Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([CH2:17][CH2:18][N:19]3[C@H:24]4[CH2:25][CH2:26][C@@H:20]3[CH2:21][CH:22]([N:27]3[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=5[N:29]=[C:28]3[CH3:36])[CH2:23]4)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:7]=[C:8]([F:10])[CH:9]=1.C(N(CC)CC)C.[CH3:44][C:45]([CH3:50])([CH3:49])[C:46](Cl)=[O:47]>ClCCl>[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([CH2:17][CH2:18][N:19]3[C@H:24]4[CH2:25][CH2:26][C@@H:20]3[CH2:21][CH:22]([N:27]3[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=5[N:29]=[C:28]3[CH3:36])[CH2:23]4)[CH2:12][CH2:13][N:14]([C:46](=[O:47])[C:45]([CH3:50])([CH3:49])[CH3:44])[CH2:15][CH2:16]2)[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cc(F)cc(Cl)c2)CCNCC1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cc(F)cc(Cl)c2)CCN(C(=O)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.2 %

Procedure:
A mixture of 1-((1R,5S)-8-{2-[4-(3-chloro-5-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole dihydrochloride (0.2 g, 0.39 mmol), triethylamine (0.11 mL, 0.78 mmol) and trimethylacetyl chloride (0.053 mL, 0.43 mmol) in dichloromethane (4 mL) was stirred at rt for 1 h before the reaction mixture was quenched with saturated sodium bicarbonate solution. The organic layer was separated, dried, concentrated and purified by two successive chromatographies on silica gel using a dichloromethane to methanol:dichloromethane 1:20 gradient to give 1-((1R,5S)-8-{2-[4-(3-chloro-5-fluorophenyl)-1-(2,2-dimethylpropanoyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole as a glass (0.06 g, 27%). 1H NMR (400 MHz, CDCl3) δ 7.67 (m, 1H), 7.29 (m, 1H), 7.17 (m, 2H), 7.09 (m, 1H), 7.00 (m, 1H), 6.93 (m, 1H), 4.72 (m, 1H), 3.90 (m, 2H), 3.37 (m; 4H), 2.61 (s, 3H), 2.47 (m, 2H), 1.89-2.11 (m, 8H), 1.78 (m, 6H), 1.27 (s, 9H). HRMS C33H42ClFN4O m/z 565.3109 (M+H)Cal., 565.3095 (M+H)Obs..
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]=1.[NH2:10][C:11]1[C:12]([C:18](O)=[O:19])=[N:13][CH:14]=[C:15]([Br:17])[CH:16]=1>CN(C=O)C.O>[Br:17][C:15]1[CH:14]=[N:13][C:12]2[C:18](=[O:19])[N:9]3[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]3=[N:10][C:11]=2[CH:16]=1
Reactant: Nc1cc(Br)cnc1C(=O)O
Reactant: COC1=NCCCCC1
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2ncc(Br)cc2nc2n1CCCCC2

Procedure:
A solution of 7-methoxy-3,4,5,6-tetrahydro-2H-azepine (1.0 g, 8.8 mmol) and 3-amino-5-bromopicolinic acid (1.9 g, 8.8 mmol) in DMF (70 mL) was stirred at 130° C. for 48 h. The reaction mixture was diluted with H2O (300 mL) and extracted with DCM (3×300 mL). The combined organic layers were washed with saturated sodium carbonate and brine, dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the desired product. MS (ESI):294, 296 (MH+).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2CCC2C=CC(OCC(O)=O)=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:36]([C:38]1[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=1)#[CH:37]>>[CH:1]1([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:37]#[C:36][C:38]2[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)COc1ccc(CCc2ccccc2-c2nc3ccccc3n2CC2CCCCC2)cc1
Reactant: C#Cc1ccc(C#N)cc1
Product: N#Cc1ccc(C#Cc2ccccc2-c2nc3ccccc3n2CC2CCCCC2)cc1

