Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.C(OC([N:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:22][N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)[CH:19]=2)[CH2:14]1)=O)C1C=CC=CC=1.[H][H]>CCO.[Pd]>[CH3:29][N:26]1[CH2:27][CH2:28][N:23]([CH2:22][C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[CH2:14][NH:13][CH2:21]3)[CH2:24][CH2:25]1
Reactant: CN1CCN(Cc2ccc3c(c2)CN(C(=O)OCc2ccccc2)C3)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CN1CCN(Cc2ccc3c(c2)CNC3)CC1
Reaction time: 1 h
Yield: 95 %

Procedure:
To a degassed solution of 5-(4-Methyl-piperazin-1-ylmethyl)-1,3-dihydro-isoindole-2-carboxylic acid benzyl ester (Step 9, 1.3 Kg, 3.55 mol) dissolved in EtOH (13 L) was added 10% Pd/C (0.065 Kg). Hydrogen was passed through the mixture at 30° C. for 4 h or until complete by NMR. The solution was then stirred for 1 h under an atmosphere of N2 and then filtered to remove the catalyst through a GF/F filter followed by filtration through a Cuno filter. The filtrate was evaporated to a small volume, azeotroped with toluene (3.9 L) and dried to constant weight yielding the title compound as a red/black oily solid (0.78 Kg) which was stored under nitrogen until required.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][OH:30])=[CH:25][CH:24]=1.O>CN(C=O)C>[N:1]1([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][OH:30])=[CH:25][CH:24]=2)[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1
Reactant: OCc1ccc(CBr)cc1
Reactant: c1ccc2c(c1)CCC21CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: OCc1ccc(CN2CCC3(CCc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.6 %

Procedure:
To a stirred solution of 2,3-dihydrospiro[indene-1,4′-piperidine] (0.4 g, 1.78 mmol) in DMF (12 mL) is added Cs2CO3 (1.4 g, 4.4 mmol) and [4-(bromomethyl)phenyl]methanol (0.36 g, 1.78 mmol) and the reaction mixture is stirred overnight at room temperature. The reaction mixture is poured into cold water and extracted with EtOAc (3×50 mL). The combined organic layer is washed with brine solution, dried over Na2SO4, and concentrated under vacuum. The crude material is purified by silica gel chromatography (gradient DCM/MeOH 8/2) to give the title compound (0.6 g, 98%). ESI/MS m/z 308.40 (M+H)+.
Reaction SMILES: [Cl-].[CH2:2]([O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][NH2+:8]1)=[O:6])[CH3:3].Cl[C:14]1[O:15][C:16]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:17]=2[N:18]=1>>[F:23][C:20]1[CH:21]=[CH:22][C:16]2[O:15][C:14]([N:8]3[CH2:9][CH2:10][CH2:11][CH2:12][C@H:7]3[C:5]([O:4][CH2:2][CH3:3])=[O:6])=[N:18][C:17]=2[CH:19]=1
Reactant: Fc1ccc2oc(Cl)nc2c1
Reactant: CCOC(=O)[C@@H]1CCCC[NH2+]1
Agent: [Cl-]
Product: CCOC(=O)[C@@H]1CCCCN1c1nc2cc(F)ccc2o1

Procedure:
The title compound was prepared by a similar method to Preparation 2 from (2S)-2-(ethoxycarbonyl)piperidinium chloride [see J. Am. Chem. Soc. (1993), 115, 9925-9938] and 2-chloro-5-fluoro-1,3-benzoxazole [see J. Med. Chem. (1988), 31, 1719-1728]. The crude product was purified by column chromatography on silica gel eluting with a solvent system of 3:1, by volume, hexane:ethyl acetate, to afford ethyl (2S)-1-(5-fluoro-1,3-benzoxazol-2-yl)-2-piperidinecarboxylate as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:24]([O:28][C:29](=[O:36])[NH:30][C:31]1([CH2:34]I)[CH2:33][CH2:32]1)([CH3:27])([CH3:26])[CH3:25]>CN(C)C=O.C(OCC)(=O)C>[C:24]([O:28][C:29](=[O:36])[NH:30][C:31]1([CH2:34][N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]3[CH:4]=[C:3]([C:15]([NH2:17])=[O:16])[C:2]([NH2:1])=[N:14][C:6]2=3)[CH2:32][CH2:33]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: NC(=O)c1cc2c(nc1N)[nH]c1ccccc12
Reactant: CC(C)(C)OC(=O)NC1(CI)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(Cn2c3ccccc3c3cc(C(N)=O)c(N)nc32)CC1
Temperature: 100 °C
Yield: 13 %

