Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].CCN(C(C)C)C(C)C.[C:27]([CH:30]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@@H:31]1C(O)=O)(O)=[O:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:27]([CH:30]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31]3)=[O:28])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
To a stirred solution of N-(3,4-dichlorophenyl)piperazine-1-carboxamide (2.00 g, 7.30 mmol) in DMF (150 ml) was added DIPEA (3.8 ml, 21.9 mmol), 3-carboxy-N-boc-proline (Arch Corporation) (1.727 g, 8.02 mmol) and HATU (3.051 g, 8.02 mmol) and the reaction stirred at ambient temperature for overnight (convenience). The solvents were then removed under reduced pressure. The resulting gum was then partitioned between EtOAc and water, extracted, the organic phase washed with saturated sodium bicarbonate solution and evaporated to dryness. The resulting foam was then purified on Isco™ Companion (40 g column. EtOAc) to give the product tert-butyl 3-[(4-{[(3,4-dichlorophenyl)amino]carbonyl}piperazin-1-yl)carbonyl]pyrrolidine-1-carboxylate as a pale yellow foam (3.396 g, 7.20 mmol, 99%).
Reaction SMILES: CC(O[C:5]1[C:9](=[O:10])[C:7](=[O:8])[C:6]=1[O:11][CH:12]([CH3:14])[CH3:13])C.[Sn:15]([Si](C)(C)C)([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19]>O1CCCC1>[CH3:14][CH:12]([O:11][C:6]1[C:7](=[O:8])[C:9](=[O:10])[C:5]=1[Sn:15]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:16][CH2:17][CH2:18][CH3:19])[CH3:13]
Reactant: CC(C)Oc1c(OC(C)C)c(=O)c1=O
Reactant: CCCC[Sn](CCCC)(CCCC)[Si](C)(C)C
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1c(OC(C)C)c(=O)c1=O
Reaction time: 2 h
Yield: 67 %

Procedure:
A solution of 0.052M n-Bu4N+CN- in tetrahydrofuran (7.69 mL, 0.4 mmol) was added dropwise to a stirred solution at -20° C. of diisopropyl squarate (3.96 g, 0.020 mol) and n-Bu3SnSi(CH3)3 (7.27 g, 0.020 mol) in tetrahydrofuran (154 mL). Stirring was continued at -20° C. for 2 hrs. The solution was concentrated and the residue chromatographed on SiO2 with diethyl ether-hexane (10:90) to afford the title compound (5.75 g, 67% yield) as a yellow oil.
Reaction SMILES: O1CCCC1.[CH3:6][O:7][C:8](=[O:24])[C@H:9]([CH:21]([CH3:23])C)[NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].C(Br)[C:26]1[CH:31]=[CH:30]C=[CH:28][CH:27]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[CH3:6][O:7][C:8](=[O:24])[C@H:9]([CH2:21][C:23]1[CH:30]=[CH:31][CH:26]=[CH:27][CH:28]=1)[NH:10][C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12]
Reactant: BrCc1ccccc1
Reactant: COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a tetrahydrofuran solution (1 ml) of the compound prepared in Example 6 (174 mg, 0.5 mmol), were succcessively added dropwise at 0° C. in a nitrogen atmosphere benzyl bromide (0.119 ml, 1.0 mmol) and a tetrahydrofuran solution of tetrabutyl ammonium fluoride (0.5 ml, 0.5 mmol). After the mixture was stirred for 1 hour at 0° C., it was poured into water and extracted with ether. The ether layer was dried over anhydrous magnesium sulfate and concentrated under vacuum. The resulting reaction mixture was subjected to column chromatography on silica gel and eluted with a 3:7 mixture of ether and hexane to give the titled compound in an amount of 122 mg (yield, 78% based on the starting materials used in Example 6)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-])=O)(=[O:14])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[Sn]Cl.CCCCCC.CCOC(C)=O>C(O)C>[NH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([NH:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:14])=[O:13]
Reactant: COc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1OC
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: COc1ccc(NS(=O)(=O)c2ccccc2N)cc1OC
Yield: 87.8 %

