Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[CH2:3]1.[NH:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=O>N1CCCCC1.CC(O)C>[O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2/[C:3]/1=[CH:17]/[C:13]1[NH:12][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccc[nH]1
Reactant: N#Cc1cc2c(s1)NC(=O)C2
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: N#Cc1cc2c(s1)NC(=O)/C2=C\c1ccc[nH]1
Temperature: 75 °C
Yield: 20.7 %

Procedure:
5,6-Dihydro-5-oxo-4H-thieno[2,3-b]pyrrole-2-carbonitrile (32 mg, 0.2 mmol) was dissolved in a solution of 1% piperidine in 2-propanol (1 ml). Pyrrole-2-carboxaldehyde (37 mg, 0.39 mmol) was added in one portion and the mixture heated at 75° C. for 1 hour. The reaction mixture was poured into an ice/water mixture (6 ml) and the precipitated solid was collected by filtration and washed with water to give 10 mg of (Z)-5,6-dihydro-5-oxo-4-[(1H-pyrrol-2-yl)methylene]-4H-thieno[2,3-b]pyrrole-2-carbonitrile as a yellow solid. MS(ES): m/e 242 [M+H].
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[OH:21][C:22]([P:34]([O:39][O:40][CH3:41])([O:36][O:37][CH3:38])=[O:35])([P:26]([O:31][O:32][CH3:33])([O:28][O:29][CH3:30])=[O:27])[CH2:23][CH2:24][NH2:25]>>[F:1][C:2]1[C:3]([NH:25][CH2:24][CH2:23][C:22]([OH:21])([P:26]([O:28][O:29][CH3:30])([O:31][O:32][CH3:33])=[O:27])[P:34]([O:36][O:37][CH3:38])([O:39][O:40][CH3:41])=[O:35])=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23
Reactant: COOP(=O)(OOC)C(O)(CCN)P(=O)(OOC)OOC
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Product: COOP(=O)(OOC)C(O)(CCNc1c(F)cc2c(=O)c(C(=O)O)cn3c2c1OCC3C)P(=O)(OOC)OOC

Procedure:
9,10-Difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid, prepared according to the procedure of example 1 of U.S. Pat. No. 4,382,892, is reacted with 3-hydroxy-3,3-bis(dimethoxyphosphono)-1-propylamine and a quantity of base sufficient to neutralize the acid groups of both reactants and the acid formed in the reaction, thus yielding 9-fluoro-3-methyl-10-[3-hydroxy-3,3-bis(dimethoxyphosphono)-1-propylamino]-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de](1,4]benzoxazine-6-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12](O)=[O:13])[C:5]([CH3:19])=[N:4][C:3]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29].C[N:31]1CC[O:34][CH2:33][CH2:32]1.ClC(OCC(C)C)=O.C(CN)O>CC(N(C)C)=O.ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([NH:31][CH2:32][CH2:33][OH:34])=[O:13])[C:5]([CH3:19])=[N:4][C:3]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29]
Reactant: Cc1ccc(C(=O)O)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Cl)c1=O
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: NCCO
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: Cc1ccc(C(=O)NCCO)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Cl)c1=O
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 59.6 %

Procedure:
To a cold solution of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (4.0 g, 9.5 mmol) in anhydrous dimethylacetamide (20 mL, −20° C.) and N-methylmorpholine (1.56 mL, 14.25 mmol) was added a solution of isobutyl chloroformate (1.84 mL, 14.25 mmol) in anhydrous dichloromethane (0.5 mL). The reaction mixture stirred under nitrogen atmosphere at −20° C. for 10 min and then at room temperature for 30 min. At which time it was cooled back down to 0° C. and ethanolamine (0.86 mL, 14.25 mmol) and DMAP (ca.) were added. The reaction mixture stirred for 30 min at 0° C., then at room temperature overnight. The solvent was removed by vacuum distillation and the residue was diluted with acetonitrile/water (1:1 v/v) to be purified by reverse phase HPLC using a 10-90% acetonitrile in water containing 0.5% TFA (30 min) gradient at a 80 mL/min flow rate. The appropriate fractions (M+H m/z=464) were collected, concentrated to a reduced volume, freeze-dried and lyophilized. The resulting white solid was diluted with dichloromethane (30 mL) and washed with 5% NaHCO3 (2×50 mL). The organic extracts were washed with water (2×25 mL) and dried over Na2SO4 (anhydrous). The organic extracts were concentrated under reduced pressure and dried in vacuo to afford the desired product (2.625 g, 59%) as a white solid. 1H-NMR (CD3OD, 400 MHz) δ 7.9 (dd, 1H, J=2 Hz), 7.69 (d, 1H, J=2 Hz), 7.62 (m, 1H), 7.5.5 (d, 1H, J=8.4 Hz), 7.01 (m, 2H), 5.58 (q, 2H, J=12.4 Hz), 3.68 (t, 2H, J=5.6 Hz), 3.46 (t, 2H, J=5.6 Hz), 2.17 (s, 3H), 2.12 (s, 3H); ES-HRMS m/z 464.1153 (M+H C22H21ClF2N3O4 requires 464.1183).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].Br[CH2:21][C:22]([O:24]CC)=[O:23].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([CH2:21][C:22]([OH:24])=[O:23])[C:9]2=[O:13])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: O=C1NCCC1c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)CN1CCC(c2ccc(F)cc2)C1=O
Reaction time: 0.5 h

