Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].C([Mg]Cl)(C)C.Br[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15].[Si:16]([O:23][CH2:24]/[CH:25]=[N:26]/[S@:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C1COCC1.C1(C)C=CC=CC=1>[Si:16]([O:23][CH2:24][C@H:25]([NH:26][S@:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28])[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[S@](=O)/N=C/CO[Si](C)(C)C(C)(C)C
Reactant: Fc1ccc(Br)c(F)c1
Agent: CC(C)[Mg]Cl
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)N[C@@H](CO[Si](C)(C)C(C)(C)C)c1ccc(F)cc1F
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a first flask was added magnesium turnings (197 mg, 8.11 mmol) and THF (7 mL). A 2.0 M solution of isopropyl magnesium chloride in THF (16 μL, 0.032 mmol) was added followed by 1-bromo-2,4-difluorobenzene (0.10 mL). The temperature of the reaction mixture raised to 30° C. Additional 1-bromo-2,4-difluorobenzene (0.91 mL) was added dropwise at such a rate that the internal temperature did not exceed 32° C. After addition, the reaction mixture was stirred at 26-28° C. for 30 minutes. To a second flask was added (S,E)-N-(2-(tert-butyldimethylsilyloxy)ethylidene)-2-methylpropane-2-sulfinamide (1.50 g, 5.41 mmol) and toluene (32 mL) under N2. The reaction mixture was cooled to −78° C. The Grignard reagent prepared in the first flask was slowly transferred to the reaction mixture in the second flask using a syringe. The reaction was allowed to slowly warm up to 0° C. The reaction was quenched by the addition of saturated aqueous NH4Cl solution. The organic layer was separated. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried and concentrated. The residue was purified by column chromatography (hexane/EtOAc, 6:1) to give (S)—N—((R)-2-(tert-butyldimethylsilyloxy)-1-(2,4-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (1.14 g, 54%) as a white solid.
Reaction SMILES: [C:1]([O:4][C@H:5]1[O:22][C@H:21]([CH2:23][O:24]C(=O)C)[C@@H:16]([O:17]C(=O)C)[C@H:11]([O:12]C(=O)C)[C@@H:6]1[O:7]C(=O)C)(=O)[CH3:2].OC1C=[CH:31][C:32]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([O:47][CH3:48])=[O:46])[CH:40]=2)=[C:33]([CH:38]=1)[C:34]([O:36][CH3:37])=[O:35]>>[CH3:48][O:47][C:45]([C:41]1[CH:40]=[C:39]([C:32]2[CH:31]=[CH:2][C:1]([O:4][C@@H:5]3[C@@H:6]([OH:7])[C@@H:11]([OH:12])[C@H:16]([OH:17])[C@@H:21]([CH2:23][OH:24])[O:22]3)=[CH:38][C:33]=2[C:34]([O:36][CH3:37])=[O:35])[CH:44]=[CH:43][CH:42]=1)=[O:46]
Reactant: CC(=O)OC[C@H]1O[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: COC(=O)c1cccc(-c2ccc(O)cc2C(=O)OC)c1
Product: COC(=O)c1cccc(-c2ccc(O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)cc2C(=O)OC)c1
Yield: 73 %

Procedure:
