Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].N1C=CC=CC=1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>CN(C)C=O>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:2][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)C(N)C(=O)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCOC(=O)C(NC(=O)c1ccc(F)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.8 %

Procedure:
To a solution of diethyl aminomalonate hydrochloride (5.0 g, 23.6 mmol) in pyridine (7.64 ml, 94.5 mmol) and dimethylformamide (60 ml) was added p-fluorobenzoyl chloride (4.19 ml, 35.4 mmol). The reaction mixture was stirred at room temperature for 15 hours. After removing the solvents, the residue was redissolved in dichloromethane, washed with water, brine and dried over Na2SO4. After removing the solvents, the crude residue was purified by flash chromatography on silica (CH2Cl2/MeOH 30:1) to yield the title compound as a white solid (4.9 g, 70%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[N:11]=[C:5]2[NH:4][C:3]1=[O:29].Br[CH2:31][C:32]1[C:33]([CH3:38])=[N:34][O:35][C:36]=1[CH3:37].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:38][C:33]1[C:32]([CH2:31][N:4]2[C:5]3=[N:11][N:10]([CH2:12][C:13]4[C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[CH:16]=[CH:15][CH:14]=4)[C:9]([C:23]4[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=4)=[C:6]3[C:7](=[O:8])[N:2]([CH3:1])[C:3]2=[O:29])=[C:36]([CH3:37])[O:35][N:34]=1
Reactant: Cn1c(=O)[nH]c2nn(Cc3cccc4ccccc34)c(-c3ccncc3)c2c1=O
Reactant: Cc1noc(C)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1c(=O)n(C)c(=O)c2c(-c3ccncc3)n(Cc3cccc4ccccc34)nc21

Procedure:
This compound was synthesized by the reaction of 5-methyl-2-(1-naphthylmethyl)-3-pyridin-4-yl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione and 4-(bromomethyl)-3,5-dimethylisoxazole using potassium carbonate as abase in DMF at 80° C. Mass: 492.94 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=O)[CH:8]=2)[CH:3]=[CH:2]1.[CH3:12][CH:13]([CH3:29])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:18]=1)=[O:15]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][N:26]3[CH2:27][CH2:28][CH:23]([C:19]4[CH:18]=[C:17]([NH:16][C:14](=[O:15])[CH:13]([CH3:12])[CH3:29])[CH:22]=[CH:21][CH:20]=4)[CH2:24][CH2:25]3)[CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1ccc2cc[nH]c2c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4cc[nH]c4c3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 1H-indole-6-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 376.2 (M+H)+.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[C:23]([O:29][CH3:30])[CH:22]=1.[OH-].[Na+]>C(Cl)Cl.O>[CH3:30][O:29][C:23]1[CH:22]=[C:21]([OH:20])[CH:28]=[CH:27][C:24]=1[CH2:25][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNC1
Reactant: COc1cc(O)ccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1cc(O)ccc1CN1CCCC1

