Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[CH:33]1[C:42]2[CH:41]=[CH:40][CH:39]=[C:38]([S:43](Cl)(=[O:45])=[O:44])[C:37]=2[CH:36]=[CH:35][N:34]=1.CCN(C(C)C)C(C)C>ClCCl>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([S:43]([C:38]3[C:37]4[CH:36]=[CH:35][N:34]=[CH:33][C:42]=4[CH:41]=[CH:40][CH:39]=3)(=[O:44])=[O:45])[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(S(=O)(=O)c3cccc4cnccc34)C2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 88.6 %

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (48.0 mg, 0.106mmol) in anhydrous dichloromethane (4 ml) was added isoquinoline -5-sulfonyl chloride (42.1 mg, 0.16 mmol) and DIEA (37.0 μl, 0.21 mmol). The reaction stirred at room temperature over 72 hours, was diluted with dichloromethane and washed with sat. NaHCO3, and brine, dried and filtered. Purification by silica gel chromatography (Isco) gave the desired product, (60.0 mg, 88% ). Calcd for C35H37F3N2O4S (M+H) 638.74, Found 639.3.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[C:17]3[C:12](=[C:13]([NH2:18])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[N:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([O:23][C:24]([NH:26][CH2:27][C:28](O)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].Cl.C(N=C=NC(C)(C)CC)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[O:29]=[C:28]([NH:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[CH:11]=[N:10][N:9]2[CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:27][NH:26][C:24](=[O:25])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22]
Reactant: Nc1cccc2c1cnn2CCN1CCCCC1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NC(C)(C)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cccc2c1cnn2CCN1CCCCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 1-(2-piperidin-1-yl-ethyl)-1H-indazol-4-ylamine (mmol), tert-butoxycarbonylamino-acetic acid (mmol), ethyldimethylpropylcarbodiimide hydrochloride (mmol), N-hydroxybenzotriazole (mmol) and N-methyl morpholine (mmol) were dissolved in 15 mL of DMF and stirred at room temperature for 6 hours. The mixture was concentrated under reduced pressure and the residue purified by flash chromatography to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.34 (m, J=4.41 Hz, 6 H), 1.41 (s, 9 H), 2.37 (m, 4 H), 2.69 (t, J=6.78 Hz, 2 H), 3.86 (d, J=6.10 Hz, 2 H), 4.46 (t, J=6.78 Hz, 2 H), 7.08 (s, 1 H), 7.32 (m, 2 H), 7.64 (m, 1 H), 8.23 (s, 1 H), 9.96 (s, 1 H); MS (DCI/NH3) m/z 469 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[N+:11]([O-])([OH:13])=[O:12].CC(CC(C1C(O)=CC(O)=C(CC=C(C)C)C=1[O-])=O)C.ClC1C(Cl)=CC([N+]([O-])=O)=CC=1C=O>S(=O)(=O)(O)O.O>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:3]=1[CH:4]=[O:5]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1cccc(Cl)c1Cl
Agent: CC(C)=CCc1c(O)cc(O)c(C(=O)CC(C)C)c1[O-]
Agent: O=Cc1cc([N+](=O)[O-])cc(Cl)c1Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: O=Cc1c([N+](=O)[O-])ccc(Cl)c1Cl
Temperature: 22.5 °C

Procedure:
A solution of 40 g of 2,3-dichlorobenzaldehyde (compound IX) in 160 mL of concentrated sulfuric acid (95-98% w/w) is heated to 40° C. and stirred to form a solution, then cooled to 20-25° C. Concentrated nitric acid (69-71% w/w; 24.7 g) is added to this solution over 20 minutes (an ice bath is used to maintain a reaction temperature of 20-30° C.). The reaction mixture is stirred at room temperature for 1 hour, and then added in portions to 600 mL of water. The resulting suspension is stirred for 2 hours and filtered. The filter cake is washed (3×50 mL of water). The filter cake is agitated with 200 mL of water for 2 hours and filtered. The filter cake is washed (3×50 mL of water) and dried in vacuo to give a mixture of the compound X and the isomer, 2,3-dichloro-5-nitrobenzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].CON(C)[C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]([CH3:33])=[N:31][N:32]=2)=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:13][C:14]([C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]3[CH:23]=[CH:24][C:25]([C:28]4[O:29][C:30]([CH3:33])=[N:31][N:32]=4)=[CH:26][CH:27]=3)=[CH:15][CH:16]=2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9]
Reactant: COc1cc(-c2ccco2)cc(Cl)c1OC
Reactant: COC(C(=O)N(C)OC)c1ccc(-c2nnc(C)o2)cc1
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4nnc(C)o4)cc3)o2)cc(Cl)c1OC

