Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][C:3]=1[O:12][CH3:13].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CC(C)=O>[CH3:13][O:12][C:3]1[CH:4]=[C:5]2[C:9]([C:8](=[O:11])[CH2:7][CH2:6]2)=[CH:10][C:2]=1[O:1][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: COc1cc2c(cc1O)C(=O)CC2
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1cc2c(cc1OC)CCC2=O
Temperature: 60 °C
Reaction time: 12 h
Yield: 30 %

Procedure:
To a stirred solution of 6-hydroxy-5-methoxy-2,3-dihydro-1H-inden-1-one 18a (0.01 mol, 1.78 g) in acetone (50 ml) was added potassium carbonate (0.02 mol, 2.80 g). The resulting mixture was refluxed for 2 hours. After cooling to room temperature ethyl 4-bromobutyrate was added. The reaction mixture was stirred at 60° C. for 12 h. The progress of the reaction was monitored by TLC. The reaction mixture was filtered and the precipitate was washed with acetone (15 ml×2). The combined filtrate was concentrated on rotavapor and the residue was diluted with ethyl acetate. The ethyl acetate solution was successively washed with water, saturated sodium bicarbonate (Na2HCO3), water and dried over magnesium sulfate (Mg2SO4). After evaporation of the solvent the crude product was purified by passing through a short silica gel column using 0-50% gradient of ethyl acetate and hexane as eluent to give the pure indanone as colorless thick liquid in 30% yield (0.87 g). 1H NMR (400 MHz, CDCl3): δ 1.21 (3H, broad t); 2.16 (2H, m); 2.44 (2H, m); 2.59 (2H, m); 2.96 (2H, m); 3.93 (3H, s); 4.04 (2H, broad t); 4.10 (2H, broad q); 6.84 (1H, m); 7.43 (1H, s); 7.12 (1H, s). MS (ESI): m/z=293.20 (M+H+).
Reaction SMILES: O=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13](C4C=CC(C=O)=CC=4)[CH:14](C4C=CC(C=O)=CC=4)[C:5]([C:6]=23)=[N:4][NH:3]1.[BH4-].[Na+].[CH3:33][OH:34]>>[CH3:13][NH:12][CH2:7][C:6]1[CH:11]=[CH:10][C:2]([N:3]2[N:4]=[C:5]3[CH2:14][CH2:13][NH:12][C:7]4[C:6]3=[C:11]([CH:10]=[CH:9][CH:8]=4)[C:33]2=[O:34])=[CH:14][CH:5]=1
Reactant: CO
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(C=O)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Product: CNCc1ccc(-n2nc3c4c(cccc4c2=O)NCC3)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 33 %

Procedure:
A mixture of 4,4′-(3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8,9-diyl)dibenzaldehyde (80 mg, 0.21 mmol) and 27% methylamine alcohol solution (94 mg, 0.82 mmol) in methanol (10 mL) was stirred at room temperature for 40 min. The mixture was then cooled to 0° C. Sodium borohydride (24 mg, 0.64 mmol) was added. After the addition, the mixture was stirred at room temperature for 4 hr. Methanol was removed under reduced pressure. The residue was washed with ethyl acetate and filtered. The filtrate was concentrated to give 8,9-bis(4-((methylamino)methyl)phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (29.5 mg, yield 33%) as a light yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 2.20 (d, J=8.8 Hz, 6H), 3.52-3.53 (d, J=2.4 Hz, 4H), 4.31-4.33 (d, J=6.4 Hz, 1H), 4.76-4.77 (d, J=6.4 Hz, 1H), 7.06-7.08 (d, J=6.4 Hz, 2H), 7.12-7.17 (m, 5H), 7.35-7.38 (t, J=6.4 Hz, 2H), 7.49-7.57 (t, J=10.0 Hz, 1H); LC-MS (ESI) m/z: 426(M+1)+.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[CH:16]=[N:17][CH:18]=[N:19][CH:20]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:26]>ClCCl>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[CH:16]=[N:17][CH:18]=[N+:19]([O-:26])[CH:20]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2cncnc2)cc1OC1CCCC1
Solvent: ClCCl
Product: COc1ccc(-c2cnc[n+]([O-])c2)cc1OC1CCCC1
Reaction time: 120 h
Yield: 26876.5 %