Procedure:
A mixture of N-(3,4-dimethoxyphenyl)-2-nitrobenzenesulfonamide (2.5 g, 7.39 mmol) and SnCl2 (8.34 g, 36.9 mmol) in ethanol was heated at 100° C. for 5 h in a sealed tube with TLC monitoring (hexane:EtOAc, 1:1). After concentration in vacuo H2O (30 mL) was added and the mixture was extracted with EtOAc (3×100 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification by gradient flash chromatography, eluting with 20-25% EtOAc in hexane yielded the title compound (2.0 g, 6.49 mmol).
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:12](Cl)(=[O:16])[O:13][CH2:14][Cl:15].C(OCC)C>ClCCl>[C:12](=[O:16])([O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1)[O:13][CH2:14][Cl:15]
Reactant: O=C(Cl)OCCl
Reactant: OCC1CC1
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(OCCl)OCC1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
To a solution of cyclopropylmethanol (0.39 ml, 5.0 mmol) and pyridine (0.40 ml, 5.0 mmol) in dichloromethane (4 ml), at 0° C. and under nitrogen, was added drop wise chloromethyl chlorocarbonate (0.40 ml, 4.5 mmol). The reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 2 h. To the mixture was added diethyl ether (15 ml) and the solid material was collected by filtration and washed with diethyl ether (10 ml). The combined organic phases were dried (MgSO4) and concentrated in vacuo to give the title compound (725 mg) which was used directly.
Reaction SMILES: [CH2:1]([N:3]([CH3:25])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([OH:22])=[C:17]([CH3:23])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:24])[N:5]=1)[CH3:2].Cl[CH2:27][C@H:28]([OH:31])[CH2:29][OH:30]>C(O)(C)C.[OH-].[Na+].CC(=O)OCC>[CH2:1]([N:3]([CH3:25])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH2:27][C@H:28]([OH:31])[CH2:29][OH:30])=[C:17]([CH3:23])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:24])[N:5]=1)[CH3:2]
Reactant: CCN(C)c1cc(-c2nc(-c3cc(C)c(O)c(C)c3)no2)cc(C)n1
Reactant: OC[C@@H](O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCN(C)c1cc(-c2nc(-c3cc(C)c(OC[C@H](O)CO)c(C)c3)no2)cc(C)n1
Yield: 37.2 %

Procedure:
To a solution of 4-{5-[2-(ethyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-2,6-dimethyl-phenol (55 mg, 0.163 mmol) in isopropanol (3 mL) and 3 N aq. NaOH (0.5 mL), (R)-3-chloro-1,2-propanediol (98 mg, 0.894 mmol) is added. The mixture is stirred at 65° C. for 72 h before another portion of (R)-3-chloro-1,2-propanediol (98 mg, 0.894 mmol) is added. Stirring is continued at 65° C. for 4 days before a third portion of (R)-3-chloro-1,2-propanediol (98 mg, 0.894 mmol) is added. After stirring for another 48 h, the mixture is diluted with EA (50 mL) and washed with 1 N aq. NaOH (10 mL) followed by brine (10 mL), dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates with DCM containing 10% of 7 N NH3 in methanol and 5% of methanol to give (R)-3-(4-{5-[2-(ethyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-2,6-dimethyl-phenoxy)-propane-1,2-diol (25 mg) as a yellow solid; LC-MS: tR=0.73 min; [M+1]+=413.14.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[CH3:12][C:13]([O:16][C:17](ON=C(C1C=CC=CC=1)C#N)=[O:18])([CH3:15])[CH3:14].C(N(CC)CC)C>O.CC(C)=O>[C:13]([O:16][C:17]([C:4]1[C:3]([CH2:2][NH2:1])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])=[O:18])([CH3:15])([CH3:14])[CH3:12]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NCc1cccc(C(=O)O)c1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1c(CN)cccc1C(=O)O
Yield: 64.2 %

Procedure:
The title compound was prepared according to a modification of standard procedures previously reported in the literature (Itoh, Hagiwara, and Kamiya (1975) Tett. Lett., 4393). 3-Aminomethylbenzoic acid (hydrochloride salt) (3.0 g, 16.0 mmol) was dissolved in 60 ml H2O. To this was added a solution of Boc-ON (4.33 g, 17.6 mmol) in 60 ml acetone followed by triethylamine (5.56 ml, 39.9 mmol). The solution turned yellow and the pH was adjusted to 9 (wet pH paper) by adding an additional 1.0 ml (7.2 mmol) triethylamine. The solution was stirred overnight at room temperature at which time the acetone was removed under reduced pressure and the remaining aqueous layer was washed three times with ether. The aqueous layer was then acidified to pH 2 with 2N HCl and then extracted three times with ethyl acetate. The combined organic layers were washed three times with H2O, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure. The material was recrystallized from ethyl acetate/ hexane to give two crops of the title compound (2.58 g, 64%) as an off-white solid. mp 123-125° C.;
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.Cl.[CH2:23]([NH2:26])[CH2:24][CH3:25]>CO.C(Cl)Cl>[C:16]1([S:15][C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([CH2:1][NH:26][CH2:23][CH2:24][CH3:25])[CH:4]=3)[NH:8][C:7]=2[C:12]([NH2:14])=[O:13])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Reactant: CCCN
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCCNCc1ccc2[nH]c(C(N)=O)c(Sc3ccccc3)c2c1