Procedure:
To a stirred solution of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 318 mg, 1.41 mmol) in N,N-dimethylformamide (17 mL) was added powdered cesium carbonate (2.29 g, 7.03 mmol), tert-butyl[1-(iodomethyl)cyclopropyl]carbamate (2.26 g, 7.61 mmol, prepared from the corresponding alcohol (J. Med. Chem. 1988, 31, 1694-7) following the procedure detailed in the preparation of xxvii below) was added. The mixture was heated at 100° C. under nitrogen for 2 h. The reaction was cooled to room temperature, diluted with ethyl acetate (150 mL) and washed thrice with water and twice with brine. The extracts were dried over magnesium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (95/5 methylene chloride/methanol to 93/7 methylene chloride/methanol gradient) to afford the titled product (63, 75 mg, 13%). NH4OAc Standard conditions. DAD Retention time =7.29 min. M+H=396; 1H NMR (300 MHz, DMSO-d6): δ 8.72 (s, 1H), 7.79 (d, J=7.3 Hz, 1H), 7.54-7.41 (m, 2H), 7.26 (dd, J=7.3 Hz, 1H), 7.20-7.11 (m, 2H), 4.34 (s, 2H), 1.35 (s, 9H), 1.18-1.05 (m, 2H), 0.65-0.54 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].Cl.Cl.[CH:21]12[CH2:28][CH2:27][CH:24]([NH:25][CH2:26]1)[CH2:23][NH:22]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:21]12[CH2:28][CH2:27][CH:24]([NH:25][CH2:26]1)[CH2:23][N:22]2[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Reactant: C1CC2CNC1CN2
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC4CCC3CN4)nc21
Yield: 90.9 %

Procedure:
A solution of 0.54 g (2.0 mmole) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 0.46 g (2.5 mmole) of 2,5-diazabicyclo[2.2.2]octane dihydrochloride [P. A. Sturm et al., J. Med. Chem., 17, 481 (1974)], 1.05 ml (7.0 mmole) of 1,8-diazabicyclo (5.4.0) undec-7-ene, and 30 ml of acetonitrile was stirred at room temperature for 23 hours. The reaction mixture was filtered and the solid was washed with acetonitrile to give 0.63 g of the title compound, mp 250°-253°.
Reaction SMILES: [C:1]([C:4]([C:19]#[N:20])=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])(=[O:3])[NH2:2].[CH2:21]([NH2:24])[C:22]#[CH:23]>C(#N)C>[C:1]([C:4]([C:19]#[N:20])=[C:5]([NH:24][CH2:21][C:22]#[CH:23])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])(=[O:3])[NH2:2]
Reactant: CSC(NCCSCc1[nH]cnc1C)=C(C#N)C(N)=O
Reactant: C#CCN
Solvent: CC#N
Product: C#CCNC(NCCSCc1[nH]cnc1C)=C(C#N)C(N)=O