Procedure:
To a suspension of 3-(4-fluorophenyl)pyrrolidin-2-one (Example 189B, 1.36 g, 7.59 mmol) in tetrahydrofuran was added potassium 2-methylpropan-2-olate (8.35 ml, 8.35 mmol). The reaction was allowed to stir for 30 minutes, during which time a yellow solution resulted. To the reaction was added ethyl 2-bromoacetate (0.92 ml, 8.35 mmol) and stirring was continued at room temperature. After stirring for 3 hours, the reaction was poured into a 1:1 mixture of ethyl acetate/1 N HCl (300 mL). The organic layer was separated, washed with brine (100 mL), dried over magnesium sulfate and concentrated. The residue was dissolved in minimal dichloromethane and loaded onto a GraceResolv 40 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 100% ethyl acetate/hexanes (Flow=40 mL/minute) over 40 minutes. The resulting ethyl ester intermediate was dissolved in methanol (10 mL) and treated with sodium hydroxide (7.59 mL, 15.18 mmol). After stirring for 1 hour, the reaction was poured into a 1:1 mixture of ethyl acetate/1 N HCl (300 mL). The organic layer was washed with brine (100 mL), dried over magnesium sulfate and concentrated to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 12.87 (s, 1H), 7.34-7.26 (m, 2H), 7.20-7.10 (m, 2H), 4.00 (s, 2H), 3.71 (t, J=9.0, 1H), 3.52-3.43 (m, 2H), 2.59-2.35 (m, 1H), 2.07-1.91 (m, 1H).
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[CH3:26][C:27]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:28]=1[CH:29]=O.CC(C)([O-])C.[K+].O>O1CCCC1>[CH3:26][C:27]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:28]=1[CH:29]=[CH:6][CH2:5][C:2]([OH:4])=[O:3]
Reactant: Cc1ccc(C=O)c(C)c1
Reactant: O=C(O)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C=CCC(=O)O)c(C)c1
Reaction time: 0.17 h
Yield: 53.9 %

Procedure:
(2-Carboxyethyl)triphenylphosphonium bromide (150 g, 361 mmol) was suspended in tetrahydrofuran (500 mL) and 2,4-dimethylbenzaldehyde (55.4 mL, 397 mmol) was added thereto. A solution of potassium t-butoxide (81.1 g, 722 mmol) in tetrahydrofuran (300 mL) was added thereto under nitrogen atmosphere over 10 minutes and the mixture was stirred under ice-cooling for 3 hours. Water was added to the reaction mixture to stop the reaction and the temperature of the liquid was returned to room temperature. The mixture was concentrated under reduced pressure, a 8N aqueous sodium hydroxide solution was added thereto to bring pH to 11 and ether was added thereto to separate it. A 12N aqueous hydrochloric acid solution was added to an aqueous phase to bring pH to 2 and ethyl acetate was added thereto to separate it. The thus obtained organic phase was separated, washed with water and a saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate, 10:1-6:1) to obtain 4-(2,4-dimethylphenyl)-3-butenoic acid (37.0 g, yield: 54%). 10% Palladium-carbon (7.96 g, 50% hydrous) was added to a solution of the obtained 4-(2,4-dimethylphenyl)-3-butenoic acid (37.0 g, 195 mmol) in methanol (400 mL) and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. After the palladium-carbon in the reaction mixture was Celite-filtered, the filtrate was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate, 10:1) to obtain the title compound (64.4 g, yield: 84%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[N:9]=[CH:8][C:7]=1[OH:14].Cl.[Br:16][C:17]1[C:22]([CH2:23]Cl)=[CH:21][CH:20]=[CH:19][N:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:16][C:17]1[C:22]([CH2:23][O:14][C:7]2[C:6]([CH:2]3[O:3][CH2:4][CH2:5][O:1]3)=[CH:11][C:10]([O:12][CH3:13])=[N:9][CH:8]=2)=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: COc1cc(C2OCCO2)c(O)cn1
Reactant: ClCc1cccnc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C2OCCO2)c(OCc2cccnc2Br)cn1
Temperature: 70 °C
Yield: 66.8 %

