Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:9]([CH2:10][OH:11])=[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:27]=[N:28][N:29]([C:31]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:30]=3)=[CH:16][CH:15]=2)[CH:7]=[C:6]([CH3:50])[N:5]=1.I[CH3:52].O.CN([CH:57]=[O:58])C>>[CH3:3][C:4]1[C:9]([C:10]([O:58][CH2:57][CH3:52])=[O:11])=[C:8]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:27]=[N:28][N:29]([C:31]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[N:30]=3)=[CH:18][CH:19]=2)[CH:7]=[C:6]([CH3:50])[N:5]=1
Reactant: Cc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(CO)c(C)n1
Reactant: CN(C)C=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1c(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)cc(C)nc1C
Reaction time: 0.17 h

Procedure:
Sodium hydride (115 mg) was added to a solution of 2,6-dimethyl-3-hydroxymethyl-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]pyridine (1.0 g) in DMF (30 ml) and the mixture was stirred for 10 minutes. Iodomethane (0.3 ml) was added and the mixture was stirred for 18 hours. Water (100 ml) was added and the mixture was extracted with ethyl acetate (2×50 ml). The combined extracts were washed with saturated sodium chloride solution (50 ml) and then dried (MgSO4). The solvent was removed by evaporation and the residue was purified by flash chromatography, eluting with a mixture of methanol and dichloromethane on a gradient from 1:50 v/v to 1:20 v/v, to give 2,6-dimethyl-3-methoxymethyl-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]pyridine (A) (0.74 g), m.p. 132°-135° C.; NMR (d6 -DMSO/d4 -acetic acid): 2.55(s,6H), 3.2(s,3H), 4.45(s,2H), 5.25(s,2H), 6.8-7.9 (complex m,24H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:10]=2[N:11]=[C:12](SC)[N:13]=1.[CH2:26]([N:28]([CH2:32][CH3:33])[CH2:29][CH2:30][NH2:31])[CH3:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:10]=2[N:11]=[C:12]([NH:31][CH2:30][CH2:29][N:28]([CH2:32][CH3:33])[CH2:26][CH3:27])[N:13]=1
Reactant: CCC(CC)n1c(=O)ccc2c(-c3ccccc3Cl)nc(SC)nc21
Reactant: CCN(CC)CCN
Product: CCC(CC)n1c(=O)ccc2c(-c3ccccc3Cl)nc(NCCN(CC)CC)nc21
Yield: 80 %

