Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[C:8]([Cl:19])[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH:20]1[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]1>>[Cl:19][C:8]1[N:9]=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:11]2[N:12]=[C:3]([CH2:2][N:20]3[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]3)[CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(CBr)ccc2n1
Reactant: CC(C)(O)C1CCNCC1
Product: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1

Procedure:
Following General Procedure B, 4-(6-(bromomethyl)-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine 7 and 2-(piperidin-4-yl)propan-2-ol were reacted to give 2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol. LCMS (MH+)=406.1. 1H-NMR (DMSO-d6): δ 8.02 (d, 1H), 7.83 (d, 1H), 4.46 (s, br, 4H), 4.01 (s, 1H), 3.78 (m, 4H), 3.68 (s, 2H), 2.88 (m, 2H), 1.96 (m, 2H), 1.65 (m, 2H), 1.25 (m, 3H), 1.03 (s, 6H)
Reaction SMILES: ClC1C=C(C=C(Cl)C=1N1C=C2C([NH:19][C:20]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22][N:21]=3)=NC=C(Cl)C2=N1)C#N.Br[C:30]1[C:35]2=[CH:36][N:37]([C:39]3[C:44]([Cl:45])=[CH:43][C:42]([F:46])=[CH:41][C:40]=3[Cl:47])[N:38]=[C:34]2[C:33]([F:48])=[CH:32][N:31]=1.CC1N=CN=C(N)C=1>>[Cl:47][C:40]1[CH:41]=[C:42]([F:46])[CH:43]=[C:44]([Cl:45])[C:39]=1[N:37]1[CH:36]=[C:35]2[C:30]([NH:19][C:20]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22][N:21]=3)=[N:31][CH:32]=[C:33]([F:48])[C:34]2=[N:38]1
Reactant: Fc1cc(Cl)c(-n2cc3c(Br)ncc(F)c3n2)c(Cl)c1
Reactant: Cc1cc(Nc2ncc(Cl)c3nn(-c4c(Cl)cc(C#N)cc4Cl)cc23)ncn1
Agent: Cc1cc(N)ncn1
Product: Cc1cc(Nc2ncc(F)c3nn(-c4c(Cl)cc(F)cc4Cl)cc23)ncn1
Yield: 36 %

Procedure:
Following the procedure described for 3,5-dichloro-4-[7-chloro-4-(6-methylpyrimidin-4-ylamino)pyrazolo[4,3-c]pyridin-2-yl]benzonitrile, 4-bromo-2-(2,6-dichloro-4-fluorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine and 6-methylpyrimidin-4-ylamine were reacted to afford the title compound as a white solid (38 mg, 36% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.72 (s, 1H), 9.26 (d, J=2.6 Hz, 1H), 8.69 (d, J=1.2 Hz, 1H), 8.36 (s, 1H), 7.98 (d, J=3.5 Hz, 1H), 7.96 (s, 1H), 7.94 (s, 1H), 2.44 (s, 3H). LCMS (Method B): RT=3.44 min, m/z: 407 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]2[NH:9][C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)=[CH:11][C:3]=12.[H-].[Na+].Cl[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26]>CN(C)C=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]2[N:9]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)=[CH:11][C:3]=12
Reactant: Cn1cc(-c2cc3c(Cl)c(Cl)cnc3[nH]2)cn1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc3c(Cl)c(Cl)cnc3n2COCC[Si](C)(C)C)cn1
Temperature: -42 °C
Reaction time: 0.5 h