Procedure:
A solution of 5-(3-Cyclopentyloxy-4-methoxyphenyl)pyrimidine (1.37 g) and 3-chloroperoxybenzoic acid (50.60%) (1.75 g) in dichloromethane (35 ml) was stirred at RT and the reaction followed by t.l.c. After 5 days, the reaction mixture was partitioned three times between dichloromethane (50 ml) and 10% aqueous Na2SO3 solution (50 ml). The combined organic phase was washed with 5% aqueous NaOH solution (3×30 ml), brine (30 ml), dried (MgSO4) and evaporated to afford a tan solid. Flash chromatography [SiO2 ; dichloromethane/EtOAc, 1:9 then dichloromethane/EtOAc/methane, 1:8:1] followed by recrystallisation from EtOAc furnished the title compound (390 g) as a white powder (mp 140°-143° C.). Found=C, 67.03; H, 6.31; N, 9.81. C16H18N2O3 requires C, 67.12; H, 6.34; N, 9.78%.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]([N:13]3[CH2:16][C:15](=O)[CH2:14]3)=[O:12])[S:8][C:7]=2[CH:18]=1.[C:21]([NH:28][CH2:29][CH2:30][NH2:31])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[C:24]([O:23][C:21](=[O:22])[NH:28][CH2:29][CH2:30][NH:31][CH:15]1[CH2:16][N:13]([C:11]([C:9]2[S:8][C:7]3[CH:18]=[C:3]([C:2]([F:20])([F:19])[F:1])[CH:4]=[CH:5][C:6]=3[CH:10]=2)=[O:12])[CH2:14]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C1CN(C(=O)c2cc3ccc(C(F)(F)F)cc3s2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCNC1CN(C(=O)c2cc3ccc(C(F)(F)F)cc3s2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.7 %

Procedure:
To a mixture of 1e (62 mg, 0.207 mmol), N-Boc-ethylenediamine 1f (100 mg, 0.62 mmol), and acetic acid (0.3 mL) in 1,2-dichloroethane (3 mL) was added Na(OAc)3BH (53 mg, 0.25 mmol). The reaction mixture was stirred at room temperature overnight, and was then quenched with aq. NaHCO3. The resulting mixture was extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated. Purification by column chromatography (silica gel, 4% MeOH/CH2Cl2) gave intermediate 1g as colorless oil (30 mg).
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][CH2:8][CH2:9]OC1C=C2C(=CC=1)N(CC1C=CC=CC=1)C(Br)=C2CC(N)=O)(=[O:6])[O:4][CH3:5].[Br:32]C1N(CC2C=CC=CC=2)C2C(C=1CC(N)=O)=CC(O)=CC=2.[H-].[Na+]>>[CH3:5][O:4][P:3]([CH2:7][CH2:8][CH2:9][Br:32])(=[O:6])[O:2][CH3:1]
Reactant: COP(=O)(CCCOc1ccc2c(c1)c(CC(N)=O)c(Br)n2Cc1ccccc1)OC
Reactant: NC(=O)Cc1c(Br)n(Cc2ccccc2)c2ccc(O)cc12
Agent: [H-]
Agent: [Na+]
Product: COP(=O)(CCCBr)OC

Procedure:
[3-[[3-(2-Amino-2-oxoethyl)-2-bromo-1-(phenylmethyl)-1H-indol-5-yl]oxy]propyl]phosphonic acid dimethyl ester. Using the procedure described in Example 81, Part A, 1.35 g (3.8 mmol) of 2-bromo-5-hydroxy-1-(phenylmethyl)-1H-indole-3-acetamide was reacted with 170 mg (4.2 mmol) of NaH/mineral oil and then 970 mg (4.2 mmol) of (3-bromopropyl)phosphonic acid dimethyl ester to give a product that was chromatographed on silica gel (eluted with a gradient, 1% MeOH/methylene chloride→3% MeOH/methylene chloride). There was obtained 520 g (27% yield) of 3-[[3-(2-amino-2-oxoethyl)-2-bromo-1-(phenylmethyl)-1H-indol-5-yl]oxy]propyl]phosphonic acid dimethyl ester, melting approximately at 100° C. after crystallizing from methylene chloride/ether.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[C:11]1[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][CH:12]=1.[K+].[C:20]([C:22]1[N:23]=[C:24]([C:35]([O-])=[O:36])[N:25]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:26]=1)#[N:21]>CO.C(Cl)Cl>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([NH:1][C:35]([C:24]2[N:25]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:26]=[C:22]([C:20]#[N:21])[N:23]=2)=[O:36])=[C:3]([C:11]2[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][CH:12]=2)[CH:4]=1)(=[O:7])[NH2:8]
Reactant: CC1(C)CC=C(c2cc(C(N)=O)ccc2N)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: CC1(C)CC=C(c2cc(C(N)=O)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Yield: 94 %

