Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([C:16]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]([CH3:25])[CH:17]=1)=O)[CH2:3][CH:4]([CH3:6])[CH3:5].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27]>O1CCOCC1>[CH3:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([C:16]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]([CH3:25])[CH:17]=1)=[S:27])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)CC(C)c1ccccc1NC(=O)c1cn(C)cc1C(F)(F)F
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1COCCO1
Product: CC(C)CC(C)c1ccccc1NC(=S)c1cn(C)cc1C(F)(F)F

Procedure:
In a sulfonation flask a mixture of 0.6 g 1-Methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid[2-(1,3-dimethylbutyl)phenyl]amide, 0.45 g P2S5 and 30 ml dioxane is heated at 70–75° C. for 3 hours. After filtration, the solvent is removed in a water jet vacuum and the residue taken up in ethylacetate. The organic phase is washed twice with water and ethylacetate is removed in a water jet vacuum. The crude material is purified by column chromatography over silica gel (eluant: ethylacetate/n-hexane=1:1). Yield: 0.53 g 1-Methyl-4-trifluoromethyl-1H-pyrrole-3-carbothioic acid [2-(1,3-dimethylbutyl)phenyl]amide in the form of a reddish resin (1H-NMR).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:9]([C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=2)[NH:10][C:11](=[O:25])[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:13]=1[CH3:14])=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>CN(C)C=O.CO>[C:30]([C:29]1[CH:28]=[CH:27][C:26]([CH:9]2[N:10]([CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:11](=[O:25])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=3)[C:13]([CH3:14])=[C:8]2[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])=[CH:33][CH:32]=1)#[N:31]
Reactant: CC1=C(C(=O)c2ccco2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC1=C(C(=O)c2ccco2)C(c2ccc(C#N)cc2)N(CC(=O)OC(C)(C)C)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred suspension of 4-{5-(2-furoyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetr-a-hydropyrimidin-4-yl}benzonitrile (Example 20A) (150 mg, 0.33 mmol) and potassium carbonate (83 mg, 0.60 mmol) in dimethylformamide (5 ml) is treated with tert.-butyl bromoacetate (71 mg, 0.36 mmol), then stirred at room temperature overnight (16 h). The reaction solution is then diluted with methanol (7 ml) and purified directly by preparative HPLC(RP18 column; eluent: acetonitrile/water 10:90→90:10).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>ClCCl>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:24](=[O:25])[O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:7][N:6]=1
Reactant: Nc1ccc(OCc2ccccn2)nc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(OCc2ccccn2)nc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
5-Amino-2-(pyridin-2-ylmethyloxy)pyridine (D2, 1.36 g, 0.0068 mole) in dichloromethane (50 ml) was cooled to 0° C. under argon. Triethylamine (1.04 ml, 0.0075 mole) was added, followed dropwise by phenyl chloroformate (0.94 ml, 0.0075 mole) and the mixture was stirred at room temperature for 4 hours, washed with water, dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica gel, eluting with ethyl acetate to leave the title compound (1.9 g, 87%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:10]#[N:11])=[C:4]([NH:8][CH3:9])[S:5][C:6]=1[CH3:7].[C:12]([N:20]=[C:21]=[O:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:10]([C:3]1[C:2]([CH3:1])=[C:6]([CH3:7])[S:5][C:4]=1[N:8]([CH3:9])[C:21]([NH:20][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:22])#[N:11]
Reactant: CNc1sc(C)c(C)c1C#N
Reactant: O=C=NC(=O)c1ccccc1
Product: Cc1sc(N(C)C(=O)NC(=O)c2ccccc2)c(C#N)c1C

Procedure:
Prepared as in Example 1a from 4,5-dimethyl-2-(methylamino)thiophene-3-carbonitrile (Example 22b) and benzoyl isocyanate. MS 314 (MH+).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[C:28](O)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:35])[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)c1ccccc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)c1ccccc1

Procedure:
The title compound, white solid (55 mg, 79%), MS (ISP) m/z=435.4 [(M+H)+], mp 221° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (70.4 mg, 0.16 mmol) and benzoic acid.
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH2:18][C@H:19]([CH3:24])[O:20][C@H:21]([CH3:23])[CH:22]=3)[CH:14]=2)[CH2:9]1)C1C=CC=CC=1.[H][H]>>[CH3:23][C@H:21]1[CH2:22][CH:17]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][NH:8][CH2:16]3)[CH2:18][C@@H:19]([CH3:24])[O:20]1
Reactant: C[C@@H]1C=C(c2ccc3c(c2)CN(Cc2ccccc2)C3)C[C@H](C)O1
Reactant: [H][H]
Product: C[C@@H]1CC(c2ccc3c(c2)CNC3)C[C@H](C)O1