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (80 mg, 0.27 mmol) with propylamine hydrochloride (28 mg, 0.30 mmol) as described in General Procedure X to afford Iae (41.0 mg, 44.8%) as an ivory colored solid, tlc Rf=0.1 (10% MeOH/CH2Cl2−0.2% Et3N), m/z obs=340 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CCN(CC)CC.[NH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[NH2:28][CH:29]1[C:38]2[N:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH2:32][CH2:31][CH2:30]1>C(Cl)Cl>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][NH:20][S:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:28][CH:29]2[C:38]3[N:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH2:32][CH2:31][CH2:30]2)=[CH:4][CH:5]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Reactant: NC1CCCc2cccnc21
Reactant: NCc1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NCc1ccccn1)c1ccc(CNC2CCCc3cccnc32)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 4-bromomethyl-benzenesulfonyl chloride (500 mg, 1.85 mmol) and Et3N (269 uL, 1.85 mmol) in CH2Cl2 (10 mL), at −78° C., was added aminomethyl pyridine (190 uL, 1.85 mmol) in one portion. The resultant solution was stirred at −78° C. for 20 minutes. A second portion of Et3N (269 uL, 1.85 mmol) was added, followed by addition of 8-amino-5,6,7,8-tetrahydroquinoline (274 mg, 1.85 mmol). The solution was stirred for 18 h at room temperature. The mixture was diluted with CH2Cl2 (100 mL/mmol), filtered through celite, and concentrated. The crude material was purified by chromatography on silica gel (CH2Cl2/MeOH/NH4OH 48:1:1) to give AMD9367 (150 mg, 20%) as a white foam. 1H NMR (300 MHz, CD3COCD3) δ 1.69-1.98 (m, 2H), 2.00-2.05 (m, 1H), 2.11-2.18 (m, 1H), 2.71-2.85 (m, 3H), 3.82 (m, 1H), 3.96 (d, 2H, J=6.0 Hz), 4.23 (br s, 2H), 6.10 (br s, 1H), 7.05-7.15 (m, 3 H), 7.38 (d, 1H, J=7.8 Hz), 7.49 (d, 2H, J=9.0 Hz), 7.55-7.58 (m, 1H), 7.79 (d, 2H, J=9.0 Hz), 8.39 (d, 1H, J=4.8 Hz), 8.44 (d, 1H, J=4.5 Hz), 13C NMR (75.5 MHz, CD3COCD3) δ 20.05, 29.14, 29.20, 47.79, 51.70, 58.09, 122.39, 123.01, 127.68, 129.07, 132.90, 137.17, 137.40, 138.24, 146.62, 147.24, 149.38, 155.21, 157.54. ES-MS m/z 409 (M+H). Anal. Calcd. for C22H24N4O2S.0.2H2O: C, 64.12; H, 5.97; N, 13.59. Found: C, 64.10; H, 5.91; N, 13.71.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl.[O:10]=[C:11](Cl)OC(Cl)(Cl)Cl.[CH:18]1([C:24]2[CH:29]=[CH:28][C:27]([NH:30][CH2:31][C:32]3[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=3)=[CH:26][CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(OCC)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:11](=[O:10])[N:30]([CH2:31][C:32]2[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=2)[C:27]2[CH:28]=[CH:29][C:24]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)=[CH:25][CH:26]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: O=C(O)c1ccc(CNc2ccc(C3CCCCC3)cc2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(CN(C(=O)Nc2cccc(Br)c2)c2ccc(C3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.7 %