6 was prepared via glycosidation between α-D-mannose pentaacetate and methyl 5-hydroxy-2-(3-methoxycarbonylphenyl)benzoate following the procedure previously described.25 Yield: 73%. 1H NMR (300 MHz, METHANOL-d4) δ ppm 3.56-3.68 (m, 4H) 3.68-3.84 (m, 3H) 3.86-3.98 (m, 4H) 4.06 (dd, J=3.30, 1.92 Hz, 1H) 5.60 (d, J=1.92 Hz, 1H) 7.29-7.43 (m, 2H) 7.45-7.53 (m, 2H) 7.56 (d, J=2.47 Hz, 1H) 7.84-7.92 (m, 1H) 7.93-8.04 (m, 1H). MS (ESI): found [M+H]+, 449.0.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:20])[C:6](=[N:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][C@@H:14]([OH:19])[C@@H:15]2[NH-:18])=[CH:11][CH:10]=1)[CH3:7].C(OC(=O)N)(C)(C)C.C(N(CC)CC)C.O=C1CCC(=O)N1[O:43][C:44]([C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[CH:48][CH:47]=1)=O>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:20])[C:6](=[N:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][C@@H:14]([OH:19])[C@@H:15]2[NH:18][C:44]([C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)=[CH:48][CH:47]=2)=[O:43])=[CH:11][CH:10]=1)[CH3:7]
Reactant: O=C(ON1C(=O)CCC1=O)c1ccc(-c2ccccc2)cc1
Reactant: COCCN(C)C(C)=Nc1ccc2c(c1)[C@@H]([NH-])[C@H](O)C2
Agent: CC(C)(C)OC(N)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCN(C)C(C)=Nc1ccc2c(c1)[C@@H](NC(=O)c1ccc(-c3ccccc3)cc1)[C@H](O)C2
Reaction time: 1 h
Yield: 50.9 %

Procedure:
Dissolve carbamic acid tert-butyl ester (R)-(6-(1-((2-methoxyethyl)methylamino)ethylideneamino)-2(R)-hydroxyindan-1-yl)amide (153.6 mg, 0.407 mmol) in excess TFA at 0° C. and allow to stir for 1 hour. Remove the solvent in vacuo. Dissolve the residue in 10 mL methylene chloride and add triethylamine (411.8 mg, 4.07 mmol) and biphenyl-4-carboxylic acid 2,5-dioxopyrrolidin-1-yl ester (118.3 mg, 0.400 mmol). Allow the reaction mixture to stir for 21 hours. Dilute the reaction mixture with methylene chloride and wash it with saturated aqueous sodium hydrogen carbonate (1×) and brine (1×). Dry the organic layer with magnesium sulfate. Filter and remove the solvent in vacuo to give 162.1 mg of crude product. Purify via Biotage chromatography (30% MeOH/EtOAc) to afford 93.1 mg of the titled product as an oil (50% yield). MS (ES): m/z 458.3(M+H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]3[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:22][C:21]=3[O:35][CH3:36])[N:10]=2)=[C:4]([C:37](=[O:40])[NH:38][CH3:39])[CH:3]=1.ClC1C(C(F)(F)[F:49])=CN=C(NC2C=CC(CP(=O)(OCC)OCC)=CC=2OC)N=1.NC1C=CC=C(F)C=1C(NC)=O>>[F:49][C:3]1[C:4]([C:37](=[O:40])[NH:38][CH3:39])=[C:5]([NH:8][C:9]2[C:14]([C:15]([F:16])([F:18])[F:17])=[CH:13][N:12]=[C:11]([NH:19][C:20]3[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:26][CH2:27][CH3:28])[O:29][CH2:30][CH3:31])=[CH:22][C:21]=3[O:35][CH3:36])[N:10]=2)[CH:6]=[CH:7][CH:2]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(F)cc3C(=O)NC)n2)c(OC)c1)OCC
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Agent: CNC(=O)c1c(N)cccc1F
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccc(F)c3C(=O)NC)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure from Example 102 (Diethyl (4-{[4-{[4-fluoro-2-(methylcarbamoyl)-phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate) using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 2-amino-6-fluoro-N-methylbenzamide (Compound 155A). 1H NMR (DMSO-d6, 400 MHz): δ=1.19 (t, J=7.07 Hz, 6H), 2.76 (d, J=4.80 Hz, 3H), 3.19-3.27 (m, 2H), 3.76 (s, 3H), 3.93-4.02 (m, 4H), 6.78-6.83 (m, 1H), 6.97-7.03 (m, 2H), 7.38 (d, J=7.07 Hz, 1H), 7.49 (d, J=6.82 Hz, 1H), 8.00 (br. s., 1H), 8.38 (s, 1H), 8.62 (d, J=3.79 Hz, 1H), 8.80 (br. s., 1H), 9.78 (s, 1H). MS (ES+): m/z 586.14 [MH+] (TOF, polar).