Procedure:
The product of Example 44, and N,N-diethylethylenediamine were reacted by the procedure of Example 60 to afford 4-(2-chloro-phenyl)-2-(2-diethylamino-ethylamino)-8-(1-ethyl-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one (371 mg, 80% yield. LC MS (m/e)=442 (MH+). Rt=1.77 min
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][C:26]3=[O:35])[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[N:36]1([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O.C(Cl)Cl>[N:36]1([CH:42]2[CH2:47][CH2:46][N:45]([C:13](=[O:14])[CH:12]([NH:16][C:17]([N:19]3[CH2:24][CH2:23][CH:22]([N:25]4[CH2:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[NH:27][C:26]4=[O:35])[CH2:21][CH2:20]3)=[O:18])[CH2:11][C:4]3[CH:5]=[C:6]4[C:10](=[C:2]([CH3:1])[CH:3]=3)[NH:9][N:8]=[CH:7]4)[CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc2cn[nH]c12
Reactant: C1CCN(C2CCNCC2)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
A stirred solution of (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid (65.7 mg, 0.138 mmol) in 2:1 dimethylformamide/methylene chloride (1.5 mL) at 0° C. was treated with 4-(1-piperidyl)-piperidine (46.5 mg, 2 equiv), diisopropylethylamine (0.048 mL, 2 equiv) and PyBOP® (75.5 mg, 1.05 equiv). The ice bath was allowed to melt and the mixture was stirred at room temperature overnight. The solvents were removed under high vacuum and the residue was purified by flash chromatography on silica gel, eluting with 18:1 methylene chloride/methanol containing 1% triethylamine, to give the product as a pale-yellow solid (80.4 mg, 93%). 1H-NMR (CD3OD, 500 MHz) δ −0.28 (1H, m), 0.75 (1H, m), 1.2-2.0 (12H, m), 2.08 (2H, m), 2.4-2.5 (3H, m), 2.59 (3H, s), 2.68 (2H, m), 2.90 (4H, m), 3.08 (4H, m), 3.9-5.1 (4H, several m), 6.81 (1H, d), 6.96 (1H, t), 7.16 (3H, m), 7.49 (1H, s), 8.03 (1H, s). Mass spec.: 627.29 (MH)+.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]2[NH:20][C:21](=[O:32])[C:22]3[N:27]([CH3:28])[N:26]=[C:25]([CH2:29][CH2:30][CH3:31])[C:23]=3[N:24]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4]([O:6]C)=O.[NH3:33]>>[OH:1][CH2:2][C@H:3]([NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]2[NH:20][C:21](=[O:32])[C:22]3[N:27]([CH3:28])[N:26]=[C:25]([CH2:29][CH2:30][CH3:31])[C:23]=3[N:24]=2)=[CH:16][CH:17]=1)(=[O:10])=[O:11])[C:4]([NH2:33])=[O:6]
Reactant: N
Reactant: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(S(=O)(=O)N[C@@H](CO)C(=O)OC)cc3)nc12
Product: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(S(=O)(=O)N[C@@H](CO)C(N)=O)cc3)nc12
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Methyl (2S)-3-hydroxy-2-({4-[(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)methyl]phenyl}sulfonamido)propanoate (280 mg, 0.0006 mol) was dissolved in 0.880 aqueous ammonia solution (10 ml), and stirred at room temperature for 60 hours. The reaction mixture was then concentrated under reduced pressure, suspended in water (10 ml), then re-concentrated under reduced pressure. Crystallisation from ethanol gave the title compound (192 mg), m.p.226-229° C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:18][CH2:19][C:20]([CH3:23])([OH:22])[CH3:21]>>[OH:22][C:20]([CH3:23])([CH3:21])[CH2:19][NH:18][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12]
Reactant: CC(C)(O)CN
Reactant: O=C(O)c1cc(OCC2CC2)c(C2CC2)cn1
Product: CC(C)(O)CNC(=O)c1cc(OCC2CC2)c(C2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 54, using 5-Cyclopropyl-4-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42c) and 1-amino-2-methylpropan-2-ol (CAN 2854-16-2) as starting materials and isolated (59 mg, 65%) as colorless oil; MS (ESI, m/z): 305.5 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24]#[C:25][CH3:26])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.[H][H].CCCCCC.C(OCC)(=O)C>[Pd].C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:24][CH2:25][CH3:26])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]([F:23])([F:21])[F:22])=[CH:17][CH:18]=1)[CH2:7]2
Reactant: CC#Cc1cc(Cl)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCc1cc(Cl)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Yield: 68.6 %

Procedure:
A mixture of 7-chloro-5-propynyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.082 g, 0.19 mmol) and 10% palladium on carbon (20 mg) in ethanol (25 mL) was reduced under 45 p.s.i. hydrogen. Workup and silica gel column chromatography using combinations 3:1 hexane-ethyl acetate afforded 7-Chloro-5-propyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.050 g, 69%). 1H NMR (300 MHz, CDCl3): δ (ppm) 0.94 (t, 3H), 1.64 (m, 2H), 2.63 (t, 2H), 4.20 (s, 2H), 4.78 (s, 2H), 7.09 (s, 1H), 7.14-7.38 (m, 5H). GC-MS: m/z 383 (M)+, 354 (M−29)+.
Reaction SMILES: N1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=N1.FC(F)(F)C([O:14][CH2:15][CH3:16])=O.[CH3:19][O-].[Na+]>CO>[C:15]1(=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:19][CH2:16]1
Reactant: CCOC(=O)C(F)(F)F
Reactant: C[O-]
Reactant: c1ccc2[nH]ncc2c1
Agent: [Na+]
Solvent: CO
Product: O=C1CCCc2ccccc21