Procedure:
Prepared in analogy to Example A62(c) from 2-benzyl-5-((2S,6R)-2,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-2,3-dihydro-1H-isoindole and hydrogen. Brown oil. MS (m/e): 232.1 ([M+H]+, 100%).
Reaction SMILES: [CH3:1][C:2]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C:13]([O:15]CC)=[O:14])=[O:12])[S:8][CH:9]=1)([CH3:4])[CH3:3].O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:4][C:2]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C:13]([OH:15])=[O:14])=[O:12])[S:8][CH:9]=1)([CH3:1])[CH3:3]
Reactant: CCOC(=O)C(=O)Nc1nc(C(C)(C)C)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1csc(NC(=O)C(=O)O)n1

Procedure:
Ethyl 4-(2-methyl-2-propyl)thiazol-2-ylcarbamoylcarboxylate (1.3 g., 5 mmoles) was combined with 40 ml. of water, 20 ml. of ethanol and 5 ml. of 1 N potassium carbonate and the mixture heated on a steam bath for 10 minutes. Completion of reaction was determined by tlc. The solution was stripped of ethanol and the aqueous residue clarified by filtration. The filtrate was cooled in an ice-water bath and the product (1.02 g.) precipitated by acidification with 1 N hydrochloric acid. Recrystallization from ethyl acetate provided purified 4-(2-methyl-2-propyl)thiazol-2-ylcarbamoylcarboxylic acid [0.72 g.; m.p. 198°-200° C. dec.)].
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Br[CH2:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+].C(O)C(N)(CO)CO>C(#N)C>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:13][C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([O:18][CH3:19])=[O:17])=[CH:9][CH:10]=1
Reactant: OCCCc1ccc(O)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: NC(CO)(CO)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccccc1COc1ccc(CCCO)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 84.1 %