Procedure:
NaB(OAc)3H (8.7 g, 0.041 mol) was added in portions for 30 min to a mixture of pyrrolidine (3.4 mL, 0.0.41 mol) and 4-hydroxy-2-methoxybenzaldehyde (5 g, 0.033 mol) in CH2Cl2 (50 mL) under vigorous stirring and cooling with an ice bath in an atmosphere of argon. The mixture was stirred for 2 h and cooled. Then 10 N NaOH (4.1 mL) and water (30 mL) were added. The organic layer was separated, the aqueous one was extracted with chloroform (2×50 mL). The organic fractions were evaporated. The residue was distributed between water and CH2Cl2. Concentrated HCl (2.98 mL) was added. The organic layer was separated and discarded. The aqueous one was alkalized with 10 N NaOH to pH 6 and extracted with chloroform (2×50 mL). The combined extracts were dried with Na2SO4, and evaporated to give the title compound (3.37 g, 07%) as yellow crystals. 1H-NMR (400 MHz)-data (dmso-d6, j, Hz): 9.25 (s, 1H ArOH), 7.02 (d, 1H, J=8.3, Ar—H), 6.36 (d, 1H, J=2.2, Ar—H) 6.30 (dd, 1H, J1=8.3, J2=2.2, Ar—H), 3.70 (s, 3H, ArOCH3), 3.44 (s, 2H, ArCH2), 2.38-2.44 (m, 4H, pyrrolidine (CH2)2N), 1.62-1.68 (m, 4H, CH2CH2CH2CH2).
Reaction SMILES: [NH2:1][C:2]([CH3:11])([CH2:6][C:7]([F:10])([F:9])[F:8])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>CO>[CH2:23]([O:22][C:20]([NH:1][C:2]([CH3:11])([CH2:6][C:7]([F:8])([F:9])[F:10])[C:3]([OH:5])=[O:4])=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(N)(CC(F)(F)F)C(=O)O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(CC(F)(F)F)(NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
A solution of 2-amino-4,4,4-trifluoro-2-methylbutanoic acid (255 mg, 1.4 mmol) and triethylamine (800 ul, 4.2 mmol) in MeOH (3 ml) was cooled to 0° C. and benzyl chloroformate (509 mg, 2.98 mmol) was added dropwise. The solution was warmed to RT overnight and concentrated in vacuo. The residue was suspended in EtOAc and extracted with sat. NaHCO3, the aqueous layers acidified with conc. HCl, and the resulting milkly suspension extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford the title compound. LRMS (ESI/APCI, negative): 304 [M−H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16](F)=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:24]#[N:25])[CH:5]=[CH:6][C:7]=1[F:8].[OH:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:26][C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:24]#[N:25])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Oc1ccncc1
Reactant: N#Cc1cnc2cc(F)c([N+](=O)[O-])cc2c1Nc1ccc(F)c(Cl)c1
Product: N#Cc1cnc2cc(Oc3ccncc3)c([N+](=O)[O-])cc2c1Nc1ccc(F)c(Cl)c1

Procedure:
The compound was prepared according to the process of Preparation 2 and with 4-(3-chloro-4-fluorophenylamino)-7-fluoro-6-nitroquinoline-3-carbonitrile and 4-hydroxypyridine as starting materials.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]1[O:9]C1)[CH:2]1[O:4][CH2:3]1.[CH2:10]([OH:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[CH2:10]([O:22][CH2:3][CH:2]1[O:4][C:7](=[O:9])[CH2:6][O:5][CH2:1]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: C(OCC1CO1)C1CO1
Reactant: CCCCCCCCCCCCO
Product: CCCCCCCCCCCCOCC1COCC(=O)O1