Reaction SMILES: Cl[C:2](=[C:5](CCCl)[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)[CH:3]=[O:4].[S-2:16].[Na+].[Na+].[CH2:19]1[CH2:23]OCC1.O>CCOCC>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]([C:5]2[S:16][CH2:23][CH2:19][C:2]=2[CH:3]=[O:4])=[CH:11][CH:10]=1
Reactant: C1CCOC1
Reactant: Cc1ccc(C(CCCl)=C(Cl)C=O)cc1
Reactant: [S-2]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(C2=C(C=O)CCS2)cc1

Procedure:
15.9 g of α-chloro-β-(2-chloroethyl)-4-methylcinnamaldehyde, prepared in B), and 22 g of sodium sulphide (9 H2O) are added to 200 ml of THF. A sufficient amount of water is added for the sodium sulphide to pass completely into solution, and the mixture is then heated to reflux for 3 hours, cooled and thereafter taken up with ether. The organic phase is separated after settling has taken place, washed with water, then dried over magnesium sulphate and evaporated under vacuum to give 13.5 g of 2-(4'methylphenyl)-4,5-dihydro-3-thiophenecarbaldehyde in the form of an oil which is used without further purification for the next step.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH2:8][CH2:7]1)=[O:5])C.[O-]CC.[Na+]>C1(C)C=CC=CC=1.O1CCOCC1.[OH-].[Na+]>[O:16]1[CH2:15][CH2:14][CH:13]([O:12][C@H:9]2[CH2:10][CH2:11][C@H:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)[CH2:18][CH2:17]1
Reactant: CCOC(=O)[C@H]1CC[C@H](OC2CCOCC2)CC1
Agent: CC[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: O=C(O)[C@H]1CC[C@H](OC2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of cis/trans-4-(tetrahydro-pyran-4-yloxy)-cyclohexanecarboxylic acid ethyl ester (7:1) (0.385 g, 1.50 mmol) and sodium ethoxide (0.204 g, 3.00 mmol) in dry toluene (1.5 ml) was heated at reflux for 20 h. The reaction mixture was cooled to room temperature, diluted with 1,4-dioxane (7.5 ml) and 2 M aqueous sodium hydroxide solution (7.5 ml). Stirring for 16 h was followed by partitioning between 2 M aqueous sodium hydroxide solution (50 ml) and dichloromethane. The layers were separated. The aqueous layer was extracted with one portion of dichloromethane. The combined organic layers were washed with two 50 ml portions of 2 M aqueous sodium hydroxide solution. The combined aqueous layers were acidified to pH 1 by addition of concentrated hydrochloric acid solution (100 ml). The aqueous layer was extracted with two 150-ml portions of dichloromethane. The combined organic layers from the acidic extraction were dried over anhydrous sodium sulfate and dried in vacuo to give the title compound (0.358 g, 93%) as yellow solid. MS m/e: 229 (M+H+)
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28]([NH2:31])(=[O:30])=[O:29]>ClCCl.N1C=CC=CC=1>[NH2:31][S:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:1](=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28]([NH2:31])(=[O:29])=[O:30])=[O:13])(=[O:29])=[O:30]
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: NS(=O)(=O)c1ccccc1NC(=O)c1ccccc1SSc1ccccc1C(=O)Nc1ccccc1S(N)(=O)=O
Temperature: 23 °C
Reaction time: 144 h
Yield: 19.6 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 2-aminobenzenesulfonamide (2.00 g, 11.6 mmol) in 16 mL of pyridine. The reaction mixture was stirred for 6 days at 23° C. under nitrogen atmosphere. The crude product was recrystallized from acetonitrile to yield 0.70 g of the title compound, mp 150°-151° C. (dec.).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH2:9]([Mg]Br)[CH3:10].[Cl-].[NH4+]>C1COCC1>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:1]([OH:8])[CH2:9][CH3:10])[CH:3]=1
Reactant: CC[Mg]Br
Reactant: O=Cc1cccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)c1cccnc1
