Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[C:12]([OH:19])[C:9]=2[C:10]=1[CH3:11])=[O:5])C.CCN=C=NCCCN(C)C.[CH3:31][O:32][C:33](=[O:55])[C@@H:34]([NH:38][S:39]([C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([NH2:54])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1)(=[O:41])=[O:40])[CH:35]([CH3:37])[CH3:36].CN(C=O)C>[Cl-].[Na+].O>[CH3:31][O:32][C:33](=[O:55])[C@@H:34]([NH:38][S:39]([C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:49]=[CH:50][C:51]([NH:54][C:4]([C:6]3[O:7][C:8]4[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[C:12]([OH:19])[C:9]=4[C:10]=3[CH3:11])=[O:5])=[CH:52][CH:53]=2)=[CH:44][CH:43]=1)(=[O:41])=[O:40])[CH:35]([CH3:37])[CH3:36]
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(C)C
Reactant: CCOC(=O)c1oc2ccc(C(C)=O)c(O)c2c1C
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4ccc(C(C)=O)c(O)c4c3C)cc2)cc1)C(C)C
Temperature: 65 °C
Reaction time: 8 h
Yield: 11.5 %

Procedure:
To 70 mg (0.3 mmol) of 5-acetyl-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester was added 115 mg (2 eq) EDCI, 109 mg (1 eq) of (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester and 2 mL of DMF. The mixture was stirred at 65° C. overnight. The reaction mixture was poured into brine, and extracted with dichloromethane. The organic solution was washed with 2N HCl and water. Removal of the solvents under vacuum gave crude product, which was purified by column chromatography on silica gel to give 20 mg (10% yield) of (S)-2-{4′-[(5-acetyl-4-hydroxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid methyl ester as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([O:23]CC)=O)[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:27][S:28][CH2:29][CH2:30][CH2:31][NH2:32]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([NH:32][CH2:31][CH2:30][CH2:29][S:28][CH3:27])=[O:23])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CSCCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Product: CSCCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Yield: 43 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (30 mg, 0.084 mmol) described in example 92 and [3-(methylthio)propyl]amine (0.02 mL, 0.589 mmol) was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-N-[3-(methylthio)propyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (15 mg, 43% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.25 (br s, 1 H), 8.57 (s, 1 H), 7.39 (s, 1 H), 7.18-7.14 (m, 2 H), 7.05-7.00 (m, 2 H), 4.14 (s, 2 H), 3.59-3.54 (m, 5 H), 2.59 (m, 2 H), 2.12 (s, 3 H), 1.95 (m, 2 H); HRMS m/z calcd for C21H23FN3O3S: 416.1438. Found: 416.1447.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][N:5]([CH3:30])[C:6]([C:8]1[C:13]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])=[CH:12][C:11]([Cl:29])=[CH:10][N:9]=1)=[O:7].[CH3:31][O:32][CH2:33]Cl>C1COCC1>[CH3:3][O:4][N:5]([CH3:30])[C:6]([C:8]1[C:13]([N:14]([CH2:31][O:32][CH3:33])[S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:16])=[O:17])=[CH:12][C:11]([Cl:29])=[CH:10][N:9]=1)=[O:7]
Reactant: COCCl
Reactant: CON(C)C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)N(C)OC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
To a suspension of sodium hydride (314 mg, 7.86 mmol) in 8 mL of THF was added a mixture of 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid methoxy-methyl-amide (3.0 g, 6.55 mmol) and chloromethyl methyl ether (0.741 mL, 9.825 mmol) in 8 mL of THF. The mixture was stirred at room temperature overnight. After the removal of the solvents the residue was purified by flash column (20% ethyl acetate in hexane) to afford 2.70 grams of the title compound as a white solid. (M+H)+ expect 502.0, found 502.0.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]2[CH2:16][CH2:15][S:14](=[O:17])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[C:6]([OH:18])[C:5]([N+:19]([O-])=O)=[CH:4][CH:3]=1.[H][H]>[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:19])=[C:6]([OH:18])[C:7]=1[S:8]([N:11]1[CH2:12][CH2:13][S:14](=[O:17])[CH2:15][CH2:16]1)(=[O:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)N2CCS(=O)CC2)c1O
Reactant: [H][H]
Agent: [Pd]
Product: Nc1ccc(Cl)c(S(=O)(=O)N2CCS(=O)CC2)c1O
Yield: 94.5 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, 6-chloro-2-hydroxy-3-nitro- 1-(1-oxidothiomorpholinosulfonyl)benzene (103 mg, 0.29mmol) was reduced with hydrogen and 10% Pd/C (59 mg) to form the desired product (89 mg, 95%). LC-MS (m/z) 325.0 (M+).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:12])=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:13][CH:14]1OC(C)OC(C)O1>>[CH3:12][C:4]1[NH:3][C:2]([CH3:1])=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]=1[CH2:13][CH3:14]
Reactant: CCOC(=O)c1cc(C)[nH]c1C
Reactant: CC1OC(C)OC(C)O1
Product: CCOC(=O)c1c(C)[nH]c(C)c1CC

