Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:5]([OH:7])[CH3:6])[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:11]1[C:16]2[N:17]([CH2:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]3)[CH:18]=[N:19][C:15]=2[CH:14]=[C:13]([Cl:28])[N:12]=1>CN(C=O)C>[Cl:28][C:13]1[N:12]=[C:11]([O:7][CH:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)[CH3:6])[C:16]2[N:17]([CH2:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]3)[CH:18]=[N:19][C:15]=2[CH:14]=1
Reactant: C[C@H]1CC[C@H](Cn2cnc3cc(Cl)nc(Cl)c32)CC1
Reactant: CC(O)C1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Oc1nc(Cl)cc2ncn(C[C@H]3CC[C@H](C)CC3)c12)C1CCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 1-cyclobutylethan-1-ol (1.76 g, 17.60 mmol) in DMF (10 mL) was added 60% NaH (1.4 g, 35.19 mmol) in several portions at 0° C. After stirring for 20 minutes, 4,6-dichloro-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine (Preparative Example 2.3, 3.5 g, 11.73 mmol) in DMF (30 mL) was added slowly over a time period of 10 minutes. The reaction was then warmed to room temperature and stirred for 16 h. After this time, the reaction was quenched with ice, diluted with water (80 mL), and extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with water (25 mL) and brine (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with (12-15% EtOAc/petroleum ether) to yield 6-chloro-4-(1-cyclobutylethoxy)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine. MS ES/APCl calc'd. for C20H28ClN3O [M+H]+ 362. found 362.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1(C)C=CC(S(O[CH2:23][CH2:24][CH:25]([CH3:31])[CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=O)=O)=CC=1>>[CH3:31][CH:25]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:24][CH2:23][O:12][C:9]1[CH:10]=[CH:11][C:2]([OH:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)CC(C)(C)C)cc1
Reactant: COC(=O)c1cc(O)ccc1O
Product: COC(=O)c1cc(OCCC(C)CC(C)(C)C)ccc1O
Yield: 76 %

