Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:43])[O:3][C@H:4]([CH3:42])[C@H:5]([NH:37][C:38](=[O:41])[O:39][CH3:40])[C:6](=[O:36])[N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C:12]1[NH:13][C:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22](B4OC(C)(C)C(C)(C)O4)[CH:23]=3)[CH:18]=2)=[CH:15][N:16]=1.Br[C:45]1[CH:50]=[CH:49][C:48]([C:51]2[NH:55][C:54]([C@@H:56]3[CH2:60][CH2:59][CH2:58][N:57]3[C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[N:53][CH:52]=2)=[CH:47][CH:46]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC>[F:1][CH:2]([F:43])[O:3][C@H:4]([CH3:42])[C@H:5]([NH:37][C:38]([O:39][CH3:40])=[O:41])[C:6]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C:12]1[NH:13][C:14]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([C:45]2[CH:46]=[CH:47][C:48]([C:51]4[NH:55][C:54]([C@@H:56]5[CH2:60][CH2:59][CH2:58][N:57]5[C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[N:53][CH:52]=4)=[CH:49][CH:50]=2)[CH:21]=[CH:20]3)=[CH:15][N:16]=1)=[O:36]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)[nH]1)[C@@H](C)OC(F)F
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)[nH]1)[C@@H](C)OC(F)F
Temperature: 85 °C
Yield: 44.7 %

Procedure:
To a solution of methyl (2S,3R)-3-(difluoromethoxy)-1-oxo-1-((S)-2-(5-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (120 mg, 0.20 mmol), (S)-tert-butyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (87 mg, 0.22 mmol), and tetrakistriphenylphosphine palladium(0) (23 mg, 0.020 mmol) in dimethoxyethane (2 mL) was added a 2M aqueous potassium carbonate solution (0.40 mL, 0.80 mmol). The mixture was degassed with a stream of argon for 15 minutes, and then heated to 85° C. for three hours. The reaction was diluted with ethyl acetate, cooled to room temperature and filtered through Celite. The filtrate was washed with water and brine, dried (MgSO4) and concentrated. The resulting residue was purified by flash chromatography to yield (S)-tert-butyl 2-(5-(4-(6-(2-((S)-1-((2S,3R)-3-(difluoromethoxy)-2-(methoxycarbonylamino)butanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (70 mg, 45%). LCMS-ESI+: calculated for C42H47F2N7O6: 783.86. observed [M+1]+: 784.72.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[C:27]([S:28]([CH:31]([CH3:33])[CH3:32])(=[O:30])=[O:29])=[CH:26][CH:25]=[CH:24][C:23]=2[F:34])[C:18]([Cl:35])=[CH:17][N:16]=1>>[Cl:35][C:18]1[C:19]([NH:21][C:22]2[C:27]([S:28]([CH:31]([CH3:32])[CH3:33])(=[O:30])=[O:29])=[CH:26][CH:25]=[CH:24][C:23]=2[F:34])=[N:20][C:15]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=3[CH:13]=2)=[N:16][CH:17]=1
Reactant: Nc1ccc2c(c1)NC(=O)CCC2
Reactant: CC(C)S(=O)(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CC(C)S(=O)(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3)ncc1Cl