Reaction time: 1 h
Yield: 67 %

Procedure:
A solution of nicotinaldehyde (0.200 mL, 0.12 mmol) in THF (2.0 mL) was slowly added to ethylmagnesium bromide (1.0 mol/L solution in THF, 3.18 mL, 3.18 mmol) at 0° C. The mixture was stirred at the same temperature for 1 hour and a saturated aqueous ammonium chloride solution was added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to give Compound A19 (194 mg, 67% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11](F)[CH:10]=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15].[N:20]1([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([N:23]2[CH2:22][CH2:21][N:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24]2)[CH:10]=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1NCc1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(NCc3cccc(Cl)c3)c2)CC1
Yield: 32.1 %

Procedure:
N-(3-Chlorobenzyl)-5-fluoro-2-nitrobenzenamine (624 mg, 2.2 mmol), t-butyl piperazine-1-carboxylate (414 mg, 2.2 mmol), N,N-diisopropylethylamine (287 mg, 2.2 mmol) were stirred at 80° C. in dry acetonitrile (10 mL) for 16 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 25% ethyl acetate in hexanes to afford the title compound (316 mg, 32% yield). 1H NMR (400 MHz, CDCl3): δ 8.77 (s, 1H), 8.05 (d, 1H), 7.32-7.21 (m, 4H), 6.18 (d, 1H), 5.72 (s, 1H), 4.46 (d, 2H), 3.49 (m, 4H), 3.27 (m, 4H), 1.45 (s, 9H); MS (ESI) m/z: Calculated for C22H27ClN4O4: 446.17; Observed: 469.4 (M++Na).
Reaction SMILES: O1CCOCC1.[F:7][C:8]([F:12])([F:11])[CH2:9][NH2:10].CCN(C(C)C)C(C)C.Cl[S:23]([CH2:26][CH2:27][NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:25])=[O:24]>C(#N)C>[F:7][C:8]([F:12])([F:11])[CH2:9][NH:10][S:23]([CH2:26][CH2:27][NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:25])=[O:24]
Reactant: O=C(NCCS(=O)(=O)Cl)OCc1ccccc1
Reactant: NCC(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CC#N
Product: O=C(NCCS(=O)(=O)NCC(F)(F)F)OCc1ccccc1
Reaction time: 0.33 h
Yield: 39 %

Procedure:
To a dioxane (1 mL) solution of 2,2,2-trifluoroethanamine (80 mg, 0.81 mmol) and DIEA (0.28 mL, 1.6 mmol) at 0° C. was added benzyl (2-(chlorosulfonyl)ethyl)carbamate (150 mg, 0.54 mmol) in acetonitrile (1 mL). The reaction was allowed to reach room temperature over a period of 20 minutes. The reaction mixture was concentrated under reduced pressure, and the residue purified using reverse phase HPLC (YMC Sunfire 5u (C18) 30×100 mm, 0-100% ACN (90% in H2O, 0.1% TFA) using gradient over 16 min with flow rate 40 mL/min and UV detection at 220 nm) to give Compound B30a (95 mg, 39% yield). HPLC: RT=3.84 (LCMS Method M). MS (ES): m/z=340.9 [M+H]+. 1H NMR (500 MHz, CHLOROFORM-d) d 7.43-7.34 (m, 5H), 5.28 (br. s., 2H), 5.15 (s, 2H), 3.86-3.68 (m, 4H), 3.35-3.24 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1(Cl)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]1[S:8][CH2:9][C:10]([F:13])([F:12])[F:11].[FH:15].[Sb](Cl)(Cl)(Cl)(Cl)Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH:9]([F:15])[C:10]([F:13])([F:12])[F:11]
Reactant: F
Reactant: FC(F)(F)CSC1C=CC=CC1(Cl)Cl
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Product: FC(Sc1ccccc1Cl)C(F)(F)F
Reaction time: 3 h

Procedure:
