Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]3[CH2:17][C@H:18]4[N:30]([CH3:31])[CH2:29][CH2:28][C@:24]56[C:25]=3[C:26]=2[O:27][C@H:23]5[C:22](=[O:32])[CH2:21][CH2:20][C@@:19]46[OH:33])=[O:12])=[CH:4][CH:3]=1.[Cl-].[NH4+]>[Zn].C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]3[CH2:17][C@H:18]4[N:30]([CH3:31])[CH2:29][CH2:28][C@@:24]5([C:25]=3[C:26]=2[OH:27])[C@@:19]4([OH:33])[CH2:20][CH2:21][C:22](=[O:32])[CH2:23]5)=[O:12])=[CH:4][CH:3]=1
Reactant: CN1CC[C@]23c4c5ccc(C(=O)NCCc6ccc(Br)cc6)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Product: CN1CC[C@]23CC(=O)CC[C@@]2(O)[C@H]1Cc1ccc(C(=O)NCCc2ccc(Br)cc2)c(O)c13
Temperature: 40 °C
Yield: 79 %

Procedure:
A mixture of (5a)-N-[2-(4-bromophenyl)ethyl]-14-hydroxy-17-methyl-6-oxo-4,5-epoxymorphinan-3-carboxamide (1) (10 g, 19.6 mmol), denatured ethanol (300 mL), zinc powder (28 g, 0.43 mol) and ammonium chloride (34.5 g, 0.65 mol) was heated at reflux for 30 min and then cooled to ˜40° C. The reaction mixture was filtered through celite and washed with denatured ethanol (300 mL, 40° C.). The volatiles were removed under vacuum and the residue partitioned between dichloromethane (200 mL) and 2% aqueous ammonia (300 mL). The aqueous phase was further extracted with dichloromethane (2×200 mL) and the combined organics were dried over MgSO4 and evaporated. The residue was purified on silica eluting with dichloromethane/methanol (95:5 to 9:1) to give N-[2-(4-bromophenyl)ethyl]-4,14-dihydroxy-17-methyl-6-oxomorphinan-3-carboxamide (2) (7.95 g, 79%) as a brown solid.
Reaction SMILES: C(Br)[Br:2].[Br-:4].[K+:5]>>[Br-:2].[Br-:4].[Br-:2].[K+:5].[K+:5].[K+:5].[K+:5].[Br-:2].[Br:4][Br:2]
Reactant: BrCBr
Agent: [Br-]
Agent: [K+]
Product: BrBr

Procedure:
Into a 500mL three-necked flask equipped with a dropping funnel, condenser, thermometer and mechanical stirrer were charged 50 grams of methylene-1,2-dioxybenzene (MDOB), 50 grams of methylene dibromide (Me2Br2) and 20 grams of 34% aqueous potassium bromide. With stirring, an aqueous potassium tribromide solution--formed from 165 grams of 34% aqueous KBr and 65 grams of elemental bromine--was added slowly over a two-hour period during which time the mildly exothermic reaction kept the reaction mixture at or slightly below 30° C. Samples were taken when 25%, 50%, 75% and 100% of the aqueous KBr3 solution had been added in order to determine the extent to which monobromination to methylene-1,2-dioxy-4-bromobenzene (BrMDOB) and dibromination to Br2MDOB had occurred. Another sample was taken after stirring the final reaction mixture for 30 minutes. Gas chromatographic analysis of these samples gave the following results (expressed in terms of percentages of the designated materials present):
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:21](O)=[O:22])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][NH:33][C:34](=[O:49])[C@H:35]([CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[NH:36][CH3:37])=[CH:27][CH:26]=1>CO.C(Cl)Cl>[OH:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][NH:33][C:34](=[O:49])[C@H:35]([CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])=[O:43])[N:36]([C:21](=[O:22])[C@H:9]([CH2:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)[NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2])[CH3:37])=[CH:27][CH:26]=1
Reactant: CN[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)NCCc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Solvent: CO
Solvent: ClCCl
Product: CN(C(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)OC(C)(C)C)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)NCCc1ccc(O)cc1