Procedure:
A mixture of the product of Step A (4.0 g, 12.8 mmole) and propargylamine (8.0 ml) in acetonitrile (40 ml) was stirred at reflux temperature under a positive pressure of nitrogen for 16 hours. The reaction mixture was cooled and evaporated to dryness under reduced pressure, and the residue was placed on silica gel and chromatographed by gradient elution using methylene chloride-methanol. Recrystallization from acetonitrile gave the title compound; mp 88°-94° (partial melt at 66°-69°).
Reaction SMILES: OO.[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([C:13]1([C:18]#[N:19])[CH2:17][CH2:16][CH2:15][CH2:14]1)(=[O:12])=[O:11].C([O-])([O-])=[O:21].[K+].[K+].CS(C)=O>O>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([C:13]1([C:18]([NH2:19])=[O:21])[CH2:17][CH2:16][CH2:15][CH2:14]1)(=[O:12])=[O:11]
Reactant: N#CC1(S(=O)(=O)c2ccccc2Br)CCCC1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)C1(S(=O)(=O)c2ccccc2Br)CCCC1
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
A 30% H2O2 solution (1.6 mL) was added drop-wise at rt to a mixture of 1-(2-bromophenylsulfonyl)cyclopentanecarbonitrile (1.6 g, 5.1 mmol), K2CO3 (2.1 g, 15 mmol), and DMSO (5 mL). The mixture was stirred for 30 min before diluting with water (40 mL) and isolating the precipitate via vacuum filtration. The precipitate was washed with water and air-dried to give the title compound (1.5 g, 89%). MS (ESI): mass calcd. for C12H19NO3S, 330.99; m/z found, 331.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.99-7.95 (m, 1H), 7.89-7.84 (m, 1H), 7.64-7.51 (m, 4H), 2.41-2.25 (m, 4H), 1.78-1.66 (m, 2H), 1.58-1.45 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH2:13]=O.[CH:15]1[CH:16]=[C:17]2[C:22]3=[C:23]([C:25]([NH:27][C:28](=[O:29])[C:21]3=[CH:20][CH:19]=[CH:18]2)=[O:26])[CH:24]=1>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:13][N:27]2[C:28](=[O:29])[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]4[C:22]=3[C:23](=[CH:24][CH:15]=[CH:16]4)[C:25]2=[O:26])[CH2:11][CH2:12]1
Reactant: C=O
Reactant: O=C1NC(=O)c2cccc3cccc1c23
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: CN(C)C=O
Product: O=C1c2cccc3cccc(c23)C(=O)N1CN1CCN(c2ccccn2)CC1

Procedure:
An equimolar mixture of 1-(2-pyridinyl)piperazine, aqueous formaldehyde, and 1,8-naphthalimide is suspended in a small amount of dimethylformamide and the mixture is heated until dissolution is complete. The solution is allowed to stand at room temperature and the resulting precipitate is filtered off and dried to yield 2-[[4-(2-pyridinyl)-1-piperazinyl]methyl]1H-benz[de]isoquinoline-1,3(2H)-dione.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[N:10]=[N:9]2)[N:3]=1.[Cl:17][C:18]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].F[C:32](F)(F)S(O[Si](C)(C)C)(=O)=O.C[Mg+].[Br-]>C1COCC1>[Cl:17][C:18]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([N:13]1[CH:14]=[CH:15][C:16]2[N:8]([C:4]3[N:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=3)[N:9]=[N:10][C:11]=2[CH:12]1[CH3:32])=[O:21]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Reactant: Cc1ccnc(-n2nnc3cnccc32)n1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1ccnc(-n2nnc3c2C=CN(C(=O)c2cccc(C(F)(F)F)c2Cl)C3C)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 16.1 %

Procedure:
To a suspension of the product of Example 252, Step 1 (200 mg, 0.94 mmol) in THF (30 mL) cooled to −78° C. was added Intermediate 12 (251 mg, 1.04 mmol). Trimethylsilyl trifluoromethanesulfonate (0.188 mL, 1.04 mmol) was then added and the reaction was stirred at −78° C. for 30 min. The resulting mixture was treated with MeMgBr (3.0 M solution in Et2O, 0.94 mL, 2.83 mmol) and stirred for 1 h. The reaction was quenched with NH4Cl and extracted with EtOAc, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel (0-5% MeOH/DCM) to provide the desired product (66 mg, 16%). MS (ESI) mass calcd. C19H14ClF3N6O, 434.1. m/z found, 435.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O>S(=O)(=O)(O)O>[Br:12][C:7]1[CH:6]=[C:5]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CS(=O)(=O)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Product: CS(=O)(=O)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.8 %

Procedure:
1-Fluoro-4-(methylsulfonyl)benzene (5.0 g, 28.7 mmol) in conc. sulfuric acid (30 mL) was cooled to 0° C. To this solution was added N-bromosuccinimide (5.62 g, 31.6 mmol). The reaction mixture was stirred at room temperature for 6 hours and then poured into ice-water. The resulting solid was collected by filtration, washed with cold water three times, and dried in a vacuum oven overnight to give the title compound (6.95 g, 27.5 mmol, 96% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([C:27]1[CH:28]=[N:29][C:30]([N:33]2[CH2:45][CH2:44][C:43]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[N:36]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C:35]=3[CH2:34]2)=[N:31][CH:32]=1)=O.[CH2:53](Cl)Cl>>[CH3:1][O:2][C:3](=[O:24])/[CH:4]=[CH:53]/[C:27]1[CH:28]=[N:29][C:30]([N:33]2[CH2:45][CH2:44][C:43]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[N:36]([C:46]([O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:47])[C:35]=3[CH2:34]2)=[N:31][CH:32]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)n1c2c(c3ccccc31)CCN(c1ncc(C=O)cn1)C2
Product: COC(=O)/C=C/c1cnc(N2CCc3c(n(C(=O)OC(C)(C)C)c4ccccc34)C2)nc1
Yield: 78 %