Procedure:
Title compound was prepared from 8-Amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-[2-fluoro-6-(propane-2-sulfonyl)-phenyl]-amine in an analogous manner to Example 1221d. Product isolated as a light grey solid (50 mg, 37%). LCMS 506.11 (M+H), HPLC purity 94%, 1H-NMR (CDCl3, 400 MHz) δ 8.23 (s, 1H), 8.16 (s, 1H), 7.86 (d, J=7.7 Hz, 1H), 7.62-7.59 (m, 2H), 7.32-7.38 (m, 1H), 7.04 (d, J=8.1 Hz, 1H), 6.94 (d, J=8.1 Hz, 1H), 6.88 (s, 1H), 3.10-3.00 (m, 1H), 2.73 (dd, J=7.1 Hz, 2H), 2.34 (dd, J=7.2 Hz, 2H), 2.20 (dd, J=6.8 Hz, 2H), 1.23 (d, J=6.9 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:4]([O:15][C:16]1[N:21]=[C:20]([O:22][CH3:23])[C:19]2[CH2:24][CH2:25][CH2:26][C:18]=2[N:17]=1)[C:5]([O:7]CC1C=CC=CC=1)=[O:6].[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH3:1][O:2][C:3]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH:4]([O:15][C:16]1[N:21]=[C:20]([O:22][CH3:23])[C:19]2[CH2:24][CH2:25][CH2:26][C:18]=2[N:17]=1)[C:5]([OH:7])=[O:6]
Reactant: [H][H]
Reactant: COc1nc(OC(C(=O)OCc2ccccc2)C(OC)(c2ccccc2)c2ccccc2)nc2c1CCC2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1nc(OC(C(=O)O)C(OC)(c2ccccc2)c2ccccc2)nc2c1CCC2

Procedure:
40 g (78.4 mmol) of benzyl 3-methoxy-2-(4-methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3,3-diphenylpropionate were dissolved in 400 ml of ethyl acetate/methanol (4:1), about 500 mg of palladium on active carbon (10%) were added, and the mixture was exposed to a hydrogen atmosphere until no further gas was taken up. The catalyst was filtered off, the solution was evaporated, and the residue was crystallized from ether.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17]2=[N:18][C:19]([C:24](OC)=[O:25])=[C:20]([OH:23])[C:21](=[O:22])[N:16]2[CH:15]=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1>CO>[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:34][C:24]([C:19]2[N:18]=[C:17]3[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:14]=[CH:15][N:16]3[C:21](=[O:22])[C:20]=2[OH:23])=[O:25])=[CH:31][CH:30]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1nc2c(NC(=O)OCc3ccccc3)cccn2c(=O)c1O
Solvent: CO
Product: O=C(Nc1cccn2c(=O)c(O)c(C(=O)NCc3ccc(F)cc3)nc12)OCc1ccccc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a suspension of methyl 9-{[(benzyloxy)carbonyl]amino}-3-hydroxy-4-oxo-4-H-pyrido[1,2-a]pyrimidine-2-carboxylate in MeOH was added p-fluorobenzylamine. The suspension was stirred at 80° C. and after 16 hours the solvent was removed under reduced pressure. The product was purified by preparative RP-HPLC, using water (0.1% TFA) and acetonitrile (0.1% TFA) as eluants (column: C18). The product was obtained after lyophilization of the pooled product fractions as bright yellow fluffy material.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[O:16][C:17]([CH2:20]I)=[CH:18][N:19]=4)=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>>[CH2:25]([N:27]([CH2:20][C:17]1[O:16][C:15]([C:14]2[N:13]=[CH:12][N:11]3[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:24][C:6]=4[C:7](=[O:23])[N:8]([CH3:22])[CH2:9][C:10]=23)=[N:19][CH:18]=1)[CH2:28][CH3:29])[CH3:26]
Reactant: CN1Cc2c(-c3ncc(CI)o3)ncn2-c2ccc(F)cc2C1=O
Reactant: CCNCC
Product: CCN(CC)Cc1cnc(-c2ncn3c2CN(C)C(=O)c2cc(F)ccc2-3)o1
Temperature: 25 °C
Reaction time: 20 h
Yield: 16 %