Procedure:
Using Procedure B, coupling of Boc-β-(2-naphthyl)alanine and Nδ-Boc-Nα-methylornithine 2-(4-hydroxyphenyl)ethylamide, followed by silica gel chromatography (2.5% MeOH/CH2Cl2): 1H NMR (400 MHz, CDCl3) 6 1.41 (m, 21H), 1.85 (m, 1H), 2.20 (m, 2H), 2.45 (m, 1H), 2.67 (m, 4H), 3.03 (m, 4H), 4.91 (m, 2H), 6.77 (m, 2H), 6.87 (d, J=8.7 Hz, 1H), 6.98 (d, J=10.0 Hz, 1H), 7.34 (m, 1H), 7.46 (m, 2H), 7.66 (m, 1H), and 7.78 (m, 3H); mass spectrum (ES+) m/e 663 (M+1).
Reaction SMILES: Br[CH:2]=[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[CH3:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.[Cl:27][C:28]1[CH:36]=[CH:35][C:34]2[NH:33][C:32]3[CH2:37][CH2:38][N:39]([C:41]([O:43][CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)=[O:42])[CH2:40][C:31]=3[C:30]=2[CH:29]=1>CN(C=O)C.[Cu]I>[Cl:27][C:28]1[CH:36]=[CH:35][C:34]2[N:33](/[CH:2]=[C:3](/[C:5]3[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=3)\[CH3:4])[C:32]3[CH2:37][CH2:38][N:39]([C:41]([O:43][CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)=[O:42])[CH2:40][C:31]=3[C:30]=2[CH:29]=1
Reactant: CC(=CBr)c1ccncc1
Reactant: O=C(OCc1ccccc1)N1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CN(C(=O)OCc1ccccc1)CC2)c1ccncc1
Temperature: 80 °C

Procedure:
4-(1-Bromoprop-1-en-2-yl)pyridine (237 mg, 1.2 mmol) was dissolved in DMF and potassium phosphate (424 mg, 2 mmol) was added followed by the addition of copper (I)iodide (19 mg, 0.1 mmol) and L-proline (23 mg, 0.2 mmol). Benzyl 8-chloro-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (340 mg, 1 mmol) was added and nitrogen gas purged for 2 min. The reaction mixture was heated at 80° C. overnight. The reaction mixture was cooled to RT and water (20 mL) was added. The compound was extracted with EtOAc (3×50 mL). The organic layer was washed with water (2×50 mL) and compound was purified through reverse phase HPLC. Yield: 13.4 mg. 1H NMR (CDCl3, free base) δ (ppm): 8.64 (d, 2H), 7.25-7.15 (m, 8H), 7.18 (d, 1H), 7.05 (m, 2H), 5.20 (s, 2H), 4.70 (s, 2H), 3.90 (m, 2H), 2.78 (m, 2H), 1.98 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:8])=[CH:5][CH:4]=1.[OH-].[Na+].[BH4-].[Na+].Cl>O>[OH:8][CH:7]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=1)[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: COc1ccc(C(=O)CCCC(=O)O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(O)CCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.2 %

