]3[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:10][CH:11]=[CH:12][C:2]=3[N:1]=[C:29]2[SH:30])=[CH:16][CH:17]=1)#[N:28]
Reactant: CCOC(=O)c1cccc(N)c1NCc1ccc(-c2ccccc2C#N)cc1
Reactant: CCOC(=S)[S-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cccc2nc(S)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Yield: 80.2 %

Procedure:
A mixture of ethyl 3-amino-2-[(2'-cyanobiphenyl-4-yl)methyl]aminobenzoate (5.6 g) and sodium O-ethyl dithiocarbonate (7.3 g) in ethanol (50 ml) was heated for 8 hours under reflux. The reaction mixture was concentrated and the residue was dissolved in water. The solution was adjusted to pH 3-4 with hydrochloric acid. Precipitating crystals were collected by filtration, followed by recrystallization from ethanol to afford yellow crystals (5.0 g, 80%), m.p. 225°-227° C.