Procedure:
125 ml of this crude solution of 8-fluoro-3-(5-iodomethyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were treated with 11.3 ml (0.109 mol) of diethylamine and stirred at room temperature for 20 hrs. The suspension obtained was completely freed from the solvents, the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and extracted. The aqueous-acidic phase was made basic and extracted with ethyl acetate. The organic phase was concentrated, the orange-brownish product was chromatographed over silica gel with ethyl acetate/methanol 17:3 as the eluent and recrystallized from hot ethyl acetate. There was obtained 0.75 g (16%) of 3-(5-diethylaminomethyl-oxazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as light beige crystals; m.p. 182-184°. A further 0.39 g of yellowish crystals was obtained from the mother liquor.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:18][C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[C:21]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:20]=1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CC1CCCO1>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([NH:18][C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[C:21]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:20]=1)=[O:6]
Reactant: CCOC(=O)c1cc(N)n(-c2ccccc2)n1
Reactant: O=C(O)c1cc(-c2ccccn2)c(Cl)cc1Cl
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC1CCCO1
Product: CCOC(=O)c1cc(NC(=O)c2cc(-c3ccccn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Temperature: 95 °C
Reaction time: 18 h
Yield: 84.8 %

Procedure:
To a solution of 2,4-dichloro-5-(pyridin-2-yl)benzoic acid (Preparation 30, 3.76 g, 14.02 mmol) and ethyl 5-amino-1-phenyl-1H-pyrazole-3-carboxylate (3.89 g, 16.83 mmol) in 2-methyltetrahydrofuran (150 mL) was added DIPEA (7.33 mL, 42 mmol) and the reaction was heated to 95° C. T3P (50% solution in EtOAc, 16.53 mL, 28 mmol) was added and the reaction was stirred at 95° C. for 18 hours. The reaction was cooled and partitioned between saturated aqueous sodium carbonate solution (200 mL) and EtOAc (200 mL). The organic layer was collected, washed with brine, dried over magnesium sulphate and concentrated in vacuo. The residue was triturated with TBME to afford the title compound (5.72 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:21]=O)=[C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9]2)[CH:7]=1.[S:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29].N1CCCCC1>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:21]=[C:27]2/[C:26](=[O:28])[NH:25][C:24](=[O:29])[S:23]/2)=[C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH2:9]2)[CH:7]=1
Reactant: O=C1CSC(=O)N1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2cc(Cl)ccc2C=O)C1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2cc(Cl)ccc2/C=C2\SC(=O)NC2=O)C1
Temperature: 25 °C
Yield: 91.2 %