Procedure:
To a stirred solution methyl(triphenylphosphoranylidene)acetate (2.39 g, 0.0071 moles) in dry DCM (20 mL) was added tert-butyl 2-[5-(formyl)pyrimidin-2-yl]-1,2,3,4-tetrahydro-9H-b-carboline-9-carboxylate (1.35 g, 0.0036 moles) at 0° C. in dry DCM (10 mL). After stirring for >12 hours, the reaction mixture was washed with 10% NaHCO3 solution (20 mL), brine (20 mL), dried (Na2SO4) and concentrated. The compound was purified through silica gel column chromatography using 15% EtOAc in hexane to give tert-butyl 2-{5-[(1E)-3-methoxy-3-oxoprop-1-enyl]pyrimidin-2-yl}-1,2,3,4-tetrahydro-9H-b-carboline-9-carboxylate (1.22 g, 78% yield). 1H NMR (DMSO-d6, 400 MHz) ppm: 8.81 (s, 2H, 2Ar—H), 8.06 (d, 1H, J=8 Hz, 1Ar—H), 7.54 (d, 1H, J=16 Hz, ═CH), 7.50 (d, 1H, J=8 Hz, 1Ar—H), 7.32-7.23 (m, 2H, 2Ar—H), 6.60 (d, 1H, J=16 Hz, —CH), 5.23 (s, 2H, CH2), 4.19 (t, 2H, CH2), 3.7 (s, 3H, OMe), 2.78 (brs, 2H, CH2), 1.68 (s, 9H, 3CH3). M/e=435 (M+1) (M, 434.488 Calcd. for C24H26N4O4).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH:28]4[CH2:33][O:32][CH2:31][CH2:30][NH:29]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][N:35]([CH3:40])[CH2:36][C:37](O)=[O:38].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH:28]4[CH2:33][O:32][CH2:31][CH2:30][N:29]4[C:37](=[O:38])[CH2:36][N:35]([CH3:40])[CH3:34])[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnn2c(CC3COCCN3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N1CCOCC1Cc1cc(-c2ccc3cn(Cc4ccccc4)nc3c2)c2c(N)ncnn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.4 %

Procedure:
A mixture of 5-(2-benzyl-2H-indazol-6-yl)-7-(morpholin-3-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.23 mmol), N,N-dimethylglycine (25 mg, 0.24 mmol), EDCl (48 mg, 0.25 mmol), HOBt (34 mg, 0.25 mmol), and N,N-diisopropylethylamine (119 μL, 0.68 mmol) in DMF (1.2 mL) was stirred at rt for 16 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 50 mg (42%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.52-8.57 (m, 1 H), 7.88-7.96 (m, 1H), 7.76-7.84 (m, 1 H), 7.48-7.55 (m, 1 H), 7.26-7.39 (m, 5 H), 7.04-7.11 (m, 1 H), 6.58-6.63 (m, 1 H), 5.64 (s, 2 H), 4.43-4.89 (m, 1 H), 3.69-4.12 (m, 3 H), 3.24-3.57 (m, 4 H), 3.09-3.23 (m, 1 H), 2.72-2.99 (m, 1 H), 2.15-2.27 (m, 1 H), 1.88-1.99 (m, 6H); ES-MS m/z 525.15 [M+H]+, HPLC RT (min) 2.17.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]([NH:15][C@H:16]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C:17]([NH:19][N:20]1[CH2:24][CH2:23][C@H:22]([N:25]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH2:21]1)=[O:18])=[O:14])(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]([NH:15][C@H:16]([CH2:37][C:38]1[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=1)[C:17]([NH:19][N:20]1[CH2:24][CH2:23][C@H:22]([N:25]([CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]2)[C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH2:21]1)=[O:18])=[O:14]
Reactant: CC(C)C(=O)N(C1CCCCC1)[C@H]1CCN(NC(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@H]2CCCN2C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(=O)N(C1CCCCC1)[C@H]1CCN(NC(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@H]2CCCN2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
To a solution of (2R)-2-{[(2R)-1-(BOC)pyrrolidine-2-yl]carbonyl}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide, prepared in Step A, (50.0 mg, 0.081 mmol) in DCM (2 mL) was added TFA (2 mL). After the reaction solution was stirred at rt for 30 min. the solvent was removed in vacuo, and the residue was purified by HPLC to give the title compound (50.0 mg, 98.2%).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].S(OC)(O[CH3:30])(=O)=O.[Na]>C(O)(C)C>[Br:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[N:17]([CH3:30])[C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)c(Cl)cc1Br
Reactant: COS(=O)(=O)OC
Agent: [Na]
Solvent: CC(C)O
Product: CC(C)OC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CCC3)c(Cl)cc1Br