Procedure:
As in Example 32 but using 2,5-dimethyl-3-carbethoxy-pyrrole and paraldehyde. Colourless crystals (75%), m.p. 105°-107° (lit18) 106°-107°). Anal. Calc. for C11H17NO2 : C, 67.66; H, 8.78; N, 7.17. Found: C, 67.54; H, 8.69; N, 7.28.
Reaction SMILES: [CH2:1]([CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])[CH3:2].C([O-])(=O)C.[Na+].[Br:18]Br>C(O)(=O)C.O>[Br:18][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4](=[O:12])[CH:3]2[CH2:1][CH3:2]
Reactant: CCC1C(=O)Nc2ccccc21
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCC1C(=O)Nc2ccc(Br)cc21

Procedure:
A solution of 3-ethyloxindole (6.0 g, 40 mmol) and sodium acetate (4 g, 48 mmol) in acetic acid (100 ml) was treated with bromine (6.4 g, 40 mmol). After 30 min. the mixture was diluted with water and extracted with EtOAc (2×); the combined organic layers were washed with water, sat. sodium hydrogen carbonate solution, and brine, dried (MgSO4) and evaporated to afford the crude product (9.2 g, 96%). A sample was recrystallized from EtOAc/hexane to obtain the subtitled compound, m.p. 130-132° C.; 1H-NMR (DMSO-d6) δ 0.74 (t, 3H, J=7.5 Hz), 1.8-2.0 (m, 2H), 3.45 (t, 1H, J=5.5 Hz,), 6.76 (d, 1H, J=8.35 Hz), 7.42 (m, 1H), 10.43 (s, 1H); MS (−ESI) m/z 238/240 (M−H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[C:3]=1[CH3:19].[Li]CCCC.[CH:25](=[O:28])[CH2:26][CH3:27]>C1COCC1>[CH3:19][C:3]1[C:4]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])=[N:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH:25]([OH:28])[CH2:26][CH3:27]
Reactant: Cc1cc(C)c(Oc2nc(C)cc(Br)c2C)c(C)c1
Reactant: CCC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(O)c1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C
Reaction time: 0.33 h

Procedure:
To a −78° C. solution of 4-bromo-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine in dry THF was added nBuLi and stirred at that temperature for 20 minutes. Excess propionaldehyde was added and stirred for 2 hours at −78° C. The mixture was quenched with water, extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated. After column chromatography, an off-white solid was obtained, mp. 119–120° C. 1H NMR(CDCl3) d 6.86(s,3H), 4.90(m,1H), 2.281(s,3H), 2.28(s,3H), 2.21(s,3H), 2.02(s,6H), 1.65–1.8(m,2H), 1.00(t,3H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=S)=[CH:4][CH:3]=1.[NH2:18][NH2:19]>C(O)C.O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[N:18][NH2:19])=[CH:4][CH:3]=1
Reactant: NN
Reactant: Fc1ccccc1C(=S)Nc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: NN=C(Nc1ccc(Br)cc1)c1ccccc1F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
N1-(4-bromophenyl)-2-fluoro-1-benzenecarbothioamide (1.50 g, 0.00485 mol) and a 1 M solution of hydrazine in tetrahydrofuran (6.3 mL, 0.0063 mol) were heated in absolute ethanol (25 mL) at reflux under nitrogen atmosphere for 14 hours. Additional 3 mL of a 1M solution of hydrazine in tetrahydrofuran was added and the stirring at reflux was continued for another 6 hours. The reaction mixture was cooled to ambient temperature, the solvent was removed under reduced pressure and the residue partitioned between saturated solution of sodium bicarbonate in water (50 mL) and ethyl acetate (50 mL). The organic phase was washed with brine, dried with magnesium sulfate and concentrated to yield N1-(4-bromophenyl)-2-fluoro-1-benzenecarbohydrazonamide (1.54 g, 0.0050 mol) as a tan solid. TLC (ethyl acetate/heptane 1:3) Rf 0.10.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]2[CH2:10][O:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:11][C:12]([CH3:17])([CH3:16])[CH2:13][CH2:14][OH:15]>CN(C=O)C.[H-].[Na+]>[CH:1]1([CH2:7][C@H:8]([OH:9])[CH2:10][O:15][CH2:14][CH2:13][C:12]([CH3:17])([CH3:16])[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCC(C[C@H]2CO2)CC1
Reactant: CC(C)(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)CCOC[C@@H](O)CC1CCCCC1
Yield: 61 %