Procedure:
A solution of Example 113D (0.17 g, 0.636 mmol) in N,N-dimethylformamide (3.5 mL) was cooled to 0° C. in an ice bath, and sodium hydride (60% dispersion in mineral oil, 0.031 g, 0.776 mmol) was added. The reaction mixture was stirred 30 minutes, cooled to −42° C., and (2-(chloromethoxy)ethyl)trimethylsilane (0.146 mL, 0.827 mol) was added dropwise over 3 minutes. The reaction was stirred at −42° C. for 1 hour and was quenched with saturated aqueous ammonium chloride (3 mL). The mixture was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by flash chromatography on a silica gel column, eluting with a gradient of 0% to 25% ethyl acetae in hexane, to provide the title compound. MS ESI(+) m/z 397.2 [M+H]+.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][C:12](=[O:14])[C:11]([S:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.C([N:34](CC)CC)C.[CH:39]1[C:52]2C3[C:46](=[CH:47][CH:48]=CC=3)[CH2:45][NH:44][C:43]=2C=C[CH:40]=1>ClCCl.C(OCC)(=O)C>[C:20]1([C:21]([NH2:34])=[O:23])[C:19]2[C:18]3[C:46](=[CH:47][CH:48]=[CH:16][CH:17]=3)[CH2:45][NH:44][C:43]=2[CH:52]=[CH:39][CH:40]=1.[Si:1]([O:8][CH:9]1[CH2:13][C:12](=[O:14])[C:11]([S:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: c1ccc2c(c1)CNc1ccccc1-2
Agent: CC(C)(C)[Si](C)(C)OC1C=C(SCCCCCC(=O)O)C(=O)C1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc2c1-c1ccccc1CN2
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
2.12 g (5.92 mmoles) of 4(RS)-t-butyldimethylsilyloxy-2-(5-carboxypentylthio)-2-cyclopentenone was dissolved in 30 ml of dichloromethane, and the solution was cooled to -40° C. To the solution were added 970 mg (920 microliters; 7.10 mmols) of isobutyl chloroformate and 896 mg (1.24 ml, 8.88 mmoles) of triethylamine were added, and the mixture was stirred at -40° C. for 30 minutes. Then, 10 ml of a dichloromethane solution of 1.29 g (7.10 mmoles) of 5,6-dihydrophenanthridine was added to the resulting mixture. The temperature was gradually raised to room temperature over 20 hours. After the reaction, ethyl acetate was added to the reaction mixture to perform extraction. The extract was washed with dilute hydrochloric acid, an aqueous solution of sodium bicarbonate and then an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated. The resulting crude product was chromatographed on a silica gel column using hexane/ethyl acetate (4/1) as an eluent to give 2.657 g (5.1 mmoles; yield 86%) of 4(RS)-t-butyldimethylsilyloxy-2-(5-carboxypentylthio)-2-cyclopentenone 5,6-dihydrophenanthridinamide.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)=[O:11])[CH2:5][CH2:4]1.[Cl:33][Si](C)(C)C>CC(CC)=O>[ClH:33].[CH3:32][N:2]([CH3:1])[C:3]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:4][CH2:5][CH:6]([CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)=[O:11])[CH2:7][CH2:8]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(CC(=O)NCCCCc2c[nH]c3ccccc23)CC1
Solvent: CCC(C)=O
Product: Cl
Reaction time: 1.5 h

Procedure:
2-(4-Dimethylamino-4-phenylcyclohexyl)-N-[4-(1H-indol-3-yl)butyl]acetamide (58 mg, 0.142 mmol) was dissolved in ethyl methyl ketone with gentle heating and chlorotrimethylsilane (0.027 ml, 0.213 mmol) was added. After 1.5 h it was possible to obtain the hydrochloride as a colourless solid in a yield of 65% (43 mg) with an m.p. of 165-174° C.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[O:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[N:30]1[C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=[CH:31]1.[F-].[Cs+].O>CN(C=O)C.[Cu]I.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>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([C:34]5[N:30]([CH:25]6[CH2:26][CH2:27][CH2:28][CH2:29][O:24]6)[CH:31]=[N:32][CH:33]=5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: CC1(C)OB(c2cncn2C2CCCCO2)OC1(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3cncn3C3CCCCO3)cc1OCC2
Temperature: 130 °C
Yield: 16.5 %

