Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11]([C:13]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:14]=2[O:15][CH2:16][C@@H:17]2[CH2:20][CH2:19][N:18]2C(OC(C)(C)C)=O)=[O:12])/[N:7]([CH2:36][C@H:37]2[CH2:41][CH2:40][CH2:39][O:38]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH:18]1[CH2:19][CH2:20][C@H:17]1[CH2:16][O:15][C:14]1[CH:28]=[CH:29][C:30]([C:32]([F:34])([F:33])[F:35])=[CH:31][C:13]=1[C:11](/[N:10]=[C:8]1\[S:9][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][N:7]\1[CH2:36][C@H:37]1[CH2:41][CH2:40][CH2:39][O:38]1)=[O:12]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1ccc(C(F)(F)F)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@H]1CCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2OC[C@@H]2CCN2)s1
Yield: 85.4 %

Procedure:
The mixture of Example 2A (478 mg, 0.8 mmol) and 2,2,2-trifluoroacetic acid (616 μL, 8.0 mmol) in CH2Cl2 (10 mL) was stirred at ambient temperature overnight. Saturated aqueous Na2CO3 (20 mL) was added followed by CH2Cl2 (30 mL). The organic layer was washed with brine and concentrated. Purification by gradient flash chromatography (silica gel, 5-30% (Et3N:MeOH, 1:10)/EtOAc) afforded 340 mg (85%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.32 (s, 9 H), 1.55-1.98 (m, 4 H), 2.04-2.34 (m, 2 H), 3.25-3.51 (m, 1 H), 3.59-3.87 (m, 4 H), 4.01-4.39 (m, 6 H), 7.26 (s, 1 H), 7.32 (d, J=8.73 Hz, 1 H), 7.74 (dd, J=8.73, 2.78 Hz, 1 H), 7.98 (d, J=2.38 Hz, 1 H); MS (ESI) m/z 498 (M+H)+.
Reaction SMILES: FC1C=C(F)C=CC=1O[C:5]1[C:6](=[O:22])[O:7][C:8]([CH3:21])([CH3:20])[C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([OH:35])=[N:33][CH:34]=1.C1CCN2C(=NCCC2)CC1>CC#N.CCOCC>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][C:5]2[C:6](=[O:22])[O:7][C:8]([CH3:20])([CH3:21])[C:9]=2[C:10]2[CH:11]=[CH:12][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:14][CH:15]=2)=[N:33][CH:34]=1
Reactant: CC1(C)OC(=O)C(Oc2ccc(F)cc2F)=C1c1ccc(S(C)(=O)=O)cc1
Reactant: Oc1ccc(Cl)cn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Solvent: CC#N
Product: CC1(C)OC(=O)C(Oc2ccc(Cl)cn2)=C1c1ccc(S(C)(=O)=O)cc1
Temperature: 67.5 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-chloroacetic acid 2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one ester (1.0 g, 3.13 mmol, prepared similarly to the compound of example 5, Step 1) and 5-chloro-2-pyridinol (0.41 g, 3.16 mmol) in CH3CN (20 mL) was added DBU (1.5 mL, 10.0 mmol) at r.t. The mixture was stirred for 1 h, then heated at 65-70° C. for 3h. The volatile solvents were removed in vacuo. The residue was chromatographed over silica gel and eluted with hexane:EtOAc (1:1) to yield a colorless oily residue which was swished in Et2O to provide the title compound as a white powder (230 mg).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([CH2:18][C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:27][C:28]1[CH:32]=[CH:31][N:30]([CH2:33][C:34]([CH3:37])([OH:36])[CH3:35])[N:29]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([CH2:18][C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[CH:13]=[N:12]2)[C:8]([NH:27][C:28]2[CH:32]=[CH:31][N:30]([CH2:33][C:34]([OH:36])([CH3:35])[CH3:37])[N:29]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Cc2c(F)cccc2F)cc1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Cc3c(F)cccc3F)cc2=O)n1