Procedure:
The title compound was prepared in analogy to Example 72, intermediate a, from 2-(2-bromo-phenyl)-1-cyclohexylmethyl-1H-benzoimidazole (Example 79, intermediate e) and 4-ethynyl-benzonitrile (CAS Reg. No. 3032-92-6). Yellow solid (22%). MS (Turbo Spray): m/z=416.6 (M+H).
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:14][C:15]([OH:17])=O.Cl.[CH:20]12[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH:21]1[NH2:30])[CH2:27]2.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH:20]12[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH:21]1[NH:30][C:15](=[O:17])[CH2:14][N:3]1[CH2:4][CH2:5][CH2:6][N:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[S:2]1(=[O:1])=[O:18])[CH2:27]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: O=C(O)CN1CCCN(c2ccccc2)S1(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCN(c2ccccc2)S1(=O)=O)NC1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.6 %

Procedure:
To 2-(1,1-dioxido-6-phenyl-1,2,6-thiadiazinan-2-yl)acetic acid (100 mg, 0.37 mmol) in DCM (5 mL), were added 2-adamantan amine HCl (105 mg, 0.56 mmol), TEA (74.9 mg, 0.74 mmol) and EDCI (212.8 mg, 1.11 mmol). The reaction mixture was agitated for 5 hr at room temperature and extracted using CH2Cl2 and brine. The organic layer was dried over MgSO4. The residue was purified by silica gel column chromatography to give N-(adamantan-2-yl)-(1,1-dioxido-6-phenyl-1,2,6-thiadiazinan-2-yl)acetamide (80 mg, 54%). 1H NMR (300 MHz, CDCl3): δ 7.41-7.26 (m, 5H), 7.02-6.99 (brd, 1H), 4.07 (m, 1H), 3.94 (s, 2H), 3.81-3.74 (m, 4H), 2.03-1.94 (m, 4H), 1.85-1.74 (m, 10H), 1.66-1.60 (m, 3H).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:25][CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][CH:29]=2)=[CH:20][CH:19]=1)=[O:17])=O)(C)(C)C.[ClH:37]>O1CCOCC1>[ClH:37].[ClH:37].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:17])[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH:25]=2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccccc1NC(=O)c1ccc(C2=CCNCC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
t-Butyl 4-{4-[({2-[(t-butoxycarbonyl)amino]phenyl}amino)carbonyl]phenyl}-3,6-dihydropyridine-1(2H)-carboxylate (Method 71, 62 mg, 0.13 mmol) was stirred and dissolved in 1,4-dioxane (0.4 ml) and a 4M solution of hydrogen chloride in 1,4-dioxane (0.4 ml) added. The reaction mixture was stirred at ambient temperature for 24 hours. The resultant precipitate was collected by filtration, washed with diethyl ether and dried in vacuo at 60° C. to yield the title compound as an off white solid (34 mg, 89%); NMR Spectrum: (DMSO-d6) 2.70 (m, 2H), 3.30 (m, 2H), 3.76 (m, 2H), 6.33 (m, 1H), 7.23 (m, 2H), 7.33 (m, 1H), 7.49 (m, 1H), 7.61 (d, 2H), 8.10 (d, 2H), 9.27 (s, 1H); Mass Spectrum: M+H+ 294.
Reaction SMILES: [SH:1][CH2:2][C:3]1([CH2:6][C:7]([OH:9])=[O:8])[CH2:5][CH2:4]1.S(=O)(=O)(O)O.[CH3:15]O>>[CH3:15][O:8][C:7](=[O:9])[CH2:6][C:3]1([CH2:2][SH:1])[CH2:5][CH2:4]1
Reactant: O=C(O)CC1(CS)CC1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CC1(CS)CC1
Temperature: 20.5 °C
Reaction time: 5 h