Procedure:
1-(5-(3-Chloro-4,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethanone was prepared from 2-(3-chloro-4,5-dimethoxyphenyl)furan and N,2-dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (70% EtOAc/hexanes) gave the product as a pale yellow solid (0.051 g, 12% yield). MS: m/z 469.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:20][CH2:19][C:18]3[CH:21]=[CH:22][C:15]([Br:14])=[CH:16][CH:17]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: NCc1ccc(Br)cc1
Reactant: CSc1ncnc2cc(N)ncc12
Product: Nc1cc2ncnc(NCc3ccc(Br)cc3)c2cn1
Temperature: 140 °C
Reaction time: 1 h
Yield: 47.7 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (234 mg, 1.22 mmol) (described in a previous experimental) and 4-bromobenzylamine (0.84 g, 4.52 mmol) is stirred under N2 at 140° C. for 1 h, and the resulting product chromatographed on silica gel (10% EtOH/EtOAc) to give 7-amino-4-(4-bromobenzylamino)pyrido[4,3-d]pyrimidine (192 mg, 48%) as a cream solid. 1H NMR (DMSO) δ 9.09 (1H, s), 8.87 (1H, t, J=5.7 Hz), 8.25 (1H, s), 7.51 (2H, d, J=8.3 Hz), 7.31 (2H, d, J=8.3 Hz), 6.46 (2H, brs), 6.37 (1H, s), 4.70 (2H, d, J=5.8 Hz).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([S:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=2)=[CH:13][CH:12]=1)=O.CO.[BH4-].[Na+]>O>[CH2:1]([NH:8][CH2:9][C:11]1[CH:12]=[CH:13][C:14]([S:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=2)=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: NC(=O)c1ccc(Sc2ccc(C=O)cc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NC(=O)c1ccc(Sc2ccc(CNCc3ccccc3)cc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
Combine benzylamine (17 mg, 0.16 mmol), 6-(4-formyl-phenylsulfanyl)-nicotinamide (40 mg, 0.16 mmol), 3 Å molecular sieves (0.1 g), and methanol (3 mL) and stir overnight at room temperature. Filter off the sieves then add sodium borohydride (25 mg, 0.64 mmol) to the reaction and stirred at room temperature for 1 hour. Pour the reaction into water then extract with ethyl acetate (3×10 mL). The combined ethyl acetate extracts were dried over sodium chloride/magnesium sulfate, filtered, and concentrated on a rotary evaporator to yield the crude product (50 mg). The crude product was purified by flash column chromatography on silica gel eluting with 10% aqueous ammonium hydroxide in ethanol and chloroform to yield 6-[4-(benzylamino-methyl)-phenylsulfanyl]-nicotinamide, (24 mg): m/z=349.99(M+1); 1H NMR (MeOD, 300.00 MHz): (8.84 (dd, 1H, J=2.3, 1.0 Hz), 8.02 (dd, 1H, J=8.6, 2.3 Hz), 7.66-7.49 (m, 4H), 7.66-7.49 (m, 4H), 7.42-7.34 (m, 5H), 6.99-6.92 (m, 1H), 3.88-3.77 (m, 4H). HPLC=99% @ 5.82 minutes (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM. By the method of Example 7 the following compounds were prepared, isolated as the free base except where noted:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:17][CH3:18])[C:9]3[C:14]([OH:15])=[CH:13][N:12]=[CH:11][C:10]=3[N:16]=2)=[N:4][O:5][N:6]=1.C([O-])([O-])=O.[K+].[K+].C(OC([N:32]1[CH2:37][CH2:36][CH:35]([CH2:38]I)[CH2:34][CH2:33]1)=O)(C)(C)C.O>CC(C)=O>[CH2:17]([N:8]1[C:9]2[C:14]([O:15][CH2:38][CH:35]3[CH2:36][CH2:37][NH:32][CH2:33][CH2:34]3)=[CH:13][N:12]=[CH:11][C:10]=2[N:16]=[C:7]1[C:3]1[C:2]([NH2:1])=[N:6][O:5][N:4]=1)[CH3:18]
Reactant: CCn1c(-c2nonc2N)nc2cncc(O)c21
Reactant: CC(C)(C)OC(=O)N1CCC(CI)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCn1c(-c2nonc2N)nc2cncc(OCC3CCNCC3)c21
Reaction time: 6 h
Yield: 39 %