Procedure:
Synthesis was carried out in the same manner as in Example 1, except for replacing methyl 2,4-dihydroxybenzoate with methyl 2,5-dihydroxybenzoate and replacing 2-ethylhexyl bromide with 3,5,5-trimethylhexyl p-toluenesulfonate, to obtain methyl 5-(3,5,5-trimethylhexyloxy)-2-hydroxybenzoate represented by the following chemical formula (hereinafter referred to as compound 10) as a colorless, clear and oily substance in a yield of 76%. The analytical results are shown below. ##STR31##
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.BrCC1CCCCO1.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[C:23]1([C:34]3=[CH:35][C:36]4[O:40][CH2:39][O:38][C:37]=4[CH:41]=[C:33]3[O:32][CH2:31]1)[C:24](=[O:30])[NH:25]2>>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[C:23]1([C:34]3=[CH:35][C:36]4[O:40][CH2:39][O:38][C:37]=4[CH:41]=[C:33]3[O:32][CH2:31]1)[C:24](=[O:30])[N:25]2[CH2:2][C:3]1[O:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: O=C1Nc2cccc(Cl)c2C12COc1cc3c(cc12)OCO3
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cccc(Cl)c2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-bromomethyl-5-(trifluoromethyl)furan to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 4′-chlorospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 4′-chloro-1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (43%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 7.36 (dd, J=8.0, 8.0 Hz, 1H), 7.20-7.18 (m, 2H), 7.08 (dd, J=0.7 Hz, 8.0 Hz, 1H), 6.77 (d, J=3.4 Hz, 1H), 6.66 (s, 1H), 6.12 (s, 1H), 5.94 (s, 2H), 5.09 (ABq, 2H), 4.92 (d, J=9.8 Hz, 1H), 4.75 (d, J=9.8 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 176.1, 156.1, 152.7, 148.6, 143.4, 141.5, 139.5 (q, 2JCF=42 Hz), 130.5, 129.7, 127.9, 123.6, 118.8 (q, 1JCF=267 Hz), 116.6, 114.0 (d, 3JCF=3 Hz), 109.9, 108.2, 102.2, 101.4, 92.9, 76.9, 57.9, 36.7; MS (ES+) m/z 464.3 (M+1), 466.3 (M+1).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C@@H:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)[CH2:12][NH:11]C1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C.O>[CH2:1]([O:8][NH:9][C@@H:13]([CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1)[CH2:12][NH2:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC[C@H](COc2ccc(Br)cc2)N1OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC[C@H](COc1ccc(Br)cc1)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of Example 3F in ethanol (300 mL) was treated with a solution of 30% (w/w) KOH in water (100 mL), heated to reflux, stirred for 8 hours, treated with additional 30% KOH in water (5 mL), stirred for 40 minutes, cooled to room temperature, concentrated to a slurry, and extracted with toluene. The extract was washed with 1M NaOH and brine, dried (Na2SO4), filtered, and concentrated to provide 48.6 g of the desired product. 1H NMR (300 MHz, DMSO-d6) δ7.45 (m, 2H), 7.33 (m, 5H), 6.90 (m, 2H), 6.67 (d, 1H, J=5 Hz), 4.63 (s, 2H), 3.95 (m, 2H), 3.08 (m, 1H), 2.73 (m, 1H), 2.62 (m, 1H), 1.40 (br s, 2H).
Reaction SMILES: [CH3:1][C:2](=[CH2:9])[C:3]#[C:4][CH:5](O)[CH:6]=[CH2:7].[BrH:10]>>[Br:10][CH2:7][CH:6]=[CH:5][C:4]#[C:3][C:2]([CH3:1])=[CH2:9]
Reactant: Br
Reactant: C=CC(O)C#CC(=C)C
Product: C=C(C)C#CC=CCBr
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
An alcoholic solution of 6-methyl-1,6-heptadien-4-yn-3-ol is added dropwise to 40 ml of fuming HBr and the mixture stirred for 1.5 hours at room temperature. The reaction mixture is poured onto ice and extracted with hexane. The organic phase is repeatedly washed with aqueous NaCl, dried and concentrated on a rotary evaporator. The oily reaction product consists (according to NMR) of a 3:1 mixture of (E)- and (Z)-1-bromo-6-methyl-2,6-heptadien-4-yne and is directly employed for further reaction.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH3:17])[C:5]([NH:7][C:8]1[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][N:9]=1)=[O:6].S(Cl)([Cl:20])=O>C1C=CC=CC=1>[Cl:20][CH2:2][CH2:3][N:4]([CH3:17])[C:5]([NH:7][C:8]1[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][N:9]=1)=[O:6]
Reactant: CN(CCO)C(=O)Nc1nnc(C(C)(C)C)s1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CN(CCCl)C(=O)Nc1nnc(C(C)(C)C)s1
Reaction time: 1 h

Procedure:
The N-(β-hydroxyethyl)-N-methyl-N'-(2-t-butyl-1,3,4-thiadiazol-5-yl)urea prepared in Example 2, thionyl chloride (5 ml) and benzene (100 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at reflux, with stirring, for a period of about one hour. After this time the benzene and unreacted thionyl chloride were stripped from the reaction mixture under reduced pressure to yield the desired product N-(β-chloroethyl)-N-methyl-N'-(2-t-butyl-1,3,4-thiadiazol-5-yl)urea as the residue.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]=O)[CH:7]=1)(=[O:3])[CH3:2].[NH2:14][N:15]1[C:19]([C:20](=[O:22])[NH2:21])=[CH:18][C:17]([C:23]([O:25][CH3:26])=[O:24])=[CH:16]1>>[O:4]([CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3=[CH:18][C:17]([C:23]([O:25][CH3:26])=[O:24])=[CH:16][N:15]3[N:14]=2)[CH:9]=[CH:10][CH:11]=1)[C:1]([CH3:2])=[O:3]
Reactant: CC(=O)OCc1cccc(C=O)c1
Reactant: COC(=O)c1cc(C(N)=O)n(N)c1
Product: COC(=O)c1cc2c(=O)[nH]c(-c3cccc(COC(C)=O)c3)nn2c1
Yield: 39 %