Procedure:
The product from Example 1308C (435 mg, 3.1 mmol) in DMF (2.0 mL), 3,3-dimethylbutanol (400 μL, 3.3 mmol) in DMF (3.0 mL) and NaH, 60% dispersion in mineral oil, (145 mg, 3.6 mmol) in DMF (7.0 mL) were allowed to react in a manner similar to that described in Example 1308D. The residue was chromatographed (silica gel; EtOAc/hexanes, 1:20) to afford a light yellow oil (458 mg, 57%). 1H NMR (CDCl13, 300 MHz) δ0.78-1.01 (m, 2H), 0.92 (s, 9H), 1.11-1.57 (m, 8H), 1.62-1.85 (m, 5H), 3.21 (dd, J=8, 9 Hz, 1H), 3.40-3.66 (m, 3H), 3.89 (m, 1H); MS (CI/NH3) m/z: (M+NH4)+ 260.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH2:4][CH2:3]1.II.S(Cl)([Cl:18])(=O)=O.O>C(O)(=O)C>[Cl:18][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH3:12])([CH3:1])[CH2:3][CH2:4]2)=[CH:9][C:8]=1[OH:11]
Reactant: CC1(C)CCc2ccc(O)cc21
Reactant: O=S(=O)(Cl)Cl
Agent: II
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)CCc2cc(Cl)c(O)cc21
Temperature: 50 °C
Yield: 55 %

Procedure:
81 g of 3,3-dimethyl-5-hydroxy-indane were dissolved in 162 g of glacial acetic acid. After adding a few grains of iodine, 68 g of sulfuryl chloride were added dropwise over the course of about 1 hour at 40°-45° C. The mixture was then warmed to 50° C for 2 hours. The reaction solution was poured into about 1.5 liters of water. The oil which separated out was taken up in chloroform and separated off. The aqueous phase was repeatedly extracted with chloroform. The combined organic phases were washed until neutral, and concentrated. Fractional distillation gave 54 g of 6-chloro-3,3-dimethyl-5-hydroxy-indane; boiling point 134°-36° C/12 mm Hg. ##STR31##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]C)=O)=[C:10](/[N:17]=[CH:18]/[N:19]([CH3:21])C)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:30]2[N:35]=[C:34](CN)[CH:33]=[CH:32][CH:31]=2)[CH2:25][CH2:24]1.C1(O)C=CC=CC=1>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[C:13](=[O:15])[N:19]([CH2:21][C:34]4[CH:33]=[CH:32][CH:31]=[C:30]([O:29][CH:26]5[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]5)[N:35]=4)[CH:18]=[N:17][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CN1CCC(Oc2cccc(CN)n2)CC1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1/N=C/N(C)C
Solvent: CCOCC
Solvent: Oc1ccccc1
Product: CN1CCC(Oc2cccc(Cn3cnc4cc(-c5ccc(Cl)cc5)sc4c3=O)n2)CC1
Temperature: 130 °C
Reaction time: 8 h
Yield: 33.7 %