Procedure:
using isopropyl 2-bromo-4-chloro-5-(1,2,4,5,6,7-hexahydro-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate and dimethyl sulphate with sodium isopropylate in isopropanol there is obtained isopropyl 2-bromo-4-chloro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, 1H--NMR (CDCl3, 400 MHz) 7.86 ppm (s, 1H), 7.74 ppm (s, 1H), 5.23 ppm (m, 1H), 3.42 ppm (s, 3H), 2.96 ppm (m, 2H), 2.82 ppm (m, 2H), 2.18 ppm (m, 2H), 1.35 ppm (d, 6H),
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([O:17][CH3:18])[CH:8]=[CH:7][C:4]=1[CH:5]=O.ClC1C(OC)=C(C=[CH:29][C:30]([OH:32])=[O:31])C=CC=1OC>>[CH3:1][O:2][C:3]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([O:17][CH3:18])[CH:8]=[CH:7][C:4]=1/[CH:5]=[CH:29]/[C:30]([OH:32])=[O:31]
Reactant: COc1ccc(C=CC(=O)O)c(OC)c1Cl
Reactant: COc1ccc(C=O)c(OC)c1-c1ccccc1
Product: COc1ccc(/C=C/C(=O)O)c(OC)c1-c1ccccc1
Yield: 96 %

Procedure:
Compound 3c was synthesized from 2c in 96% yield using the procedure described for 3a. 1H NMR (DMSO-d6): δ 7.81 (d, J=8.8 Hz, 1H), 7.74 (d, J=16.0 Hz, 1H), 7.28-7.42 (m, 5H), 6.97 (d, J=8.8 Hz, 1H), 6.47 (d, J=16.0 Hz, 1H), 3.73 (s, 3H), 3.25 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6]2[N+:7]([O-])=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:9]=[N:10][C:5]=2[C:4]([CH3:19])([CH3:18])[O:3]1.C1CCCCC=1>[Pd].C(O)C>[CH3:1][C:2]1([CH3:20])[C:6]2[N:7]=[C:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:9]=[N:10][C:5]=2[C:4]([CH3:19])([CH3:18])[O:3]1
Reactant: CC1(C)OC(C)(C)c2c1nnc(-c1ccccc1)[n+]2[O-]
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CC1(C)OC(C)(C)c2nc(-c3ccccc3)nnc21

Procedure:
To a solution of 0.271 grams (0.001 mole) 5,7-dihydro-5,5,7,7-tetramethyl-3-phenylfuro-[3,4-e]-as-triazine-4-oxide and 0.246 grams (0.003 mole) cyclohexene in 4 ml. absolute ethanol is added 10 milligrams of 10% palladium on charcoal and the resulting mixture is refluxed under an atmosphere of nitrogen for 18 hours. The catalyst is removed by filtration and the filtrate evaporated to dryness. The residue is recrystallized from ether/hexane to give 5,7-dihydro-5,5,7,7-tetramethyl-3-phenylfuro[3,4-e]-as-triazine, m.p. 90°-91°C.
Reaction SMILES: FC1C=CC(OC)=C(C2C(C(O)=O)=CC([N+]([O-])=O)=CC=2)C=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1[C:32]1[C:33]([C:41]([O:43]C)=[O:42])=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=1>>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1[C:32]1[C:33]([C:41]([OH:43])=[O:42])=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cc(OC)ccc1OC
Agent: COc1ccc(F)cc1-c1ccc([N+](=O)[O-])cc1C(=O)O
Product: COc1ccc(OC)c(-c2ccc([N+](=O)[O-])cc2C(=O)O)c1
Yield: 97.5 %