Procedure:
3-Bromoaniline (1.4 g, 8.1 mmol) was dissolved in diethyl ether (50 mL) and 3.5 M dry HCl in ethyl acetate (2.3 mL) was added. The mixture was concentrated in vacuo. The residue was added toluene (100 mL) and concentrated in vacuo. The residue was added toluene (100 mL) and diphosgene (8.1 g, 41 mmol) and the resulting mixture was refluxed for 1.5 hour. After cooling, the mixture was concentrated in vacuo. The residue was dissolved in toluene (100 mL) and concentrated in vacuo. The residue was dissolved in DMF (30 mL) and 4-[(4-cyclohexylphenylamino)methyl]benzoic acid (1.3 g, 4.1 mmol) was added. The mixture was stirred at room temperature for 16 hours. The mixture was added ethyl acetate (150 mL) and washed with water:brine (1:1) (2×100 mL). The organic phase was dried with sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting first with a mixture of ethyl acetate:n-heptane:triethylamine (7:2:1), then with ethyl acetate and finally with methanol to afford 1.95 g (94%) of 4-[3-(3-bromophenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoic acid.
Reaction SMILES: O.[OH-].[Li+].[O:4]=[S:5]1(=[O:25])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:8]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=2)[CH2:7][CH2:6]1>O.C1COCC1.CO>[O:4]=[S:5]1(=[O:25])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:8]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=2)[CH2:7][CH2:6]1
Reactant: COC(=O)c1ccc(C2CCS(=O)(=O)c3ccccc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(C2CCS(=O)(=O)c3ccccc32)cc1
Yield: 98 %

Procedure:
Lithium hydroxide hydrate (0.195 g, 4.65 mmol) dissolved in water (1 mL) was added to a solution of methyl 4-(1,1-dioxido-3,4-dihydro-2H-1-benzothiopyran-4-yl)benzoate from reaction 33d (0.49 gm, 1.55 mmol) in THF (5 mL) and methanol (1 mL) under nitrogen atmosphere at room temperature. The reaction was stirred over night, concentrated then partitioned between 1 N HCl and ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate and concentrated to give 4-(1,1-dioxido-3,4-dihydro-2H-1-benzothiopyran-4-yl)benzoic acid (0.46 g, 98%) as an solid. MS found: (M−H)+=301.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=2[CH3:18])[CH2:7][CH2:6]1)=[O:4].[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][C:27]=2[OH:36])[CH2:22][CH2:21]1.[C:37](=[O:40])([O-:39])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[C:27]([OH:36])(=[O:4])/[CH:28]=[CH:29]/[C:37]([OH:39])=[O:40].[CH3:19][N:20]1[CH2:21][CH2:22][N:23]([C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][C:27]=2[O:36][CH2:2][C:3]([N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=3[CH3:18])[CH2:7][CH2:6]2)=[O:4])[CH2:24][CH2:25]1
Reactant: CN1CCN(c2c(O)ccc3ccccc23)CC1
Reactant: Cc1cccc(N2CCN(C(=O)CCl)CC2)c1C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(N2CCN(C(=O)COc3ccc4ccccc4c3N3CCN(C)CC3)CC2)c1C
Product: O=C(O)/C=C/C(=O)O

Procedure:
Compound 36A (477 mg, 1.79 mmol) and compound 38A (370 mg; 1.52 mmol) are stirred at room temperature under a nitrogen atmosphere in dimethylformamide (15 ml) in the presence of cesium carbonate (1.25 g, 3.82 mmol) for 12 h. The reaction mixture is then diluted with water and extracted three times with ethyl acetate. The organic phases are combined and washed three times with saturated sodium chloride solution and then dried over magnesium sulfate and concentrated. The crude reaction product is purified by flash chromatography with a mixture (90/9/1) of dichloromethane/methanol/aqueous ammonia.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])(=[O:11])=[O:10])=[C:4]([C:21]([F:24])([F:23])[F:22])[CH:3]=1.Cl.[CH2:26]([O:28][C:29](=[O:33])[C@H:30]([CH3:32])[NH2:31])[CH3:27].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:26]([O:28][C:29](=[O:33])[CH:30]([NH:31][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[S:9](=[O:11])(=[O:10])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:21]([F:22])([F:23])[F:24])[CH3:32])[CH3:27]
Reactant: O=C(O)c1ccccc1S(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Reactant: CCOC(=O)[C@H](C)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)NC(=O)c1ccccc1S(=O)(=O)Nc1ccc(F)cc1C(F)(F)F