Procedure:
4-(3-Hydroxypropyl)phenol (1.0 g, 6.57 mmol) and methyl 2-(bromomethyl)benzoate (1.66 g, 7.23 mmol) was dissolved in acetonitrile (10 ml). Potassium carbonate (1.82 g, 13.14 mmol) was added and the mixture was stirred at 60° C. for three hours. Polymer supported trisamine (0.3 eqv) was added and the solution was stirred at room temperature overnight. The PS-trisamine was filtered off and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic layer was washed with 3 portions of water (3×10 ml). The organic phase was dried (MgSO4) and the solvent was removed by evaporation to give 1.66 gram of methyl 2-{[4-(3-hydroxypropyl)phenoxy]-methyl}benzoate (yield 84.2%).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH3:18])[C:7](=[O:17])[N:8]([CH2:9][CH2:10][N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:4]=2[C:3]=1[O:21][CH2:22][CH:23]1[CH2:26][CH2:25][CH2:24]1.C=O.O.[C:30]([BH3-])#N.[Na+]>O1CCCC1>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH3:18])[C:7](=[O:17])[N:8]([CH2:9][CH2:10][N:11]3[CH2:12][CH2:13][N:14]([CH3:30])[CH2:15][CH2:16]3)[C:4]=2[C:3]=1[O:21][CH2:22][CH:23]1[CH2:26][CH2:25][CH2:24]1
Reactant: [BH3-]C#N
Reactant: Cn1c(=O)n(CCN2CCNCC2)c2c(OCC3CCC3)c(Br)ccc21
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(CCn2c(=O)n(C)c3ccc(Br)c(OCC4CCC4)c32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
A solution of 5-bromo-4-(cyclobutylmethoxy)-1-methyl-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2H-benzimidazol-2-one (40.0 mg, 0.0945 mmol) in tetrahydrofuran (2.0 mL) was treated with a 1.23M solution of formaldehyde in water (384 μL, 0.474 mmol). The resultant reaction mixture was stirred at RT for 30 min, followed by the addition of sodium cyanoborohydride (17.8 mg, 0.284 mmol). After stirring at RT for 2 h, the reaction mixture was quenched with acetic acid (0.5 mL) and concentrated in vacuo to give the crude product. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (38 mg, 92%). LCMS calculated for C20H30BrN4O2 (M+H)+: m/z=437.2, 439.2. found: 437.1, 439.1.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C@@H:14]2[C@@H:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[O:17][C:16]([CH3:27])([CH3:26])[O:15]2)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH:33](=[O:36])[CH2:34][CH3:35]>C1COCC1>[CH2:1]([N:8]1[C:12]([CH:33]([OH:36])[CH2:34][CH3:35])=[C:11]([CH2:13][C@@H:14]2[C@@H:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[O:17][C:16]([CH3:26])([CH3:27])[O:15]2)[N:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC=O
Reactant: CCCCCCC[C@H]1OC(C)(C)O[C@@H]1Cc1cn(Cc2ccccc2)nn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCC[C@H]1OC(C)(C)O[C@@H]1Cc1nnn(Cc2ccccc2)c1C(O)CC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1-benzyl-4-(((4R,5R)-5-heptyl-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-1,2,3-triazole (11 mg, 0.029 mmol) in THF (0.3 mL) at −78° C. was added n-butyllithium (21 μL, 1.6M) to produce a deep red solution. After 5 minutes, propanal (2.3 μL, 1.1 eq) was added and the mixture was warmed to room temperature. After standard workup, the title compound was isolated by silica gel chromatography (7 mg, 54%). 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 3H), 7.30 (m, 2H), 5.35 (d, 7.6 Hz, 1H), 5.32 (d, 7.6 Hz, 1H), 4.52 (m, 1H), 3.86 (m, 1H), 3.64 (m, 1H), 3.03 (dd, 3.6 Hz, 16.4 Hz, 1H) 2.96 (dd, 6.8 Hz, 16.4 Hz, 1H), 1.55-1.17 (m, 12H), 1.27 (s, 3H), 1.25 (s, 3H), 1.00 (t, 7.3 Hz, 3H), 0.88 (t, 5.2 Hz, 3H). LRMS (APCI+) found 430.6, [M]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[Li]C(C)(C)C.[Si:14]([O:21][CH2:22][C@@H:23]([N:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][N:41]=[C:40](S(C)(=O)=O)[N:39]=2)=[CH:34][C:33]1=[O:48])[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([F:31])[CH:25]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].O>C1COCC1>[Si:14]([O:21][CH2:22][C@@H:23]([N:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)[N:39]=2)=[CH:34][C:33]1=[O:48])[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([F:31])[CH:25]=1)([C:17]([CH3:20])([CH3:18])[CH3:19])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(F)c1)n1ccc(-c2ccnc(S(C)(=O)=O)n2)cc1=O
Reactant: Cc1cc(N)ccn1
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(-c3ccn([C@H](CO[Si](C)(C)C(C)(C)C)c4ccc(Cl)c(F)c4)c(=O)c3)n2)ccn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
2-Methylpyridin-4-amine (0.28 g, 2.6 mmol) was placed in THF (5 mL) and cooled to −78° C. t-BuLi (1.5 mL, 2.6 mmol) was added dropwise, and the solution was warmed to 0° C. for 30 minutes. This solution was then added dropwise to a −78° C. THF solution (5 mL) of (S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (0.070 g, 0.13 mmol). The reaction was stirred for an additional 30 minutes at −78° C., then poured into water, and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered, and concentrated to give the crude product, which was purified by column chromatography (500:10-500:20 DCM/MeOH) to give the product (S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((2-methylpyridin-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.028 g, 38% yield).
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:8]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[N+:17]([O-])=O)[C:4]([O:6][CH3:7])=[O:5].[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[OH:1][CH2:2][CH:3]([N:8]([S:20]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)(=[O:22])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[NH2:17])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(CO)N(Cc1cc(C)ccc1[N+](=O)[O-])S(=O)(=O)c1ccc(OC)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)C(CO)N(Cc1cc(C)ccc1N)S(=O)(=O)c1ccc(OC)cc1

Procedure:
To a solution of 3.4 g of methyl 3-hydroxy-2-[(4-methoxybenzenesulfonyl)-(5-methyl-2-nitrobenzyl)-amino]propionate in 200 ml of ethanol-ethyl acetate (1:1) was added 0.34 g of 10% palladium on carbon (wet -50% H2O). The mixture was then shaken in a Parr hydrogenator under 35 psi of hydrogen for 2.5 hours. The mixture was filtered through diatomaceous earth and the filtrate concentrated under vacuum to give 2.86 a of a brown oil. Anal. for Cl19H4N2O6S: Calc'd: C,55.9; H,5.9; N,6.9: Found: C,55.6; H,5.9; N,6.4: Mass spectrum (ES) 409 (M+H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[Br:15][CH2:16][C:17](Br)=[O:18].O>ClCCl>[Br:15][CH2:16][C:17]([N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:18]
Reactant: O=C(Br)CBr
Reactant: CNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CN(C(=O)CBr)c1ccccc1