Procedure:
According to the general preparation methods described in example 5 above, 3-formylbenzyl acetate reacts with compound 3 to give compound IIIb as offwhite solid in 39.0% yield. m.p. 202-203° C. 1H NMR (300 MHz, DMSO-d6): δ 12.29 (s, 1H), 8.19 (d, J=1.7 Hz, 1H), 7.96 (s, 1H), 7.92 (dt, J=1.7, 7.2 Hz, 1H), 7.58-7.53 (m, 2H), 7.24 (d, J=1.7 Hz, 1H), 5.16 (s, 2H), 3.81 (s, 3H), 2.10 (s, 3H). LC-MS: 342 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH2:7][NH:8][C:9]([C:11]1[N:12]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[CH:13]=[C:14]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[CH3:27])=[O:18])[N:15]=1)=[O:10])=[O:4].[CH3:39][NH:40][CH3:41]>C1COCC1>[CH3:39][N:40]([CH3:41])[CH2:2][C:3]([O:5][CH2:6][CH2:7][NH:8][C:9]([C:11]1[N:12]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:33][CH:34]=2)[CH:13]=[C:14]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[CH3:27])=[O:18])[N:15]=1)=[O:10])=[O:4]
Reactant: CNC
Reactant: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)NCCOC(=O)CCl)n1
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)NCCOC(=O)CN(C)C)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
114.5 mg (0.2 mmol) of 2-[({4-({[(4-chloro-2-methylphenyl)amino]carbonyl}amino)-1-[4-(trifluoromethyl)benzyl]-1H-imidazol-2-yl}carbonyl)amino]ethyl chloroacetate (Example 26A) are dissolved in 2 ml of a 2 molar solution of dimethylamine in THF. The reaction mixture is shaken in a tightly closed reaction vessel at RT for 16 h and then left to stand at RT for 64 h. The reaction solution is then evaporated, and the residue from the evaporation is dissolved in DMF, filtered and purified by preparative HPLC (Method 9).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([O:26][CH2:27][CH2:28][OH:29])[CH2:22][CH2:21]3)[C:5]=2[CH:4]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([O:45][CH3:46])[C:42]=1[O:43][CH3:44])[C:37](Cl)=[O:38]>>[F:31][C:2]([F:30])([F:1])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:17][CH2:18][CH2:19][N:20]3[CH2:21][CH2:22][CH:23]([O:26][CH2:27][CH2:28][O:29][C:37](=[O:38])[C:36]4[CH:35]=[C:34]([O:33][CH3:32])[C:42]([O:43][CH3:44])=[C:41]([O:45][CH3:46])[CH:40]=4)[CH2:24][CH2:25]3)[C:5]=2[CH:4]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: OCCOC1CCN(CCCN2c3ccccc3Sc3ccc(C(F)(F)F)cc32)CC1
Product: COc1cc(C(=O)OCCOC2CCN(CCCN3c4ccccc4Sc4ccc(C(F)(F)F)cc43)CC2)cc(OC)c1OC
Yield: 32.9 %

Procedure:
Using the procedure of Example XXXV, 18.7 g (0.04 mole) of 2-trifluoromethyl-10-[3-(4-β-hydroxyethoxy-piperidino)-propyl]-phenothiazine (prepared in Example XXIII) and 9.2 g (0.04 mole) of 3,4,5-trimethoxy-benzoyl chloride were reacted to obtain 8.5 g (33% yield) of 2-trifluoromethyl-10-[ 3{ 4-[2-(3,4,5-trimethoxy-benzoyloxy)-ethoxy]-piperidino}-propyl]-phenothiazine as a clear amber oil
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[CH3:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1B(O)O>CN(C=O)C>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:26]5[CH:27]=[N:28][CH:29]=[CH:30][C:25]=5[CH3:24])=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: Cc1ccncc1B(O)O
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Solvent: CN(C)C=O
Product: Cc1ccncc1-c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)sc1CCO2
Yield: 35 %