Procedure:
To a 3 L flask, a solution of 1-(mercaptomethyl)cyclopropaneacetic acid (330.7 g) in methanol (1500 ml) was charged. 96% sulfuric acid (36 g) was added, and the reaction mixture was stirred for 5 h at 19-22° C. The reaction mixture was concentrated to ¼ of its volume at 50° C. under reduced pressure, and the residue was partitioned between water (1000 ml) and ethyl acetate (500 ml). The organic phase was separated, washed with 10% NaHCO3 and 5% NaCl (200 ml), and dried overnight over anhydrous sodium sulfate. The mixture was filtered and evaporated at 50° C. under reduced pressure, to afford 315.7 g of the crude 1-(mercaptomethyl)cyclopropaneacetic acid methyl ester, as a colored liquid with a strong, unpleasant odor.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]=[C:40]=[O:41])=[CH:35][CH:34]=1>C1COCC1>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:40]([NH:39][C:36]4[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=4)=[O:41])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: COc1ccc(N=C=O)cc1
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)Nc2ccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc3c2)cc1
Reaction time: 16 h

Procedure:
A solution of 80 mg (0.21 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 4 ml of THF is mixed with 59.6 μl (0.43 mmol) of triethylamine and 63.8 mg (0.43 mmol) of 4-methoxyphenyl isocyanate. After 16 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 55 mg (52.8% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[CH:5][C:4]([C:7]#[C:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][CH:18]([CH2:21][OH:22])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.ClCCl.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(O)(C)C>[C:1]1([CH3:23])[CH:2]=[CH:3][C:4]([C:7]#[C:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][CH:18]([CH:21]=[O:22])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(C#Cc2ccc(C3CCC(CO)CC3)cc2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CC(C)O
Product: Cc1ccc(C#Cc2ccc(C3CCC(C=O)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
36.6 g of [4-(4-p-tolylethynylphenyl)cyclohexyl]methanol were mixed with 300 ml of dichloromethane, and a mixture of 21 g of Celite and 28.5 g of pyridinium chlorochromate (PCC) were added under a nitrogen atmosphere. The reaction mixture was stirred overnight at RT. 100 ml of isopropanol were then added to the black suspension, and the mixture was stirred at RT for 1½ hours in order to destroy the excess PCC. This suspension was then filtered, and the filtrate was subjected to conventional work-up, giving 4-(4-p-tolylethynylphenyl)cyclohexanecarbaldehyde in the form of a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([O:16]C)=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1.[OH-].[Li+].CO>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([OH:16])=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1cccc(F)c1

Procedure:
The title compound was synthesized from methyl 4-(3-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.075 g, 0.274 mmol) and lithium hydroxide (0.053 g, 1.37 mmol in 3 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (6 mL) was used. The resulting product was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-100% EtOAc/heptane to afford the title compound: 30 mg, 42% yield. 1H NMR (400 MHz, METHANOL-d) δ ppm 2.05-2.15 (m, 1H), 2.50-2.60 (m, 1H), 2.60-2.65 (m, 2H), 2.75-2.85 (m, 2H), 3.21-3.28 (m, 1H), 6.30 (s, 1H), 6.85-6.95 (m, 2H), 7.00-7.05 (d, 1H), 7.25-7.35 (q, 1H); 19F NMR δ ppm (m, −116.7); LCMS-MS (ESI−) 258.0 (M−H); HPLC (UV=100%), (ELSD=100%).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:12][N:11]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@@H:22]([CH2:24]CS([O-])(=O)=O)[O:21][C:20]3=[O:30])=[CH:15][C:14]=2[F:31])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N-:32]=[N+:33]=[N-:34].[Na+].CO.C(Cl)(Cl)Cl.[N-]=[N+]=[N-]>CN(C)C=O.C(OCC)(=O)C>[Si:1]([O:8][CH:9]1[CH2:12][N:11]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@H:22]([CH2:24][N:32]=[N+:33]=[N-:34])[O:21][C:20]3=[O:30])=[CH:15][C:14]=2[F:31])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)OC1CN(c2ccc(N3C[C@@H](CCS(=O)(=O)[O-])OC3=O)cc2F)C1
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC1CN(c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)C1
Temperature: 65 °C