Procedure:
To a mixture of N-methyl aniline (5 mL) and potassium carbonate (9.6 g) in 100 mL dichloromethane was added bromoacetyl bromide (8.1 mL) (exotherm). The mixture was stirred for 4.5h then water was added. The phases were separated and the organic layer was concentrated. The crude product was purified by silica gel chromatography eluting with 0-100% EtOAc/cyclohexane. The relevant fractions were combined and evaporated and the residue was taken up in dichloromethane and washed with water. The organic layer was stirred with another portion of water for a few minutes and then the layers were separated. Evaporation of the organic layer gave the sub-titled compound (10.2 g) as a straw coloured solid.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:4][CH3:5].C(N(CC)CC)C>CS(C)=O>[O:1]=[CH:2][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:4][CH3:5]
Reactant: CC[C@H](CO)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC[C@H](C=O)NC(=O)OC(C)(C)C
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
A solution of (R)-tert-butyl 1-hydroxybutan-2-ylcarbamate (5.0 g, 26.4 mmol) in DMSO (50 mL) was chilled to 15° C., followed by the addition of triethylamine (10.99 mL, 79 mmol) and a solution of sulfur trioxide-pyridine complex (12.62 g, 79 mmol) in DMSO (50 mL) in succession. The mixture was stirred at 15° C. for 30 minutes, then allowed to warm to ambient temperature overnight. The reaction was quenched with 200 mL 1.0 M citric acid, and extracted twice with 250 mL MTBE. The organic phase was washed with 200 mL water and 200 mL brine, separated, dried over Na2SO4, filtered, and concentrated. The residue was chromatographed on a Grace Reveleris 80 g column, eluted with 0-35% EtOAc in Hexanes (40 mL/min) to provide the title compound (4.561 g, 24.36 mmol, 92.2% yield) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 9.42 (d, J=0.7, 1H), 7.27 (d, J=6.8, 1H), 3.73 (dd, J=13.3, 7.8, 1H), 1.78-1.58 (m, 1H), 1.54-1.28 (m, 10H), 0.87 (t, J=7.4, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].ClC(Cl)(Cl)[C:13]([NH:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[C:19]([CH3:26])[N:20]=[N:21]2)=[O:14].C1CCN2C(=NCCC2)CC1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:6][C:13]([NH:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[C:19]([CH3:26])[N:20]=[N:21]2)=[O:14]
Reactant: Cc1cc2c(NC(=O)C(Cl)(Cl)Cl)cccc2nn1
Reactant: NCc1ccc(Cl)c(Cl)c1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc2c(NC(=O)NCc3ccc(Cl)c(Cl)c3)cccc2nn1