Procedure:
Prepared from the glycidyl ether of dodecanol.
Reaction SMILES: C(OC(N1C[CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH2:9]1)=O)(C)(C)C.NCC([OH:35])C>>[OH:35][CH2:9][CH:10]([NH:13][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: CC(O)CN
Product: CC(CO)NC(=O)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 1-amino-2-propanol instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 317 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (1H, s) 10.29 (1H, s) 8.01 (1H, d, J=5.47 Hz) 7.78 (1H, d, J=5.27 Hz) 7.69 (1H, d, J=8.00 Hz) 7.46 (1H, d, J=5.27 Hz) 7.27-7.33 (1H, m) 6.79 (1H, d, J=5.47 Hz) 6.43 (1H, dd, J=3.51, 1.95 Hz) 4.71 (1H, t, J=5.76 Hz) 3.97-4.09 (1H, m) 3.27-3.48 (2H, m) 1.09 (3H, d, J=6.64 Hz)
Reaction SMILES: [CH2:1]([C@@H:8](/[CH:24]=[CH:25]/[CH2:26][C:27]([N:29]1[C@@H:33]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:32][O:31][C:30]1=[O:41])=[O:28])[C:9]([N:11]1[C@@H:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][O:13][C:12]1=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:42][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI.[NH4+].[Cl-]>C1COCC1>[CH2:1]([C@@H:8](/[CH:24]=[CH:25]/[C@H:26]([CH3:42])[C:27]([N:29]1[C@@H:33]([CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:32][O:31][C:30]1=[O:41])=[O:28])[C:9]([N:11]1[C@@H:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][O:13][C:12]1=[O:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(C/C=C/[C@H](Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: C[C@@H](/C=C/[C@H](Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of (S,E)-2-benzyl-1,6-bis((S)-4-benzyl-2-oxooxazolidin-3-yl)hex-3-ene-1,6-dione (250 mg, 0.450 mmol) in THF (50 mL) at −78° C., a solution of NaHMDS (1 M in THF, 0.54 mL, 0.54 mmol) in diluted in THF (2.5 mL) was added dropwise. The reaction mixture was stirred for 1 hr at −78° C. and then methyl iodide (0.078 g, 0.55 mmol) was added in two portions. The reaction mixture was warmed to rt and allowed to stir overnight. Saturated aqueous NH4Cl (3 mL) was added to the reaction mixture and crude product was extracted with ethyl acetate (5 mL). The organic layer was separated, dried (Na2SO4) and concentrated to afford crude product, which was purified using silica gel chromatography to afford (2S,5S,E)-2-benzyl-1,6-bis((S)-4-benzyl-2-oxooxazolidin-3-yl)-5-methylhex-3-ene-1,6-dione (137 mg, 0.243 mmol, 54% yield). Anal. Calcd. for C34H34N2O6 m/z 566.2. found 565.2 (M−): 1H NMR (400 MHz, CDCl3) δ ppm 7.36-7.30 (m, 5H), 7.29-7.26 (m, 5H), 7.25-7.18 (m, 3H), 7.08-7.05 (m, 2H), 5.75-5.62 (m, 2H), 4.72-4.57 (m, 3H), 4.36-4.29 (m, 1H), 4.23-4.12 (m, 4H), 3.28-3.21 (m, 2H), 3.10 (m, 1H), 2.84 (m, 1H), 2.76 (m, 1H), 2.61 (m, 1H), 1.24 (d, J=6.8 Hz, 3H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:8][C:9](=[O:19])[NH:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:18])[CH2:6][CH3:7].C(O)(=O)C.N([O-])=O.[Na+]>O>[CH2:5]([O:8][C:9](=[O:19])[NH:10][C:11]1[C:12]([CH3:18])=[CH:13][C:14]([N+:1]([O-:4])=[O:2])=[CH:15][C:16]=1[CH3:17])[CH2:6][CH3:7]
Reactant: CCCOC(=O)Nc1c(C)cccc1C
Reactant: O=[N+]([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCOC(=O)Nc1c(C)cc([N+](=O)[O-])cc1C
Temperature: 0 °C
Yield: 42 %

Procedure:
To a solution of concentrated nitric acid (6.4 mL) in water (30 mL) was added (2,6-dimethyl-phenyl)-carbamic acid propyl ester (2.72 g), acetic acid (30 mL) and sodium nitrite (1.0 g). The reaction mixture was refluxed for 16 hours, water (200 mL) was added and the mixture was cooled to 0° C. The product was collected by filtration and dried in vacuo to furnish 1.40 g (42% yield) of the title compound as a yellow solid. The crude product was used without further purification. 1H NMR (500 MHz, DMSO-d6): 0.92 (t, 3H), 1.63 (m, 2H), 2.29 (s, 6H), 4.04 (t, 2H), 7.98 (s, 2H), 9.11 (b, 1H).
Reaction SMILES: C(O[C:4]1[C:7](=[O:8])[C:6](=[O:9])[C:5]=1[NH:10][C:11]1[CH:12]=[C:13]([CH:18]2[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([CH3:28])[NH:21][C:20]([CH3:29])=[C:19]2[C:30]([O:32][CH3:33])=[O:31])[CH:14]=[CH:15][C:16]=1[F:17])C.[CH3:34][N:35]([CH:37]=O)[CH3:36]>>[CH:34]1([N:35]2[CH2:37][CH2:36][N:35]([CH2:37][CH2:4][CH2:5][NH:10][C:4]3[C:7](=[O:8])[C:6](=[O:9])[C:5]=3[NH:10][C:11]3[CH:12]=[C:13]([CH:18]4[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([CH3:28])[NH:21][C:20]([CH3:29])=[C:19]4[C:30]([O:32][CH3:33])=[O:31])[CH:14]=[CH:15][C:16]=3[F:17])[CH2:34][CH2:36]2)[CH2:13][CH2:12][CH2:11][CH2:16][CH2:15]1
Reactant: CCOc1c(Nc2cc(C3C(C(=O)OC)=C(C)NC(C)=C3C(=O)OC)ccc2F)c(=O)c1=O
Reactant: CN(C)C=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccc(F)c(Nc2c(NCCCN3CCN(C4CCCCC4)CC3)c(=O)c2=O)c1

