Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]([CH2:18][NH:19][C:20]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]2[C:21]=1[CH:22]=[N:23][N:24]2[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36]C)[CH:31]=1)([OH:17])[CH2:4][C:5]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[O:15]C)([CH3:7])[CH3:6].[I-].[Li+]>CN1CCCC1=O>[F:14][C:12]1[CH:11]=[CH:10][C:9]([OH:15])=[C:8]([C:5]([CH3:7])([CH3:6])[CH2:4][C:3]([OH:17])([CH2:18][NH:19][C:20]2[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]3[C:21]=2[CH:22]=[N:23][N:24]3[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=2)[C:2]([F:1])([F:38])[F:39])[CH:13]=1
Reactant: COc1cccc(-n2ncc3c(NCC(O)(CC(C)(C)c4cc(F)ccc4OC)C(F)(F)F)cc(C)cc32)c1
Agent: [I-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: Cc1cc(NCC(O)(CC(C)(C)c2cc(F)ccc2O)C(F)(F)F)c2cnn(-c3cccc(O)c3)c2c1
Temperature: 220 °C
Yield: 31.7 %

Procedure:
A mixture of 1,1,1-trifluoro-4-[5-fluoro-2-(methyloxy)phenyl]-4-methyl-2-[({6-methyl-1-[3-(methyloxy)phenyl]-1H-indazol-4-yl}amino)methyl]-2-pentanol (Example 22, 137 mg, 0.25 mmol) and lithium iodide (1 g, 7.5 mmol) in N-methylpyrrolidinone (6 mL) was heated in a microwave at 220° C. for 55 minutes. The solvent was removed using a vacuum centrifuge and the residue was partitioned between water (25 mL) and dichloromethane (50 mL) and passed through a hydrophobic frit. The organic filtrate was evaporated under reduced pressure and purified by silica gel chromatography (20 g cartridge) eluting with a 100:0 to 0:100 gradient of cyclohexane:ethyl acetate over 30 minutes to give the title compound (41 mg).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)[CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl>CO.[Pd]>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[C:23]([O:26][C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)[CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:10][CH2:9]1
Reactant: Cc1ccc(Oc2cccc3[nH]c(C(=O)NC4CCN(Cc5ccccc5)CC4)cc23)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1ccc(Oc2cccc3[nH]c(C(=O)NC4CCNCC4)cc23)cc1

Procedure:
Pd—C (1 g) is placed into a flask filled with argon and covered with methanol. 186 (1.4 g, 3.2 mmol) is dissolved in 100 ml of methanol and 1.6 ml of 2M HCl and added. After hydrogenation at room temperature for 5 h the mixture is filtrated over celite and evaporated.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:25]=4[F:34])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])(C)([CH3:3])[CH3:2].Cl.C(N(CC)CC)C.ClC(OC(C)C)=O>O1CCOCC1.O.C(OCC)(=O)C>[CH:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:25]=4[F:34])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4F)ncnc32)CC1
Agent: CC(C)OC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4F)ncnc32)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 34.9 %

Procedure:
A mixture of 4-[4-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 60; 90 mg, 0.18 mmol) and 4 M HCl in dioxane (2 mL) was stirred at room temperature for 5 h. The solvent was evaporated and the residue was dried in vacuo to give a solid. To the solid were added ethyl acetate (3 mL) and triethylamine (74 mg, 0.73 mmol). The mixture was cooled to 10° C. and isopropyl chloroformate (1 M in toluene; 0.22 mL, 0.22 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred overnight. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were dried (sodium sulfate), filtered, evaporated, and purified by flash chromatography, eluting with 30% ethyl acetate/hexanes, to give 4-[4-(2-fluoro-4-methanesulfonyl-phenoxy)pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid isopropyl ester (30 mg, 35%) as an off-white solid. Mass spectrum (ES) MH+=478.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[C:9]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]=1.P([O-])(O)(O)=[O:34].[Na+].Cl[O-].[Na+].OO>C(#N)C.O>[CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]([OH:34])=[O:12])=[C:9]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]=1
Reactant: COc1c(C)c(Cc2ccc(C=O)c(OCc3ccccc3)c2)c(OC)c(OC)c1OC
Reactant: O=P([O-])(O)O
Agent: OO
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC#N
Solvent: O
Product: COc1c(C)c(Cc2ccc(C(=O)O)c(OCc3ccccc3)c2)c(OC)c(OC)c1OC
Yield: 101.5 %