Procedure:
The title compound was prepared using 3,4-dichlorobenzylamine, the product from Example 16A, DBU and the procedure described in Example 1B. MS (ESI+) m/z 362 (M+)+; 1H NMR (DMSO-d6) δ 2.88 (s, 3H), 4.36 (d, 2H), 7.10 (t, 1H), 7.34 (dd, 1H), 7.59 (m, 2H), 7.76 (t, 1H), 8.04 (d, 2H), 8.19 (d, 1H), 8.93 (s, 1H).
Reaction SMILES: C([O:4][CH:5]([C:8]1[C:9]([S:14]([NH:17][C:18]([NH:20][C:21]2[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=2)=[O:19])(=[O:16])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1)[CH2:6][Cl:7])(=O)C.O[Li].O.O.Cl>CO>[Cl:7][CH2:6][CH:5]([C:8]1[C:9]([S:14]([NH:17][C:18]([NH:20][C:21]2[N:22]=[C:23]([O:29][CH3:30])[CH:24]=[C:25]([O:27][CH3:28])[N:26]=2)=[O:19])(=[O:15])=[O:16])=[N:10][CH:11]=[CH:12][CH:13]=1)[OH:4]
Reactant: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ncccc2C(CCl)OC(C)=O)n1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ncccc2C(O)CCl)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 140 mg of 3-(1-acetoxy-2-chloroethyl)-N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-2-pyridinesulfonamide in 20 ml of methanol is added 20 mg of LiOH.H2O and 0.5 ml of water. After stirring at room temperature for 3 hours the solution is acidified to pH 4.5 with 5% aq. HCl. The resultant solution is extracted three times with CH2Cl2. The organic phase is evaporated and the trituration of the residue with Et2O yields the solid product.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[NH:15][C:16](=[O:33])[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[C:27]([CH3:32])=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:21]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[C:27]([CH3:32])=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:21]=3)[CH2:17][C:16](=[O:33])[NH:15][C:9]=2[CH:10]=1
Reactant: Cc1ncccc1-c1cccc(C(=O)CC(=O)Nc2cc(F)ccc2NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ncccc1-c1cccc(C2=Nc3ccc(F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from (4-fluoro-2-{3-[3-(2-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M15) (250 mg, 0.539 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (143 mg).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:32]2([CH3:33])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:34])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[C@@H:21]([O:23][CH2:24][C:25]([OH:27])=[O:26])[CH3:22])[CH2:12][C@@H:11]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:43][CH2:44][CH:45](O)[CH2:46][CH3:47].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[Si:1]([O:8][C@@H:9]1[C@@:32]2([CH3:33])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:34])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[C@@H:21]([O:23][CH2:24][C:25]([O:27][CH:45]([CH2:46][CH3:47])[CH2:44][CH3:43])=[O:26])[CH3:22])[CH2:12][C@@H:11]([O:35][Si:36]([C:39]([CH3:41])([CH3:40])[CH3:42])([CH3:37])[CH3:38])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@H](OCC(=O)O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCC(O)CC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(CC)OC(=O)CO[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 36.5 %

Procedure:
[{1α,3β-Bis(tert-butyldimethylsilyloxy)pregna-5,7-dien-20(S)-yl}oxy]acetic acid (91 mg, 0.147 mmol) was treated with 3-pentanol (39 mg, 0.443 mmol), N,N′-dicyclohexylcarbodiimide (61 mg, 0.296 mmol) and 4-(dimethylamino)pyridine (54 mg, 0.443 mmol) in dichloromethane (1.5 ml) in the same manner as shown in Example 17(3) (at room temperature for 15 hours), followed by work up and purification using preparative thin layer chromatography (0.5 mm×3 plates, hexane:ethyl acetate=5:1, developed once) to give the titled compound (37 mg, 37%) as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[OH:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1>C(OC(=O)C)(=O)C>[OH:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[CH:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:11][CH:10]=1
Reactant: Cc1ccncc1
Reactant: O=Cc1ccc(O)cc1
Solvent: CC(=O)OC(C)=O
Product: Oc1ccc(C=Cc2ccncc2)cc1

Procedure:
By the reaction of 20.0 g of γ-picolin and 26.2 g of p-hydroxybenzaldehyde in 65.8 g of acetic anhydride, there was obtained 4-[2-(4-hydroxyphenyl)-ethenyl]-pyridine. In 10 cm3 of N,N-dimethylacetamide, 2 g of the reaction product was dissolved and 1.23 g of triethylamine was further added thereto. This mixture was ice cooled and 1.34 g of methacrylic acid chloride was dropwise added thereto. After the reaction was completed, water was added to deposit crystals, which were separated by filtration. The separated crystals were recrystallized via a mixed solvent of ethyl acetate and hexane, to afford 2.16 g (80% in yield) of 4-[2-(4-methacryloyloxyphenyl)-ethenyl]-pyridine. The melting point of the crystals was 156° to 158° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=1.Cl[CH2:14][CH:15]=O>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[CH:14]=[CH:15][N:12]=[C:8]2[CH:7]=1
Reactant: O=CCCl
Reactant: COCCOc1ccnc(N)c1
Solvent: C1CCOC1
Product: COCCOc1ccn2ccnc2c1
Temperature: 75 °C
Yield: 102.7 %

Procedure:
A mixture of 4-(2-methoxyethoxy)pyridin-2-amine (20.0 g, 119 mmol), 2-chloroacetaldehyde (32.2 ml, 250 mmol) and tetrahydrofuran (100 mL) were heated in a sealed tube to 75° C. over 3 days. The reaction mixture was concentrated under reduced pressure and dissolved in ethyl acetate. The resulting solution was washed twice sodium bicarbonate. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure to yield title compound (23.5 g, quantitative yield) MS APCI (+) m/z 193 (M+1) detected.