Procedure:
A mixture of the product from Example 283 (0.1 g, 0.406 mmol) and K2CO3 (0.112 g, 0.812 mmol) in acetone (3 ml) at −78° C. was treated with 4-iodomethylpiperidine-1-carboxylic acid tert-butyl ester (Villalobos, A; et al, J. Med. Chem., 1994, 37(17), 2721) (0.145 g, 0.447 mmol) and heated at reflux for 18 hours. A further portion of 4-iodomethylpiperidine-1-carboxylic acid tert-butyl ester (0.145 g, 0.447 mmol) was then added and the heating continued for a further 6 hours. The reaction was then cooled, poured into water, extracted with dichloromethane, dried with NaSO4 and reduced. The residue was chromatographed on silica gel eluting with ethyl acetate to afford the title compound, (0.071 g, 39%); MS (ES+) m/e 444 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[C:11]2[CH2:12][CH2:13][N:14]3[C:18]([C:10]=2[NH:9][N:8]=1)=[CH:17][C:16]([C:19]([N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])=[CH:15]3)=[O:5].Cl[CH2:32]Cl.CI>O>[CH3:1][C:2]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[C:11]2[CH2:12][CH2:13][N:14]3[C:18]([C:10]=2[N:9]([CH3:32])[N:8]=1)=[CH:17][C:16]([C:19]([N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])=[CH:15]3)=[O:5]
Reactant: Cc1ccc(C(=O)Nc2n[nH]c3c2CCn2cc(C(=O)N4CCCC4)cc2-3)c(C)c1
Reactant: ClCCl
Solvent: O
Solvent: CI
Product: Cc1ccc(C(=O)Nc2nn(C)c3c2CCn2cc(C(=O)N4CCCC4)cc2-3)c(C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
After dissolving the compound 2,4-dimethyl-N-[8-(pyrrolidin-1-ylcarbonyl)-4,5-dihydro-1H-pyrazolo[4,3-g]indolizin-3-yl]benzamide (A35-M1-B8, Entry 200, Table III), obtained as described in the example 9, in dichloromethane 2 equivalent of methyl iodide were added. After four hours of stirring at room temperature, water was added and the phases were separated. The organic layer was Dried over Na2SO4 and the crude was purified through preparative HPLC. LCMS m/z 418 [M+H]+@ Rt2.87 min.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[S:44]1[C:48]2[CH:49]=[CH:50][C:51]([C:53](O)=[O:54])=[CH:52][C:47]=2[CH:46]=[CH:45]1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:53]([C:51]3[CH:50]=[CH:49][C:48]4[S:44][CH:45]=[CH:46][C:47]=4[CH:52]=3)=[O:54])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)c1ccc2sccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccc5sccc5c4)c3C2=O)C(=O)N1
Reaction time: 0.17 h
Yield: 50.8 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxopiperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 1-benzothiophene-5-carboxylic acid (0.4 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight and was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL), washed with water (3×40 mL) and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc: CH2Cl2 3:7) to afford benzo[b]thiophene-5-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide (0.5 g, 53%) as a white solid: mp 261-263° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=4.22 min. (99%); 1H NMR (DMSO-d6) δ 2.07-2.11 (m, 1H), 2.55-2.65 (m, 2H), 2.86-2.98 (m, 1H), 4.99 (d, J=5.6 Hz, 2H), 5.16-5.22 (dd, J=5.0 and 12.4 Hz, 1H), 7.59 (d, J=5.4 Hz, 1H), 7.79-7.92 (m, 5H), 8.11 (d, J=8.4 Hz, 1H), 8.48 (s, 1H), 9.24 (t, J=5.5 Hz, 1H), 11.16 (s, 1H); 13C NMR (DMSO-d6) δ 21.99, 30.93, 38.44, 48.88, 121.85, 122.50, 122.91, 122.95, 124.39, 127.14, 128.84, 130.39, 131.54, 133.07, 134.79, 139.18, 139.38, 141.92, 166.79, 166.97, 167.55, 169.83, 172.74; Anal. Calcd. for C23H17N3O5S+0.2H2O: C, 61.24; H, 3.89; N, 9.32; S, 7.11. Found: C, 61.04; H, 3.57; N, 8.96; S, 7.19.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[N:13]=[C:14]=[O:15].[CH2:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]3[CH:36]=[C:35]([NH:37][CH3:38])[N:34]=[CH:33][N:32]=3)=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)[CH3:17]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[NH:13][C:14](=[O:15])[N:37]([C:35]1[CH:36]=[C:31]([NH:30][C:27]2[CH:26]=[CH:25][C:24]([N:21]3[CH2:20][CH2:19][N:18]([CH2:16][CH3:17])[CH2:23][CH2:22]3)=[CH:29][CH:28]=2)[N:32]=[CH:33][N:34]=1)[CH3:38]
Reactant: COc1cc(OC)c(Cl)c(N=C=O)c1Cl
Reactant: CCN1CCN(c2ccc(Nc3cc(NC)ncn3)cc2)CC1
Solvent: Cc1ccccc1
Product: CCN1CCN(c2ccc(Nc3cc(N(C)C(=O)Nc4c(Cl)c(OC)cc(OC)c4Cl)ncn3)cc2)CC1
Reaction time: 1.5 h