Procedure:
To a solution of 4-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzaldehyde (735 mg, 1.69 mmol) in acetonitrile (5 ml) were added an aqueous solution (2 ml) of sodium dihydrogen phosphate (157 mg, 1.31 mmol), an aqueous solution (7 ml) of sodium hypochlorite (795 mg, 80%, 7.07 mmol) and an aqueous hydrogen peroxide (0.5 ml, 30%) and the mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The extract was washed with a 10% aqueous solution of sodium hydrosulfite (Na2S2O4) and a saturated saline, dried and concentrated to give the title compound (603 mg, 1.33 mmol, 79%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[O:9]1[CH2:13][CH2:12][O:11][CH:10]1[C:14]1[S:15][C:16]([Sn](CCCC)(CCCC)CCCC)=[CH:17][N:18]=1.C(Cl)Cl.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.O>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:16]2[S:15][C:14]([CH:10]3[O:11][CH2:12][CH2:13][O:9]3)=[N:18][CH:17]=2)[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(C2OCCO2)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2cnc(C3OCCO3)s2)n1
Temperature: 110 °C
Reaction time: 48 h
Yield: 53.5 %

Procedure:
A sealed tube was charged with 2,6-dibromopyridine (525 mg, 2.21 mmol), 2-[1,3]dioxolan-2-yl-5-tributylstannanyl-thiazole (J. Med. Chem. 2007, 50, 6303) (990 mg, 2.21 mmol), Pd(PPh3)4 (256 mg, 0.22 mmol), [1,1-Bis(diphenylphosphino)ferrocene]palladium(II) chloride. CH2Cl2 (30 mg, 0.036 mmol) and anhydrous and degassed toluene (8 ml) and heated to 110° C. with stirring for 48 h. The cooled reaction mixture was treated with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure before purification by column chromatography on SiO2 using combiflash Companion®, eluting with cyclohexane/ethyl acetate 100/0 to 44/56 to afford the title compound as a white solid (370 mg, 54%). 1H NMR (DMSO-d6, 300 MHz): δ=8.55 (s, 1H), 8.06 (dd, J=7.7-0.7 Hz, 1H), 7.85 (dd, J=7.9-7.7 Hz, 1H), 7.61 (dd, J=7.9-0.7 Hz, 1H), 6.08 (s, 1H), 4.15-4.00 (m, 4H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]3[N:15]([C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@@H:24]4[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][C@@H:31]([OH:34])[CH2:32][OH:33])[CH2:25]4)[N:18]=2)[CH:14]=[CH:13][S:12]3)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]3[N:15]([C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@@H:24]4[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][C@@H:31]([OH:34])[CH2:32][OH:33])[CH2:25]4)[N:18]=2)[CH:14]=[CH:13][S:12]3)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(C[C@@H](O)CO)C3)n2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: OC[C@H](O)CN1CCC[C@@H](Nc2nccc(-c3c(-c4cccc(O)c4)nc4sccn34)n2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
The (2R)-3-[(3R)-3-({4-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)piperidin-1-yl]propane-1,2-diol (150 mg, 0.312 mmol) in methylene chloride (10 ml) was cooled to −78° C. and slowly treated with 1 molar solution of boron tribromide in methylene chloride (2.5 ml). The reaction mixture was kept at −78° C. for one hour then was allowed to warm to room temperature for 18 hours. The mixture was quenched by the addition of methanol (5 ml) at −78° C. and was stirred at room temperature for an additional hour. The mixture was concentrated in vacuo and the crude product was purified by flash chromatography (6:1 EtOAc/MeOH+drops of aq. NH4OH), affording the title compound as a pale yellow solid (71 mg, 49%). M.p.=185-187° C. 400 MHz 1H NMR (DMSO-d6) δ: 9.39 (s, 1H), 8.72 (br. s, 1H), 8.12 (d, J=5.1 Hz, 1H), 7.43 (d, J=4.4 Hz, 1H), 7.32 (br. s, 1H), 7.26-7.20 (m, 1H), 7.00-6.95 (m, 2H), 6.84-6.81 (m, 1H), 6.45 (d, J=5.5 Hz, 1H), 5.28-5.03 (br. s, 1H), 4.90-4.65 (br. s, 1H), 4.34-4.22 (m, 1H), 3.98-3.84 (m, 1H), 3.47-3.38 (m, 1H), 3.35-3.25 (m, 1H), 3.15-2.65 (m, 4H), 2.10-1.88 (m, 2H), 1.87-1.72 (m, 2H), 1.65-1.40 (m, 2H). LCMS: 467 [M+H].
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13]Br)=[CH:9][CH:8]=2)=[N:3]1.[F:15][C:16]([F:44])([F:43])[O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:32]2[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:34][CH:33]=2)([OH:31])[CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:20][CH:19]=1.C(N(CC)C(C)C)(C)C.CC(C)=O>CS(C)=O.C(Cl)Cl>[CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][N:28]3[CH2:29][CH2:30][CH:25]([C:24]([C:21]4[CH:20]=[CH:19][C:18]([O:17][C:16]([F:15])([F:43])[F:44])=[CH:23][CH:22]=4)([C:32]4[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:34][CH:33]=4)[OH:31])[CH2:26][CH2:27]3)=[CH:9][CH:8]=2)=[N:3]1
Reactant: Cn1nnc(-c2ccc(CBr)cc2)n1
Reactant: OC(c1ccc(OC(F)(F)F)cc1)(c1ccc(OC(F)(F)F)cc1)C1CCNCC1
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cn1nnc(-c2ccc(CN3CCC(C(O)(c4ccc(OC(F)(F)F)cc4)c4ccc(OC(F)(F)F)cc4)CC3)cc2)n1
Yield: 32.9 %