Procedure:
The compound of Example 2 (147 mg, 0.321 mmol) and 4-cyclohexyl-1-piperazine-1-propanamine (72 mg, 0.320 mmol) were stirred in 2 mL DMF at room temperature for 64 hours. The crude reaction mixture was evaporated to dryness under high vacuum (0.1 mmHg) at 50-55° C. The resulting gum was triturated with methylene chloride followed by the addition of hexanes. The titled compound precipitated out as fine creamy white crystalline solid (158 mg, 77.5%): mp 229-230° C.; 1H NMR (DMSO-d6) δ 9.37 (br. s, 1H), 8.96 (br. s, 1H), 8.03 (br. 1H), 7.79 (d, 1H, J=7.6 Hz), 7.59 (dd, 1H, J=8.98, 5.21 Hz), 7.07 (dd, 1H, J=8.46, 11.37 Hz), 6.2 (m, 1H), 4.84 (s, 1H), 3.62-3.60 (m, 2H), 3.54 (s, 6H), 2.45 (m, 5H), 2.33-2.26 (m, 4H), 2.26 (s, 6H), 1.70-1.68 (m, 7H), 1.59-1.52 (br. 1H), 1.18-1.04 (m, 6H), 13C NMR (DMSO-d6) δ 179.63, 169.50, 167.31, 146.22, 129.07, 126.75, 125.98, 122.13, 119.68, 100.93, 62.55, 54.87, 50.60, 48.22, 42.13, 28.20, 27.62, 25.86, 25.57, 25.21, 18.31. Anal Calcd. for C34H44FN5O6•0.05 H2O: C, 63.94; H, 6.96; N, 10.97. Found: C, 63.95; H, 6.94; N, 10.74.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][N:3]=1.BrC1C=CC(S(C)=[O:18])=NC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:9])=[O:18])=[CH:4][N:3]=1
Reactant: CSc1ccc(Br)nc1
Reactant: CS(=O)c1ccc(Br)cn1
Product: CS(=O)c1ccc(Br)nc1

Procedure:
The title compound was prepared from 2-bromo-5-methylsulfanyl-pyridine following a procedure analogous to that described for 5-bromo-2-methanesulfinyl-pyridine in Example 182. Mass spectrum (ESI+): m/z=220/222 (Br) [M+H]+.
Reaction SMILES: [SH:1][CH2:2][C:3]1([OH:9])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[C:10]1(=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]1=[O:20]>>[O:6]1[CH2:7][CH2:8][C:3]2([O:9][C:13]3[C:14]4[C:19]([C:10](=[O:21])[C:11](=[O:20])[C:12]=3[S:1][CH2:2]2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:4][CH2:5]1
Reactant: O=C1C=Cc2ccccc2C1=O
Reactant: OC1(CS)CCOCC1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCOCC1)O2

Procedure:
The crude 4-(mercaptomethyl)tetrahydro-2H-pyran-4-ol was then reacted with naphthalene-1,2-dione as outlined in procedure F [both step (i) and (ii)] to afford crude 2′,3′,5′,6′-tetrahydrospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-pyran]-5,6-dione. The crude 2′,3′,5′,6′-tetrahydrospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-pyran]-5,6-dione was purified by flash column chromatography (SiO2, 100% dichloromethane) to afford the product as a purple solid. M.p.=195-197° C.; 400 MHz 1H NMR (CDCl3) δ: 8.06 (dd, J=7.6 1.0 Hz, 1H), 7.79 (dd, J=7.6 0.8 Hz, 1H), 7.67 (td, J=8.0 1.6 Hz 1H), 7.50 (td, J=8.0 1.2 Hz, 1H), 3.96-3.83 (m, 4H), 2.97 (s, 2H), 2.10-2.05 (m, 2H), 1.95-1.87 (m, 2H); LCMS: 303 [M+H].
Reaction SMILES: CO[C:3]([C:5]1[C:10]([Br:11])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].[CH3:12][C:13]1[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][N:14]=1>>[CH3:12][C:13]1[CH:18]=[C:17]([NH:19][C:3]([C:5]2[C:10]([Br:11])=[N:9][CH:8]=[CH:7][N:6]=2)=[O:4])[CH:16]=[CH:15][N:14]=1
Reactant: Cc1cc(N)ccn1
Reactant: COC(=O)c1nccnc1Br
Product: Cc1cc(NC(=O)c2nccnc2Br)ccn1