Procedure:
The title compound was prepared by adding 2,6-dichloro-3,5-dimethoxyphenyl-isocyanate (1.25 eq.) to a solution of N-[4-(4-ethyl-piperazin-1-yl)-phenyl]-N′-methyl-pyrimidine-4,6-diamine (2.39 g, 7.7 mmol, 1 eq.) in toluene and stirring the reaction mixture for 1.5 h at reflux. Purification of the crude product by silica gel column chromatography (DCM/MeOH+1% NH3aq, 95:5) affords the title compound as a white solid: ESI-MS: 560.0/561.9 [MH]+; tR=3.54 min (purity: 100%, gradient J); TLC: Rf=0.28 (DCM/MeOH+1% NH3aq, 95:5). Analysis: C26H31N7O3Cl2, calc. C, 55.72%; H, 5.57%; N, 17.49%; O, 8.56%; Cl, 12.65%. Found C, 55.96%; H, 5.84%; N, 17.17%; O, 8.46%; Cl, 12.57%. The title compound was characterized by XRPD, thermal and other methods as described below.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([C:18]([NH2:20])=[O:19])[O:15][C:14]3=[O:21])=[CH:9][C:8]=2[F:22])[CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([C:18]([NH2:20])=[O:19])[O:15][C:14]3=[O:21])=[CH:9][C:8]=2[F:22])[CH2:3][CH2:2]1
Reactant: NC(=O)[C@H]1CN(c2ccc(C3=CCOCC3)c(F)c2)C(=O)O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NC(=O)[C@H]1CN(c2ccc(C3CCOCC3)c(F)c2)C(=O)O1