Procedure:
This compound was prepared in a manner analogous to that of Step D of Example 12, with 0.3 gram (0.001 mole) of 4-(2-methyl-2H-tetrazol-5-yl)phenylmethyl bromide, 0.5 gram (0.001 mole) of 4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine (prepared as in Step C of Example 12), and 0.6 gram (0.004 mole) of N,N-diisopropylethylamine in about 5 mL of dimethyl sulfoxide as reagents. The crude reaction product was subjected to column chromatography on silica gel, with 3:7 acetone:methylene chloride as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding about 0.2 gram of N-[4-(2-methyl-2H-tetrazol-5-yl)phenylmethyl]-4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:27])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].I[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(OCCCC)CCC.[Cu]>[CH3:26][N:23]1[CH2:22][CH2:21][N:20]([S:17]([C:14]2[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:27])=[CH:16][CH:15]=2)(=[O:19])=[O:18])[CH2:25][CH2:24]1
Reactant: Ic1ccccc1
Reactant: CN1CCN(S(=O)(=O)c2ccc(CCC(=O)c3ccccc3N)cc2)CC1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCOCCCC
Product: CN1CCN(S(=O)(=O)c2ccc(CCC(=O)c3ccccc3Nc3ccccc3)cc2)CC1
Temperature: 160 °C

Procedure:
A mixture of 1-(2-aminophenyl)-3-[4-(4-methylpiperazine-1-sulfonyl)-phenyl]-propan-1-one (1.16 g), copper powder (90 mg), KI (19.7 mg), K2CO3 (495 mg) and iodobenzene (1.3 mL) in dibutyl ether (25 mL) was heated at 160° C. (oil bath temperature) overnight. A second aliquot of KI (19.7 mg), K2CO3 (495 mg) and iodobenzene (1.30 mL) was added, and the resulting mixture again heated at 160° C. overnight. The reaction mixture was then cooled and concentrated under reduced pressure. The residue was partitioned between water (50 mL) and EtOAc (50 mL), the organic layer separated, and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (DCM/MeOH, 98:2 for 5 minutes, 95:5 from minutes 10 to 15) to afford 3-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-1-(2-phenylaminophenyl)-propan-1-one (258 mg). MS=464.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:13][CH2:14][OH:15])[CH2:10][NH:11][CH3:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)(O)[O-].[Na+].[C:21]([C:23]1[C:24]([O:36][CH3:37])=[C:25]([C:33](Cl)=[O:34])[C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)#[N:22]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:13][CH2:14][OH:15])[CH2:10][N:11]([CH3:12])[C:33]([C:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:32]=[C:23]([C:21]#[N:22])[C:24]=2[O:36][CH3:37])=[O:34])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1c(C#N)cc2ccccc2c1C(=O)Cl
Reactant: CNC[C@@H](CCO)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1c(C#N)cc2ccccc2c1C(=O)N(C)C[C@@H](CCO)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
N-[(S)-2-(3,4-Dichlorophenyl)-4-hydroxybutyl]-N-methylamine (Miller, S C; WO 9512577) dissolved in DCM and added to a 10% aqueous sodium bicarbonate solution. The mixture was cooled to 0° C. and a solution of 3-cyano-2-methoxy-1-naphthoyl chloride in DCM was added dropwise over 30 min. After stirring overnight the organic phase was concentrated, and purified by column chromatography to afford N-[2-(S)-(3,4-dichlorophenyl)-4-hydroxybutyl]-N-methyl-3-cyano-2-methoxy-1-naphthamide [1H NMR (300 MHz, DMSO-d6) δ9.70-9.64 (m), 8.67-8.57 (m), 8.07-7.97 (m), 7.80 (s), 7.72-7.55 (m), 7.52-7.48 (m), 7.40-7.33 (m), 7.12-7.10 (d), 7.04-7.02 (d), 6.87-6.83 (m), 6.37-6.29 (d), 4.53-4.44 (t), 4.11-4.00 (m), 3.94 (s), 3.92 (s), 3.91-3.73 (m), 3.71 (s), 3.45-3.38 (m), 3.33 (s), 3.14 (s), 2.97-2.95 (d), 2.63 (s), 2.60 (s); MS APCI, m/z=455 (M+)].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][C@H:23]([CH2:25][NH2:26])[O:22][C:21]4=[O:27])=[CH:16][CH:15]=3)([CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:36]([O:38][CH3:39])=[O:37]>C1COCC1.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:24][C@H:23]([CH2:25][NH:26][C:36]([O:38][CH3:39])=[O:37])[O:22][C:21]4=[O:27])=[CH:18][CH:19]=3)([CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CC2(c2ccc(N3C[C@H](CN)OC3=O)cc2)C1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)NC[C@H]1CN(c2ccc(C34CC3CN(C(=O)OC(C)(C)C)C4)cc2)C(=O)O1
Temperature: 0 °C
Yield: 67.4 %

