Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:6]1[CH:19]=[CH:18][C:9]2[NH:10][C:11]([CH2:13][CH2:14][CH2:15][CH2:16]Cl)=[N:12][C:8]=2[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH:20]([NH2:23])([CH3:22])[CH3:21]>>[C:2]([C:6]1[CH:19]=[CH:18][C:9]2[NH:10][C:11]([CH2:13][CH2:14][CH2:15][CH2:16][NH:23][CH:20]([CH3:22])[CH3:21])=[N:12][C:8]=2[CH:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1ccc2[nH]c(CCCCCl)nc2c1
Reactant: CC(C)N
Agent: Cl
Product: CC(C)NCCCCc1nc2cc(C(C)(C)C)ccc2[nH]1
Temperature: 25 °C
Yield: 51.3 %

Procedure:
A solution of 5-tert-butyl-2-(4-chloro-butyl)-1H-benzoimidazole hydrochloride (500 mg, 1.66 mmol) in isopropylamine (6 ml, 70.04 mmol) was heated to 80° in a sealed tube overnight. The reaction was cooled to RT and solvent evaporated. The residue was purified by flash column chromatography over silica gel, eluted with MeOH in DCM from 2% to 10% gradually to yield 245 mg (51%) of clean product as a yellow oil; MS (ESI+) for C18H29N3 m/z 1 [M+H]+, 288.50; HPLC purity 99% (ret. time, 1.12 min). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.10 (6H, d, J=6.26 Hz), 1.37 (9H, s), 1.60 (2H, quin, J=7.06 Hz), 1.90 (2H, quin, J=7.25 Hz), 2.66 (2H, t, J=6.79 Hz), 2.82 (1H, spt, J=6.23 Hz), 2.93 (2H, t, J=7.17 Hz), 7.22-7.30 (1H, m), 7.46 (1H, d, J=8.39 Hz), 7.54 (1H, s).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26]([OH:28])=O)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:30]=[C:31]([NH2:38])[CH2:32][C:33]1([CH2:36][OH:37])[CH2:35][CH2:34]1>>[OH:37][CH2:36][C:33]1([CH2:32][C:31]2[N:38]=[C:26]([CH:12]3[CH2:13][CH:14]([C:16]4[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:20][CH:21]=4)[CH2:15][N:10]([C:8]([N:5]4[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]4)=[O:9])[CH2:11]3)[O:28][N:30]=2)[CH2:35][CH2:34]1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Reactant: NC(CC1(CO)CC1)=NO
Product: O=C(N1CCC(O)CC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(CC3(CO)CC3)no2)C1

Procedure:
100 mg (0.25 mmol) of the compound from Example 99A and 62 mg (0.38 mmol) of the compound from Example 67A were reacted according to the General Method 2. Yield: 66 mg (52% of theory)
Reaction SMILES: [OH:1][CH:2]([P:11](=[O:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:10].C/C(/[O-])=C/C(C)=O.C(OO)(C)(C)C>ClC1C=CC=CC=1>[Cl:10][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:3]=1[C:2]([P:11](=[O:24])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:1]
Reactant: O=P(c1ccccc1)(c1ccccc1)C(O)c1c(Cl)cccc1Cl
Agent: CC(=O)/C=C(/C)[O-]
Agent: CC(C)(C)OO
Solvent: Clc1ccccc1
Product: O=C(c1c(Cl)cccc1Cl)P(=O)(c1ccccc1)c1ccccc1
Reaction time: 5 h
Yield: 64 %

Procedure:
To 15 g (0.04 mol) of α-hydroxy-(2,6-dichlorobenzyl)-diphenyl phosphine oxide and 0.4 g (1.5 mmol) of vanadyl(IV) bis-acetylacetonate in 100 g of chlorobenzene there were added 12.9 g (0.1 mol) 70 wt % strength aqueous tert-butylhydroperoxide, and the mixture was kept at 70° C. for 5 h. The product was isolated by crystallization. Yield: 64%, mp 156°-158° C.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH2:15])[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[CH:19][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:21]1[CH:30]=[CH:29][C:28]2[CH2:27][N:26]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:25][CH2:24][C:23]=2[N:22]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>O1CCOCC1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:21]4[CH:30]=[CH:29][C:28]5[CH2:27][N:26]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:25][CH2:24][C:23]=5[N:22]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[CH:19][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ncc2c3ccncc3n(C3CCCC3)c2n1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Cl)ccc2C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2nc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)ccc2C1
Temperature: 150 °C
Yield: 72.4 %