Procedure:
Methyl 5-(4-chlorophenyl)-3-{[(1E)-(dimethylamino)methylene]amino}thiophene-2-carboxylate (1.39 g, 4.29 mmol) and 1-{6-[(1-methylpiperidin-4-yl)oxy]pyridin-2-yl}methanamine (0.950 g, 4.29 mmol, from step b above) were mixed with 4 g of phenol and heated to 130° C. on an oil bath for 1 h. When the mixture had cooled down it was diluted with 150 mL of diethyl ether. The mixture became opaque and left overnight. Very little had precipitated but when evaporation of ether was commenced much precipitate was formed and filtered off. The material was recrystallized from ethanol, filtered, washed with ethanol and dried to give 0.675 g (32%) of the desired compound. Mp 202-203° C. 1H NMR (600 MHz, CD3OD) δ 8.43 (s, 1H), 7.75 (m, 2H), 7.65 (s, 1H), 7.60 (t, 1H), 7.45 (m, 2H), 6.95 (d, 1H), 6.55 (d, 1H), 5.30 (s, 2H), 4.55 (br, 1H), 2.52 (m, 2H), 2.05 (s, 3H), 1.84 (m, 2H), 1.70 (m, 2H), 1.51 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 162.7, 157.9, 157.0, 151.9, 151.6, 149.1, 140.1, 135.9, 131.7, 129.7, 127.9, 123.0, 121.1, 115.7, 111.2, 51.4, 50.3, 44.6, 28.7, 22.1. MS (ESI+) 467/469 (M+1H+).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.[CH:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([CH3:13])[CH3:12].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH:11]([N:14]1[CH2:19][CH2:18][N:17]([C:8]([C@H:5]2[CH2:4][CH2:3][C@@H:2]([OH:1])[CH2:7][CH2:6]2)=[O:10])[CH2:16][CH2:15]1)([CH3:13])[CH3:12]
Reactant: O=C(O)[C@H]1CC[C@@H](O)CC1
Reactant: CC(C)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)N1CCN(C(=O)[C@H]2CC[C@@H](O)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 428 mg (3.0 mmol) of cis-4-hydroxycyclohexanecarboxylic acid (commercially available), 318 mg (1.5 mmol) of 1-(isopropyl)-piperazine (commercially available), 1.14 g (3.6 mmol) of TBTU and 900 mg (9 mmol) of triethylamine in 3 ml DMF was stirred for 12 h at room temperature. The mixture was purified by column chromatography on silica eluting with CH2Cl2 and methanol=9:1. Evaporation of the combined product fractions yielded 460 mg (61%) of the title compound as light brown oil. MS (m/e): 255.2 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]Cl)=[C:6]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:5]=1)([O-:3])=[O:2].[CH2:16]([NH2:19])[CH:17]=[CH2:18]>>[CH2:16]([NH:19][S:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[C:12]([Cl:15])([Cl:14])[Cl:13])[CH:17]=[CH2:18]
Reactant: C=CCN
Reactant: O=[N+]([O-])c1ccc(SCl)c(C(Cl)(Cl)Cl)c1
Product: C=CCNSc1ccc([N+](=O)[O-])cc1C(Cl)(Cl)Cl
Yield: 94.6 %

Procedure:
As in Example 4, 61.4 g of 4-nitro-2-trichloromethylbenzenesulfenyl chloride is reacted with 23 g of allylamine. The hydrochloride is filtered off and the ether phase is concentrated. There is obtained 62 g (95% of theory) of N-allyl-4-nitro-2-trichloromethylphenylsulfenamide as a pale oil.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:9]1)C1C=CC=CC=1.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C(Cl)Cl>[CH2:27]([O:26][C:24]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:9]1)=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(OCc1ccccc1)C1CCN(Cc2ccccc2)C1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)C1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 40.7 %