Procedure:
The title compound, MS: m/e=294.9 (M+H+), was prepared in accordance with the general method of example 1, step 2 from 3-bromo-pyrazine-2-carboxylic acid methyl ester (Example A) and 2-methyl-pyridin-4-ylamine (Example B).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](Br)[CH:27]=1>ClCCl>[Br:25][C:26]1[CH:27]=[C:28]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([N:2]([CH3:14])[CH3:1])[CH:4]=3)[C:9]2=[O:13])[CH:29]=[CH:30][CH:31]=1
Reactant: CN(C)c1ccc2c(c1)CCNC2=O
Reactant: Brc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CN(C)c1ccc2c(c1)CCN(c1cccc(Br)c1)C2=O
Temperature: 150 °C
Yield: 67.8 %

Procedure:
6-Dimethylamino-3,4-dihydro-2H-isoquinolin-1-one (762 mg, 4.01 mmol), cuprous iodide (153mg, 0.802 mmol) and potassium carbonate (554 mg, 4.01 mmol) were deposited in a sealed type vessel. 6 mL DMSO and 1,3-dibromobenzene (1.89 g, 8.01 mmol) were added. Argon was bubbled through the mixture for 2 minutes and the lid was tightly closed. This was heated at 150° C. for 24 hours. Cuprous iodide (153 mg, 0.802 mmol) was added and the mixture was heated at 150° C. for an additional 24 hours. This was diluted with dichoromethane and filtered through a pad of celite. The filtrate was partitioned between dichloromethane and 5% aq. ammonium hydroxide. The dichloromethane layer was dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 25 to 100% ethyl acetate/hexanes) to yield 2-(3-Bromo-phenyl)-6-dimethylamino-3,4-dihydro-2H-isoquinolin-1-one (939 mg, 2.72 mmol). MS (ESI) 345.0 (M+H)+.
Reaction SMILES: [CH:1]([NH:4][C:5]([CH:7]1[C:15]2[C:10](=[CH:11][C:12]([Cl:35])=[C:13]([NH:16][C:17]([C:19]3[N:20]([C:28]4[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][N:29]=4)[N:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=3)=[O:18])[CH:14]=2)[CH2:9][CH:8]1O)=[O:6])([CH3:3])[CH3:2].C(N(S(F)(F)[F:43])CC)C.O>ClCCl>[CH:1]([NH:4][C:5]([CH:7]1[C:15]2[C:10](=[CH:11][C:12]([Cl:35])=[C:13]([NH:16][C:17]([C:19]3[N:20]([C:28]4[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][N:29]=4)[N:21]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:23]=3)=[O:18])[CH:14]=2)[CH2:9][CH:8]1[F:43])=[O:6])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)NC(=O)C1c2cc(NC(=O)c3cc(C(F)(F)F)nn3-c3ncccc3Cl)c(Cl)cc2CC1O
Solvent: ClCCl
Solvent: O
Product: CC(C)NC(=O)C1c2cc(NC(=O)c3cc(C(F)(F)F)nn3-c3ncccc3Cl)c(Cl)cc2CC1F
Reaction time: 2 h