Procedure:
To 4.44 g of 4-(4-methoxybenzoyl)butanoic acid was added a solution of 0.8 g of sodium hydroxide in 30 ml of water, and to this solution was added 1.5 g of sodium borohydride, followed by stirring of the mixture at room temperature for 24 hours. The mixture was neutralized with diluted hydrochloric acid, extracted with ether, washed with water and dried, followed by evaporation of the solvent to give 4.4 g of 5-hydroxy-5-(4-methoxyphenyl)pentanoic acid as yellow oily product.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].C([O-])(=O)C.[NH4+].CC1(C)C(C)(C)[O:16][B:15]([C:20]2[CH:25]=[CH:24][C:23]([N:26]([C:43](=[O:52])/[CH:44]=[CH:45]/[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:27][C:28]([N:30]3[CH2:34][CH2:33][C@H:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:31]3)=[O:29])=[CH:22][CH:21]=2)[O:14]1>O.CC(C)=O>[B:15]([C:20]1[CH:21]=[CH:22][C:23]([N:26]([C:43](=[O:52])/[CH:44]=[CH:45]/[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:27][C:28]([N:30]2[CH2:34][CH2:33][C@H:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:31]2)=[O:29])=[CH:24][CH:25]=1)([OH:14])[OH:16]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(C(=O)/C=C/c2ccccc2)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(C(=O)/C=C/c2ccccc2)c2ccc(B(O)O)cc2)C1
Temperature: 25 °C
Reaction time: 64 h
Yield: 79.8 %

Procedure:
Sodium periodate (2.06 g, 9.6 mmol) and ammonium acetate (0.74 g, 9.6 mmol) in water (20 mL) were added to [(S)-1-(2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-[(E)-(3-phenylacryloyl)]amino}acetyl)pyrrolidin-3-yl]-carbamic acid, tert-butyl ester 4 (1.85 g, 3.2 mmol) in acetone (30 mL) and the reaction stirred at room temperature for 64 h. The reaction mixture was concentrated in vacuo and 1M NaOH was added. The mixture was stirred for 4 h and then shaken with dichloromethane and filtered. The two layers were separated and the NaOH layer washed with dichloromethane. The aqueous basic layer was acidified to pH1 with conc. hydrochloric acid and extracted with ethyl acetate (×2). The combined organic layers were washed with brine, dried (Na2SO4) and evaporated to dryness. The resultant residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate→5% methanol/ethyl acetate→10% methanol/ethyl acetate→methanol, to give the title compound as a glass (1.26 g, 80%) which was used directly in the next stage.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[OH2:7].[F:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH2:28][C:29]([OH:31])=[O:30])=[C:14]([CH3:27])[C:15]2=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=2)=[CH:11][C:10]=1[O:32][CH3:33].CO>CC(C)=O>[F:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH2:28][C:29]([OH:31])=[O:30])=[C:14]([CH3:27])[C:15]2=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:26])=[O:7])=[CH:21][CH:20]=2)=[CH:11][C:10]=1[O:32][CH3:33]
Reactant: O
Reactant: COc1cc2c(cc1F)C(=Cc1ccc(SC)cc1)C(C)=C2CC(=O)O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)=O
Solvent: CO
Product: COc1cc2c(cc1F)C(=Cc1ccc(S(C)=O)cc1)C(C)=C2CC(=O)O
Temperature: 25 °C

Procedure:
A solution of sodium periodate, 4.28 g. (20 mole) in 40 ml. of water is added dropwise to 6-fluoro-5-methoxy-2-methyl-1-(ρ-methylthiobenzylidene)-3-indenyl acetic acid, 3.70 g. (10 mole) in 300 ml. methanol and enough acetone to cause solution. This solution is stirred over night at room temperature and filtered. The filtrate is evaporated at 30° to a small volume which causes the product to precipitate. The suspension is diluted with several volumes of water, cooled and collected. After rinsing with water and cold methanol-water (1:1), the product is dried in vacuo over potassium hydroxide pellets, and then in a vacuum oven at 70° C. The crude product is recrystallized from methylene chloride-petroleum ether to give 6-fluoro-5-methoxy-2-methyl-1-(ρ-methylsulfinylbenzylidene)-3-indenyl acetic acid (M.P. 190°-193°).
Reaction SMILES: Cl.[OH:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.Br[CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([F:17])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:17][C:13]1[CH:12]=[C:11]([CH2:10][N:5]2[CH2:6][CH2:7][CH2:8][C@@H:3]([OH:2])[CH2:4]2)[CH:16]=[CH:15][N:14]=1
Reactant: Fc1cc(CBr)ccn1
Reactant: O[C@@H]1CCCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O[C@@H]1CCCN(Cc2ccnc(F)c2)C1
Yield: 88.8 %