Procedure:
A 100 mL round bottom flask was charged with a magnetic stir bar, (S)-tert-butyl 1-(5-chloro-2-formylphenyl)pyrrolidin-3-ylcarbamate (Method 78) (1.100 g, 3.39 mmol), thiazolidine-2,4-dione (0.397 g, 3.39 mmol), and ethanol (11.29 ml). Piperidine (0.034 mL, 0.34 mmol) was added and the reaction was heated to reflux for 2 h. Once the reaction was judged to be complete by LCMS, it was allowed to cool to ambient temperature and conc. in vacuo to afford the title compound (1.310 g, 91%) which was used in the next step without further purification; m/z 425.
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:6]=2[CH:7]=O)[CH2:3][CH2:2]1.[CH3:16][NH2:17].[BH4-].[Na+]>CO>[CH:1]1([S:4][C:5]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:6]=2[CH2:7][NH:17][CH3:16])[CH2:3][CH2:2]1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1SC1CC1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1cc([N+](=O)[O-])ccc1SC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
To a stirred solution of 2-(cyclopropylthio)-5-nitrobenzaldehyde (5 g, 22.40 mmol, see WO 2008/079759 for preparation) in MeOH (50 mL) was added methylamine (6.32 g, 67.2 mmol) dropwise and stirred for 1 h at 25° C. The reaction mixture was cooled to 0° C. and sodium borohydride (1.695 g, 44.8 mmol) was added portionwise with stirring. The reaction mixture was allowed to warm to rt and stirred overnight. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (250 mL), washed with water (2×100 mL), brine (1×100 mL) and dried (Na2SO4). Solvent was removed under reduced pressure to give Intermediate 6A (5 g, 20.98 mmol, 94% yield) as a orange oil. It was utilized in the subsequent step without any further purification. 1H NMR (400 MHz, chloroform-d) δ 8.11 (d, J=2.6 Hz, 1H), 8.04 (dd, J=8.8, 2.6 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 3.69 (s, 2H), 2.40 (s, 3H), 2.13-2.09 (m, 1H), 1.18-1.12 (m, 2H), 0.73-0.67 (m, 2H); MS (ESI) m/z: 239.2 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@:8]3([OH:29])[CH2:9][CH2:10][C@@H:11]2/[CH:21]=[CH:22]/[CH:23]=[CH:24]/[C:25](OC)=[O:26])[CH2:3]1>O1CCCC1.[AlH](CC(C)C)CC(C)C.CCCCCC>[OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@:8]3([OH:29])[CH2:9][CH2:10][C@@H:11]2/[CH:21]=[CH:22]/[CH:23]=[CH:24]/[CH2:25][OH:26])[CH2:3]1
Reactant: COC(=O)/C=C/C=C/[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=C/C=C/CO)CC[C@]12O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
To a solution of 7.95 g of methyl (E,E)-5-(3β,14β-dihydroxy-5β-androstane-17β-yl)-2,4-pentadienoate (Boutagy J. and Thomas R., Aust. J. Pharm. Chem., 1972, NS1, 67) in 390 ml of dry tetrahydrofuran, 133 ml of 1M i-Bu2AlH in hexane were added dropwise under nitrogen at -78° C. After 2 hrs the reaction was quenched with aqueous sodium sulfate (63 g in 390 ml of water) and stirred at room temperature overnight. The mixture was then filtered through Celite and washed with ethyl acetate. The organic solution was dried over anhydrous sodium sulfate and evaporated to dryness to give 4.90 g of (E,E)-5-(3β,14β-dihydroxy-5β-androstane-17β-yl)-2,4-pentadien-1-ol as an off-white solid.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@H:6]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C:7]([OH:9])=[O:8].[CH2:25](O)[CH3:26]>C(OCC)(=O)C>[NH2:5][C@H:6]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C:7]([O:9][CH2:25][CH3:26])=[O:8]
Reactant: CCO
Reactant: N[C@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@H](N)CCCCNC(=O)OCc1ccccc1
Temperature: -25 °C
Reaction time: 3 h

Procedure:
3.9 cm3 of thionyl chloride are added to a stirred suspension of 7.9 g of (2R)-2-amino-6-{[(benzyloxy)carbonyl]amino}hexanoic acid (Nε-CBZ-D-lysine) in 120 cm3 of anhydrous ethanol cooled to a temperature in the region of −25° C. The mixture is stirred for 3 hours at this temperature and is then allowed to warm to about 20° C. After leaving for 3 days, the reaction mass is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained is taken up in 200 cm3 of ethyl acetate and the resulting solution is washed with aqueous sodium carbonate solution and then with aqueous sodium chloride solution. The organic solution is dried over magnesium sulfate, filtered and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 7.4 g of ethyl (2R)-2-amino-6-{[(benzyloxy)-carbonyl]amino}hexanoate are obtained in the form of a pale yellow oil. (αD20=−11.7±0.6 at a concentration of 0.5% in methanol).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].[C:12]1(=[O:17])[O:16][CH2:15][CH2:14][O:13]1>>[CH3:9][O:8][Si:5]([O:10][CH3:11])([O:6][CH3:7])[CH2:4][CH2:3][CH2:2][NH:1][C:12](=[O:17])[O:13][CH2:14][CH2:15][OH:16]
Reactant: O=C1OCCO1
Reactant: CO[Si](CCCN)(OC)OC
Product: CO[Si](CCCNC(=O)OCCO)(OC)OC
Reaction time: 24 h