Procedure:
A mixture of 4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-ol (980 mg, 4.97 mmol, 1 eq.), 2-bromo-3-(chloromethyl)pyridine hydrochloride (1.2 g, 4.93 mmol, 1 eq.) and K2CO3 (2.7 g, 19.88 mmol, 4 eq.) in DMF (10.0 mL) was heated at 70° C. for 2 h. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 5-((2-bromopyridin-3-yl)methoxy)-4-(1,3-dioxolan-2-yl)-2-methoxypyridine (1.21 g, 66%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.26 (dd, J=4.7, 1.9 Hz, 1H), 7.83 (dd, J=7.6, 1.9 Hz, 1H), 7.74 (s, 1H), 7.25 (dd, J=7.6, 4.8 Hz, 1H), 6.86 (s, 1H), 6.10 (s, 1H), 5.09 (s, 2H), 4.07-3.93 (m, 4H), 3.82 (s, 3H). LRMS (MAT) m/z 367.0.
Reaction SMILES: CS[C:3](SC)=[C:4]1[C:13](=[O:14])[C:12]([CH3:18])([CH2:15][CH2:16][CH3:17])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:19].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29]([NH2:32])(=[O:31])=[O:30]>C1(C)C=CC=CC=1>[O:31]=[S:29]1(=[O:30])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][C:3]([C:4]2[C:13](=[O:14])[C:12]([CH3:18])([CH2:15][CH2:16][CH3:17])[C:11]3[C:6]([C:5]=2[OH:19])=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:32]1
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: CCCC1(C)C(=O)C(=C(SC)SC)C(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: CCCC1(C)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Yield: 99.3 %

Procedure:
A solution of Example 26F (0.092 g, 0.287 mmol) and 2-amino-benzenesulfonamide (0.052 g, 0.301 mmol) in toluene (7 mL) was refluxed for 6 hours. The solution was cooled to 25° C. and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane followed by 20% and 30% ethyl acetate in hexane to give the desired product (0.113 g, 99%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[CH3:15][C:16]([O:19][C:20]([CH2:22][C@H:23]([NH:36][C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])[C:24](OC1C=CC([N+]([O-])=O)=CC=1)=[O:25])=[O:21])([CH3:18])[CH3:17].C(N(CC)CC)C.C(OCC)(=O)C>CN(C)C=O>[NH:36]([C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])[C@H:23]([C:24]([NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:25])[CH2:22][C:20](=[O:21])[O:19][C:16]([CH3:15])([CH3:18])[CH3:17]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1

Procedure:
3.0 g of phenylalanine methyl ester hydrochloride together with 6.17 g of Z-Asp(OtBu)-ONP are dissolved in 25 ml of absolute N,N-dimethylformamide to give a clear solution and are mixed with 1.93 ml of triethylamine whilst stirring. The deep yellow solution is stirred overnight at room temperature, is then taken up in a large amount of ethyl acetate, and is washed 3 times with dilute aqueous citric acid solution, 5 times with dilute aqueous soda solution and finally with saturated aqueous sodium chloride solution until the wash liquid remains neutral. After drying over sodium sulphate the solution is evaporated and the resulting oil, which is soluble in ether and in chloroform, is purified by column chromatography on silica gel (the substance is eluted with toluene and toluene/ether, 4 : 1); a colourless oily product is obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH3:12])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)[NH2:17]>CN1CCCC1=O>[Cl:13][C:14]1[CH:15]=[C:16]([NH:17][C:2]2[C:3]3[N:10]([CH2:11][CH3:12])[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1
Reactant: CCn1ccc2ncnc(Cl)c21
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Solvent: CN1CCCC1=O
Product: CCn1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c21
Yield: 52.8 %

Procedure:
To a solution of 4-chloro-5-ethyl-5H-pyrrolo[3,2-d]pyrimidine (85 mg) in 1-methyl-2-pyrrolidone (0.94 mL) was added 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (177 mg). The title compound (98 mg) was obtained as a pale-purple powder crystals by the reaction in the same manner as in Example 29.
Reaction SMILES: [CH:1]12[CH2:13][CH:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=31)[CH2:5][CH2:4][NH:3][CH2:2]2.[CH2:14]=O.[OH-].[Na+]>C(O)=O>[CH3:14][N:3]1[CH2:4][CH2:5][CH:6]2[CH2:13][CH:1]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=32)[CH2:2]1
Reactant: C=O
Reactant: c1ccc2c(c1)C1CCNCC2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CN1CCC2CC(C1)c1ccccc12
Yield: 68 %