Procedure:
To a solution of 9-cyclopentyl-9H-pyrido[4′,3′:4,5]pyrrolo[2,3-d]pyrimidin-2-amine (prepared as described in WO 2009/085185) (152 mg, 0.6 mmol) in dioxane (6 mL) were added tert-butyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (177 mg, 0.66 mmol), tris(dibenzylideneacetone)dipalladium (0) (28 mg, 0.030 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (52 mg, 0.090 mmol), and sodium t-butoxide (86 mg, 0.9 mmol). The reaction mixture thus obtained was heated at 150° C. under microwave irradiation for 1 hour. The reaction mixture was diluted with DCM, washed with brine, and then dried. The solvent was evaporated and the residue was purified by flash chromatography on silica gel eluting with 10% to 50% solvent A (DCM/MeOH/NH4OH, 100:10:1) in DCM to give the title compound as a light yellow solid (211 mg, 72% yield). 1H NMR (500 MHz, CDCl3) δ 1.52 (9H, s), 1.88-1.90 (2H, m), 2.14-2.21 (4H, m), 2.45-2.47 (2H, m), 2.92-2.94 (2H, m), 3.76-3.79 (2H, m), 4.59 (2H, m), 5.37 (1H, m), 7.49 (1H, d, J=10.0 Hz), 7.85 (1H, d, J=5.0 Hz), 8.14 (1H, br. s), 8.37 (1H, d, J=10.0 Hz), 8.52 (1H, d, J=5.0 Hz), 8.92 (1H, s), 9.11 (1H, s) ppm; LCMS m/z: 486 (M+1).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].[Cl:11][C:12]1[C:13]([C:29]#[N:30])=[C:14]([CH:26]=[CH:27][CH:28]=1)[O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>>[C:1]([C:4]1[S:8][C:7]([NH:9][S:22]([C:19]2[CH:18]=[CH:17][C:16]([O:15][C:14]3[CH:26]=[CH:27][CH:28]=[C:12]([Cl:11])[C:13]=3[C:29]#[N:30])=[CH:21][CH:20]=2)(=[O:23])=[O:24])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)c1sc(N)nc1C
Reactant: N#Cc1c(Cl)cccc1Oc1ccc(S(=O)(=O)Cl)cc1
Product: CC(=O)c1sc(NS(=O)(=O)c2ccc(Oc3cccc(Cl)c3C#N)cc2)nc1C

Procedure:
The tide compound was prepared from 5-acetyl-2-amino-4-methylthiazole and 4-(3-chloro-2-cyanophenoxy)benzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (9.9 mg) with purity >90%. LCMS (pos) m/z 448.0; LCMS (neg) m/z 446.0.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C(O[SiH](OCC)OCC)C.N[CH2:16][CH2:17][CH2:18][Si:19]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>[Rh].CC1C=CC(C)=CC=1>[CH2:1]([NH2:4])[CH:2]=[CH2:3].[NH2:4][CH:17]([CH3:16])[CH2:18][Si:19]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]
Reactant: CCO[Si](CCCN)(OCC)OCC
Agent: [Rh]
Agent: CCO[SiH](OCC)OCC
Solvent: Cc1ccc(C)cc1
Solvent: C=CCN
Product: CCO[Si](CC(C)N)(OCC)OCC
Temperature: 110 °C