Procedure:
(3R)-3-hydroxypiperidine hydrochloride (0.188 g) was added to a solution of 4-(bromomethyl)-2-fluoropyridine (0.26 g) [see Porter et al, WO 9622978] and potassium carbonate (0.189 g) in acetonitrile (15 ml). The reaction mixture was refluxed for 5 days, after which time the solvent was removed under reduced pressure and the residue partitioned between dichloromethane and water. The organic layer was separated and the aqueous was adjusted to pH 12 and the product extracted with dichloromethane. The combined organic layers were dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent system of 95:5, by volume, chloroform:methanol to afford (3R)-1-[(2-fluoro-4-pyridinyl)methyl]-3-piperidinol (0.255 g) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:25][CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:28])[CH:3]=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[F:44][C:45]1[CH:50]=[CH:49][C:48]([CH2:51][C:52]([N:54]=[C:55]=[S:56])=[O:53])=[CH:47][CH:46]=1.C(#N)C.C(=O)([O-])O.[Na+]>C(O)C.C(OCC)(=O)C>[F:28][C:4]1[CH:3]=[C:2]([NH:1][C:55]([NH:54][C:52](=[O:53])[CH2:51][C:48]2[CH:49]=[CH:50][C:45]([F:44])=[CH:46][CH:47]=2)=[S:56])[CH:27]=[CH:26][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:25][CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: Nc1ccc(Oc2cc(NC(=O)N3CCC(N4CCC4)CC3)ncn2)c(F)c1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC#N
Product: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2cc(NC(=O)N3CCC(N4CCC4)CC3)ncn2)c(F)c1
Reaction time: 0.08 h
Yield: 37.8 %

Procedure:
After adding potassium thiocyanate (65.3 mg) and acetonitrile (4 ml) to 2-(4-fluorophenyl)acetyl chloride (58 mg) under a nitrogen atmosphere, the mixture was stirred for 2 hours at 60° C. The reaction mixture was cooled to room temperature, and then ethyl acetate (30 ml) and saturated aqueous sodium hydrogencarbonate (20 ml) were added to the reaction mixture and stirring was continued for 30 minutes. After partitioning the reaction mixture, the separated organic layer was washed with saturated aqueous sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to provide a crude product of 2-(4-fluorophenyl)acetyl isothiocyanate as a yellow oil. After dissolving 4-(azetidin-1-yl)piperidine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (70 mg) in ethanol (2 ml), D-10-camphorsulfonic acid (43 mg) was added and the mixture was stirred for 5 minutes under a nitrogen atmosphere. Then, 2-(4-fluorophenyl)acetyl isothiocyanate-acetonitrile (0.5 ml×3) was added and the mixture was stirred for 2 hours. Ethyl acetate (30 ml) and saturated aqueous sodium hydrogencarbonate (20 ml) were added to the reaction mixture for partition, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml) and then dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:5), and then fractions containing the target compound were concentrated under reduced pressure. Diethyl ether (0.5 ml) and hexane (4 ml) were added to the resultant residue to produce a suspension of the solid. After filtering the solid, it was subjected to aeration drying to provide the title compound (36.9 mg, 37.8%) as white powder.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[CH:3][CH:2]=1.[C:13]1([S:19]Cl)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Fe].C(Cl)(Cl)(Cl)Cl>[C:13]1([S:19][C:9]2[S:8][C:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:12])=[CH:2][CH:3]=3)=[CH:11][CH:10]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc(-c2cccs2)cc1
Reactant: ClSc1ccccc1
Agent: [Fe]
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(-c2ccc(Sc3ccccc3)s2)cc1
Reaction time: 96 h
Yield: 28.3 %