Procedure:
The title compound was prepared by the procedure of Example 11, step (f) using 4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-benzamide (as prepared in the previous step, 51.0 mg, 0.209 mmol) and potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 11, step (d), 70.2 mg, 0.230 mmol). Silica gel chromatography (0-2% MeOH/DCM) afforded the title compound (91 mg, 94%) as a white solid. Mass spectrum (ESI, m/z): Calcd. for C26H35N5O3Si, 494.3 (M+H), found 494.1.
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]([CH3:29])([CH3:28])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([C:23]([O:25]CC)=[O:24])([CH3:22])[CH3:21])[S:15][CH2:14][CH2:13][CH2:12][S:11]1)C.[OH-].[K+].Cl>C(O)C.O>[C:23]([C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][CH2:17][CH2:16][C:10]1([CH2:9][CH2:8][CH2:7][CH2:6][C:5]([CH3:29])([CH3:28])[C:4]([OH:30])=[O:3])[S:15][CH2:14][CH2:13][CH2:12][S:11]1)([OH:25])=[O:24]
Reactant: CCOC(=O)C(C)(C)CCCCC1(CCCCC(C)(C)C(=O)OCC)SCCCS1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(CCCCC1(CCCCC(C)(C)C(=O)O)SCCCS1)C(=O)O
Yield: 95.5 %

Procedure:
A solution of 6-[2-(5-ethoxycarbonyl-5-methyl-hexyl)-[1,3]dithian-2-yl]-2,2-dimethyl-hexanoic acid ethyl ester (870 mg, 1.89 mmol) and potassium hydroxide (85%, 750 mg, 11.33 mmol) in ethanol (16 mL) and water (4 mL) was heated under reflux for 3 h. The reaction mixture was diluted with water (100 mL) and acidified to pH 4 with 1 N HCl (8 mL). The emulsion was extracted with dichloromethane (3 75 mL). The combined organic phases were washed with water (50 mL), dried over MgSO4, concentrated in vacuo, and dried in high vacuo to furnish 6-[2-(5-carboxy-5-methyl-hexyl)-[1,3]dithian-2-yl]-2,2-dimethyl-hexanoic acid (730 mg, 95%) as a viscous, yellowish oil. 1H NMR (300 MHz, CDCl3/TMS): (ppm): 2.80 (m, 4H), 1.94 (m, 2H), 1.85 (m, 4H), 1.56 (m, 4H), 1.41 (m, 4H), 1.30 (m, 4H), 1.19 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): (ppm): 185.08, 53.36, 42.28, 40.52, 38.27, 26.18, 25.69, 25.23, 25.11, 24.73. HRMS (LSIMS, nba): Calcd. for C20H37O4S2 (MH+): 405.2133, found: 405.2115.
Reaction SMILES: C([Li])CCC.Br[C:7]1[N:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][CH:8]=1.[C:15]([N:19]=[C:20]=[O:21])([CH3:18])([CH3:17])[CH3:16].[NH4+].[Cl-]>C1COCC1>[C:15]([NH:19][C:20]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([O:13][CH3:14])[N:12]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: COc1cccc(Br)n1
Reactant: CC(C)(C)N=C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cccc(C(=O)NC(C)(C)C)n1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 84.8 %