Procedure:
A three-neck flask equipped with a reflux condenser, stirring rod and thermometer was charged with 14 grams of allylamine (0.25 mole), 41 grams of triethoxy silane (0.25 mole), 20 ml. of p-xylene and 0.1% by mole (calculated as rhodium), per mole of triethoxysilane, of [Rh(μ-P Ph2) (COD)]2, that is [rhodium(μ-diphenyl phosphide) (1,5-cyclooctadiene) dimer], and heated on an oil bath maintained at a temperature of 110° C. About 1 hour after the beginning of the reaction, the reaction temperature reached 110° C. At the end of the period the reaction mixture was subjected to gas chromatography analysis. It was found that gamma-aminopropyl triethoxy silane was obtained in a yield of 81% on an allylamine basis, while the yield of beta-aminopropyl triethoxy silane was 0.7% on a triethoxy silane basis.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[CH:25]=O)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].NO.CC([Si](Cl)(C)C)(C)C.[NH:37]1C=CN=C1>C(O)C.CCOC(C)=O.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[C:25]#[N:37])=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(Cl)cc2C=O)[nH]1
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: NO
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(Cl)cc2C#N)[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 51.2 %

Procedure:
2-[5-(4-Chloro-2-formyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (985 mg, 2.62 mmol) was dissolved in ethanol (20 mL) and hydroxylamine (50% w/w in H2O, 642 μL, 10.48 mmol) was added. After stirring at room temperature for 15 h, the solution was concentrated. To the crude oxime was added TBSCl (474 mg, 3.14 mmol), imidazole (357 mg, 5.24 mmol) and DMF (10 mL). The reaction mixture was stirred at 120° C. for 80 minutes at which point more TBSCl (237 mg, 1.58 mmol) and imidazole (177 mg, 2.60 mmol) were added. The reaction mixture was stirred an additional 17 hours at 120° C. then cooled to room temperature, diluted with EtOAc. The organic phase was washed with saturated aqueous NaHCO3 and brine then dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (25% to 50% EtOAc/Hexane) to afford the title compound 2-[5-(4-Chloro-2-cyano-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 51%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][CH3:10])[CH:6]=[CH:5][CH:4]=1.C1C(=O)N([I:18])C(=O)C1>CN(C=O)C>[I:18][C:4]1[CH:5]=[CH:6][C:7]([NH:9][CH3:10])=[N:8][C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1I
Reactant: CNc1cccc(OC)n1
Solvent: CN(C)C=O
Product: CNc1ccc(I)c(OC)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
6-Methoxy-N-methyl-2-pyridinamine (17.24 g, 124 mmol) is dissolved in DMF (160 mL) and cooled to 0° C. followed by the addition of NIS (28 g, 124 mmol, 1 equiv), at a rate which keeps the reaction temperature below 10° C. The reaction is then allowed to warm to room temperature and stirred for 1 h. The reaction is distilled to dryness in vacuo and the residue is dissolved in CH2Cl2 and passed through a silica plug eluting with heptane/EtOAc (9/1) affording 32 g of crude 5-iodo-6-methoxy-N-methyl-2-pyridinamine. The crude 5-iodo-6-methoxy-N-methyl-2-pyridinamine is dissolved in diethyl ethoxymethylenemalonate (32 mL) and the mixture is heated at 140° C. for 2 h, then cooled to room temperature and passed through a silica plug eluting with heptane/EtOAc (19/1, 0/1). The product is then dissolved in Eaton's reagent (132 mL) and heated at 100° C. for 40 min, cooled to rt and poured into Na2CO3. The basic aqueous layer is then extracted with CH2Cl2 (3×), washed with water, and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography (heptane/EtOAc, 4/1, 1/1, CH2Cl2/MeOH 19/1) the desired product is then triturated with MeOH to afford 7.9 g (16%) of ethyl 6-iodo-7-methoxy-1-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylate. Physical characteristics are as follows: 1H NMR (CDCl) δ9.04, 8.52, 4.41, 4.13, 3.91, 1.43; IR (diffuse reflectance) 2491, 2427, 2350, 2282, 2242, 1678, 1632, 1613, 1579, 1384, 1309, 1275, 1227, 1106, 804, cm−1; MS (EI) m/z 388, 344, 343, 317, 316, 185, 159, 86, 84, 51; Anal calcd for C13H13IN2O4: C, 40.23; H, 3.38; N, 7.22. Found: C, 40.20; H, 3.40; N, 7.16
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[N:29]=3)[N:24]=[CH:23][C:22]=2[F:33])[C:17](OC)=[O:18])[CH2:11][CH2:10]1)=[O:7])([CH3:4])[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[F:33][C:22]1[CH:23]=[N:24][C:25]2[C:30]([C:21]=1[CH:16]([CH2:17][OH:18])[CH2:15][N:12]1[CH2:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:3])([CH3:4])[CH3:1])[CH2:14][CH2:13]1)=[N:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2
Reactant: COC(=O)C(CN1CCC(NC(=O)OC(C)(C)C)CC1)c1c(F)cnc2ccc(OC)nc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2ncc(F)c(C(CO)CN3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Temperature: -10 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
A solution of methyl 3-[4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1-piperidinyl]-2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]propanoate (26.63 g, containing about 9% DMF by weight, estimate 52.5 mmol) was stirred under argon at −70° C. and treated with a 1M solution of lithium aluminium hydride in THF (60 ml). The mixture was allowed to warm to −10° C., stirred in an ice bath for 2 hours, treated with water (4.5 ml), 2N NaOH solution (8.44 ml) and water (9.7 ml) and stirred a further 30 minutes. The solid was filtered off and washed with THF and the filtrate evaporated. Chromatography of the residue (methanol/dichloromethane gradient) gave the product (18.28 g).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([O:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:30]5[CH:31]=[N:32][C:27]([O:26][CH2:24][CH3:25])=[CH:28][CH:29]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CCOc1ccc(B(O)O)cn1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: CCOc1ccc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cn1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 60 mg, 0.161 mmol) and 6-ethoxypyridine-3-boronic acid (ABCR, Karlsruhe, Germany, 36 mg, 0.211 mmol) to give the title compound as a white solid. (HPLC: tR 2.69 min (Method A); M+H=415 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.96 (s, 1H), 8.32-8.24 (m, 1H), 8.15-8.05 (m, 2H), 7.92-7.85 (m, 1H), 7.79-7.72 (m, 1H), 7.47 (s, 1H), 6.94-6.87 (m, 1H), 4.32 (q, 2H), 3.90 (s, 3H), 3.57 (s, 3H), 1.95 (s, 3H), 1.32 (t, 3H))
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:4][CH2:3]1.[H-].[Na+].I[CH3:22].O>CN(C=O)C.C(OCC)(=O)C>[CH3:22][O:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]2[C:9](=[O:18])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]2=[O:17])[CH2:6][CH2:7]1
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CO[C@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)CC1