Procedure:
Under the conditions of Example 2(a), 3.633 g (10 mmol) of 2-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]benzoic acid, 1.536 g (10 mmol) of L-alanine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: Cl.[S:2]([N:12]1[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH2:22])[N:20]=[C:15]2[CH:14]=[CH:13]1)([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:23](N1C=CN=C1)(N1C=CN=C1)=[S:24].[NH:35]1[CH2:39][CH2:38][CH:37]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:36]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[S:2]([N:12]1[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH:22][C:23]([N:35]3[CH2:39][CH2:38][CH:37]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:44])([CH3:46])[CH3:45])[CH2:36]3)=[S:24])[N:20]=[C:15]2[CH:14]=[CH:13]1)([C:5]1[CH:6]=[CH:7][C:8]([CH3:9])=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CN)cnc32)cc1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=S)N4CCC(NC(=O)OC(C)(C)C)C4)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
To a slurry of (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride (0.50 g, 1.5 mmol, Example #5, Step C) in DCM (10 mL) at about 0° C. was added TEA (0.226 mL, 1.62 mmol). To the homogeneous reaction mixture was added a solution of 1,1′-thiocarbonyldiimidazole (0.29 g, 1.6 mmol) in DCM (10 mL). After about 30 min, a slurry of tert-butyl pyrrolidin-3-ylcarbamate (0.83 g, 4.4 mmol, TCI) in DCM (10 mL) was added to the reaction mixture. After stirring for about 20 min, the reaction mixture was allowed to warm to ambient temperature. After stirring for about 15 h, saturated aqueous NaHCO3 (30 mL) was added to the reaction mixture. The organic layer was separated, concd in vacuo, and purified by chromatography on silica gel eluting with 20-40% EtOAc in DCM to provide tert-butyl 1-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)pyrrolidin-3-ylcarbamate (0.54 g, 69%) as a yellow glass: LC/MS (Table 1, Method a) Rt=2.37 min; MS m/z: 531 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[O:7][C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:22]([O:29][NH2:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C>[CH2:22]([O:29][N:30]1[C:6]([C:13]([OH:15])=[O:14])=[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[C:8]1=[O:7])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)c1oc(=O)c2ccc(Cl)cc2c1-c1ccccc1
Solvent: CCO
Product: O=C(O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1OCc1ccccc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 88.9 %

Procedure:
A mixture of 6-chloro-1-oxo-4-phenyl-1H-isochromen-3-carboxylic acid (300 mg), O-benzylhydroxylamine (620 mg) and ethanol (6.0 ml) was stirred at 90° C. for 12 hrs. in a sealed tube. After cooling, the reaction mixture was concentrated under reduced pressure and the residue was washed with ethyl acetate/diethyl ether=1/10 to give the title compound (360 mg) as a colorless powder.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:39])[N:9]([CH3:38])[CH:10]([CH3:37])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[C:16]([C:29]#[C:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:15]=1)=[O:12])([CH3:6])([CH3:5])[CH3:4].[CH3:40]OS(OC)(=O)=O>C1COCC1>[C:3]([O:7][C:8](=[O:39])[N:9]([CH3:38])[CH:10]([CH3:37])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]([CH3:40])[C:21]([CH:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[O:22])=[C:16]([C:29]#[C:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:15]=1)=[O:12])([CH3:5])([CH3:6])[CH3:4]
Reactant: COS(=O)(=O)OC
Reactant: CC(C(=O)Nc1ccc(NC(=O)C2CCOCC2)c(C#Cc2ccccc2)n1)N(C)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C(=O)Nc1ccc(N(C)C(=O)C2CCOCC2)c(C#Cc2ccccc2)n1)N(C)C(=O)OC(C)(C)C
Reaction time: 0.33 h

Procedure:
At RT NaH (60% dispersion in mineral oil, 2.3 mg, 0.0.06 mmol) is added to tert-butyl-N-methyl-N-[1-[[5-(oxane-4-carbonylamino)-6-(2-phenylethynyl)pyridin-2-yl]amino]-1-oxopropan-2-yl]carbamate E5b (35 mg, 0.04 mmol) in THF (1 ml). After stirring for 10 minutes dimethylsulfate (4 μl, 0.06 mmol) is added to the mixture and stirring continued for 20 minutes. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 5 mg (23%). HPLC-MS: M+H=521; tR=2.06 min (*Method—2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:24][CH:23]=1.C(N(CC)CC)C.[I-].C[N+]1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C@H:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][CH:27]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCCC[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=O)O
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCC[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=O)Nc1ccc(CC(=O)OCC)cc1
Yield: 87 %

Procedure:
The procedure described in Example 177 was repeated, except that (R)-2-(4-chlorobenzenesulfonylamino)hexanoic acid (3 g) and ethyl 4-aminophenylacetate hydrochloride (1.9 g) were condensed in chloroform (100 ml) in the presence of triethylamine (5.4 ml) and 1-methyl-2-chloropyridinium iodide (3.01 g) to obtain as a colorless oily substance (R)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)hexanamide (3.58 g).