Procedure:
Crude (R)-[[3-[4-[3-[(tert-butyldimethylsilyl)oxy]-1-azetidinyl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]methanesulfonate (9.42 mmol) was dissolved in dry N,N-dimethylformamide (50 mL) and treated with sodium azide (4.42 g, 68.0 mmol) at ambient temperature. The reaction mixture was warmed to 65° C. under nitrogen for 4 h. TLC analysis (5% methanol/chloroform) at this time revealed the reaction to be complete. The reaction mire was diluted with ethyl acetate (100 mL) and washed with water (3×25 mL) and brine, dried over sodium sulfate, filtered and concentrated in vacuo to an amber solid. Chromatography over silica gel (125 g), eluting with a gradient of 10-20% ethyl acetate/hexane, afforded, after concentration of appropriate fractions, 2.21 g (56% for 3 steps) of the title azide as a white solid with mp 121°-122.5° C. and MS(EI) 421 (M+).
Reaction SMILES: [CH:1]1([C:4]2[C:5](O)=[N:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][N:8]=3)[CH2:3][CH2:2]1.O=P(Cl)(Cl)[Cl:17]>CN(C=O)C>[Cl:17][C:5]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: Oc1nc2ncccc2cc1C1CC1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1nc2ncccc2cc1C1CC1
Temperature: 120 °C

Procedure:
A mixture of naphthyridine 2-4 (14 g, 77 mmol) and 100 mL POCl3 and 0.1 mL DMF was refluxed at 120° C. for 3 hr and concentrated. The residue was treated with 300 mL ice-water and solid K2CO3 until pH=9. The mixture was extracted three times with ethyl acetate, washed with brine and dried over MgSO4. After solvent removal, the desired compound 2-5 was obtained as a yellowish solid.
Reaction SMILES: [CH2:1]([C:8]1[O:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[CH:21]([NH:26]S(C(C)(C)C)=O)[C:22]([CH3:25])([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1>CO>[CH2:1]([C:8]1[O:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[CH:21]([NH2:26])[C:22]([CH3:24])([CH3:23])[CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(NS(=O)C(C)(C)C)c1nc(-c2cc(F)ccc2F)oc1Cc1ccccc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(C)C(N)c1nc(-c2cc(F)ccc2F)oc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of (±)-N-(1-(5-benzyl-2-(2,5-difluorophenyl)oxazol-4-yl)-2,2-dimethylpropyl)-2-methylpropane-2-sulfinamide (340 mg, 0.738 mmol) in MeOH (10 mL) was added 4 M HCl in dioxane (369 μL, 1.476 mmol). The reaction mixture was stirred at room temperature for 1 h. After quenched with saturated NaHCO3 solution and diluted with EtOAc, the reaction mixture was stirred for 15 min and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude (±)-1-(5-benzyl-2-(2,5-difluorophenyl)oxazol-4-yl)-2,2-dimethylpropan-1-amine was obtained in 91% yield (240 mg), which was used for the next step without further purification (a major side product, methyl 2-methylpropane-2-sulfinate, was completely removed under high vacuum). LC/MS (uplc): MH+ 340.2 (—NH2), 0.91 min.
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[C:20]([CH3:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].BrC1C2C(=CC=CC=2)C(C2C=CC(Cl)=CC=2)=C(C(OC(C)(C)C)C(OC)=O)C=1C.[NH2:60][C:61]1[CH:66]=[CH:65]C(B(O)O)=[CH:63][N:62]=1>>[NH2:60][C:61]1[N:62]=[CH:63][C:23]([C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[C:12]([CH:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:7]([OH:9])=[O:8])[C:21]=2[CH3:22])=[CH:65][CH:66]=1
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)c(C)c2ccccc2c1-c1ccc(Cl)cc1
Reactant: Nc1ccc(B(O)O)cn1
Agent: COC(=O)C(OC(C)(C)C)c1c(C)c(Br)c2ccccc2c1-c1ccc(Cl)cc1
Product: Cc1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1-c1ccc(N)nc1