Procedure:
To a solution of 2-(trans-4-hydroxy-cyclohexyl)-isoindole-1,3-dione (Glennon et al. J. Med. Chem. 1996, 39, 1, 314-322) (1.0 g, 40.77 mmol) in DMF (4.0 mL) was added NaH (60% in oil, 0.41 g, 10.2 mmol) followed by iodomethane (5.79 g, 40.7 mmol). The reaction mixture was stirred for 16 h before water (15 mL) and ethyl acetate (25 mL) was added and the phases were separated. The organic phase was washed with water (2×10 mL), dried over MgSO4 and the solvent was removed in cacuo. The residue was purified on silica gel (EtOAc-heptane) to give 0.810 g (77%) 2-(trans-4-methoxy-cyclohexyl)-isoindole-1,3-dione. 2-(trans-4-methoxy-cyclohexyl)-isoindole-1,3-dione (0.710 g, 2.74 mmol) in absolute ethanol (10 mL) was added hydrazine hydrate (0.130 g, 4.11 mmol) and the reaction mixture was stirred for 2 h at 50° C. The oilbath was removed and the mixture was stirred for 16 h at room temperature. The volatiles were removed in vacuo and the residue was added NaOH (20 mL, 10 N) and extracted with diethyl ether (3×10 mL). The organic phase was dried with MgSO4 and concentrated in vacuo to give 0.300 g (85%) of 4-trans-methoxy-cyclohexylamine. 4-Trans-methoxy-cyclohexylamine (100 mg, 0.78 mmol) and cyclopentanone (72 mg, 0.85 mmol) in THF-MeOH 2:1 (2 mL) and acetic acid (0.1 mL) was added sodium cyanoborohydride (73 mg, 1.02 mmol) in small portions over 15 min. The reaction mixture was stirred for 16 h before the volatiles were removed in vacuo. The residue was added HCl (1N, 50 mL) and stirred for 16 h at rt. The mixture was added NaOH (10N, 2.5 mL), extracted with diethyl ether (2×10 mL) and dried over MgSO4. The solvent was removed in vacuo to give 134 mg (88%) of cyclopentyl-(4-methoxy-cyclohexyl)-amine.
Reaction SMILES: [CH3:1][C:2]1([C:11]([OH:13])=[O:12])[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.C(Cl)(Cl)=O.[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([C:33]3[N:34]=[C:35]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[O:36][C:37]=3[C:38]([F:41])([F:40])[F:39])=[O:32])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1.C(N(CC)CC)C>C(Cl)Cl.C1COCC1>[CH3:1][C:2]1([C:11]([OH:13])=[O:12])[CH2:3][CH2:4][CH:5]([C:8]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:25]=[CH:26][C:27]([NH:30][C:31]([C:33]4[N:34]=[C:35]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[O:36][C:37]=4[C:38]([F:39])([F:40])[F:41])=[O:32])=[CH:28][CH:29]=3)[CH2:20][CH2:19]2)=[O:10])[CH2:6][CH2:7]1
Reactant: O=C(Nc1ccc(C2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CC1(C(=O)O)CCC(C(=O)O)CC1
Agent: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC1(C(=O)O)CCC(C(=O)N2CCC(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)CC2)CC1
Reaction time: 0.5 h
Yield: 24.3 %