Yield: 49 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[4-(2,6-difluoro-benzyl)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 65) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-2-[4-(2,6-difluoro-benzyl)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide as a white solid (33.7 mg, 49%); ES+-HRMS m/e calcd for C26H31N5O3F2 [M+H+] 500.2468, found 500.2465. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.08 (m, 1H) 1.04 (s, 3H) 1.06 (s, 3H) 1.20-1.74 (m, 8H) 1.84-1.98 (m, 1H) 2.19-2.30 (m, 1H) 3.88 (s, 2H) 3.97 (s, 2H) 4.66 (s, 1H) 5.46 (dd, J=11.1, 4.5 Hz, 1H) 6.37 (d, J=2.1 Hz, 1H) 6.45 (br s, 1H) 7.18 (t, J=8.0 Hz, 2H) 7.39-7.50 (m, 1H) 7.51 (d, J=2.1 Hz, 1H) 7.92 (d, J=2.1 Hz, 1H) 10.80 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH3:20])[C:11]3[C:16]([C:17]=2[C:18]#[N:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:6]=[N:7][CH:8]=1.C1CCN2C(=NCCC2)CC1.[CH:32]([S:35](Cl)(=[O:37])=[O:36])([CH3:34])[CH3:33]>ClCCCl>[C:18]([C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH3:20])[C:9]=1[C:5]1[CH:4]=[C:3]([CH2:2][NH:1][S:35]([CH:32]([CH3:34])[CH3:33])(=[O:37])=[O:36])[CH:8]=[N:7][CH:6]=1)#[N:19]
Reactant: Cn1c(-c2cncc(CN)c2)c(C#N)c2ccccc21
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)S(=O)(=O)NCc1cncc(-c2c(C#N)c3ccccc3n2C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A flask is charged with 2-(5-aminomethyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (130 mg, 0.5 mmol), DBU (304 mg, 2.0 mmol) and DCE (15 mL), and isopropylsulfonyl chloride (142 mg, 1.0 mmol) is added. The mixture is stirred at room temperature for 1 h and concentrated in vacuo. The residue is purified by silica gel flash chromatography (dichloromethane-methanol, 1:0 to 97:3) to give propane-2-sulfonic acid [5-(3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amide. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.24 (d, J=6.8 Hz, 6H), 3.18-3.26 (m, 1H), 3.79 (s, 3H), 4.37 (d, J=6.1 Hz, 2H), 7.34-7.38 (m, 1H), 7.41-7.46 (m, 1H), 7.70-7.79 (m, 3H), 8.08 (t, J=2.0 Hz, 1H), 8.77 (d, J=2.3 Hz, 1H), 8.81 (d, J=2.3 Hz, 1H). HRMS (ESI) m/z 369.1389 [(M+H)+ Calcd for C19H21N4O2S: 369.1385].
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.Cl>CO>[C:1]([C:5]1[CH:10]=[C:9]([S:11][C:17]2([S:11][C:9]3[CH:8]=[C:7]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:6]([OH:16])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=3)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCCCCC1
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1cc(SC2(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CCCCCC2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
To a solution of 2,6-di-t-butyl-4-mercaptophenol (3.00 g, 12.6 mmol) in methanol (10 mL) was added cycloheptanone (1.63 mL, 13.8 mmol) and a catalytic amount of concentrated hydrochloric acid. The mixture was stirred at a room temperature overnight. The generated precipitate was separated by a filtration and dried to give objective bis(3,5-di-t-butyl-4-hydroxyphenylthio)cycloheptane (yield 2.74 g and 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:18]([N:25]=[C:26]=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCCCCC.CCOC(C)=O>C1COCC1>[CH2:18]([NH:25][C:26]([N:15]1[CH2:16][CH2:17][N:12]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[CH:8][CH:7]=2)[CH2:13][CH2:14]1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: O=C=NCc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(NCc1ccccc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
7-Chloro-4-(piperazin-1-yl)quinoline (62 mg, 0.25 mmol) and benzyl isocyanate (37 μL, 0.30 mmol) in THF (10 mL) are reacted according to method C yielding the title product as a colorless oil after column chromatography with hexane-EtOAc.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:30])[C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:20][CH:19]=3)[CH2:9]2)=[CH:4][CH:3]=1.[Cu][C:32]#[N:33].N>CN1CCCC1=O>[C:32]([C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:30])[C:18]3[CH:19]=[CH:20][C:21]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][CH:23]=3)[CH2:9]2)=[CH:4][CH:3]=1)#[N:33]
Reactant: N#C[Cu]
Reactant: O=C(NCCCCN1CCc2ccc(Br)cc2C1)c1ccc(-c2ccccc2)cc1
Agent: N
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2c(c1)CN(CCCCNC(=O)c1ccc(-c3ccccc3)cc1)CC2
Temperature: 0 °C
Yield: 46.5 %