Procedure:
A mixture of (5R)-(−)-3-[4-(3,6-dihydro-2H-pyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide (EXAMPLE 9, Step 2, 200 mg, 0.653 mmol) and 10% palladium-on-carbon (139 mg, 0.131 mmol) in methanol (26 mL) is shaken under a 40 psi hydrogen atmosphere on a Parr apparatus for 5 h. The catalyst is then removed by filtration through a pad of Celite, and the filtrate is concentrated under reduced pressure and chromatographed on a Flash 40S 40 g silica gel (32-63 μm) cartridge, eluting with a gradient of methanol/methylene chloride (2/98-3/97). Pooling and concentration of those fractions with an Rf=0.37 by TLC (methanol/chloroform, 2×5/95) gives the title compound, mp 153-156° C.; MS (ESI−) for C15H17N2O4F m/z 307 (M−H); [α]25D=−21 (c 0.87, DMSO).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([CH3:36])[C:32](=[O:33])[CH2:31][CH2:30][C@@:29]2([CH3:34])[C:9]1=[CH:10][CH2:11][C@@H:12]1[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:35])[C@H:13]1[CH2:14][CH:15]=[C:16]2[C@H:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22].O>C(OCC)C>[OH:33][C@H:32]1[CH2:31][CH2:30][C@@:29]2([CH3:34])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:35])[C@H:13]3[CH2:14][CH:15]=[C:16]2[C@H:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:8]1([CH3:36])[CH3:7]
Reactant: CC(C)CCC[C@@H](C)C1=CC[C@H]2[C@@H]3CC=C4C(C)(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC(C)CCC[C@@H](C)C1=CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1.5 h
Yield: 106.6 %

Procedure:
To a suspension of lithium aluminium hydride (80 mg, 2 mmol) in diethyl ether (15 mL) was added 4,4-dimethylcholesta-5,16-dien-3-one (220 mg, 0.5 mmol) in 10 mL ether and the whole was stirred for 1.5 hours. Water was added and the solution filtered through a plug of Celite. The aqueous phase was extracted with ether, washed with 4N HCl, brine, dried over magnesium sulphate and concentrated under reduced pressure to give 3β-hydroxy-4,4-dimethylcholesta-5,16-diene (220 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[CH:5]=1.CS(C)=[O:26]>OO.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([NH2:11])=[O:26])=[C:6]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[CH:5]=1
Reactant: CS(C)=O
Reactant: COC(=O)c1ccc(C#N)c(OCCc2ccc(Cl)cc2Cl)c1
Agent: OO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(N)=O)c(OCCc2ccc(Cl)cc2Cl)c1

Procedure:
To a solution of 100 mg 4-Cyano-3-[2-(2,4-dichloro-phenyl)-ethoxy]-benzoic acid methyl ester in 2 ml DMSO 93 mg K2CO3 and 68 μl H2O2 (35%) were added at RT. After stirring the reaction over night the mixture was taken up in 5 ml ethyl acetate and 3 ml water and filtered through a chem elut® cartridge by elution with ethyl acetate. After removal of the solvent the crude product was subjected to the subsequent reaction.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][CH:6]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:14]>C(OCC)(=O)C.CO>[Br:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([O:12][CH3:14])=[O:11])=[CH:7][CH:6]=1
Reactant: O=C(O)c1ccc(CCCBr)s1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CCCBr)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.1 %

Procedure:
To a solution consisting of 5-(3-bromopropyl)thiophene-2-carboxylic acid (from procedure above, 24 g, 78 mmol) in ethyl acetate (150 mL) and methanol (15 mL) at 0° C. was added TMS-diazomethane (50 mL, 100 mmol, 2 M) dropwise over one hour. The reaction mixture was then allowed to warm to room temperature and was stirred for 16 hours, The reaction mixture was concentrated under reduced pressure without workup. The residue was purified by silica gel chromatography. Elution with ethyl acetate-heptane (1:80 v/v) afforded the title compound as a white solid (4.95 g; 24% over two steps); TLC Rf 0.45 (solvent system: 15:85 v/v ethyl acetate-hexanes); MS (ESI+) m/z 263, 265 (isotopic bromines, each (M+H)+); 1HNMR (CDCl3) δ 7.5 (d, 1H), 6.7 (d, 1H), 3.75 (s, 3H), 3.3 (t, 2H), 2.9 (t, 2H), 2.1-2.0 (m, 2H).
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](Cl)(=[O:20])=[O:19].[CH3:22][O:23][CH:24]([CH3:27])[CH2:25][NH2:26].C(#N)C>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](=[O:20])(=[O:19])[NH:26][CH2:25][CH:24]([O:23][CH3:22])[CH3:27]
Reactant: COC(C)CN
Reactant: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)Cl)c2)N1C
Agent: Br
Solvent: CCO
Solvent: CC#N
Product: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)NCC(C)OC)c2)N1C