Procedure:
Synthetic Scheme III shows the procedure for preparation of 4,5-dihydrobenz g!indazole compounds embraced by Formula I. In step 1, ethyl trifluoroacetate is reacted with base, such as 25% sodium methoxide in a protic solvent, such as methanol, and a 1-tetralone derivative (9) to give the intermediate diketone (10). In step 2, the diketone (10) in an anhydrous protic solvent, such as absolute ethanol or acetic acid, is treated with the free base or hydrochloride salt of a phenylhydrazine at reflux for 24 hours to afford a mixture of pyrazoles (11) and (12). Recrystallization gives the 4,5-dihydro benz g!indazolyl-benzenesulfonamide (11). ##STR13##
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH2:20]([N:22]=[C:23]=[O:24])[CH3:21].CCN(CC)CC.OP([O-])(O)=O.[K+]>C(Cl)Cl.CO>[C:16]([C:15]1[CH:14]=[CH:13][C:12]([C:7]2[C:6]3[CH2:5][CH2:4][CH2:3][CH:2]([NH:1][C:23]([NH:22][CH2:20][CH3:21])=[O:24])[C:11]=3[CH:10]=[N:9][CH:8]=2)=[CH:19][CH:18]=1)#[N:17]
Reactant: CCN=C=O
Reactant: N#Cc1ccc(-c2cncc3c2CCCC3N)cc1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCNC(=O)NC1CCCc2c(-c3ccc(C#N)cc3)cncc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
A cooled (0° C.) solution of (rac)-4-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)benzonitrile (example 1) (62.3 mg, 250 μmol) in CH2Cl2 (5 mL) was treated with ethyl isocyanate (51.6 μL, 625 μmol) in CH2Cl2 (0.6 mL) and Et3N (69.7 μL, 500 μmol). After ½ h the solution was stirred at room temperature for 1 h and treated with MeOH (0.2 mL). The reaction mixture was poured on aq. 10% KH2PO4 solution followed by extraction with AcOEt (3×). The organic phases were washed once with aq. sat. NaCl solution. The combined organic phases were dried (Na2SO4), filtered and purified by flash chromatography (50 g SiO2, Telos-cartridge, CH2Cl2/MeOH (1 to 3%)). Precipitation from CH2Cl2 with n-pentane gave the title compound (64 mg, 80%) as off-white powder. MS: 321.2 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[S:9][CH:10]=1)=[O:5])[CH3:2].[ClH:24].C(O)C>C(OCC)C>[ClH:24].[NH:14]1[CH2:15][CH2:16][CH:11]([C:8]2[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=2)[CH2:12][CH2:13]1
Reactant: CCOC(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1csc(C2CCNCC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1,1-dimethylethyl 4-[4-(ethoxycarbonyl)-2-thiazolyl]-1-piperidine-carboxylate (11.1 g, 32.7 mmol) (i.e. the product of Example 1, Step A) in 100 mL of diethyl ether was treated with a solution of 2 M hydrogen chloride in diethyl ether (166 mL, 331 mmol) at 0° C. The resulting reaction precipitate was dissolved with 100 mL of absolute ethanol and was stirred overnight at room temperature. The reaction mixture was evaporated in vacuo, re-dissolved in ethanol and evaporated again to give a solid. The resulting solid was placed under a high vacuum for several hours to give 10.38 g of the title compound as a hygroscopic white powder.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=2[O:2]1.[CH3:12][O:13][C:14](=[O:32])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23](Cl)[C:24]3[C:29]([CH3:30])=[CH:28][S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1>>[CH3:12][O:13][C:14](=[O:32])[C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:22]=[C:23]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:10]4[O:11][CH2:1][O:2][C:3]=4[CH:4]=3)[C:24]3[C:29]([CH3:30])=[CH:28][S:27][C:25]=3[N:26]=2)=[CH:19][CH:20]=1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c(C)csc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc4c(c3)OCO4)c3c(C)csc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-methylenedioxy-benzylamine is reacted with 4-(4-chloro-5-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-methylenedioxybenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[O:12])=[CH:4][C:3]=2[O:2]1.Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:46]=[CH:45][CH:44]=[CH:43][C:35]=2[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:30][CH:29]=1>>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:46]=[CH:45][CH:44]=[CH:43][C:35]=4[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:30][CH:29]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[O:12])=[CH:4][C:3]=2[O:2]1
Reactant: CC(C)c1ccc(S(=O)(=O)NC(=O)Cc2ccc3c(c2)OCO3)cc1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Product: CC(C)c1ccc(S(=O)(=O)NC(=O)C(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc3c(c2)OCO3)cc1
Yield: 69 %

Procedure:
Using the general procedure described in Example 6 the dianion derived from the product of Example 1 (0.419 g; 1.16 mmol) was alkylated with tert-butyl 2-(4-bromomethylphenyl)benzoate. The crude reaction mixture was partitioned between EtOAc and 10% aqueous NaHSO4, separated dried and evaporated. The residue was purified on a silica gel flash chromatography eluted with CHCl3 -MeOH--NH4OH (80:15:1). Evaporation of the purified fractions and drying in vacuo afforded 0.501 g (69%) of the title compound.
Reaction SMILES: [CH2:1]([PH:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH:2]([CH3:4])[CH3:3].CN([CH2:13][C-:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19]N(C)C)C.[CH-:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1.[Fe+2:28]>C(O)(=O)C>[CH2:1]([P:5]([CH2:13][C-:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][P:5]([CH2:6][CH:27]([CH3:26])[CH3:23])[CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][CH:7]([CH3:9])[CH3:8])[CH:2]([CH3:4])[CH3:3].[CH-:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1.[Fe+2:28]
Reactant: CN(C)Cc1ccc[c-]1CN(C)C
Reactant: CC(C)CPCC(C)C
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: CC(=O)O
Product: CC(C)CP(Cc1ccc[c-]1CP(CC(C)C)CC(C)C)CC(C)C