Procedure:
n-Butyllithium (18.25 mmole) was added dropwise to a cooled solution of 6-bromo-2-methoxypyridine (3.12 g, 16.6 mmole, prepared from 2,6-dibromopyridine (Aldrich) according to Comins and Killpack, J. Org. Chem., 55:69-73 (1990)) in 40 mL of THF at -78° C., the resulting orange solution was stirred for 20 minutes at -78° C., and t-butylisocyanate (26.3 mmole) was added with a syringe. The mixture was stirred for 30 minutes at -78° C., warmed to room temperature, then saturated NH4Cl (20 mL) was added. The layers were separated, and the aqueous layer was extracted with methylene chloride (2×20 mL). The combined organic layers were dried over MgSO4 and concentrated, and the residue was chromatographed on silica gel, eluting with 10% to 25% ethyl acetate in hexane, to provide 2.93 g of the title compound as an oil. MS: 209 (M+H)+ ; 1H NMR (CDCl3) δ: 7.85-7.68 (m, 3H), 6.87 (d, J=8 Hz, 1H), 3.96 (s, 3H), 1.49 (s, 9H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:15]=[C:14]([N:16]2[C@H:20]([CH3:21])[CH2:19][CH2:18][S:17]2(=[O:23])=[O:22])[CH:13]=[CH:12][C:6]=1[C:7]([O:9]CC)=O)(=[O:4])=[O:3].[CH:24]1([C:27]2[C:28]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[N:29][CH:30]=[C:31]([CH:33]3[CH2:35][CH2:34]3)[CH:32]=2)[CH2:26][CH2:25]1>>[CH:24]1([C:27]2[C:28]([N:36]3[CH2:37][CH2:38][N:39]([C:7]([C:6]4[CH:12]=[CH:13][C:14]([N:16]5[C@H:20]([CH3:21])[CH2:19][CH2:18][S:17]5(=[O:22])=[O:23])=[CH:15][C:5]=4[S:2]([CH3:1])(=[O:3])=[O:4])=[O:9])[CH2:40][CH2:41]3)=[N:29][CH:30]=[C:31]([CH:33]3[CH2:35][CH2:34]3)[CH:32]=2)[CH2:25][CH2:26]1
Reactant: CCOC(=O)c1ccc(N2[C@H](C)CCS2(=O)=O)cc1S(C)(=O)=O
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Product: C[C@@H]1CCS(=O)(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C3CC3)CC2)c(S(C)(=O)=O)c1
Yield: 30.8 %

Procedure:
Using ethyl (R)-2-methanesulfonyl-4-(3-methyl-1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoate (361 mg) described in Preparation Example 28 and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine (243 mg) described in Preparation Example 88 and by the reaction and treatment in the same manner as in Example 109, the title compound (172 mg) was obtained.
Reaction SMILES: [OH:1][C@:2]1([CH3:21])[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH2:3]1.[F:22][C:23]([F:35])([CH3:34])[CH2:24][O:25][C:26]1[C:31]([CH2:32][NH2:33])=[CH:30][N:29]=[CH:28][N:27]=1.CCN(C(C)C)C(C)C>C1COCC1>[F:35][C:23]([F:22])([CH3:34])[CH2:24][O:25][C:26]1[C:31]([CH2:32][NH:33][C:11]2[N:10]=[C:9]([NH:8][C@H:4]3[CH2:5][CH2:6][CH2:7][C@:2]([OH:1])([CH3:21])[CH2:3]3)[C:14]([C:15]#[N:16])=[CH:13][N:12]=2)=[CH:30][N:29]=[CH:28][N:27]=1
Reactant: C[C@@]1(O)CCC[C@H](Nc2nc(S(C)(=O)=O)ncc2C#N)C1
Reactant: CC(F)(F)COc1ncncc1CN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(F)(F)COc1ncncc1CNc1ncc(C#N)c(N[C@H]2CCC[C@@](C)(O)C2)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 24.4 %

Procedure:
A mixture of 4-(((1S,3R)-3-hydroxy-3-methylcyclohexyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (80 mg, crude), (4-(2,2-difluoropropoxyl)pyrimidin-5-yl)methanamine (50 mg 0.246 mmol), and DIEA (85 mg, 0.66 mmol) in THF (2 mL) was stirred at 100° C. in a microwave reactor for 1 h. The reaction was cooled to room temperature and the mixture was concentrated. The residue was purified by standard methods to give the desired product (26.1 mg, 0.060 mmol, 24% yield). 1H NMR (400 MHz, CD3OD) δ (ppm) 8.69 (s, 1H), 8.41 (s, 1H), 8.11 (s, 1H), 4.73-4.50 (m, 4H), 4.34-4.23 (m, 1H), 1.92-1.08 (m, 14H). MS (ESI) m/z 434.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.Cl[C:16]1[N:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[N:17]=1>>[CH3:23][C:18]1[CH:19]=[C:20]([CH3:22])[N:21]=[C:16]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)=[CH:9][CH:10]=2)[N:17]=1
Reactant: Cc1cc(C)nc(Cl)n1
Reactant: Cc1cc(-c2ccc(N)cc2)ccn1
Product: Cc1cc(-c2ccc(Nc3nc(C)cc(C)n3)cc2)ccn1