A 500 ml polytetrafluoroethylene reactor equipped with stirrer, thermometer and reflux condenser is charged with 24.7 g (0.094 mol) of 1,1-dichloro-2,2,2-trifluoroethylthiobenzene which are subsequently condensed with 50 g of hydrogen fluoride. 4.2 g (0.014 mol; corresponding to 15 mol%) of antimony pentachloride are added at a temperature of 20° C. The resultant hydrogen chloride is removed from the reactor through the reflux condenser. After 3 hours a further 1.4 g (5 mol%) and after 4 hours a further 2.8 g (10 mol%) of antimony pentachloride are added. After a total reaction time of 5 hours, the hydrogen fluoride is removed by distillation, the residue is dissolved in 150 ml of methylene chloride and the solution is extracted with water. The solution is separated by distillation, affording 1-chloro-1,2,2,2-tetrafluoroethylthiobenzene. Boiling point 178°-179° C., nD20 =1.4732.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[C:1]([CH:9]([Br:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)CC(=O)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(Br)C(=O)c1ccccc1

Procedure:
To a stirred solution of benzoylacetic acid, ethyl ester (0.01 mol) in a solvent such as, for example, chloroform is added N-bromosuccinimide (NBS, 0.01 mol), and the mixture is stirred. Reaction progress may be followed by TLC or HPLC. When a sufficient amount of benzoyl-bromoacetic acid, ethyl ester is formed, ethyl acetate is added, and the mixture is rotary evaporated to remove chloroform. To the resulting ethyl acetate mixture is added thiocarbamic acid, benzyl ester, which may be prepared as described in Step (a) above, and a suitable non-nucleophilic base such as those described in Example 17 above, and the mixture is stirred. Reaction progress may be followed by TLC or HPLC. When a sufficient amount of the desired product is formed, the reaction is washed with 0.01 M hydrochloric acid, water, brine, and dried over sodium sulfate. The mixture is rotary evaporated to give 2-benzyloxy-4-phenyl-thiazol-5-carboxylic acid, ethyl ester, which may be purified, if needed or desired, by chromatography on silica gel or crystallization.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24]C)=[O:22]>CN(C=O)C>[CH3:24][O:23][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CCOC(=O)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCn1c2ccccc2c2ccccc21
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 51.7 %

Procedure:
To a round bottom flask fitted with reflux condenser containing carbazole (1.00 g, 5.98 mmol) and sodium hydride (60 wt. % in mineral oil, 0.29 g, 7.18 mmol), was added DMF (22 mL). After stirring at 50° C. for 20 min, ethyl 5-bromopentanoate (0.95 mL, 5.98 mmol) was added and the mixture stirred at 80° C. overnight. The reaction was quenched by addition of 5% aqueous NH4Cl (100 mL), transferred to a separatory funnel and extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with brine (2×20 mL), dried (Na2SO4) and concentrated. Purification by MPCC (0-40% gradient of ethyl acetate in hexane) afforded the title compound (0.87 g, 49%). 1H NMR (400 MHz, CDCl3): δ 8.14 (d, 2H, J=7.8 Hz), 7.51 (t, 2H, J=7.2 Hz), 7.43 (d, 2H, J=8.2 Hz), 7.27 (t, 2H, J=7.4 Hz), 4.35 (t, 2H, J=7.1 Hz), 4.13 (q, 2H, J=7.1 Hz), 2.35 (t, 2H, J=7.3 Hz), 1.98-1.91 (m, 2H), 1.79-1.72 (m, 2H), 1.25 (t, 3H, J=7.1 Hz). 13C NMR APT (100 MHz, CHCl3): δ 173.2 (up), 140.3 (up), 125.6 (down), 122.89 (up), 120.4 (down), 118.9 (down), 108.6 (down), 60.4 (up), 42.7 (up), 33.9 (up), 28.4 (up), 22.7 (up), 14.2 (down). ESI-HRMS (m/z): [M+H]+ calcd. for C19H21NO2, 296.1645. found, 296.1650.