Procedure:
Methyl-cyclohexane-1,4-dicarboxylic acid (34.1 mg, 0.183 mmol) in dry CH2Cl2 (3 mL) was treated with phosgene (2M in CH2Cl2, 366 uL, 0.732 mmol) for 30 minutes. THF (0.5 mL) was added and stirred for an additional 30 minutes. The reaction was evaporated and re-evaporated from toluene three times and re-dissolved in 5 mL CH2Cl2. 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide (76.2 mg, 0.183 mmol) and triethylamine (77 uL, 0.549 mmol) in 3 mL of CH2Cl2 were added dropwise over 15 minutes to the above solution. The mixture was stirred at room temperature for 90 minutes and then diluted with 10 mL CH2Cl2. Following work-up, the crude residue was purified by flash chromatography to yield 1-methyl-4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carbonyl)-cyclohexanecarboxylic acid as a white solid (26 mg, 24%). ES-MS calcd for C31H32F3N3O5 (m/e) 583.61, obsd 584 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([OH:16])=[C:11]([NH2:15])[CH:12]=2)[CH2:7][N:6]1[C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])=[O:4].O.C(=O)(O)[O-].[Na+].Cl[CH:30]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([Cl:49])[CH:43]=2)=[CH:36][CH:35]=1)[C:31](Cl)=[O:32]>CCOC(C)=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[C:10]([O:16][C@@H:30]([C:34]4[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]5[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([Cl:49])[CH:43]=5)=[CH:36][CH:35]=4)[C:31](=[O:32])[NH:15]3)=[CH:9][C:8]=2[CH2:7][N:6]1[C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])=[O:4]
Reactant: COC(=O)[C@@H]1Cc2cc(N)c(O)cc2CN1C(=O)OC(C)C
Reactant: O=C(Cl)C(Cl)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(S)-6-amino-7-hydroxy-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-isopropyl ester 3-methyl ester (1.8 g) was dissolved in 10 mL EtOAc, 20 mL water and 5.0 g sodium bicarbonate added. 2-Chloro-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-acetyl chloride in 10 mL of EtOAc was added and the mixture stirred at rt for 1.5 h. The organic layer was washed with brine, dried and evaporated. The residue was dissolved in 15 mL DMF and potassium carbonate (4.1 g) added. The mixture stirred at r.t. for 3 h and was poured onto water and EtOAc. The organic was washed with 1N HCl, dried and evaporated. The residue was purified over silica (hexanes-EtOAc-2M ammonia in MeOH) to provide (S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-isopropyl ester 7-methyl ester (2.0 g). LC-MS (m/z) 600.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.O=P(Cl)(Cl)Cl.CN([CH:20]=[O:21])C>>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([CH:20]=[O:21])=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: CN1CCCc2ccccc21
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCCc2cc(C=O)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
To a solution of 1-methyl-1,2,3,4-tetrahydroquinoline (4.4 g, ca. 30.0 mmol) in DMF (30 mL) was added POCl3 (2.8 mL, 30.0 mmol, 1.0 eq) at 0° C. The mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured onto ice then extracted with Et2O (3×50 mL). The combined organic layers were dried over Na2SO4 then concentrated to give a crude product which was purified by flash column chromatography (0-20% EtOAc in hexanes) to afford the title compound (2.17 g, 12.4 mmol, 41% over two steps).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[Br:13])[C:6](C2C(=O)NC(=O)C=2C2C3C(=CC=CC=3)NC=2)=[CH:5]1)[CH:2]=[CH2:3]>CO>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[Br:13])[CH:6]=[CH:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1cc(C2=C(c3c[nH]c4ccccc34)C(=O)NC2=O)c2cccc(Br)c21
Solvent: CO
Product: C=CCn1ccc2cccc(Br)c21