Procedure:
3-Aminopropyltrimethoxysilane (20 g, 0.111 mol) was added to ethylene carbonate (9.82 g, 0.111 mol). The mixture homogenized while stirred and then became slightly warm. Stirring continued for 24 hours to give 2-hydroxylethyl N-(3-trimethoxysilylpropyl)carbamate. Distilled water (18 g) was added drop-wise under stirring to a mixture of 2-hydroxylethyl N-(3-trimethoxysilylpropyl)carbamate (15 g), methanol (5 g) and acetic acid (0.1 g) to form a hazy solution. Stirring continued for 12 hours resulting in clear water-miscible liquid (39.37 wt. % of hydroxyl-functional carbamoyl organosilicon compound(s)).
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:14])([CH3:13])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:12])[CH2:8][CH2:9][Mg]Cl.[CH:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1)([CH3:17])[CH3:16].Cl>O1CCCC1>[CH:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]([OH:23])[CH2:9][CH2:8][CH:7]([CH3:12])[CH2:6][CH2:5][CH2:4][C:3]([CH3:14])([O:2][CH3:1])[CH3:13])=[CH:20][CH:19]=1)([CH3:17])[CH3:16]
Reactant: CC(C)c1ccc(C=O)cc1
Reactant: COC(C)(C)CCCC(C)CC[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: COC(C)(C)CCCC(C)CCC(O)c1ccc(C(C)C)cc1
Temperature: 25 °C

Procedure:
To the 7-methoxy-3,7-dimethyloctylmagnesium chloride (0.155 mol) in tetrahydrofuran (200 ml) under nitrogen was added p-isopropylbenzaldehyde (37 g, 86.94% pure) in tetrahydrofuran (50 ml) over 20 min. The reaction was exothermic, causing solvent to boil during the course of addition. After stirring at room temperature continued thereafter for a total of 23 h, the reaction mixture was poured into dilute hydrochloric acid, and extracted with pentane. The extracts were washed with bicarbonate, brine, and dried. Upon solvent evaporation, an oil weighing 65.1 g was obtained which was shown to contain 18.31% of the alcohol product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([NH2:13])[N:7]=[N:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([NH:13][N+:14]([O-:16])=[O:15])[N:7]=[N:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1cc(N)nnc1OCC
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOc1cc(N[N+](=O)[O-])nnc1OCC
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
5,6-Diethoxypyridazin-3-ylamine (analogously to T. Horie in Chemical & Pharmaceutical Bulletin (1963), 11(9), 1157-67; 160 mg) was initially charged dissolved in concentrated sulfuric acid (4 ml) at RT. The mixture was then cooled to 0° C. and 2 ml of a 1:1 mixture of concentrated nitric acid and concentrated sulfuric acid were added dropwise. After 20 min at 0° C., the ice bath was removed and the mixture was stirred for 4 h. Then it was cooled again to 0° C., a further 0.5 ml of the acid mixture was added and the mixture was stirred at 0° C. for another hour. Then it was admixed with ice while cooling with ice. After adding DCM, the phases were separated and extracted three times with DCM. The combined DCM phases were dried over sodium sulfate, filtered and concentrated. 188 mg of the title compound were obtained. LC-MS rt: 0.81 min [M+H]+: 236.2 (met. b)
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([NH:15][C:16](=[O:41])[C:17]2[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[C:19]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([N:33]4[CH2:38][CH2:37][CH2:36][CH:35]([CH2:39][CH3:40])[CH2:34]4)=[O:32])=[CH:27][N:26]=3)[CH:18]=2)[CH2:14][CH2:13]1>C(Cl)(Cl)Cl.CO>[CH:12]1([NH:15][C:16](=[O:41])[C:17]2[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[C:19]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([N:33]4[CH2:38][CH2:37][CH2:36][CH:35]([CH2:39][CH3:40])[CH2:34]4)=[O:32])=[CH:27][N+:26]=3[O-:9])[CH:18]=2)[CH2:14][CH2:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCC1CCCN(C(=O)c2ccc(-c3cc(C(=O)NC4CC4)cc(F)c3C)nc2)C1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCC1CCCN(C(=O)c2ccc(-c3cc(C(=O)NC4CC4)cc(F)c3C)[n+]([O-])c2)C1
Temperature: 60 °C