Procedure:
2-(4-(6-Aminopyridin-3-yl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (143) was prepared in a manner similar to 2-tert-butoxy-2-(1-(4-chlorophenyl)-3,4-dimethylnaphthalen-2-yl)acetic acid of Example 125, except using methyl 2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate as the starting material and 2-aminopyridin-5-yl-boronic acid pinacolate ester in the Suzuki reaction, giving the title compound (mono trifluoroacetic acid salt). 1H-NMR: (400 MHz, DMSO-d6): δ 8.06-7.86 (m, 4H), 7.76-7.68 (m, 2H), 7.56-7.37 (m, 5H), 7.26 (d, J=8.6 Hz, 1H), 7.17-7.13 (m, 1H), 5.13 (s, 1H), 2.33 (s, 3H), 0.96 (s, 9H). 19F-NMR: (377 MHz, DMSO-d6): δ-74.2 (s). LCMS-ESI+ (m/z): [M+H]+ calcd for C28H28ClN2O3: 475.2; Found: 475.2.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:15][CH2:16]Cl)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C@H:25]([NH2:27])[CH3:26])=[CH:21][CH:20]=1.CCO.O>CCN(C(C)C)C(C)C>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C@H:25]([N:27]2[CH2:16][CH2:15][N:4]([S:5]([C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=3)(=[O:7])=[O:6])[CH2:3][CH2:2]2)[CH3:26])=[CH:21][CH:20]=1
Reactant: C[C@@H](N)c1ccc(Br)cc1
Reactant: Cc1ccc(S(=O)(=O)N(CCCl)CCCl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N2CCN([C@H](C)c3ccc(Br)cc3)CC2)cc1
Temperature: 125 °C
Yield: 81.9 %

Procedure:
N,N-Bis(2-chloroethyl)-4-methylbenzenesulfonamide (4.0 g, 13.50 mmol) and (R)-1-(4-bromophenyl)ethanamine (2.57 g, 12.83 mmol) in DIPEA (5 mL) were stirred and heated at 125° C. for 32 hours. The resulting dark mixture was cooled to 80° C. then a mixture of EtOH/water (70/30, 20 mL) added slowly to give a brown precipitate. The precipitate was collected by filtration, washed with EtOH/water (70/30) and iso-hexane and air dried to afford (R)-1-[1-(4-bromophenyl)ethyl]-4-tosylpiperazine (4.45 g, 78%) as a brown solid, which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.[H-].[Na+].Br[CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>CN(C)P(=O)(N(C)C)N(C)C>[CH3:7][C:5]1[O:4][N:3]=[C:2]([O:1][CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:6]=1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: Cc1cc(O)no1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(Oc1cc(C)on1)C(=O)OCC
Temperature: 25 °C
Yield: 84.3 %

Procedure:
A solution of 3.468 g of 3-hydroxy-5-methylisoxazole in 35 ml of hexamethylphosphoric triamide was added dropwise to a suspension of 1.527 g of sodium hydride (as a 55% w/w dispersion in mineral oil) in 20 ml of hexamethylphosphoric triamide, whilst ice-cooling. The mixture was then stirred at room temperature for an hour. A solution of 8.367 g of diethyl 2-bromomalonate in 35 ml of hexamethylphosphoric triamide was then added dropwise to the mixture, whilst cooling it with ice-water. The mixture was stirred at room temperature for 1 hour and then poured into ice-water. It was then extracted twice with ethyl acetate. The combined extracts were washed with water, dried and concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through 200 g of silica gel. 7.593 g of the title compound were isolated as an oily material from the fractions eluted with mixtures of ethyl acetate and hexane ranging from 1:10 to 15:100 by volume.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:16])([CH3:15])[C:7](=[O:14])[N:8]2[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+].[CH2:69]([NH2:76])[C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.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.C(Cl)(Cl)Cl.[Pd].[Pd]>[CH2:69]([NH:76][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:16])([CH3:15])[C:7](=[O:14])[N:8]2[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1)[C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1
Reactant: NCc1ccccc1
Reactant: CC(C)N1C(=O)C(C)(C)c2ccc(Br)cc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)N1C(=O)C(C)(C)c2ccc(NCc3ccccc3)cc21
Temperature: 70 °C