Procedure:
To a 10 ml round bottom flask were added 1.50 g (0.00867 ) of 1,2,3,4,5,6-hexahydro-1,6-methano-3-benzazocine, 2ml of formic acid and 2 ml of 40% formaldehyde. The mixture was heated at 95-105° for 3 hours, cooled, 60 ml of 15% sodium hydroxide added, and the aqueous layer extracted with four 60-ml portions of methylene chloride. The combined extracts were concentrated in vacuo in the presence of benzene to remove water. The residue, 1.55 g (0.00829 mol), was distilled (90°-115° bath temperature, 0.1 mm) to give colorless 3-methyl-1,2,3,4,5,6-hexahydro-1,6-methano-3-benzazocine (1.1g, 68% yield). The amine was dissolved in ether and hydrogen chloride gas passed into the solution. The white precipitate obtained was filtered and recrystallized from acetone-ether: m.p. 215°-216° (d); m/e 187 (M+ -HCl).
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:10](=[O:18])[CH2:11][C:12]([CH3:17])([CH3:16])[CH2:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:19]O>C(O)(=O)C>[CH2:1]([S:8]([C:9]1[C:14](=[O:15])[CH2:13][C:12]([CH3:16])([CH3:17])[CH2:11][C:10]=1[OH:18])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(=O)C(SCc2ccccc2)=C(O)C1
Reactant: OO
Solvent: CC(=O)O
Product: CC1(C)CC(=O)C(S(=O)Cc2ccccc2)=C(O)C1
Temperature: 0 °C
Reaction time: 22 h

Procedure:
A solution of 10.3 g. (0.0391 mole) of 2-benzylthio-3-hydroxy-5,5-dimethyl-2-cyclohexen-1-one and 4.43 g. (0.0391 mole) of 30 percent hydrogen peroxide in 50 ml. of glacial acetic acid was allowed to stand at room temperature for 22 hours and was then poured into ice water and the mixture extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate, filtered and the solvent removed by evaporation in vacuo, leaving 9.2 g. of amber viscous oil. After some difficulty in inducing crystallization, seed crystals were obtained by an ether solution of a small portion of the oil in a Dry Ice methylene chloride bath. The seed crystals, thus obtained, were used to induce crystallization of the main portion of the oil from ether-hexane to give 7.8 g. of light-pink crystals, m.p. 82°-83°C. A second recrystallization from ether-hexane gave the pure substance as light pink crystals, m.p. 82.5°-83.5°C.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][NH:7][C:8](=[O:38])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:37])[C:29]2([CH2:35]Cl)[CH:34]=[CH:33][CH:32]=[CH:31][NH:30]2)[CH:10]=1.[CH3:44][NH2:45]>ClCCl>[F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][NH:7][C:8](=[O:38])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:37])[C:29]2([CH2:35][NH:45][CH3:44])[CH:34]=[CH:33][CH:32]=[CH:31][NH:30]2)[CH:10]=1
Reactant: CN
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)C2(CCl)C=CC=CN2)c1
Solvent: ClCCl
Product: CNCC1(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)C=CC=CN1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74 %

Procedure:
Into a 10-mL vial, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-(2-(chloromethyl)picolinamido)-5-(piperidin-1-yl)phenyl)isonicotinamide (150 mg, 0.25 mmol, 1.00 equiv) in dichloromethane (5 mL), methylamine (2 mL). The resulting solution was stirred for 48 h at 25° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:10-1:5). The product was obtained as 110 mg (74%) of a yellow solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][CH2:4][O:5][CH2:6][C:7]1[N:12]=[C:11]([NH2:13])[CH:10]=[CH:9][CH:8]=1.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>>[F:29][C:17]([F:16])([F:28])[C:18]1[CH:19]=[C:20]([S:24]([NH:13][C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([CH2:6][O:5][CH2:4][CH2:3][C:2]([F:1])([F:14])[F:15])[N:12]=2)(=[O:25])=[O:26])[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc(COCCC(F)(F)F)n1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: O=S(=O)(Nc1cccc(COCCC(F)(F)F)n1)c1cccc(C(F)(F)F)c1