Procedure:
To a mixture of 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 250 mg, 0.67 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole (204 mg, 0.73 mmol) in dry DMF (2.5 mL) under nitrogen was added CsF (254 mg, 1.68 mmol), CuI (13 mg, 0.067 mmol) and Pd(PPh3)4 (39 mg, 0.034 mmol). The reaction mixture was heated at 130° C. for 40 min under microwave. Cooled to room temperature, the resulting mixture was poured into water and extracted with EtOAc. Dried organics over sodium sulfate and purified by pre-TLC (100% EtOAc) to give 242 as a yellow solid (49.3 mg, yield: 17%). 1H NMR (DMSO-d6, 400 MHz): δ8.49 (d, J=8.4 Hz, 1H), 8.11 (s, 1H), 7.97 (s, 1H), 7.92 (s, 1H), 7.28 (dd, J1=1.6 Hz, J2=8.4 Hz, 1H), 7.18 (d, J=6.8 Hz, 2H), 5.92-5.89 (m, 1H), 5.19 (d, J=9.2 Hz, 1H), 4.55-4.52 (m, 4H), 4.04 (d, J=11.2 Hz, 1H), 3.60-3.56 (m, 1H), 2.29-1.90 (m, 3H), 1.58-1.48 (m, 9H). MS: (ESI, m/z)=446 [M+H]+
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:23]=1.[C:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[C:30]([F:32])[CH:31]=1)#[N:25]>>[O:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[C:7]1([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[C:6]2[CH:23]=[C:2]([C:28]3[CH:27]=[C:26]([CH:31]=[C:30]([F:32])[CH:29]=3)[C:24]#[N:25])[CH:3]=[CH:4][C:5]=2[NH:11][C:10](=[O:12])[CH2:9][O:8]1
Reactant: O=C1COC(c2ccco2)(c2ccco2)c2cc(Br)ccc2N1
Reactant: N#Cc1cc(F)cc(B(O)O)c1
Product: N#Cc1cc(F)cc(-c2ccc3c(c2)C(c2ccco2)(c2ccco2)OCC(=O)N3)c1

Procedure:
Prepared from 7-bromo-5,5-di(2-furyl)-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3-cyano-5-fluorobenzeneboronic acid generally according to the coupling procedure of example 1. 1H NMR (DMSO-d6): δ 10.34 (s, 1H), 7.73-7.87 (m, 5H), 7.59 (dt, J=10.25, 1.95 Hz, 1H), 7.35 (d, J=8.3 Hz, 1H), 6.98 (d, J=1.95 Hz, 1H), 1H, 6.52 (dd, J=3.42, 1.95 Hz, 2H), 6.29 (dd, J=3.42, 0.98 Hz, 2H), 4.16 (s, 2H); MS (ESI) m/z 415 ([M+H]+); MS (ESI) m/z 413 ([M−H]−); Anal. calcd for C24H15FN2O4: C: 69.56; H: 3.65; N: 6.76. Found: C: 67.60; H: 3.77; N: 5.81.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:32]=[CH:31][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=4)=[O:18])=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1.Cl[C:34]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[O:35]>>[CH3:40][O:39][CH2:38][CH2:37][O:36][C:34](=[O:35])[NH:2][C:3]1[CH:32]=[CH:31][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([C:27]([F:29])([F:30])[F:28])[CH:21]=4)=[O:18])=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1
Reactant: COCCOC(=O)Cl
Reactant: Nc1ccc2c(c1)ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: Cl
Product: COCCOC(=O)Nc1ccc2c(c1)ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from 1-[4-(5-aminobenzimdazol-1-yl)phenyl]-3-(4-chloro-3-(trifluoro-methyl)phenyl)urea hydrochloride and methoxyethyl chloroformate by the same method as in Example 41.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([NH:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:41]>>[ClH:41].[ClH:41].[CH3:32][O:31][C:29]([CH2:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([N:18]2[CH2:19][CH2:20][CH:15]([CH:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[NH:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:16][CH2:17]2)=[CH:26][CH:25]=1)=[O:30]
Reactant: COC(=O)COc1ccc(N2CCC(C(NCc3ccccc3)C3CCN(C(=O)OC(C)(C)C)CC3)CC2)cc1
Agent: Cl
Product: COC(=O)COc1ccc(N2CCC(C(NCc3ccccc3)C3CCNCC3)CC2)cc1

Procedure:
Prepared from 4-[(1-tert-butyloxycarbonylpiperidin-4-yl)-N-benzylaminomethyl]-1-(4-methoxycarbonylmethyloxyphenyl)piperidine and ethereal hydrochloric acid.
Reaction SMILES: [S:1]1[C:5](=[O:6])[CH2:4][NH:3][C:2]1=[O:7].[CH3:8][C:9]([CH3:15])=[CH:10][CH2:11][N:12]=[C:13]=[O:14].CC(C)=CCN.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1.ClCCl.N1C=CC=CC=1>[CH3:8][C:9]([CH3:15])=[CH:10][CH2:11][NH:12][C:13]([N:3]1[CH2:4][C:5](=[O:6])[S:1][C:2]1=[O:7])=[O:14]
Reactant: O=C1CNC(=O)S1
Reactant: CC(C)=CCN=C=O
Agent: CC(C)=CCN
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)=CCNC(=O)N1CC(=O)SC1=O