Procedure:
To a solution of solution of compound (400 mg, 1.1 mmol) obtained in Step 1, in THF (20 mL) was added triethylamine (0.45 mL, 3.2 mmol). The resulting solution was cooled to 0° C. and methyl chloroformate (0.12 mL, 1.6 mmol) was added dropwise. The reaction mixture was stirred at r.t. and progress of the reaction was monitored by TLC. On completion, the reaction mixture was diluted with DCM (60 mL). The organic layer was washed with water (25 mL), brine (25 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 2:8 EtOAc:Pet. ether) to provide the title compound (320 mg, 70%) as white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[S:16][C:15]2[C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[N:13][C:12]([CH3:23])=[N:11][C:10]=2[CH:9]=1)=[O:7].[NH:24]1[C:32]2[C:27](=C[CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1B(O)O>>[NH:24]1[C:32]2[C:27](=[C:23]([C:12]3[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:15]4[S:16][C:8]([C:6]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[O:7])=[CH:9][C:10]=4[N:11]=3)[CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25]1
Reactant: OB(O)c1cc2ccccc2[nH]1
Reactant: COCCNC(=O)c1cc2nc(C)nc(N3CCOCC3)c2s1
Product: COCCNC(=O)c1cc2nc(-c3cccc4[nH]ccc34)nc(N3CCOCC3)c2s1

Procedure:
2-Methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carboxylic acid (2-methoxyethyl)-amide was reacted with indole boronic acid in general procedure A. Purification on silica yielded 189. NMR: 400MHz; CDCl3 3.44 (3H, s); 3.60 (2H, m); 3.70 (2H, m); 3.92 (4H, t, J=4.8 Hz); 4.15 (4H,t,J=4.8Hz); 6.74 (1H,br t); 7.30 (1H,d,J=7.8Hz); 7.35 (1H,m); 7.52 (1H,d,J=8.0Hz); 7.57 (1H,s); 7.82 (1H,s); 8.2 0(1H,d,J=7.4Hz); 8.30 (1H,br s). MS: (ESI+) M+H (438)
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]([CH:27]1[CH2:30][CH2:29][CH2:28]1)=[O:26])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH3:40][Mg]Br>O1CCCC1>[F:39][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]([CH:27]1[CH2:28][CH2:29][CH2:30]1)([OH:26])[CH3:40])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: C[Mg]Br
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(=O)C2CCC2)n1
Solvent: C1CCOC1
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(C)(O)C2CCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
To a solution of (2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)(cyclobutyl)methanone (Preparation 29, 28 mg; 0.050 mmol) in tetrahydrofuran (0.5 mL) was added methylmagnesium bromide (50 uL; 0.15 mmol; 3.0M in diethyl ether). The reaction was stirred at room temperature for 2 hours. The reaction was quenched with 2 drops water and 1 drop aqueous 2N hydrochloric acid. The mixture was diluted with ethyl acetate and filtered over a column containing silica gel and sodium sulfate. The crude was purified over 4 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 10-50% ethyl acetate in heptane) to give 22 mg (76% yield) of the title compound as a colorless gum. MS (ES−): Calc: 581.4, Found: 580.6 (M−H). 1H NMR (400 MHz, CDCl3) δ ppm 7.78 (s, 1H), 7.74 (s, 2H), 7.42 (d, 1H), 7.41 (s, 1H), 7.33 (d, J=9.13 Hz, 1H), 5.27(d, J=16.60 Hz, 1H), 5.15 (d, J=16.18 Hz, 1H), 4.85 (s, 2H), 4.18 (s, 3H), 2.97 (m, 1H), 2.12-1.69 (m, 6H), 1.43 (s, 3H).
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[H-].[Na+].[CH3:12][C:13]([CH3:17])=[CH:14][CH2:15]Br>CN(C)C=O>[CH3:12][C:13]([CH3:17])=[CH:14][CH2:15][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9]
Reactant: CC(C)=CCBr
Reactant: O=Cc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)=CCOc1ccccc1C=O
Reaction time: 1 h
Yield: 87.9 %