Procedure:
A mixture of 7-Bromo-2-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline (3.84 g, 8.3 mmol) and copper (I) cyanide (1.04 g, 11.4 mmol) in N-methyl-2-pyrrolidinone (20 ml) was heated at reflux for 1.5 h. The cooled mixture was poured onto 0.880 ammonia (50 ml) and crushed ice (~50 g) with stirring. The product was extracted into ethyl acetate (100 ml) and washed further with 0.880 ammonia (2×30 ml), then brine. Drying (Na2SO4) and evaporation of the solvent in vacuo afforded a brown oil. Chromatography on silica using 20-100% ethyl acetate-pentane gradient elution afforded the title compound as a colourless gum (1.58 g, 47%).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([C:36]#[N:37])([CH3:35])[C:20]([N:22]([CH:32]2[CH2:34][CH2:33]2)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=2[Cl:31])=[O:21])=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:36]([C:19]([CH3:35])([CH2:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][OH:8])=[CH:17][CH:16]=1)[C:20]([N:22]([CH:32]1[CH2:34][CH2:33]1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[Cl:31])=[O:21])#[N:37]
Reactant: CC(C#N)(Cc1ccc(CCCO[Si](C)(C)C(C)(C)C)cc1)C(=O)N(Cc1cccc(Cl)c1Cl)C1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C#N)(Cc1ccc(CCCO)cc1)C(=O)N(Cc1cccc(Cl)c1Cl)C1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-[4-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)phenyl]-2-cyano-N-cyclopropyl-N-(2,3-dichlorobenzyl)-2-methylpropanamide from the previous step (1 eq.) in THF (0.2 M) was added tetrabutylammonium fluoride (1.0 M THF solution, 8 eq.). The resulting reaction mixture was stirred at RT for 4 h. After quenching the reaction with 10% aq. HCl, the mixture was extracted with ether. The combined organic extracts were washed with sat. aq. NaHCO3 and brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded a pale yellow oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 10:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:33])[NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[C:18]([C:27]#[C:28][Si](C)(C)C)[CH:17]=2)[CH3:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:33])[NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH3:26])(=[O:24])=[O:25])=[C:18]([C:27]#[CH:28])[CH:17]=2)[CH3:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](NC(=O)Nc1ccc(C(C)(C)C)cc1)c1ccc(NS(C)(=O)=O)c(C#C[Si](C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cc([C@@H](C)NC(=O)Nc2ccc(C(C)(C)C)cc2)ccc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 73.6 %