Procedure:
mCPBA (57-86%, 10 mg) dissolved in chloroform (0.1 ml) was added to a solution of N-cyclopropyl-3-{5-[(3-ethylpiperidin-1-yl)carbonyl]pyridin-2-yl}-5-fluoro-4-methylbenzamide (Intermediate 33, 10.5 mg) in chloroform (2 ml) at 60° C. and the reaction maintained at 60° C. for 5 hrs. The reaction was allowed to cool, diluted with methanol, and passed through an aminopropyl SPE (1 g). The filtrate was reduced to dryness under vacuum and the residue triturated with ether to give N-cyclopropyl-3-{5-[(3-ethyl-1-piperidinyl)carbonyl]-1-oxido-2-pyridinyl}-5-fluoro-4-methylbenzamide as a white solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]([C:6]2[C:7]([CH3:25])=[C:8]([CH:18]=[CH:19][C:20]=2[S:21]([CH3:24])(=[O:23])=[O:22])[C:9]([C:11]2[CH:12]=[N:13][N:14]([CH3:17])[C:15]=2[OH:16])=[O:10])=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C>[CH2:32]([O:16][C:15]1[N:14]([CH3:17])[N:13]=[CH:12][C:11]=1[C:9](=[O:10])[C:8]1[CH:18]=[CH:19][C:20]([S:21]([CH3:24])(=[O:23])=[O:22])=[C:6]([C:3]2[CH2:4][CH2:5][O:1][N:2]=2)[C:7]=1[CH3:25])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCc1ccccc1
Reactant: Cc1c(C(=O)c2cnn(C)c2O)ccc(S(C)(=O)=O)c1C1=NOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)c2cnn(C)c2OCc2ccccc2)ccc(S(C)(=O)=O)c1C1=NOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
0.45 g of 4-[3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoyl]-5-hydroxy-1-methylpyrazole was dissolved in 15 ml of DMF, and 0.26 g of potassium carbonate, then 0.25 g of benzyl bromide were added. The resulting solution was stirred at room temperature overnight. The reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water, then with a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled out under reduced pressure. Methanol was added to the residue. The obtained crystals were separated by filtration to give 0.42 g of the title compound as white crystals. m.p. 151.5~153° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1C=O.[OH:15]O>OS(O)(=O)=O.CO.O>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[OH:15]
Reactant: COc1ccc(C=O)c(OC)c1OC
Reactant: OO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: COc1ccc(O)c(OC)c1OC

Procedure:
A solution of 2,3,4-trimethoxybenzaldehyde (1.00 g, 5.10 mmol) and 30 wt/v % hydrogen peroxide (0.672 mL, 6.52 mmol) in conc. H2SO4 (0.102 mL) and MeOH (10.19 mL) was stirred overnight at 25° C. under N2. After this time the mixture was diluted with water (20 mL) and extracted with CH2Cl2 (3×30 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Biotage Horizon, 40M, Si, ˜30 mL/min, 100% hexanes for 360 mL, gradient to 50% EtOAc in hexanes over 2088 mL) to afford 2,3,4-trimethoxyphenol, as a colorless oil. Rf=0.93 (50% EtOAc/hexanes). LCMS calc.=185.1; found=185.2 (M+H)+. 1H NMR (600 MHz, CDCl3): δ 6.62 (d, J=9.0 Hz, 1 H); 6.55 (d, J=8.9 Hz, 1 H); 5.49 (s, 1 H); 3.94 (s, 3 H); 3.89 (s, 3 H); 3.80 (s, 3 H).