Procedure:
Following the procedure for 128, 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 4-methylpyridin-3-ylboronic acid were reacted. The crude material was dissolved in DMF and purified by reverse phase HPLC to provide 139 (89 mg, 35%). 1H NMR (400 MHz, DMSO) δ 8.57-8.29 (m, 3H), 8.12 (d, J=15.0, 1H), 7.38 (dd, J=8.3, 2.4, 2H), 7.20 (d, J=8.3, 1H), 5.73 (dt, J=13.1, 6.6, 1H), 4.45 (t, J=4.9, 2H), 3.49 (t, J=4.9, 2H), 2.37 (s, 3H), 1.48 (d, J=6.6, 6H). MS (ESI(+)): m/z 404.1 (M+H).
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:7][CH:6]=1.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.C([O:42][C:43](=[O:51])[CH2:44][C@H:45]([NH2:50])[CH2:46][N:47]=[N+:48]=[N-:49])C1C=CC=CC=1.CN(C1C=CC=CN=1)C>CN(C=O)C>[NH2:2][N:3]=[CH:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:18])[CH2:13][CH2:14][C:15]([NH:50][C@@H:45]([CH2:46][N:47]=[N+:48]=[N-:49])[CH2:44][C:43]([OH:51])=[O:42])=[O:17])=[CH:9][CH:10]=1
Reactant: [N-]=[N+]=NC[C@@H](N)CC(=O)OCc1ccccc1
Reactant: NN=Cc1ccc(NC(=O)CCC(=O)O)cc1
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@@H](CC(=O)O)NC(=O)CCC(=O)Nc1ccc(C=NN)cc1
Reaction time: 0.08 h

Procedure:
4-[[4-(aminoiminomethyl)phenyl]amino]-4-oxobutanoic acid hydrochloride prepared in Example 1, Step 1 (4.6 g, 18.5 mmol) was added to dry DMF (250 ml) followed by N-methylmorpholine (1.8 g, 18.5 mmol) and isobutyl chloroformate (2.8 g, 17 mmol) at 25° C. The mixture was stirred for 5 min. Benzyl-3-amino-4-azido-(3S)-butyrate hydrochloride (1 eq; from Step 1, Example 22) was added followed by dimethylaminopyridine. After 1 h the solvent was removed under reduced pressure and the product purified by reverse phase chromatography (water/acetonitrile) to result in 3.0 g of a white solid. A portion (750 mg) of the benzyl ester was subjected to the saponification conditions as previously described and purified by reverse phase chromatography (water/acetonitrile) to result in 340 mg of a white solid: 1H NMR (d6 -DMSO) δ2.44 (m, 4H), 2.6 (m, 2H), 3.35 (bs, 2H), 4.18 (m, 1H), 7.78 (s, 4H), 8.1 (d, 1H,J=8 Hz), 8.27 (bs, 2H), 9.15 (bs, 2H), 10.40 (s, 1H); MS (FAB) m/z 362.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.I[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:11][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[C:8](=[O:10])[CH3:9])[CH3:18]
Reactant: CCOC(=O)CI
Reactant: CC(=O)c1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(F)cc1C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5′-Fluoro-2′-hydroxyacetophenone 2.0 g, ethyl iodoacetate 4.16 g and potassium carbonate 2.7 g were added to acetone 43 ml in a nitrogen atmosphere, and the mixture was stirred overnight under reflux with heating. After cooled to room temperature, the potassium carbonate was filtered off through Celite, and the filtrate was partitioned by adding water and ethyl acetate. The organic layer was washed with water and then with brine, dried over magnesium sulfate anhydride, and evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system), whereby the title compound 3.07 g, 99% was obtained as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=3)=[N:6][C:5]=2[C:4]([CH2:22][CH2:23][CH3:24])=[N:3]1>[Pd]>[NH2:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][C:7]1[NH:8][C:9](=[O:11])[C:10]2[N:2]([CH3:1])[N:3]=[C:4]([CH2:22][CH2:23][CH3:24])[C:5]=2[N:6]=1
Reactant: CCCc1nn(C)c2c(=O)[nH]c(Cc3cccc([N+](=O)[O-])c3)nc12
Agent: [Pd]
Product: CCCc1nn(C)c2c(=O)[nH]c(Cc3cccc(N)c3)nc12
Reaction time: 3 h