Procedure:
To a solution of 6-bromo-1-isopropyl-3,3-dimethylindolin-2-one (1.99 g, 7.08 mmol, 70%) in THF (20.0 ml) was added BINAP (227 mg, 354 μmol) and sodium tert-butoxide (1.74 g, 17.7 mmol), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (378 mg, 354 μmol) and benzylamine (766 mg, 782 μl, 7.08 mmol) under an argon atmosphere. The reaction mixture was heated to 70° C. for 18 hours. An aqueous solution of Na2CO3 was added to the reaction mixture at room temperature, the aqueous phase was extracted with tert-butyl methyl ether, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel chromatography using ethyl acetate/heptane as eluent. The title compound was obtained as yellow foam (1.60 g).
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4]1.[Cl:9][C:10]1[CH:11]=[C:12]2[C:21](=[C:22]3[C:27]=1[CH:26]=[CH:25][CH:24]=[N:23]3)[NH:20][S:19](=[O:29])(=[O:28])[C:18]1[C:13]2=[CH:14][C:15](F)=[CH:16][CH:17]=1.OS([O-])(=O)=O.[K+]>CN1C(=O)CCC1>[Cl:9][C:10]1[CH:11]=[C:12]2[C:21](=[C:22]3[C:27]=1[CH:26]=[CH:25][CH:24]=[N:23]3)[NH:20][S:19](=[O:29])(=[O:28])[C:18]1[C:13]2=[CH:14][C:15]([O:8][CH:3]2[CH2:7][CH2:6][CH2:5][CH2:4]2)=[CH:16][CH:17]=1
Reactant: OC1CCCC1
Reactant: O=S1(=O)Nc2c(cc(Cl)c3cccnc23)-c2cc(F)ccc21
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=S1(=O)Nc2c(cc(Cl)c3cccnc23)-c2cc(OC3CCCC3)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 13 %

Procedure:
NaH (60% in mineral oil; 53 mg, 1.34 mmol) was added to a solution of cyclopentanol (115 mg, 1.34 mmol) in NMP (3 ml) and the mixture was stirred at room temperature for 15 min. 12-chloro-9-fluoro-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide 503 (150 mg, 0.44 mmol) was added and the mixture was heated at 180 C in a microwave for 2 h. After cooling, the mixture was poured into ice cold water and neutralized using sat aq. KHSO4 solution. The resulting precipitate was collected by filtration and dried. The crude solid was purified by column chromatography with n-hexane/DCM (30:70) as the eluent to give the title compound (23 mg, 20%).
Reaction SMILES: O[CH2:2][CH2:3][C@H:4]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:15][C:7]2[C:8]3[CH:9]=[N:10][NH:11][C:12]=3[CH:13]=[CH:14][C:6]=2[CH2:5]1.S(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].[NH:34]1[CH2:39][CH2:38][CH:37]([N:40]2[CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[NH:42][C:41]2=[O:50])[CH2:36][CH2:35]1>ClCCl>[CH2:19]([N:16]1[C:17](=[O:18])[C@H:4]([CH2:3][CH2:2][N:34]2[CH2:35][CH2:36][CH:37]([N:40]3[CH2:49][C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[NH:42][C:41]3=[O:50])[CH2:38][CH2:39]2)[CH2:5][C:6]2[CH:14]=[CH:13][C:12]3[NH:11][N:10]=[CH:9][C:8]=3[C:7]=2[CH2:15]1)[C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: CC(C)(C)CN1Cc2c(ccc3[nH]ncc23)C[C@@H](CCO)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)(C)CN1Cc2c(ccc3[nH]ncc23)C[C@@H](CCN2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
(S)-7-(2-hydroxyethyl)-9-neopentyl-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one (15 mg, 0.04 mmol) was dissolved in dichloromethane (1 mL). Thionyl chloride (100 μL) was added to the mixture. Reaction stirred at room temperature for 2 hours. Thionyl chloride (500 μL) was added to the mixture. Reaction stirred at room temperature for 2 hours and then was warmed to reflux for 2 hours. Reaction mixture was concentrated in vacuo. Residue was dissolved in acetonitrile (1 mL). Potassium carbonate (25 mg, 0.18 mmol) was added to the mixture followed by 3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (16 mg, 0.07 mmol). Reaction was heated at reflux for 2 hours. Preparatory HPLC purification afforded the title compound as white solid in 25% yield. High resolution MS m/e (M+H)+=529.3282.