Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])=[N:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:4].C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[N:8]([S:45]([CH3:44])(=[O:47])=[O:46])[C:7](=[O:9])[C@H:6]1[CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])=[N:15][C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])=[O:4]
Reactant: COC(=O)[C@@H]1NC(=O)[C@H]1CCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H]1[C@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)C(=O)N1S(C)(=O)=O
Yield: 37 %

Procedure:
To a vigorously stirred methylene chloride (10 mL) solution of compound 7 (0.8 g, 1.6 mmol) and triethylamine (4.86 g, 48 mmol ) was added methanesulfonyl chloride (5.52 g, 48 mmol) dropwise. The reaction mixture was diluted with additional CH2Cl2 and washed with pH 7.0 aqueous buffer. The organic phase was dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography (CH2Cl2 : MeOH/99:1) to afford 340 mg (37%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[C@H:13]2[CH2:18][CH2:17][C@H:16]([S:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:38])C=1.S([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C>C(Cl)Cl>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[C@H:13]2[CH2:14][CH2:15][C@H:16]([S:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)=[O:38])[CH2:17][CH2:18]2)=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(/C=C/C=C/[C@H]2CC[C@H](SCc3ccc(Cl)cc3)CC2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=S(Cc1ccc(Cl)cc1)[C@H]1CC[C@H](/C=C/C=C/c2ccc(C(F)(F)F)cc2)CC1
Reaction time: 0.08 h

Procedure:
In 20 ml of methylene chloride were dissolved 211 mg (0.48 mmol) of 4-chlorobenzyl trans-4-[(1E,3E)-4-[4-(trifluoromethyl)phenyl]-1,3-butadienyl]cyclohexyl sulfide, and 104 mg (0.48 mmol) of m-chloroperbenzoic acid (purity: 80%) were added to the solution at 0° C. followed by stirring of the resulting mixture for 5 minutes. An aqueous sodium sulfite solution and ethyl acetate were added to the reaction mixture and the organic layer was washed with an aqueous sodium hydrogencarbonate solution and an aqueous NaCl solution. After the mixture was dried, the crude product obtained by evaporation of the solvent was recrystallized from a mixed solvent of ethyl acetate-hexane to obtain 168 mg (yield: 77%) of the title compound having a melting point of 212 to 214° C.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1C1C=CC(OCC(C)(C)CO)=CC=1.CC(=CC)C.Cl([O-])=[O:32].[Na+].OP([O-])(O)=O.[Na+]>C(#N)C.C(OCC)(=O)C.O.C(O)(C)(C)C>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[CH:2][CH:10]=2)[C:6]([C:11]([OH:12])=[O:32])=[CH:7]1
Reactant: [O-][Cl+][O-]
Reactant: CC(C)(CO)COc1ccc(-c2cc3c(C=O)c[nH]c3cc2Cl)cc1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CC(C)(C)O
Product: O=C(O)c1c[nH]c2ccccc12
Reaction time: 0.03 h
Yield: 73 %

Procedure:
To a solution of 6-chloro-5-[4-(3-hydroxy-2,2-dimethylpropoxy)phenyl]-1H-indole-3-carbaldehyde (60 mg, 0.17 mmol) in acetonitrile (3 mL) was added tert-butanol (3 mL), water (3 mL) and 2-methyl-2-butene (1.38 mL). The reaction mixture was stirred for 2 min then treated with sodium chlorite (338 mg, 3.76 mmol) and sodium phosphate monobasic (787 mg, 5.04 mmol). The mixture was stirred at room temperature overnight. The reaction was quenched with sodium sulfite and concentrated in vacuo to give a residue, which was dissolved with ethyl acetate (50 mL), washed with brine (3×15 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by prep-HPLC to give 2,2-dimethylpropoxy)phenyl]-1H-indole-3-carboxylic acid (20 mg, 32%) as an off-white solid. MS (ES−) 372.1 (M−H)−. 1H NMR (400 MHz, CD3OD) δ 8.01 (s, 1H), 7.99 (s, 1H) 7.56 (s, 1H), 7.35 (d, 2H), 6.98 (d, 2H), 3.80 (s, 2H), 3.49 (s, 2H), 1.04 (s, 6H).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.[CH2:14](O)[CH:15]=[CH2:16].C(B(CC)CC)C>C1COCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:16]([C:3]1[C:4]2[C:5]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=[CH:8][C:9]=2[NH:1][CH:2]=1)[CH:15]=[CH2:14]
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: C=CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCB(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCc1c[nH]c2cccc(C(=O)OC)c12
Temperature: 70 °C
Yield: 87.8 %