Procedure:
The title compound was prepared in analogy to example 62 from 4-(2-methyl-pyridin-4-yl)-phenylamine and 2-chloro-4,6-dimethylpyrimidine. Obtained as a yellowish solid (Yield=33%). MS ISP (m/e): 291.1 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.73 (s, 1H), 8.43 (d, 1H), 7.97 (d, 2H), 7.73 (d, 2H), 7.55 (s, 1H); 7.47 (d, 1H), 6.67 (s, 1H), 2.50 (s, 3H hidden in DMSO-peak), 2.34 (s, 6H).
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:35]=[CH:34][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:20]([C:30]([F:33])([F:32])[F:31])[CH:19]=3)[S:17][C:13]=2[CH:12]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:32][C:30]([F:31])([F:33])[C:20]1[CH:19]=[C:18]([C:16]2[S:17][C:13]3[CH:12]=[C:11]([CH2:10][NH:9][CH2:8][CH2:7][C:6]([OH:36])=[O:5])[CH:35]=[CH:34][C:14]=3[N:15]=2)[CH:23]=[CH:22][C:21]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)CCNCc1ccc2nc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)sc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCNCc1ccc2nc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)sc2c1
Temperature: 25 °C
Yield: 36.2 %

Procedure:
3-{[2-(2-Trifluoromethyl-biphenyl-4-yl)-benzothiazol-6-ylmethyl]-amino }-propionic acid tert-butyl ester (31 mg, 0.0605 mmol) is dissolved in TFA/CH2Cl2 (1/1) (1 mL). The solution is stirred at room temperature for an hour. The mixture is concentrated and purified by reversed phase preparative LC/MS to give 10 mg of 3-{[2-(2-trifluoromethyl-biphenyl-4-yl)-benzothiazol-6-ylmethyl]-amino}-propionic acid: 1H NMR (CD3OD, 400 MHz) δ 8.54 (s, 1 H), 8.35 (d, 1 H), 8.22 (s, 1 H), 8.18 (d, 2 H),7.58 (d, 1 H), 7.45 (m, 3 H), 7.37 (m, 2 H), 4.44 (s, 2 H), 3.36 (m, 2 H), 2.80 (m, 2 H); MS (ES+) 45.70 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:12]([Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:11]=[CH:10][N:9]([Si](C)(C)C)[CH:8]=1.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:21][N:22]([CH3:26])[C:23]([N:9]1[CH:10]=[CH:11][C@H:12]([Si:13]([CH3:16])([CH3:15])[CH3:14])[C:7]([CH:3]2[CH2:4][CH2:5][CH2:6][N:2]2[CH3:1])=[CH:8]1)=[O:24]
Reactant: CN1CCCC1C1=CN([Si](C)(C)C)C=CC1[Si](C)(C)C
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)C(=O)N1C=C[C@H]([Si](C)(C)C)C(C2CCCN2C)=C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59 %

Procedure:
To a stirred solution of 3-(1-methylpyrrolidin-2-yl)-1,4-bis-trimethylsilanyl-1,4-dihydropyridine i (0.2 mL, 1.36 mmol) in CH2Cl2 (6 mL) under Ar was added dropwise dimethylcarbamyl chloride (0.19 mL, 2.04 mmol). The reaction mixture was stirred at RT for 1 day. It was then poured into a saturated solution of NaHCO3 (3 mL). The aqueous phase was extracted with CH2Cl2 (5 times). The combined organic layers were washed with water and brine and dried over MgSO4. Evaporation of the solvent under reduced pressure afforded 0.49 g of crude material that was purified by RPLC (silica gel, 5% EtOAc/hex) to give 59% (0.2506 g) of 3-(1-methylpyrrolidin-2-yl)-4-trimethylsilanyl-4H-pyridine-1-carboxylic acid dimethylamide iii as a clear oil. IR (thin film, neat, NaCl): 3363, 2924, 2348, 1657, 1449, 1377 cm−1; 1H NMR (300 MHz, CDCl3) δ 6.65 (d, 1H, J=6.9 Hz), 6.35 (s 1H), 4.83-4.78 (m, 1H), 3.14-3.09 (m, 1H), 2.88 (s, 6H), 2.80-1.25 (m, 13H), 0.085 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 149.29, 147.15, 128.04, 124.49, 120.09, 106.29, 68.23, 57.35, 41.47, 38.53, 33.04, 30.34, 29.91, 22.37, 0.63, −2.00. HRMS Calcd for C16H29N3OSi: 308.2157 [M+H]+. Found: 308.2157 [M+H]+. [α]25D −15.17 (CH2Cl2, c=0.145).
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([OH:24])=O)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1([CH2:39][NH2:40])[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]1>>[F:1][C:2]1[C:3]([C:22]([NH:40][CH2:39][C:32]2([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[F:25])[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=[O:24])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)O)c3F)s2)c1
Reactant: CN1CCC(CN)(c2ccccc2F)CC1
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5F)CCN(C)CC4)c3F)s2)c1