Procedure:
To a stirred solution or partial solution of 2,5-thiazolidinedione (0.010 mol) in tetrahydrofuran (THF) is added neat (or a solution in dichloromethane or THF) (3-methyl-but-2-en-1-yl)-isocyanate (0.010 mol), prepared by allowing (3-methyl-but-2-en-1-yl)amine with 0.33 mol equivalents of triphosgene in dichloromethane optionally in the presence of a tertiary amine base or pyridine, and the mixture is stirred. Reaction progress may be followed by thin layer chromatography (TLC) or high performance liquid chromatography (HPLC). When a sufficient amount of desired product is formed, the mixture (or, optionally, the residue which is obtained after first rotary evaporating off the reaction solvent) is partitioned between ethyl acetate and an excess of about 0.1 M hydrochloric acid. The organic layer is washed with brine, dried over sodium sulfate, and rotary evaporated to give 3-(3-methyl-but-2-en-1-yl)aminocarbonyl-2,5-thiazolidinedione, which may be purified, if needed or desired, by chromatography on silica gel or crystallization.
Reaction SMILES: [CH2:1]([O:5][P:6]([O-:8])[O-:7])[CH2:2][CH2:3][CH3:4].C[Si](C)(C)N[Si](C)(C)C.[C:18]([O:21][C@@H:22]([CH3:26])[C:23](Cl)=[O:24])(=[O:20])[CH3:19]>>[PH:6](=[O:8])([O:7][C:23](=[O:24])[C@@H:22]([O:21][C:18](=[O:20])[CH3:19])[CH3:26])[O:5][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCOP([O-])[O-]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: CCCCO[PH](=O)OC(=O)[C@H](C)OC(C)=O
Temperature: 15 °C
Yield: 109.9 %

Procedure:
A mixture of di-ter.butylphosphite (2.13 g; 0.11 mol) and hexamethyldisilazane (8.87 g; 0.055 mol) was kept under nitrogen at 100° C. for 2 hours. The mixture was slowly cooled at 15° C. 2(S)-acetoxypropionyl chloride (15.0 g; 0.1 mol) was added under nitrogen at 15° C. in 15 minutes, thereafter the low-boiling compounds were removed by distillation under vacuum (20°-30° C./10 mmHg). Di-ter.butyl 2(S)-acetoxypropionyl phosphonate (27.72 g) was thereby obtained as oil.
Reaction SMILES: [OH:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([CH:15]=[O:16])=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[OH:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([CH2:15][OH:16])=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc2c(c1)C(=O)c1cccc(O)c1-2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1c2cc(CO)ccc2-c2c(O)cccc21

Procedure:
A stirred mixture of 405.2 mg (1.8 mmol) of aldehyde prepared in Step G and 804.3 mg (3.8 mmol) of sodium triacetoxyborohydride in 27 mL of anhydrous THF was refluxed under nitrogen for 1 hour. The cooled mixture was partitioned between EtOAc, ice-water and saturated NaHCO3, and the organic phase was separated, washed with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo. Purification by PLC with CH2Cl2-EtOAc (2:1) yielded 303.7 mg of the crystalline, title product.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]([CH3:10])([CH3:9])[C:6](=[O:8])[CH3:7]>C(OCC)C>[Br:1][CH2:7][C:6](=[O:8])[C:5]([O:4][CH3:3])([CH3:10])[CH3:9]
Reactant: BrBr
Reactant: COC(C)(C)C(C)=O
Solvent: CCOCC
Product: COC(C)(C)C(=O)CBr
Yield: 68.4 %