Procedure:
A solution of 18 g (61 mmol) of (R/S)-1-benzyl-pyrrolidin-3-yl carboxylic acid, benzyl ester (from Step A) in 100 mL of CH2Cl2 at 0° C. was treated with 21.3 mL (231 mmol) of benzyl chloroformate while maintaining the internal temperature at less than 6° C. The reaction was allowed to warm to rt overnight. After 24 hours at rt, an additional 10 mL (10.8 mmol) of benzyl chloroformate was added. After 24 hours of stirring at rt, the reaction was concentrated. The residue was purified on a 40L Biotage column using 19:1 v/v hexane/acetone as the eluant to afford 8.42 g (39%) of the title compound as a colorless oil: RF: 0.14 (9:1 v/v hexane/acetone); 1H-NMR (500 MHz) δ 2.19-2.22 (m, 2H), 3.15 (m, 1H), 3.45-3.75 (m, 4H), 5.13-5.20 (m, 4H), 7.33-7.41 (m, 10H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:4][C:5]3[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]4[CH2:20]CCC[CH2:16]4)[C:11](O)=[O:12])[C:7](=[O:21])[C:6]=3[O:22][C:23]=2[CH:24]=[CH:25][CH:26]=1.C(Cl)(=O)C(Cl)=O.[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=1>C(Cl)Cl.O>[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([NH:40][C:11](=[O:12])[C@@H:10]([N:8]2[CH2:9][C:5]3[CH2:4][C:3]4[C:2]([Cl:1])=[CH:26][CH:25]=[CH:24][C:23]=4[O:22][C:6]=3[C:7]2=[O:21])[CH2:14][CH:15]([CH3:16])[CH3:20])=[N:38][CH:39]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1CC2=C(Oc3cccc(Cl)c3C2)C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)Nc1ccc(Cl)cn1)N1CC2=C(Oc3cccc(Cl)c3C2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.4 %

Procedure:
A solution of (S)-2-(8-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid (200 mg, 2.1 mmol) (from Example 3, Step 1c), in methylene chloride (10 mL) was treated with oxalyl chloride (0.12 mL, 1.07 mmol) at 0° C. The mixture was warmed to 25° C. and stirred for additional 2 hours. Then, the reaction mixture was cooled to 0° C., and N,N′-diisopropylethyl amine (0.61 mL, 3.57 mmol) and commercially available 5-chloro-pyridin-2-ylamine (137 mg, 1.07 mmol), were added. The reaction mixture was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradiant elution, afforded (S)-2-(8-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid (5-chloro-pyridin-2-yl)-amide (145 mg, 36.3%), as a white solid. 1H NMR (DMSO-d6) δ: 11.11 (s, 1H), 8.40 (d, J=2.4 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.90 (dd, J=8.8, 2.4 Hz, 1H), 7.21-7.38 (m, 2H), 7.09 (dd, J=7.1, 2.2 Hz, 1H), 5.06 (dd, J=10.5, 4.6 Hz, 1H), 4.42 (d, J=18.6 Hz, 1H), 4.07 (d, J=19.1 Hz, 1H), 3.75 (s, 2H), 1.77-1.89 (m, 1H), 1.61-1.73 (m, 1H), 1.46 (br. s., 1H), 0.93 (t, J=6.4 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12]C)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.Cl.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([OH:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: COc1cc(Cl)cc2cccnc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: Oc1cc(Cl)cc2cccnc12
Temperature: 150 °C
Yield: 60.4 %

Procedure:
6-Chloro-8-methoxyquinoline (Preparation 43, 10 g, 51.6 mmol) was added to pyridine hydrochloride (43 g, 375 mmol) and the mixture heated at 150° C. 1 hour. The reaction mixture was diluted with water (200 mL), basified to pH=8 with saturated aqueous sodium bicarbonate solution, filtered and concentrated in vacuo. The resulting crude product was purified with silica gel chromatography eluting with 5 to 10% EtOAc in petroleum ether to yield the title compound as a pale yellow solid (5.6 g, 70%):
Reaction SMILES: O[CH2:2][CH:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:5][S:6][CH3:7].[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:21]=[C:19]1[C:18]2[C:17](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16](=[O:26])[N:20]1[CH2:2][CH:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:5][S:6][CH3:7]
Reactant: CSCCC(CO)NC(=O)OC(C)(C)C
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CSCCC(CN1C(=O)c2ccccc2C1=O)NC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl [1-hydroxy-4-(methylsulfanyl)butan-2-yl]carbamate (18.5 g, 84.5 mmol) in THF (400 mL) was added phthalimide (14.9 g, 0.101 mol) and triphenylphosphine (26.9 g, 0.101 mol) under a nitrogen atmosphere. Diethylazodicarboxylate (27.3 g, 0.135 mol) was added dropwise at room temperature. After 2 hours, the reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel to give tert-butyl {1-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-(methylsulfanyl)butan-2-yl}carbamate. MS ESI calc'd. for C18H25N2O4S [M+H]+ 365. found 365. 1H NMR (400 MHz, CDCl3) δ 7.87-7.71 (m, 4H), 4.72 (s, 1H), 4.16-4.07 (m, 1H), 3.76 (d, J=6.6 Hz, 2H), 2.68-2.54 (m, 2H), 2.13 (s, 3H), 1.75-1.55 (m, 2H), 1.35 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][C:15]([NH2:17])=[O:16])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1.[CH3:18][N:19]([CH3:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH3:18][N:19]([CH3:29])[C:20]1[CH:25]=[CH:24][C:23]([C:2]2[N:11]=[C:10]([NH:12][CH2:13][CH2:14][C:15]([NH2:17])=[O:16])[C:9]3[C:4](=[N:5][CH:6]=[CH:7][N:8]=3)[CH:3]=2)=[CH:22][CH:21]=1
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: NC(=O)CCNc1nc(Cl)cc2nccnc12
Product: CN(C)c1ccc(-c2cc3nccnc3c(NCCC(N)=O)n2)cc1