Procedure:
The title compound was prepared in accordance with the procedure of Example 10 employing di-iso-butylphosphine (Strem 486 mg, 3.33 mmol), 1,2-bis(dimethylaminomethyl)ferrocene (0.5 g, 1.66 mmol) and anhydrous acetic acid (100 ml). Yield 0.372 g.
Reaction SMILES: FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=[O:4].[CH3:22][C:23]([CH3:58])([CH2:56][CH3:57])[CH2:24][C:25]1[N:26]=[C:27]([CH:36]([OH:55])[C:37]2([C:43]3[CH:48]=[CH:47][C:46]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=4)=[CH:45][CH:44]=3)SCCCS2)[N:28]([S:30]([N:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])[CH:29]=1>C(#N)C.O>[CH3:22][C:23]([CH3:58])([CH2:56][CH3:57])[CH2:24][C:25]1[N:26]=[C:27]([CH:36]([OH:55])[C:37](=[O:4])[C:43]2[CH:48]=[CH:47][C:46]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=3)=[CH:45][CH:44]=2)[N:28]([S:30]([N:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])[CH:29]=1
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(O)C2(c3ccc(-c4ccccn4)cc3)SCCCS2)n1
Solvent: CC#N
Solvent: O
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(O)C(=O)c2ccc(-c3ccccn3)cc2)n1
Temperature: 0 °C

Procedure:
[Bis(trifluoroacetoxy)iodo]benzene (184 mg, 0.48 mmol) was added to a 0° C. solution of 4-(2,2-dimethylbutyl)-2-{hydroxy[2-(4-pyridin-2-ylphenyl)-1,3-dithian-2-yl]methyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide (110 mg, 0.20 mmol) in acetonitrile/water (3:1) (4 mL). After stirring at 0° C. until no further reaction (LCMS), the reaction mixture was quenched with saturated aqueous sodium thiosulfate/saturated aqueous sodium bicarbonate (1:1) and extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo to afford 4-(2,2-dimethylbutyl)-2-[1-hydroxy-2-oxo-2-(4-pyridin-2-ylphenyl)ethyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide which was used in the next step without further purification.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]1[CH:12]=C(C#N)[CH:10]=[CH:9][C:6]=1[C:7]#[N:8].[C:16]([OH:22])([C:18](F)(F)F)=[O:17].[H][H]>[Pt]=O>[NH2:8][C:7]1[C:6]2[CH2:9][CH2:10][CH:18]([C:16]([OH:22])=[O:17])[CH2:12][C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: O=C(O)C(F)(F)F
Reactant: [H][H]
Reactant: CN(C)/C=C/c1cc(C#N)ccc1C#N
Agent: O=[Pt]
Product: Nc1nccc2c1CCC(C(=O)O)C2
Temperature: 60 °C

Procedure:
The product from Example 147 Part D (1.0 g, 3.31 mmol) and platinum oxide (87 mg, 0.38 mmol) were added together with 21 mL of TFA. The reaction mixture was placed under a balloon of hydrogen gas and then warmed to 60° C. for 16 h. The mixture was cooled to RT and filtered through Celite to remove platinum oxide. The solvent was removed, and the residue was purified by reverse phase HPLC to give 0.21 g of the desired product as the TFA salt. LC/MS: 193.1, (M+H)+. 1HNMR (400 MHz, d4-MeOH) δ 2.00 (m, 1H), 2.28 (m, 1H), 2.57 (m, 2H) 2.85 (m, 1H), 3.02 (d, J=7.03 Hz, 2H), 6.75 (d, J=6.59 Hz, 1H), 7.61 (d, J=6.59 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]1[CH:20]=[C:21]([NH:25][C:26]([O:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][C:32]=2[CH3:40])=[O:27])[CH:22]=[CH:23][CH:24]=1)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C:42]1[CH:43]=[C:44]2[C:49](=[CH:50][CH:51]=1)[C:48]([N:52]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])=[N:47][CH:46]=[CH:45]2.O.[C:68]([OH:72])(=[O:71])[CH:69]=O>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]1[CH:20]=[C:21]([NH:25][C:26]([O:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH:69]([NH:41][C:42]3[CH:43]=[C:44]4[C:49](=[CH:50][CH:51]=3)[C:48]([N:52]([C:53]([O:55][C:56]([CH3:57])([CH3:58])[CH3:59])=[O:54])[C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])=[N:47][CH:46]=[CH:45]4)[C:68]([OH:72])=[O:71])=[CH:33][C:32]=2[CH3:40])=[O:27])[CH:22]=[CH:23][CH:24]=1)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C[C@H](NC(=O)OCc1ccccc1)c1cccc(NC(=O)OCCc2ccc(B(O)O)cc2C)c1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Reactant: O=CC(=O)O
Solvent: O
Product: CCOC(=O)C[C@H](NC(=O)OCc1ccccc1)c1cccc(NC(=O)OCCc2ccc(C(Nc3ccc4c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc4c3)C(=O)O)cc2C)c1
Yield: 96 %