Procedure:
This compound was prepared in a manner similar to that of 5'-fluoro-2'-methoxy-4-nitro-2-biphenylcarboxylic acid (EXAMPLE 107) from methyl 2',5'-dimethoxy-4-nitro-2-biphenylcarboxylate (2.07 g) to afford 1.93 g (99%) of 2',5'-dimethoxy-4-nitro-2-biphenylcarboxylic acid as a white solid. Data for 2',5'-dimethoxy-4-nitro-2-biphenylcarboxylic acid: 1H NMR (400 MHz, acetone-d6) 8.64 (d, J=2.5, 1H), 8.43 (dd, J=8.4, 2.6, 1H), 7.67 (d, J=8.5, 1H), 6.94 (m, 2H), 3.80 (s, 3H), 3.68 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][CH:8]([CH3:12])[CH2:7][C:5]=2[N:6]=1.C([C:15](=O)[C:16]([O-:18])=[O:17])C.[C:20]1(C)C=CC=C[CH:21]=1.CC(C)([O-])C.[Li+]>C1COCC1>[Br:1][C:2]1[S:3][C:4]2[C:10](=[O:11])/[C:9](=[CH:15]/[C:16]([O:18][CH2:20][CH3:21])=[O:17])/[CH:8]([CH3:12])[CH2:7][C:5]=2[N:6]=1
Reactant: CC1CC(=O)c2sc(Br)nc2C1
Reactant: Cc1ccccc1
Reactant: CCC(=O)C(=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C1/C(=O)c2sc(Br)nc2CC1C
Reaction time: 4.5 h

Procedure:
A 3.0 L round-bottom flask was charged with 2-bromo-5-methyl-5,6-dihydrobenzo[d]thiazol-7(4H)-one (75.0 g, 305 mmol, 1.00 equiv), anhydrous THF (750 mL), and a 50% w/v solution of ethylglyoxylate in toluene (211 mL, 1.07 mol, 3.50 equiv). The resulting solution was placed in a water bath. Solid lithium tert-butoxide (48.9 g, 610 mmol, 2.0 equiv) was steadily added over a 1 min period. The reaction was capped and stirred for 4.5 h. TLC (20% EtOAc/80% hexane indicated full consumption of 2-bromo-5-methyl-5,6-dihydrobenzo[d]thiazol-7(4H)-one). Saturated aqueous NH4Cl (750 mL) was added quickly. The reaction was stirred for 15 min. H2O (250 mL) was added. Most of the solids dissolved. 1.0 M aqueous HCl (180 mL) was added over a 5 min period. After a short time the pH of the aqueous layer was ˜3.5. The organic phase was collected, and the aqueous layer was extracted with EtOAc (2×375 mL). Combined organic layers were washed with brine (500 mL), dried (MgSO4), filtered, and concentrated to a minimum volume with a bath temperature of 50-60° C. and 10 mmHg vacuum. DCM (40 mL) was added. The resulting solution was transferred to a Combiflash XL solid loading cartridge by gravity loading. The solid cartridge was assembled in line with a 1.5 kg Combiflash XL silica gel column equilibrated with hexane. The following gradient elution sequence was used: [100% Hexane (5 column volumes, isocratic)→10% EtOAc/90% Hexane (10 column volumes, linear gradient)→10% EtOAc/90% Hexane (7 column volumes, isocratic))→100% EtOAc (8 column volumes, isocratic)]. Fractions containing product were combined, concentrated, and dried under high vacuum to give desired product. LCMS-ESI+ calc'd for C12H12BrNO3S: 330.0 and 332.0 (M+H+); found: 330.0 and 332.0 (M+H+). 1H NMR (400 MHz, CDCl3): δ 6.77 (s, 1H), 4.60-4.53 (m, 1H), 4.30-4.21 (m, 2H), 3.23 (dd, J=17.6, 5.8 Hz, 1H), 3.07 (d, J=5.8 Hz, 1H), 1.33 (t, J=7.2 Hz, 3H), 1.23 (d, J=7.0 Hz, 3H).