Procedure:
The title compound was prepared according to the procedure of Compound 1 (B) using 3-(7-chloropyrido[4,3-b]pyrazin-5-ylamino)propanamide prepared above and 4-(dimethylamino)phenylboronic acid. MS (m/z): 337 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[CH:21]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[CH:32]=[C:31]2[C:27]([CH2:28][C:29](=[O:33])[NH:30]2)=[CH:26][CH:25]=1.N1CCCC1>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2/[CH:21]=[C:28]2\[C:29](=[O:33])[NH:30][C:31]3[C:27]\2=[CH:26][CH:25]=[C:24]([Cl:23])[CH:32]=3)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)cc2C=O)CC1
Solvent: C1CCNC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)cc2/C=C2\C(=O)Nc3cc(Cl)ccc32)CC1
Yield: 92.8 %

Procedure:
In a manner similar to the method described in Example 1b, 4-(4-chloro-2-formyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (8 g, 25 mmol) was reacted with 6-chlorooxindole (4.1 g, 25 mmol) and pyrrolidine (1.8 g, 25 mmol) in methanol (50 mL) to give the title compound as a yellow solid (11 g).
Reaction SMILES: Cl[CH2:2][C@@H:3]1[CH2:7][O:6]C(C)(C)[O:4]1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:27]3[C:26](=[O:28])[NH:25][CH:24]=[N:23][C:22]=3[N:21]([CH3:29])[C:20](=[O:30])[C:19]=2[CH3:31])=[C:13]([F:32])[CH:12]=1.Cl>>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:27]3[C:26](=[O:28])[N:25]([CH2:2][C@@H:3]([OH:4])[CH2:7][OH:6])[CH:24]=[N:23][C:22]=3[N:21]([CH3:29])[C:20](=[O:30])[C:19]=2[CH3:31])=[C:13]([F:32])[CH:12]=1
Reactant: Cc1c(Nc2ccc(Br)cc2F)c2c(=O)[nH]cnc2n(C)c1=O
Reactant: CC1(C)OC[C@@H](CCl)O1
Agent: Cl
Product: Cc1c(Nc2ccc(Br)cc2F)c2c(=O)n(C[C@@H](O)CO)cnc2n(C)c1=O

Procedure:
The title compound was prepared according to the procedure used for Example 9 synthesis by reaction of (S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane with compound 9F, followed by hydrolysis with 1N HCl. 1H NMR (400 MHz, MeOD) δ ppm 1.71 (s, 3H) 3.44-3.51 (m, 1H) 3.59 (d, J=5.31 Hz, 2H) 3.74 (s, 3H) 3.76-3.82 (m, 1H) 3.91-4.01 (m, 1H) 4.41 (dd, J=13.64, 3.28 Hz, 1H) 6.77 (t, J=8.59 Hz, 1H) 7.26 (d, J=9.09 Hz, 1H) 7.39 (d, J=2.02 Hz, 1H) 8.38 (s, 1H)) [M+H] calc'd for C18H18BrFN4O4, 454. found, 454.