Procedure:
Using a procedure analogous to that used to prepare 2D, 34E (400 mg, 0.73 mmol) was reacted with Intermediate 1 and glyoxylic acid monohydrate to afford 34F (670 mg, 96%) as a yellow foam. MS (ESI) m/z 697.15 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:10][CH2:9][CH2:8][C:7]2[N:6]=[CH:5][C:4]3[CH:11]=[CH:12][CH:13]=[CH:14][C:3]=3[C:2]1=2.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23](Cl)=[O:24].ClCCl>CCOCC>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]([N:1]1[CH2:10][CH2:9][CH2:8][C:7]2[N:6]=[CH:5][C:4]3[CH:11]=[CH:12][CH:13]=[CH:14][C:3]=3[C:2]1=2)=[O:24]
Reactant: O=C(Cl)Cc1ccccc1Cl
Reactant: c1ccc2c3c(ncc2c1)CCCN3
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(Cc1ccccc1Cl)N1CCCc2ncc3ccccc3c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Powdered 1,2,3,4-tetrahydrobenzo[c]-1,5-naphthyridine (8.29 g) was added to ice cold, stirred 2-chlorophenylacetyl chloride (30 ml) without external cooling. A thick suspension of crystalline material formed and a mild exothermic reaction was observed. After stirring overnight at room temperature the suspension was gradually diluted with anhydrous ether to give a tacky solid which formed a gummy mass. On continued stirring the material solidified and disintegrated to give a suspension. The material was isolated by vacuum filtration and washed well with ether. A solution of the filter cake and water (300 ml) was basified with 10% sodium hydroxide solution and extracted with dichloromethane (2×250 ml). The combined turbid organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to an oil. A solution of the oil and toluene (150 ml) was concentrated to remove any residual moisture, whereupon the material solidified. Thin layer chromatographic analysis (silica gel, ethyl acetate) indicated the presence of 40-50% starting material. A solution of the solid in dichloromethane (200 ml) was added to stirred, ice-cold 2-chlorophenylacetyl chloride (27 ml) without external cooling. After three hours, the solution was concentrated to reduce the reaction volume, whereupon a suspension formed. Sufficient dichloromethane (200 ml) was added to afford a solution which was allowed to stand for 48 hours at room temperature. The solution was concentrated to remove most of the dichloromethane and the residual oil was treated with excess ethereal hydrogen chloride and diluted with ether (400 ml) to give a tacky precipitate. The ether was decanted and the precipitate was triturated with fresh ether (solidified). The solid was isolated by vacuum filtration, washed well with ether and converted to the free base. Thin layer chromatographic analysis (silica gel, ethyl acetate) indicated the presence of a small amount of starting amine, the product and two higher Rf spots. The mixture was separated by HPLC (silica gel; sample applied in 200 ml of dichloromethane; eluted with ethyl acetate; 200 ml/min flow rate; recycle technique utilized to optimize the separation). The appropriate fractions were combined and concentrated to give a solid (7.97 g) which was triturated with ether, filtered, and dried in vacuo at 40° C., m.p. 176°-178° C.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[C:7]([CH2:9][CH2:10][CH2:11][C:12]([CH3:17])([CH3:16])[C:13](O)=[O:14])#[N:8]>ClCCl>[C:7]([CH2:9][CH2:10][CH2:11][C:12]([CH3:17])([CH3:16])[C:13]([Cl:4])=[O:14])#[N:8]
Reactant: CC(C)(CCCC#N)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)(CCCC#N)C(=O)Cl
Reaction time: 3 h

Procedure:
Oxalyl chloride (0.39 mL, 4.5 mmol) was added to a 0-5° C. solution of 5-cyano-2,2-dimethyl-pentanoic acid (0.462 g, 2.98 mmol) in 3 mL of dichloromethane, and the mixture was stirred for 3 h then concentrated to afford crude 5-cyano-2,2-dimethyl-pentanoyl chloride as a yellow oil, which was immediately used in the next step.