Procedure:
(R)—N-(4-{1-[3-(4-tert-Butyl-phenyl)ureido]ethyl}-2-trimethylsilanylethynyl-phenyl)methanesulfonamide (11 mg, 0.023 mmol) was dissolved in THF. The reaction mixture was cooled down to 0° C. 1.0 M solution of tetrabutylammoniumfluoride in THF (0.068 ml, 0.068 mmol, 3 eq.) was added into the reaction mixture. The reaction mixture was stirred for 1.5 hrs. The reaction mixture was concentrated in vacuo and purified with column chromatography (n-Hx:EA=1:1) to yield title compound (7.0 mg, 74%) as a solid.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[Si]([O:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][CH:40]([N:43]2[CH:47]=[C:46](B3OC(C)(C)C(C)(C)O3)[CH:45]=[N:44]2)[CH2:39][CH2:38]1)(C(C)(C)C)(C)C.C(=O)(O)[O-].[Na+].O1CCOCC1>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>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH:7]([CH3:26])[CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:46]4[CH:45]=[N:44][N:43]([CH:40]5[CH2:39][CH2:38][N:37]([CH2:36][CH2:35][OH:34])[CH2:42][CH2:41]5)[CH:47]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[N:15]=1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CC1(C)OB(c2cnn(C3CCN(CCO[Si](C)(C)C(C)(C)C)CC3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1Cc2ccc(-c3cnn(C4CCN(CCO)CC4)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 23.5 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine (12 mg, 0.029 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol), and sodium bicarbonate (6.0 mg, 0.072 mmol) in a solution of 1,4-dioxane (0.2 mL) and water (0.1 mL) in a reaction vial was stirred at 90° C. overnight. After cooling it was concentrated. The residue was treated with methanol. After solid was filtered off the filtrate was concentrated. The resulting residue was dissolved in 1.5 ml of 1% HCl ethanol solution and stirred at r.t. overnight. Then it was purified with RP-HPLC (pH=10) to afford the desired product (2.5 mg). LCMS (M+H)+:m/z=532.3.
Reaction SMILES: [N+:1]([N:4]1[C:8]2[C:9]([O:19][CH2:20][CH:21]3[CH2:25][CH2:24][O:23][CH2:22]3)=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:7]=2[O:6][CH2:5]1)([O-])=O>[Zn]>[NH2:1][N:4]1[C:8]2[C:9]([O:19][CH2:20][CH:21]3[CH2:25][CH2:24][O:23][CH2:22]3)=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:7]=2[O:6][CH2:5]1
Reactant: O=[N+]([O-])N1COc2ccc(-c3ccccc3)c(OCC3CCOC3)c21
Agent: [Zn]
Product: NN1COc2ccc(-c3ccccc3)c(OCC3CCOC3)c21

Procedure:
Prepared by the method of Example 47b), from 2-(3-nitro-4-(3-tetrahydrofuranylmethoxy)-5-phenylbenzoxazole (150 mg, 0.36 mmol) and powdered zinc (235 mg, 3.6 mmol) the subtitle compound was obtained (115 mg, 83%). 1H NMR (DMSO) δ 7.98(d, 1H), 7.79(d, 1H), 7.73(m, 2H), 7.65(dd, 1H), 7.54–7.36(m, 5H), 7.02(d, 1H), 4.01(m, 2H), 3.88–3.76(m, 2H), 3.68(m, 1H), 3.59(m, 1H), 2.71(m, 1H), 2.07(m, 1H), 1.70(m, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14]1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)(Cl)Cl.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[C:34](Cl)=[O:35]>O>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH:15]([O:18][C:34](=[O:35])[C:33]3[CH:32]=[C:31]([O:30][CH3:29])[C:39]([O:40][CH3:41])=[C:38]([O:42][CH3:43])[CH:37]=3)[CH2:14]1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1[nH]c2ccccc2c1CCN1CCC(O)C1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)OC2CCN(CCc3c(C)[nH]c4ccccc34)C2)cc(OC)c1OC
Reaction time: 24 h

Procedure:
To a suspension of 5 g. (0.02 mole) of 2-methyl-3-[2-(3-hydroxypyrrolidinyl)ethyl]indole and 8 g. (0.075 mole) of sodium carbonate in 40 ml. of chloroform was added 4.2 g. (0.018 mole) of 3,4,5-trimethoxybenzoyl chloride in 30 ml. of chloroform. The mixture was stirred under anhydrous conditions for 24 hours, then treated with 25 ml. of water and stirred an additional hour. The chloroform layer was separated, dried over magnesium sulfate and evaporated on a rotating evaporator to a viscous oil.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].C(=O)([O-])[O-].[Na+].[Na+]>>[C:22](=[O:23])([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[O:19][C:1](=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OC(=O)OCc1ccccc1