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.O>[CH3:23][O:19][C:18]([C:17]1[CH:16]=[CH:15][C:14]([C@@H:10]2[O:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]2)=[CH:22][CH:21]=1)=[O:20]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(C(=O)O)cc2)C1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc([C@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-4-(4-(tert-Butoxycarbonyl)morpholin-2-yl)benzoic acid [CAS 1131220-40-0], (500 mg, 1.63 mmol) was dissolved in dimethylformamide (8.6 ml). Potassium carbonate (675 mg, 4.88 mmol) and iodomethane (346 mg, 0.152 ml, 2.44 mmol) were added. The reaction mixture was shaken at room temperature overnight. The solution was diluted with water (25 ml) and extracted with ethyl acetate (2×40 ml). The combined organic layer was dried over MgSO4 and evaporated to give a light yellow oil. The crude material was purified by flash chromatography (silica gel, 25% ethyl acetate in heptane). Isolation of a white solid (427 mg, 82%), MS (ISP): 266.1 (100%, [M-tBu+H]+), 222.1 (40%, [M-BOC+H]+), 322.2 (7%[M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:22]3[CH2:25][CH2:24][CH2:23]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:20][CH3:21])[CH:11]=3)=[CH:4][CH:3]=1.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([N+]([O-])=O)=C[CH:31]=1)=[O:28].N1C=CC=CC=1.C1(C(C)O)CC1>C(Cl)Cl.ClCCCl>[CH:35]1([CH:30]([O:29][C:27](=[O:28])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:9]([CH:22]4[CH2:23][CH2:24][CH2:25]4)[C:10]4[C:15]([C:16]=3[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:20][CH3:21])[CH:11]=4)=[CH:6][CH:7]=2)[CH3:31])[CH2:34][CH2:33]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOc1ccc2c(C#N)c(-c3ccc(N)cc3)n(C3CCC3)c2c1
Agent: CC(O)C1CC1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CCOc1ccc2c(C#N)c(-c3ccc(NC(=O)OC(C)C4CC4)cc3)n(C3CCC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.1 %

Procedure:
2-(4-Aminophenyl)-1-cyclobutyl-6-ethoxy-1H-indole-3-carbonitrile (50 mg, 0.15 mmol), prepared as in example 1CM, step B, is combined with 4-nitrophenyl chloroformate (76 mg, 0.38 mmol), DCE (0.5 mL), and pyridine (30 μL, 0.37 mmol). This suspension is stirred at room temperature for 1 h. Rac-cyclopropyl methyl carbinol (100 μL, 0.98 mmol) is added. This mixture is heated at 75° C. overnight. The reaction mixture is then diluted in CH2Cl2 and is washed with dilute aqueous NaOH to remove the yellow nitrophenol byproduct. The organic layer is dried and concentrated. Purification by silica gel chromatography (CH2Cl2) yields rac-[4-(3-cyano-1-cyclobutyl-6-ethoxy-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (40 mg, 60%) as a white solid.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH3:4].C(NC(C)C)(C)C.Br[C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=1>C(#N)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:19][C:17]1[CH:16]=[N:15][CH:14]=[C:13]([C:1]#[C:2][CH2:3][CH3:4])[CH:18]=1
Reactant: Brc1cncc(Br)c1
Reactant: C#CCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: CCC#Cc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
But-1-yne (g) was during 5 min gently bubbled through anhydrous acetonitrile cooled in an ice-water bath. The resulting solution contained about 170 mg but-1-yne per mL. The solution of but-1-yne (4.57 mL, 14.36 mmol) and diisopropylamine (3.72 mL, 26.11 mmol) were added sequentially to a mixture of 3,5-dibromopyridine (3.09 g, 13.06 mmol), bis(triphenylphosphine)-palladium(II) chloride (0.458 g, 0.65 mmol) and CuI (0.249 g, 1.31 mmol) in acetonitrile (15 mL) under an argon atmosphere. The resulting mixture was stirred at r.t. overnight, diluted with EtOAc and passed through a short plug of silica. The solvents were evaporated and the residue was purified by flash chromatography on silica (gradient elution 0-20% EtOAc in heptane) to give 2.40 g of the title compound (87% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 1.17 (t, 4 H), 2.47 (q, 3 H), 8.11 (t, 1 H), 8.57 (d, 1 H), 8.65 (d, 1 H); MS (ES+) m/z 210 [M+H]+.