Procedure:
244 g (2 mols) of salicylaldehyde in 400 ml of dimethylformamide are added dropwise to a suspension of 60 g (2 mols) of 80% strength sodium hydride in 2,000 ml of absolute dimethylformamide, while cooling and stirring. After one hour at room temperature, 312.9 g (2.1 mols) of dimethylallyl bromide are added dropwise, again at 0° C. The mixture is stirred at room temperature overnight and thereafter the solvent is largely evaporated off and the residue is carefully hydrolyzed. The product is extracted with three 400 mL portions of methylene chloride and the combined organic phases are washed with two 400 ml portions of water. After drying over sodium sulphate and stripping off the solvent, the residue which remains is distilled in vacuo. 334.4 g (88% of theory) of 2-(3-methyl-2-butenyloxy)-benzaldehyde of boiling point 110° C./10 mm Hg are obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:18][N:7]2[C:8]3[CH:9]=[C:10]([C:15]([OH:17])=O)[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:19])[NH:4][CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:33][C:34]1[O:38][N:37]=[C:36]([NH2:39])[CH:35]=1.N1(C2CCCCCCCCCC2)CCCN=CCCCCC1>C1COCC1>[CH3:20][C:2]1([CH3:1])[CH2:18][N:7]2[C:8]3[CH:9]=[C:10]([C:15]([NH:39][C:36]4[CH:35]=[C:34]([CH3:33])[O:38][N:37]=4)=[O:17])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:19])[NH:4][CH2:3]1
Reactant: CC1(C)CNC(=O)c2cc3ccc(C(=O)O)cc3n2C1
Reactant: Cc1cc(N)no1
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)c2ccc3cc4n(c3c2)CC(C)(C)CNC4=O)no1
Temperature: 55 °C
Reaction time: 0.17 h
Yield: 60.6 %

Procedure:
To a solution of 4,4-dimethyl-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxylic acid (100 mg, 0.37 mmol) in THF (2 mL) is added 1,1′-carbonyldiimidazole (149 mg, 0.92 mmol). The reaction mixture is heated at 55° C. for 1 h. The mixture is cooled to room temperature and 5-methyl-3-aminoisoxazole (144 mg, 1.47 mmol) is added. After stifling 10 min, 1,8-diazabicycloundec-7-ene (0.14 mL, 0.92 mmol) is added and the reaction is heated at 60° C. for 16 h. After cooling to room temperature, the solvent is evaporated and the residue is purified by preparative HPLC using 10-85% acetonitrile/water with 0.1% TFA to afford the title compound (79 mg, 61%). LCMS (ESMS): m/z 353.45 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.P(Cl)(Cl)Cl>O>[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:12]([C:3]2[C:2]([OH:1])=[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=[N:10]3)=[CH:5][CH:4]=2)=[O:14])=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccc2cccnc2c1O
Reactant: Nc1ccc(Cl)cc1
Solvent: O
Solvent: ClP(Cl)Cl
Product: O=C(Nc1ccc(Cl)cc1)c1ccc2cccnc2c1O
Reaction time: 8 h
Yield: 32.8 %

Procedure:
A solution of 8-hydroxyquinoline-7-carboxylic acid (3.78 g) of Preparation 1 and 4-chloroaniline (2.55 g) in 250 mL xylenes is heated to reflux. To this is added dropwise PCl3 (1.37 g). Refluxing is continued overnight. The reaction is then cooled and water is added to destroy excess PCl. The resulting solid is collected, washed with water and dried. The crude product is recrystallized from EtOAc/hexanes to yield 1.96 g of the title product as an orange solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Cl:12][C:13]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:14]=1[NH2:15]>>[Cl:12][C:13]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1ccc(Cl)cc1Cl
Product: O=C(O)Cc1ccccc1Nc1ccc(Cl)cc1Cl

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid was condensed with 2,4-dichloroaniline to yield 2-[(2,4-dichlorophenyl)amino]phenylacetic acid.