Procedure:
1-Methyl-5-(3-nitrobenzyl)-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one (5.92 g, 0.019 mol) was suspended in industrial methylated spirit (300 ml). Palladium on charcoal (10%, 610 mg) was added and the resulting mixture was hydrogenated at 50 p.s.i and room temperature for 3 hours.
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:8][NH:9][C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH2:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:12]=2[CH:11]=1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:8][N:9]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH2:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:15]([C:17]([F:18])([F:19])[F:20])=[N:16][C:12]=2[CH:11]=1)[S:4]([CH:1]1[CH2:3][CH2:2]1)(=[O:6])=[O:5]
Reactant: CNc1ccc2c(c1)nc(C(F)(F)F)n2CC1CCOCC1
Reactant: O=S(=O)(Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccc2c(c1)nc(C(F)(F)F)n2CC1CCOCC1)S(=O)(=O)C1CC1
Yield: 97 %

Procedure:
Following the procedure in Example 5, using cyclopropanesulfonyl chloride (34 mg, 0.24 mmol), N-methyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-2-(trifluoromethyl)-1H-benzimidazol-5-amine (63 mg, 0.20 mmol) (for preparation, see the step G in example 1), DIPEA (49 uL, 36 mg, 0.28 mmol) and DMAP (5 mg, 0.04 mmol) in DCM (6 mL) at 0° C. The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 81 mg (97%) of a white solid as the title compound. 1HNMR (400 MHz, METHANOL-D4): δ 0.85-0.92 (m, 2 H), 0.93-1.01 (m, 2 H), 1.37-1.52 (m, 4 H), 2.18-2.31 (m, 1 H), 2.55-2.65 (m, 1 H), 3.30-3.36 (m, 2 H), 3.38 (s, 3 H), 3.86-3.95 (m, 2 H), 4.32 (d, J=7.62 Hz, 2 H), 7.58 (dd, J=8.89, 2.05 Hz, 1 H), 7.76 (d, J=8.79 Hz, 1 H) 7.86 (d, J=1.95 Hz, 1 H). MS (ESI) (M+H)+=418.0. Anal. Calcd for C18H22F3N3O3S+0.10 H2O+0.20 CH3OH (425.66): C, 51.36; H, 5.45; N, 9.87. Found: C, 51.39; H, 5.49; N, 9.92.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[I:16]Cl>>[I:16][C:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[N:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:9]=1
Reactant: Clc1ncnc2c1ccn2C1CCCC1
Reactant: ClI
Product: Clc1ncnc2c1c(I)cn2C1CCCC1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine (1A, 116 g, 0.52 mole) in 1200 mL CH2CL2 was slowly added a dark brown solution of iodine monochloride (1.0 M, 785 mL) at room temperature over 30 minutes. The reaction mixture was refluxed for 22 h, cooled to room temperature and concentrated. The residue was redissolved in EtOAc, washed with saturated Na2SO3, H2O and brine. The organic layer was dried over Na2SO4 and concentrated. The residue was then recrystalized from i-PrOH to furnish 95 g white crystalline product.
Reaction SMILES: Br[CH:2]([CH3:6])[CH2:3][CH:4]=[CH2:5].[Mg].Cl[SiH:9]1[CH2:14][CH2:13][CH:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=3)[CH2:17][CH2:16]2)[CH2:11][CH2:10]1>C1COCC1>[F:30][C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][C@H:18]2[CH2:19][CH2:20][C@H:15]([C@H:12]3[CH2:13][CH2:14][Si@H:9]([CH2:5][CH2:4][CH2:3][CH:2]=[CH2:6])[CH2:10][CH2:11]3)[CH2:16][CH2:17]2)[CH:28]=[CH:27][C:26]=1[F:29]
Reactant: Fc1ccc(CC[C@H]2CC[C@H](C3CC[SiH](Cl)CC3)CC2)cc1F
Reactant: C=CCC(C)Br
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCCC[Si@H]1CC[C@H]([C@H]2CC[C@H](CCc3ccc(F)c(F)c3)CC2)CC1