Procedure:
Bromine (26.42 g, 0.165 mole) was slowly added to a stirred solution of 19.2 g (0.165 mole) of 3-methoxy-3-methyl-2-butanone in 400 ml. diethyl ether at 15° C. After the addition was complete, the solvent was evaporated, and the residual orange oil distilled to give 22 g (68% yield) of 1-bromo-3-methoxy-3-methyl-2-butanone, b.p. 57°-59° C./1.7 mm. Hg.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[NH:19][C:18]4[N:26]=[CH:27][CH:28]=[CH:29][C:17]=4[N:16]3[C:30]=2[C:31]2[CH:36]=[CH:35][C:34]([C:37]3([NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:39][CH2:38]3)=[CH:33][CH:32]=2)=[CH:9][CH:8]=1)(=O)=O.[NH2:51][C:52]([C:54]1[CH:59]=[CH:58][C:57](B(O)O)=[CH:56][CH:55]=1)=[O:53]>C1(C)C=CC=CC=1.CCO.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:52]([C:54]1[CH:59]=[CH:58][C:57]([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[N:14]=[C:15]4[C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[NH:19][C:18]5[N:26]=[CH:27][CH:28]=[CH:29][C:17]=5[N:16]4[C:30]=3[C:31]3[CH:32]=[CH:33][C:34]([C:37]4([NH:41][C:42](=[O:43])[O:44][C:45]([CH3:47])([CH3:46])[CH3:48])[CH2:38][CH2:39][CH2:40]4)=[CH:35][CH:36]=3)=[CH:11][CH:12]=2)=[CH:56][CH:55]=1)(=[O:53])[NH2:51]
Reactant: NC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(OS(=O)(=O)C(F)(F)F)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(-c5ccc(C(N)=O)cc5)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 100 °C
Yield: 75.8 %

Procedure:
To a solution of 4-[3-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-2-yl]phenyl trifluoromethanesulfonate (30 mg, 0.043 mmol) in toluene (1 mL) and EtOH (1 mL) was added saturated 1M-K3PO4aq, 4-aminocarbonylphenylboronic acid (21 mg, 0.13 mmol) and Pd (PPh3)4 (5 mg, 0.0043 mmol). The reaction was degassed for 2 minutes and then heated at 100° C., 2.5 h. The reaction mixture was cooled to room temperature, then was diluted with EtOAc (15 mL) and washed with brine. The organic phase was dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (SiO2, 20% to 50% to 100% EtOAc in hexane) gave the title compound as a white solid (22 mg, 76%); LCMS: 675 [M+H].
Reaction SMILES: [Cl-].[CH3:2][C:3]1[S:32][C:6]2=[N:7][C:8]([CH2:12][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:9][C:10](=[O:11])[N:5]2[C:4]=1[CH3:33].[H-].[Na+].[CH:36]1([CH2:39][O:40][C:41]2[C:48]([O:49][CH3:50])=[CH:47][CH:46]=[CH:45][C:42]=2[CH:43]=O)[CH2:38][CH2:37]1.C1(COC2C(OC)=CC=CC=2/C=C/C2N=C3SC=CN3C(=O)C=2I)CC1>CS(C)=O>[CH:36]1([CH2:39][O:40][C:41]2[C:48]([O:49][CH3:50])=[CH:47][CH:46]=[CH:45][C:42]=2/[CH:43]=[CH:12]/[C:8]2[N:7]=[C:6]3[S:32][C:3]([CH3:2])=[C:4]([CH3:33])[N:5]3[C:10](=[O:11])[CH:9]=2)[CH2:37][CH2:38]1
Reactant: COc1cccc(C=O)c1OCC1CC1
Reactant: Cc1sc2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc(=O)n2c1C
Agent: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC1CC1
Agent: [Cl-]
Agent: [H-]
Solvent: CS(C)=O
Product: COc1cccc(/C=C/c2cc(=O)n3c(C)c(C)sc3n2)c1OCC1CC1

Procedure:
A stirred suspension of Step 2 intermediate (1.0 g, 2.00 mmol) in dry DMSO (12 ml) was treated with NaH (89 mg, 2.240 mmol) and 2-(cyclopropylmethoxy)-3-methoxybenzaldehyde (462 mg, 2.240 mmol) according to the procedure described in Step 3, Intermediate 2 to yield a crude solid which was purified by column chromatography using 2% ethyl acetate in DCM to afford 600 mg of the desired compound as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 0.32-0.35 (m, 2H), 0.54-0.58 (m, 2H), 1.15-1.21 (m, 1H), 2.26 (s, 3H), 2.59 (s, 3H), 3.73-3.75 (m, 2H), 3.79 (s, 3H), 6.13 (s, 1H), 6.99-7.00 (m, 3H), 7.29-7.31 (m, 1H), 8.03 (d, J=16.2 Hz, 1H).
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]C.CC(CCCCCCCCC)CO.C(C(CCCCCCC)CO)CC>>[CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: CCCCCCCC(CO)CCC
Agent: CCCCCCCCCC(C)CO
Product: CCCCCCCCCCCCCCCCCO