Procedure:
Example 3 is repeated to react oleic acid with benzyl chloroformate in the presence of dry sodium carbonate.
Reaction SMILES: [OH-].[Na+].[CH:3]([NH:5][C:6]1[S:7][C:8]([Cl:20])=[C:9]([C:11](=[N:17][O:18][CH3:19])[C:12]([O:14]CC)=[O:13])[N:10]=1)=[O:4]>>[CH:3]([NH:5][C:6]1[S:7][C:8]([Cl:20])=[C:9]([C:11](=[N:17][O:18][CH3:19])[C:12]([OH:14])=[O:13])[N:10]=1)=[O:4]
Reactant: CCOC(=O)C(=NOC)c1nc(NC=O)sc1Cl
Agent: [Na+]
Agent: [OH-]
Product: CON=C(C(=O)O)c1nc(NC=O)sc1Cl
Reaction time: 4 h
Yield: 86.1 %

Procedure:
1N-Aqueous sodium hydroxide (195 ml.) was added dropwise to an aqueous suspension (190 ml.) of ethyl 2-(2-formamido-5-chlorothiazol-4-yl)-2-methoxyiminoacetate (18.9 g.) under ice-cooling and stirred for 4 hrs. The reaction mixture was washed with ethyl acetate, and ethyl acetate was added to the aqueous solution, adjusted to pH 1.0 with 6N-hydrochloric acid and then saturated with sodium chloride. The ethyl acetate layer was separated and the remaining aqueous layer was washed with ethyl acetate. The ethyl acetate layer obtained above and the washings were combined, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and then evaporated in vacuo. The residue was pulverized with diisopropyl ether and the precipitates were collected by filtration and dried to give 2-(2-formamido-5-chlorothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 14.7 g.), m.p. 175° to 177° C.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].[CH2:8]([N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[C:35](OCC)=[O:36])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH:6][C:35]([C:27]1[N:26]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=1)=[O:36]
Reactant: CN(C)CCCN
Reactant: CCCCCCCCCCCCCCCCCCn1c(C(=O)OCC)nc2ccccc21
Product: CCCCCCCCCCCCCCCCCCn1c(C(=O)NCCCN(C)C)nc2ccccc21
Temperature: 125 °C
Reaction time: 15 h
Yield: 87.5 %

Procedure:
N,N-Dimethyl-1,3-propanediamine (0.818 g) was added to ethyl 1-octadecyl-1H-benzimidazole-2-carboxylate (1.771 g) and the mixture was stirred for 15 hours at 125° C. The reaction mixture was purified by silica gel column chromatography (silica gel 60 g, chloroform:methanol=30:1), thereby yielding the entitled compound (1.746 g) as pale yellow oil.
Reaction SMILES: Br[C:2]1[C:7]2[N:8]3[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=4[Cl:23])[C:9]3=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH:29](=[O:32])[CH2:30][CH3:31]>O1CCCC1.[Cl-].[NH4+]>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[N:11]1[C:9]2=[N:10][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH:29]([OH:32])[CH2:30][CH3:31])[C:7]=3[N:8]2[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Clc1ccc(N2CCCCn3c2nc2cccc(Br)c23)c(Cl)c1
Reactant: CCC=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)c1cccc2nc3n(c12)CCCCN3c1ccc(Cl)cc1Cl
Reaction time: 0.17 h
Yield: 18.6 %