Procedure:
3.0 g (20 mmol) of 4-bromopentene was dripped into a mixture of 0.5 g (21 mmol) of magnesium and 50 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 7.1 g of 1-chloro-4-(trans-4-(2 -(3,4-difluorophenyl) ethyl) cyclohexyl)-1-silacyclohexane. The silacyclohexane rings of the reacted mixture thus obtained were a mixture of trans isomers and cis isomers. After a conventional after treatment, they were separated by means of chromatography to obtain 6.5 g (yield 83%) of trans-4-(trans-4-(2-(3,4-difluorophenyl) ethyl) cyclohexyl)-1-(4-pentenyl)-1-silacyclohexane.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[S:11]([NH:14][CH2:15][CH2:16][OH:17])(=[O:13])=[O:12]>CO.[Pd]>[NH2:8][C:5]1[CH:4]=[C:3]([S:11]([NH:14][CH2:15][CH2:16][OH:17])(=[O:13])=[O:12])[CH:2]=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NCCO)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(S(=O)(=O)NCCO)c1
Reaction time: 8 h
Yield: 99.7 %

Procedure:
2-Chloro-N-(2-hydroxyethyl)-5-nitro-benzenesulfonamide (1.00 g, 3.57 mmol) was dissolved in methanol (35 ml) and placed under an atmosphere of nitrogen prior to the addition of 10% Pd/C (10 Wt %, 100 mg) in one portion. The reaction was evacuated, placed under an atmosphere of hydrogen (1 bar) and stirred vigorously overnight. The reaction was filtered through celite and the filtrate was concentrated in vacuo to afford the named product (0.77 g, 100%); LCMS Rt=1.44 min, m/z (ES+) 217 (M+H).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][N:8]([CH3:29])[C:9]([C:11]1[C:20]2[O:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:17]([CH3:27])[C:16](=[O:28])[C:15]=2[CH:14]=[CH:13][CH:12]=1)=[O:10]>ClCCl.C(OCC)C>[CH3:29][N:8]([CH2:7][CH2:6][Cl:3])[C:9]([C:11]1[C:20]2[O:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:17]([CH3:27])[C:16](=[O:28])[C:15]=2[CH:14]=[CH:13][CH:12]=1)=[O:10]
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)N(C)CCO)cccc2c1=O
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)oc2c(C(=O)N(C)CCCl)cccc2c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1.1 ml of thionyl chloride in 2 ml of dichloromethane was added to a solution of 3.37 g of Intermediate XIII in 20 ml of dichloromethane, and the mixture was stirred for 4 hours at ambient temperature. Removal of the solvent gave an oil which was taken up in diethyl ether. The title compound precipitated as a white solid which was filtered off for use without further purification. m.p. (118) 126°-128° C. (diethyl ether).
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH2:8][Cl:9].[OH2:10]>>[ClH:9].[CH3:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH2:8][OH:10]
Reactant: O
Reactant: Cc1nc[nH]c1CCl
Agent: Cl
Product: Cc1nc[nH]c1CO
Reaction time: 4.5 h
Yield: 73 %

Procedure:
67 parts of 4-methyl-5-chloromethyl-imidazole hydrochloride are dissolved in 200 parts of water and the mixture is stirred for 4.5 hours at 50°-60° C. The water is then substantially distilled off under reduced pressure from a waterpump and the crystal slurry is recrystallized from ethanol, the solution being cooled in ice. 43.4 parts (73%) of 4-methyl-5-hydroxymethyl-imidazole hydrochloride of melting point 238°-240° C. are obtained (the melting point given in the literature is 240°-242° C., cf. A. J. Ewins, J. Chem. Soc. 99 (1911), 2052.
Reaction SMILES: Br[C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[C:16]([O:20][CH3:21])(=[O:19])[CH:17]=[CH2:18].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:21][O:20][C:16]([CH:17]=[CH:18][C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1)=[O:19]
Reactant: C=CC(=O)OC
Reactant: COC(=O)c1cc(C(=O)OC)c(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C=Cc1cnc(C(=O)OC)cc1C(=O)OC

Procedure:
500 mg of dimethyl 5-bromo-pyridine-2,4-dicarboxylate (from Example 3) are heated at 140° C. in an autoclave with 10 ml of methyl acrylate, 0.5 ml of triethylamine, 11 mg of palladium diacetate and 22 mg of triphenylphosphine for 14 hours. After cooling, the mixture is diluted with ethyl acetate, the solid is filtered off and the solvent is evaporated together with the excess methyl acrylate. The product is chromatographed (silica gel) to give 330 mg of a white solid.