Procedure:
This material was prepared in analogy to example 1 from 6-(3,3,3-Trifluoro-propoxymethyl)-pyridin-2-ylamine (0.075 g) and 3-(trifluoromethyl)-benzenesulfonyl chloride (0.092 g) as a light yellow gum (0.048 g). MS (ESI−): 427.1 ([M−H]−).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=2)=[CH:7][CH:6]=1)=[O:4]>CO.CC(O)=O.[Zn]>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2ccn(Cc3cccc([N+](=O)[O-])c3)c2c1
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc2ccn(Cc3cccc(N)c3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.3 %

Procedure:
To a solution of 1-(3-nitrobenzyl)-1H-indole-6-carboxylic acid methyl ester (1.3 g, 4.2 mmol) in MeOH (40 mL) and AcOH (3 ml) was added Zinc dust (1.9 g, 29 mmol). After stirring at room temperature for 3 hr, the solids were filtered and the filtrate was diluted with ethyl acetate (150 ml) and washed with sat. NaHCO3 (200 ml). The organic layer was dried (MgSO4), filtered and concentrated to collect 1.24 g (100% yield) of 1-(3-aminobenzyl)-1H-indole-6-carboxylic acid methyl ester. 1H NMR (300 MHz, DMSO) δ 8.02 (s, 1H), 7.64 (m, 3H), 6.92 (t, 1H, J=7.6 Hz), 6.58 (d, 1H, J=3.0 Hz), 6.40 (d, 1H, J=7.6 Hz), 6.27 (m, 2H), 5.36 (s, 2H), 5.07 (s, 2H), 3.81 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]2[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=1.C([Sn](CCCC)(CCCC)[C:44]1[S:48][C:47]([NH:49][C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[N:46][CH:45]=1)CCC>C1(C)C=CC=CC=1.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>[C:34]([O:33][C:32]([NH:31][C@H:26]1[CH2:27][CH2:28][CH2:29][CH2:30][C@H:25]1[NH:24][C:4]1[N:3]=[C:2]([C:44]2[S:48][C:47]([NH:49][C:50](=[O:56])[O:51][C:52]([CH3:54])([CH3:53])[CH3:55])=[N:46][CH:45]=2)[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]=1[F:23])=[O:38])([CH3:35])([CH3:36])[CH3:37]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(NC(=O)OC(C)(C)C)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(-c4cnc(NC(=O)OC(C)(C)C)s4)c3C2=O)c(OC)c1
Yield: 64.7 %

Procedure:
A solution of tert-butyl (1S,2R)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (50 mg, 0.091 mmol), tert-butyl 5-(tributylstannyl)thiazol-2-ylcarbamate (53.5 mg, 0.109 mmol), and tetrakis(triphenylphosphine)palladium(0) (105 mg, 0.091 mmol) in toluene (1 mL) was heated to 102° C. for 24 h. After removal of the solvent, the resulting crude material was reconstituted in MeOH/DMF (6.0 mL) and purified via preparative HPLC eluting with water (0.05% TFA) and ACN (70-75% gradient, 0.035% TFA). The collected fractions were stripped to dryness via rotary evaporation to yield the title compound (42 mg, 64%). [M+H] calc'd for C35H45FN6O7S, 713. found, 713.
Reaction SMILES: CN1CCOCC1.[NH:8]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12].ClC(OCC(C)C)=O.[NH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(N(CC)CC)C.CN(C)C=O>[NH:8]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C@H:9]([C:14]([NH:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[O:16])[CH2:10][CH:11]([CH3:12])[CH3:13]
Reactant: CCOC(=O)CN
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 0.01 h
Yield: 73.1 %

Procedure:
1.86 Milliliters of N-methylmorpholine was dissolved in 60 ml of tetrahydrofuran and to this solution 4.85 g of Z-Leu-OH was added. The mixture was cooled to -15° C. and 2.41 ml of isobutyl chloroformate was added and then vigorously stirred for 30 seconds. To this reaction mixture, 40 ml of a dimethylformamide solution containing 2.54 g of H-Gly-OC2H5, and 2.56 ml of triethylamine were added and stirred for 1 minute. After the reaction mixture was warmed at 0° C. for 5 minutes, then at 40° C. for 2 minutes and was stirred at a room temperature for 15 minutes. Tetrahydrofuran and dimethylformamide were removed by distillation to obtain the residue, then 1M-citric acid was added to this residue and the crystals thus formed were collected by filtration. The crystals were washed with water until the filtrate become neutral, and the crystals were dried, reprecipitated from ethyl acetate-ether to obtain 4.68 g of Z-Leu-Gly-OC2H5.