Procedure:
To a solution of 7-bromo-1-(2,4-dichlorophenyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazole (570 mg, 1.39 mmol) in tetrahydrofuran (10 mL) was added n-butyllithium (1.60 M solution in n-hexane, 0.97 mL, 1.55 mmol) at −78° C., and the mixture was stirred for 10 min. To the mixture was added propionaldehyde (0.30 mL, 4.16 mmol), and the mixture was stirred at −78° C. for 10 min, at 0° C. for 3 hr. The mixture was diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 5-25% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate to give the title compound as a colorless crystal (101 mg, 0.259 mmol, 19%).
Reaction SMILES: [OH:1][C@@:2]1([CH3:29])[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C:17]([C@@H:18]([C:20]4[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=4)[CH2:19][C@:3]12[CH3:4])=[C:16]1[C:11](=[CH:12][C:13](=[O:28])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[Br:30]N1C(=O)CCC1=O>O1CCCC1>[Br:30][C:12]1[C:13](=[O:28])[CH2:14][CH2:15][C:16]2[C:11]=1[CH2:10][CH2:9][C@@H:8]1[C:17]=2[C@@H:18]([C:20]2[CH:21]=[CH:22][C:23]([CH:24]=[O:25])=[CH:26][CH:27]=2)[CH2:19][C@@:3]2([CH3:4])[C@H:5]1[CH2:6][CH2:7][C@@:2]2([OH:1])[CH3:29]
Reactant: C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(C=O)cc3)C[C@@]21C
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: C[C@]1(O)CC[C@H]2[C@@H]3CCC4=C(Br)C(=O)CCC4=C3[C@@H](c3ccc(C=O)cc3)C[C@@]21C
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.6 %

Procedure:
781 mg of 4-(17β-hydroxy-17α-methyl-3-oxoestra-4,9-dien-11β-yl)benzaldehyde is dissolved in 25 ml of tetrahydrofuran and mixed with 356 mg of N-bromosuccinimide. The mixture is stirred for 2 hours at room temperature, then poured into 200 ml of ice water. The precipitate is filtered off, washed neutral and dried. After purification by means of preparative layer chromatography, 475 mg of 4-(4′-bromo-17β-hydroxy-17α-methyl-3-oxoestra-4,9-dien-11β-yl)benzaldehyde is obtained as a foam, which is incorporated directly into the oximization analogously to Example 1 with hydroxylammonium hydrochloride in pyridine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:11]([O:13][CH2:14]Cl)[CH3:12]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([O:8][CH2:14][O:13][CH2:11][CH3:12])[N:7]=1
Reactant: CCOCCl
Reactant: Oc1cccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOCOc1cccc(Cl)n1
Reaction time: 0.08 h
Yield: 41.5 %

Procedure:
To a solution of 13.4 g (0.1 mol) of 6-chloro-2-pyridinol in 200 mL methylene chloride at -23° C. was added 3 g sodium hydride (80%, 0.1 mol) slowly, and stirring was continued for 5 min. 10 mL of Chloromethyl ethyl ether (0.11 mol) was added dropwise at -23° C. After stirring for 15 min. at -23° C, and an additional 1 hr at room temperature, the reaction was quenched with 50 mL of water. The mixture was extracted with two 50 mL portions of methylene chloride, and the combined organic layers were washed with water and brine. After drying over sodium carbonate, the solvents were evapoated under reduced pressure. The residue was purified by radial PLC (5% ethyl acetate/hexanes) to give 7.78 g (42%) of product as a colorless oil (bp 72° C., 0.25 mmHg) and 2.14 g of recovered starting material. 1H NMR (300 MHz, CDCl3) δ 7.55 (t, 1 H, J=7.7 Hz), 6.94 (d, 1 H, J=8.5 Hz), 6.71 (d, 1 H, J=8.0 Hz), 5.55 (s, 2 H), 3.77 (q, 2 H, J=7.1 Hz), 1.25 (t, 3 H, J=7.1 Hz). 13C NMR (75 MHz, CDCl3) δ 162.4, 148.5, 141.0, 117.2, 109.3, 91.4, 65.7, 15.2. Analysis Calculated for C8H10ClNO2 : C, 51.21; H, 5.37; N, 7.47. Found: C, 51.33; H, 5.35; N, 7.46.