Procedure:
6.5 g of 4-(4-chloro-3-chlorosulfonylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol-hydrobromide were reacted as prescribed in Example 76 with 5 g of 2-methoxypropyl amine in 100 ml of ethanol and worked up. Colorless crystalline solid substance, melting point: 148° C (acetonitrile/active charcoal).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19])[C:9]([CH3:25])([CH3:24])[CH2:8]2)=[O:4].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.Cl.CN1CCOCC1.[NH2:55][CH:56]1[CH2:59][N:58]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:57]1>ClCCl>[C:63]([O:62][C:60]([N:58]1[CH2:57][CH:56]([NH:55][C:18]([C:17]2[CH:16]=[C:15]([CH:10]3[C:9]([CH3:25])([CH3:24])[CH2:8][C:7]4[C:12](=[CH:13][CH:14]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=4)[NH:11]3)[CH:23]=[CH:22][CH:21]=2)=[O:19])[CH2:59]1)=[O:61])([CH3:66])([CH3:65])[CH3:64]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)O)c1)N2
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)NC3CN(C(=O)OC(C)(C)C)C3)c1)N2
Reaction time: 0.5 h
Yield: 107.7 %

Procedure:
To a suspension of 3-(6-(methoxycarbonyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid (150 mg, 0.44 mmol, 1.0 eq.) in dichloromethane (10.0 ml) was added N-hydroxy benzotriazole (89.2 mg, 0.66 mmol, 1.5 eq.) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.hydrochloric acid (253.0 mg, 1.32 mmol, 3.0 eq.), followed by 4-methylmorpholine (133.5 mg, 1.32 mmol) and the resultant mixture was stirred at room temperature for 30 min. Then tert-butyl 3-aminoazetidine-1-carboxylate (90.9 mg, 0.53 mmol, 1.2 eq.) was added to the flask and the reaction mixture was stirred for an additional 30 min. LC-MS showed the reaction was complete. The reaction was quenched with water, separated, and the aqueous layer was extracted with dichloromethane (twice). The combined organic layers were washed with 2% sodium hydroxide aqueous solution (twice) and brine (3 times), dried over anhydrous magnesium sulfate. Removal of the solvent in vacuo gave 234 mg of methyl 2-(3-(1-(tert-butoxycarbonyl) azetidin-3-ylcarbamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a white solid, which was used in next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10]([C:12]1[CH:13]=[C:14]([S:19]([NH:22][C:23]2[S:27][N:26]=[CH:25][N:24]=2)(=[O:21])=[O:20])[CH:15]=[CH:16][C:17]=1F)#[N:11]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][C:17]1[CH:16]=[CH:15][C:14]([S:19]([NH:22][C:23]2[S:27][N:26]=[CH:25][N:24]=2)(=[O:21])=[O:20])=[CH:13][C:12]=1[C:10]#[N:11]
Reactant: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1F
Reactant: Oc1ccc(F)cc1Br
Product: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1Oc1ccc(F)cc1Br

Procedure:
Prepared according to the process of Preparation 51, using 2-bromo-4-fluorophenol and 3-cyano-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (Preparation 65). LCMS Rt=3.01 min MS m/z 284 [MH]+ 1HNMR (d6-DMSO): δ 6.8 (m, 1H), 7.4 (m, 1H), 7.6 (m, 1H), 7.8 (m, 1H), 8.0 (m, 1H), 8.3 (m, 1H), 8.5 (s, 1H).