Procedure:
(±)-Trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione may be prepared by reacting 1-allyl-7-bromo-1H-indole with (COCl)2 (oxalyl chloride) and sodium methoxide in a polar aprotic solvent such as dichloromethane to yield (1-allyl-7-bromo-1H-indol-3-yl)-oxo-acetic acid methyl ester, which is subsequently reacted with 2-(1H-indol-3-yl)-acetamide and tBuOK (potassium tert-butoxide) in THF to yield 3-(1-allyl-7-bromo-1H-indol-3-O-4-(1H-indol-3-yl)-pyrrole-2,5-dione. Reduction of the 3-(1-allyl-7-bromo-1H-indol-3-yl)-4-(1H-indol-3-yl)-pyrrole-2,5-dione by Mg in refluxing methanol, as in Example 2 procedure C, yields 3-(1-allyl-7-bromo-1H-indol-3-O-4-(1H-indol-3-O-pyrrolidine-2,5-dione, which is treated with 9-BBN (9-borabicyclo[3.3.1]nonane) and Pd(PPh3)4 (tetrakis(triphenylphosphine)palladium) to yield (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH:12]([C:25]1[CH:26]=[C:27]([Si:30]([CH3:33])([CH3:32])[CH3:31])[O:28][CH:29]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(N(CC)CC)C>ClCCl>[O:11]=[C:12]([C:25]1[CH:26]=[C:27]([Si:30]([CH3:33])([CH3:32])[CH3:31])[O:28][CH:29]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCCCCCCCCCCCC(=O)c1coc([Si](C)(C)C)c1
Reaction time: 0.08 h

Procedure:
A mixture of dimethyl sulfoxide (0.5 ml) and dichloromethane (5 ml) was added dropwise to a solution of oxalyl chloride (0.36 ml, 4.18 mmol) in dichloromethane (5 ml) at -78° under argon. After 5 minutes, a solution of 4-(1-hydroxytridecyl)-2-trimethylsilylfuran (Compound 25, 1.01 g, 2.98 mmol) in dichloromethane (5 ml), followed by triethylamine (1.66 ml, 11.9 mmol) after 20 minutes, was added. Stirring was continued for 3 hours while the cooling bath attained room temperature. The mixture was quenched with water and extracted with dichloromethane. The dried (magnesium sulfate) extracts on evaporation gave a residue which was purified by a silica column using 2.5% ethyl ether/hexane. Fractions with Rf of about 0.27 (5% ethyl ether/hexane) on evaporation gave the titled ketone as an off-white solid.