Procedure:
Into 500 ml of reagent carbon tetrachloride were added 61 g (0.35 mole) of 2-p-tolylthiophene, 41 ml (51 g, 0.35 mole) of benzenesulfenyl chloride and 0.05 g of powdered iron. The reaction mixture was allowed to stand four days at room temperature after which the carbon tetrachloride was distilled off and the 45-gram residue washed with a mixture of 80 ml of ether and 250 ml of petroleum ether. Recrystallization of the washed solid from 300 ml of ethanol gave 28 g (29%) of 2-phenylthio-5-p-tolylthiophene, m.p. 85°-86° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].C([O-])([O-])=[O:19].[Na+].[Na+].OO>C(O)C.CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=[O:19])[NH2:17])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(C#N)c2c1C
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Product: CCOC(=O)c1oc2cccc(C(N)=O)c2c1C

Procedure:
To 213 mg of 4-cyano-3-methyl-benzofuran-2-carboxylic acid ethyl ester (Example 20, Step 2) in 6 mL of ethanol and 6 mL of DMSO was added 3 mL of Na2CO3 (3M), followed by 3 mL of H2O2 (30% in water). After 24 h of reaction, the mixture was worked up to give 4-carbamoyl-3-methyl-benzofuran-2-carboxylic acid ethyl ester in quantitative yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.4 (t, J=7.1 Hz, 3 H) 2.6 (s, 3 H) 4.4 (q, J=7.1 Hz, 2 H) 7.4 (dd, J=7.3, 1.0 Hz, 1 H) 7.5 (dd, J=8.3, 7.3 Hz, 1 H) 7.7 (s, 1 H) 7.8 (m, 1 H) 8.0 (s, 1 H).
Reaction SMILES: [CH3:1][CH:2]1[N:7]([C:8]2[S:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:9]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[ClH:26]>CO>[ClH:26].[CH3:1][CH:2]1[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[C:8]1[S:12][N:11]=[C:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:9]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1c1nc(-c2ccccc2)ns1
Agent: Cl
Solvent: CO
Product: CC1CNCCN1c1nc(-c2ccccc2)ns1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.2 %

Procedure:
To tert-butyl 3-methyl-4-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine-1-carboxylate (6.70 g, 18.6 mmol) was added a solution of 2N hydrogen chloride in methanol (400 ml) and the mixture was stirred at room temperature for 12 hours, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of ether and methanol to obtain the desired product (4.54 g, 82.2%) as a solid.
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH2:8][CH:7]([CH3:11])[C@H:3]1[C:4]([OH:6])=O.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N1CCOCC1)C.[Cl:42][C:43]1[C:48]([C:49]([F:52])([F:51])[F:50])=[CH:47][CH:46]=[CH:45][C:44]=1[CH2:53][NH2:54]>ClCCl.CN(C)C=O>[Cl:42][C:43]1[C:48]([C:49]([F:51])([F:52])[F:50])=[CH:47][CH:46]=[CH:45][C:44]=1[CH2:53][NH:54][C:4](=[O:6])[C@@H:3]1[CH:7]([CH3:11])[CH2:8][C:9](=[O:10])[N:2]1[CH3:1]
Reactant: CC1CC(=O)N(C)[C@@H]1C(=O)O
Reactant: NCc1cccc(C(F)(F)F)c1Cl
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1CC(=O)N(C)[C@@H]1C(=O)NCc1cccc(C(F)(F)F)c1Cl
Reaction time: 8 h
Yield: 48.8 %