Procedure:
1-octadecanol; 2-methyl-1-undecanol; 2-propyl-1-nonanol;
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[N:16]=[C:15]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[C:19]([CH2:25][CH3:26])[CH:18]=4)[O:14][N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:30][C@@H:31]([OH:34])[CH2:32][OH:33]>C(O)(C)C.[OH-].[Na+].CC(=O)OCC>[CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[N:16]=[C:15]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH2:30][C@@H:31]([OH:34])[CH2:32][OH:33])=[C:19]([CH2:25][CH3:26])[CH:18]=4)[O:14][N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1cc(-c2nc(-c3cc(OC)nc(C4CCCC4)c3)no2)cc(C)c1O
Reactant: OC[C@H](O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCc1cc(-c2nc(-c3cc(OC)nc(C4CCCC4)c3)no2)cc(C)c1OC[C@@H](O)CO
Temperature: 70 °C
Reaction time: 48 h
Yield: 53 %

Procedure:
A mixture of 4-[3-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-2-ethyl-6-methyl-phenol (150 mg, 395 μmol) and (S)-3-chloro-propane-1,2-diol (366 mg, 3.31 mmol) in isopropanol (4 mL) and 3 N aq. NaOH (1 mL) is stirred at 70° C. for 48 h. The mixture is diluted with EA (50 mL), washed with 1 M aq. NaOH solution (20 mL) followed by brine (20 mL), dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC to give the title compound (95 mg) as a pale brown oil; LC-MS**: tR=0.88 min, [M+H]+=454.08; 1H NMR (CDCl3): δ1.34 (t, J=7.0 Hz, 3H), 1.67-1.79 (m, 2H), 1.82-1.96 (m, 4H), 2.04-2.15 (m, 2H), 2.43 (s, 3H), 2.79 (q, J=7.0 Hz, 2H), 3.18-3.29 (m, 1H), 3.81-3.99 (m, 4H), 4.01 (s, 3H), 4.15-4.22 (m, 1H), 7.30 (s, 1H), 7.49 (s, 1H), 7.93 (s, 1H), 7.94 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:22](I)[CH3:23].O(C1C=CC(C(C=CC(O)=O)=O)=CC=1)C1C=CC=CC=1.CI>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([CH:13]=[CH:14][C:15]([O:17][CH2:22][CH3:23])=[O:16])=[O:12])=[CH:9][CH:8]=2)=[CH:20][CH:21]=1
Reactant: CCI
Reactant: Cc1ccc(Oc2ccc(C(=O)C=CC(=O)O)cc2)cc1
Agent: O=C(O)C=CC(=O)c1ccc(Oc2ccccc2)cc1
Solvent: CI
Product: CCOC(=O)C=CC(=O)c1ccc(Oc2ccc(C)cc2)cc1
Yield: 76.4 %

Procedure:
The procedure in Example 12(1) was followed, except that 5.64 g of 3-[4-(4-methylphenoxy)benzoyl]acrylic acid and 5.98 g of ethyl iodide were used in place of 3-(4-phenoxybenzoyl)acrylic acid and methyl iodide, respectively, to give 4.74 g of ethyl 3-[4-(4-methylphenoxy)benzoyl]acrylate in the form of an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([S:15][C:16]=2[CH:17]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)([O-])=O>[Pd].CCO.C1COCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([S:15][C:16]=2[CH:17]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: O=[N+]([O-])c1ccc2c(c1)Sc1ccccc1N2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc2c(c1)Sc1ccccc1N2
Yield: 97 %

Procedure:
Reduction of the nitro function of 3-nitro-10H-phenothiazine (J. Org. Chem. (1972) 37, 2691) is carried out in the presence of Pd/C in an EtOH/THF mixture under the conditions described for intermediate 2.2. A grey solid is obtained with a yield of 97%. Melting point: 150–156° C.