Procedure:
A solution of 5-chloro-2-hydroxy-6-{[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl]-amino}-indane carboxylic acid isopropylamide (100 mg, 0.18 mmol) in dichloromethane is cooled to 0° C., treated with diethylaminosulfurtrifluoride (29 mg, 1.8 mmol), stirred for 2 hours, and treated with water. Organic layer is separated, dried over sodium sulfate, filtered, and evaporated. Purification by chromatography using ethyl acetate/hexane as eluent gives 5-chloro-2-fluoro-6-{[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl]-amino}-indane carboxylic acid isopropylamide as solid; LC/MS: 542/544 (M+1)+; m.p.: 98-99° C.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]3)=[C:6]([O:30][CH3:31])[CH:5]=1)=[S:3].Br[CH2:33][C:34](=O)[CH2:35][CH3:36]>CCO>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C@H:18]1[C:19]2[C:15](=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][C:7]3[CH:28]=[CH:29][C:4]([C:2]4[S:3][CH:33]=[C:34]([CH2:35][CH3:36])[N:1]=4)=[CH:5][C:6]=3[O:30][CH3:31])=[CH:21][CH:20]=2)[CH2:16][CH2:17]1)[CH3:27]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(C(N)=S)cc3OC)ccc21
Reactant: CCC(=O)CBr
Solvent: CCO
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(-c4nc(CC)cs4)cc3OC)ccc21
Temperature: 70 °C
Reaction time: 6 h
Yield: 50.4 %

Procedure:
Ethyl ((1S)-5-{3-[4-(aminocarbonothioyl)-2-methoxyphenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (90 mg, 0.2 mmol) (Example 146) and 1-bromo-2-butanone (36.7 mg, 0.24 mmol) were dissolved in EtOH (anhydrous, 8 mL) and stirred at 70° C. for 6 h. The reaction was cooled to rt, and concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc:hexane (v/v)=1:2) gave 50 mg (51%) of the title compound as a clear oil. LC-MS: RT=4.07 min; (M+H)+ 496.2.
Reaction SMILES: [OH-].[Na+].[C:3]([NH:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4].Br.Br[CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>C(O)C>[C:3]([NH:6][C:7]([CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4]
Reactant: BrCc1ccncc1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccncc1)(NC(C)=O)C(=O)OCC
Temperature: 20 °C
Yield: 82.9 %

Procedure:
To 750 mL of ethanol, about 9 g of sodium hydroxide is added dropwise, while stirring under an inert atmosphere. After the addition of sodium hydroxide, the temperature of reaction mixture is maintained at about 20° C., and 42 g of diethyl acetamidomalonate is slowly added then the mixture is stirred at a temperature of about 20° C. for 1 hour and 30 minutes. A suspension of 61.5 g of 4-bromomethyl-pyridine hydrobromide in 250 mL of ethanol is then quickly added and the resulting suspension is stirred at a temperature of about 20° C. for 18 hours. The reaction medium is then concentrated under reduced pressure (2 kPa) at a temperature of about 40° C. The residue is taken up in 200 mL of distilled water and is neutralized with 1N aqueous hydrochloric acid until the pH is equal to 7. The obtained suspension is cooled at a temperature of about 0° C., filtered and the insoluble material is washed with 2 times 50 mL of ice-cold water, then dried in an oven under reduced pressure (10 kPa) at a temperature of about 40° C. for 18 hours. Thus 49.4 g of diethyl 2-(acetylamino)-2-(4-pyridinylmethyl)malonate is obtained in the form of a white-pinkish solid. [Infrared spectrum CH2Cl2: 3409; 2895; 1741; 1681; 1603; 1496; 1302; 1198; 1057; 855; 557 and 524 cm−1].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][N:6]=[C:5]([OH:12])[CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C.O>[Si:23]([O:22][CH2:21][CH2:20][O:12][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][N:6]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: COc1cc(O)ncc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OCCO[Si](C)(C)C(C)(C)C)ncc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 94.5 %

Procedure:
Step A To a solution of 4-methoxy-5-nitropyridin-2-ol (0.5 g, 2.9 mmol) in anhydrous DMF (12 mL) were added K2CO3 (0.82 g, 5.9 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (0.7 g, 2.9 mmol) sequentially. The reaction mixture was heated at 70° C. for 2 h. The mixture was cooled to room temperature, and diluted with water. The mixture was extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated to give 2-(2-(tert-butyldimethylsilyloxy)ethoxy)-4-methoxy-5-nitropyridine as a white solid (0.9 g, 93%).