Procedure:
1,3-Dimethyl-5-oxoproline (0.620 g, 3.6 mmol, prepared as described below),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.822 g, 4.3 mmol), 1-Hydroxybenzotriazole (0.581 g, 4.3 mmol), N-ethyl morpholine (1.4 ml, 10.8 mmol), and {[2-chloro-3-(trifluoromethyl)phenyl]methyl}amine (0.828 g, 3.96 mmol) were combined in a mixture of dichloromethane (10 ml) and dimethylformamide (5 ml) and stirred under argon overnight. The mixture was then washed sequentially with water (50 ml), 0.5 N aqueous hydrogen chloride (50 ml), water (50 ml), saturated aqueous sodium hydrogen carbonate (50 ml) and water (50 ml). The dichloromethane layer was passed through a hydrophobic frit and evaporated in vacuo to give the crude product. This was further purified by mass-directed automated HPLC (10×0.100 g injections) to give pure N-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-1,3-dimethyl-5-oxoprolinamide (0.613 g).
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([CH:26]2[CH2:28][CH2:27]2)[S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)(=[O:15])=[O:14])[CH2:8][CH2:7]1)=[O:5].N1C=CC=CC=1.Cl[CH2:40][CH2:41][O:42][C:43](Cl)=[O:44]>C(Cl)(Cl)Cl.CCOC(C)=O>[CH:26]1([N:12]([CH:9]2[CH2:10][CH2:11][N:6]([C:4](=[O:5])[C:3]3[CH:29]=[CH:30][CH:31]=[CH:32][C:2]=3[N:1]3[CH2:40][CH2:41][O:42][C:43]3=[O:44])[CH2:7][CH2:8]2)[S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)(=[O:15])=[O:14])[CH2:28][CH2:27]1
Reactant: Nc1ccccc1C(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Reactant: O=C(Cl)OCCCl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(c1ccccc1N1CCOC1=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
N-[1-(2-Amino-benzoyl)-piperidin-4-yl]-N-cyclopropyl-3-trifluoromethyl-benzenesulfonamide (11) (0.170 g, 0.34 mmol) and pyridine (0.035 g, 0.45 mmol) was taken up in 1 ml of CHCl3. Chloroformic acid 2-chloroethyl ester (0.049 g, 0.34 mmol) was added over 5 minutes, and stirred at room temperature for 2 h. The reaction mixture was diluted with 30 ml of EtOAc and washed with 10 ml of H2O. The organic layer was dried over MgSO4 and concentrated to dryness. The crude product was purified through a column of silica gel with a gradient of 70% to 100% EtOAc in hexane to afford the title compound 12 (colorless amorphous, 152 mg, 83%). LC: 100%. MS: m/z=537.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH:36]1([CH2:39]Br)[CH2:38][CH2:37]1>CN(C=O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:14]4=[N:15][CH:16]=3)=[N:7][N:8]2[CH2:39][CH:36]2[CH2:38][CH2:37]2)=[CH:4][CH:3]=1
Reactant: BrCC1CC1
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC4CC4)c4cc(Cl)ccc34)nc12
Temperature: 0 °C
Reaction time: 15 h
Yield: 74.5 %

Procedure:
2-(6-Chloro-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (120 mg, 247 μmol) was dissolved in DMF (1 mL) and cooled to 0° C. Sodium hydride (12.9 mg, 322 μmol) was added. After 30 min cyclopropylmethyl bromide (50.1 mg, 0.0360 mL, 371 μmol) was added and the mixture warmed to room temperature. After 15 h, the mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica, 40 g Analogix column, 20-50% ethyl acetate in hexanes, 15 min gradient) to give 2-(6-chloro-1-(cyclopropylmethyl)-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (99 mg, 184 μmol, 74.2%) as a yellow powder. 1H NMR (CDCl3) δ: 9.27 (s, 1H), 8.43-8.50 (m, 2H), 8.31 (d, J=8.3 Hz, 1H), 7.54 (s, 1H), 7.23 (s, 1H), 5.73 (s, 2H), 4.40-4.56 (m, 1H), 4.35 (d, J=6.8 Hz, 2H), 3.54-3.64 (m, 2H), 1.42 (d, J=6.4 Hz, 7H), 0.89-1.00 (m, 2H), 0.62-0.71 (m, 2H), 0.51 (q, J=4.9 Hz, 2H), −0.07-−0.01 (m, 9H)