Procedure:
The compound was prepared following the amide bond forming procedure given in example 37, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)picolinic acid (intermediate B in example 1) and (4-(2-fluorophenyl)-1-methylpiperidin-4-yl)methanamine (amine intermediate “Z”) were reacted to give the title compound. LC/MS (M+H)+: 567. Ret. time: 1.45 min. (Condition G); analytical HPLC Ret. time: 5.83 min (Condition H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[C:24](Br)[CH:23]=[CH:22][N:21]4[C:27]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:35]1(B(O)O)[CH2:37][CH2:36]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[C:24]([CH:35]5[CH2:37][CH2:36]5)[CH:23]=[CH:22][N:21]4[C:27]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(Br)ccn4c3-c3ccccc3)cc2)CCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(C5CC5)ccn4c3-c3ccccc3)cc2)CCC1
Temperature: 90 °C
Reaction time: 0.02 h
Yield: 88.9 %

Procedure:
A mixture of {1-[4-(7-bromo-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (200 mg, 0.38 mmol), cyclopropylboronic acid (166 mg, 1.93 mmol, 5.0 equiv), tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.015 mmol, 4 mol %) and K3PO4 (164 mg, 0.77 mmol, 2.0 equiv), in toluene (4.5 mL) was heated at the reflux temperature for 16 h with monitoring by UPLC-MS. The resulting mixture was heated at 90° C. for 1 h in a microwave apparatus, then concentrated under reduced pressure. The remaining material was treated with water (25 mL), and was then extracted with EtOAc (2×25 mL). The combined organic phases were washed with water (25 mL), dried (Na2SO4 anh), and concentrated under reduced pressure. The remaining material (205 mg) was was purified using MPLC (Biotage Isolera Flash NH2 Snap 10 reverse phase column; 100% CH2Cl2 for 1 min., gradient to 90% CH2Cl2/10% MeOH over 10 min.; 90% CH2Cl2/10% MeOH for 4 min.) to give {1-[4-(7-cyclopropyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (162 mg, 87%):
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C([Li])CCC.C([O:28][B:29](OC(C)C)[O:30]C(C)C)(C)C>C1COCC1>[F:17][C:16]([F:19])([F:18])[O:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([B:29]([OH:30])[OH:28])=[CH:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: FC(F)(F)Oc1ccc(Oc2ccc(Br)cc2)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
To a solution of 1-bromo-4-(4-(trifluoromethoxy)phenoxy)benzene (5.07 g, 15.2 mmol) in THF (76 ml) at −78° C. was added n-butyl lithium (7.6 ml, 2.5 M in hexanes, 19.0 mmol) dropwise. The reaction mixture was stirred 0.5 hours at −78° C., and triisopropylborate (7.0 ml, 30.4 mmol) was added. The reaction was stirred 4 hours at room temperature, quenched with 1 N HCl and stirred 0.5 hours at 0° C. The aqueous layer was extracted with ethyl acetate. The combined organic layers were extracted with brine and dried over magnesium sulfate. Purification by silica gel chromatography (0-10% methanol in dichloromethane) provided 4.38 g (4-(4-(trifluoromethoxy)phenoxy)phenyl)boronic acid (97% yield) as a light brown viscous oil. 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=8.9 Hz, 1H), 7.26 (d, J=8.9 Hz, 1H), 7.07-7.14 (m, 2H).