Procedure:
To a stirring mixture of methyl indole-4-carboxylate (5.20 g, 29.68 mmol), allyl alcohol (2.02 mL, 29.68 mmol), and triethyl borane (1.0M solution in THF, 8.90 mL, 8.90 mmol) in THF (120 mL) at room temperature under an atmosphere of nitrogen was added Pd(PPh3)4 (1.71 g, 1.48 mmol). The mixture was heated at 70° C. for 16 h then cooled to room temperature. The mixture was diluted with ethyl acetate (500 mL) and washed with saturated aqueous sodium bicarbonate solution (200 mL), brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by column chromatography (silica gel, 0 to 30% ethyl acetate in hexanes) afforded methyl 3-allyl-1H-indole-4-carboxylate (5.61 g, 88%) as a pale yellow oil: 1H NMR (500 MHz, CDCl3) δ 8.44 (bs, 1H), 7.59 (m, 1H), 7.44 (m, 1H), 7.16 (m, 1H), 7.04 (s, 1H), 6.05 (m, 1H), 5.00 (m, 2H), 3.96 (s, 3H), 3.64 (m, 2H); MS (ESI+) m/z 150 (M+H).
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(O[C:6](C)(C)[CH3:7])=O.[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]=2[C:38]([O:40]C)=[O:39])(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(O)C.[Li+].[OH-]>C1COCC1>[CH2:6]([N:27]([S:24]([C:21]1[CH:20]=[CH:19][C:18]([F:17])=[CH:23][CH:22]=1)(=[O:25])=[O:26])[C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]=1[C:38]([OH:40])=[O:39])[CH3:7]
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2)ccc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCN(c1ccc2ccccc2c1C(=O)O)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Macroporous polystyrene-bound triphenylphosphine resin (56 mg, 0.17 mmol) was treated with di-tert-butyl azodicarboxylate (29 mg, 0.13 mmol) in THF (0.5 mL), shaken at ambient temperature for 15 minutes, treated with a solution of Example 98A (30 mg, 0.08 mmol) in THF (1 mL), shaken at ambient temperature for 15 minutes, treated with ethanol (0.006 mL, 0.11 mmol), shaken for 16 hours at 60° C., filtered, and concentrated. The residue was dissolved in 2:1 dioxane/water (1 mL), treated with LiOH (25 mg, 0.6 mmol), and heated to 160° C. for 30 minutes in a microwave reactor. The reaction mixture was concentrated and purified by C18 reverse-phase HPLC using acetonitrile/water/0.1% TFA to provide the desired product. MS (DCI) m/e 391 (M+NH4)+; 1H NMR (500 MHz, DMSO-d6) δ 7.99 (m, 2H), 7.92 (m, 1H), 7.81 (br s, 2H), 7.64 (br s, 2H), 7.46 (t, 2H), 7.02 (d, 1H), 3.60 (br s, 2H), 0.99 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C@@H:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=O)[CH2:12][C:11]2([CH3:22])[CH3:21])[CH:7]=[N:8][CH:9]=1)=[O:4].Cl.[CH3:24][O:25][NH2:26].N1C=CC=CC=1>CO.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([C@@H:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)/[C:13](=[N:26]/[O:25][CH3:24])/[CH2:12][C:11]2([CH3:22])[CH3:21])[CH:7]=[N:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1cncn1[C@@H]1c2ccccc2C(=O)CC1(C)C
Reactant: CON
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: c1ccncc1
Product: CO/N=C1\CC(C)(C)[C@H](n2cncc2C(=O)OC)c2ccccc21
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To a solution of (R)- or (S)-3-(2,2-dimethyl-4-oxo-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid methyl ester (0.091 g, 0.299 mmol), which can be prepared as described in Example 13, and methoxyamine hydrochloride (0.076 g, 0.897 mmol) in methanol (2 mL) is added pyridine (0.24 g, 2.99 mmol) and the mixture is heated to 50° C. After 1.5 hours, the mixture is diluted with ethyl acetate and washed twice with aqueous copper sulfate, twice with 1:9 v/v aqueous ammonium hydroxide-saturated aqueous ammonium chloride, water, and brine. The organic layer is dried over MgSO4, filtered, and concentrated to furnish (R)- or (S)-3-{4-[(E)-methoxyimino]-2,2-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl}-3H-imidazole-4-carboxylic acid methyl ester as a 19:1 ratio of geometric isomer without the need for further purification. 1H NMR (400 MHz, MeOD) δ ppm 0.94 (s, 3 H), 1.10 (s, 3 H), 2.52 (d, J=17.9 Hz, 1 H), 2.99 (d, J=17.9 Hz, 1 H), 4.03 (s, 3 H), 4.06 (s, 3 H), 6.65 (s, 1 H), 7.17-7.26 (m, 1 H), 7.41-7.49 (m, 2 H), 8.18-8.22 (m, 2 H), 8.27 (br. s., 1 H).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:12]2[NH:11][N:10]=[CH:9][C:8]=2[C:7]2[CH2:13][N:14]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[C:15](=[O:22])[C@H:16]([CH2:18][C:19](O)=[O:20])[CH2:17][C:6]=2[CH:5]=1.Cl.[O:31]=[C:32]1[N:41]([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33]1.ClC1C2NN=CC=2C2CN(CC(C)(C)C)C(=O)[C@H](CC(=O)N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)CC=2C=1>>[Cl:3][C:4]1[C:12]2[NH:11][N:10]=[CH:9][C:8]=2[C:7]2[CH2:13][N:14]([CH2:23][C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)[C:15](=[O:22])[C@H:16]([CH2:18][C:19](=[O:20])[N:45]3[CH2:44][CH2:43][CH:42]([N:41]4[CH2:40][C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[NH:33][C:32]4=[O:31])[CH2:47][CH2:46]3)[CH2:17][C:6]=2[CH:5]=1
Reactant: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Agent: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Agent: Cl
Product: O=C(C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Yield: 27 %

Procedure:
(S)-2-(4-Chloro-8-oxo-9-(pyridin-4-ylmethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid dihydrochloride (90 mg, 0.23 mmol) and 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidine hydrochloride (75 mg, 0.28 mmol) were reacted following a procedure analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Title compound was obtained as white solid in 27% yield. MS m/e (M+H)+=598.2. 1H NMR (500 MHz, DMSO-D6): δ=13.47 (s, 1H), 9.19 (s, 1H), 8.31 (s, 2H), 8.23 (s, 1H), 7.22 (s, 1H), 7.12 (s, 3H), 6.99 (m, 1H), 6.84 (m, 2H), 6.77 (s, 1H), 5.40 (d, J=15.26, 1H), 4.65 (m, 3H), 4.54 (d, J=10.38, 1H), 4.40 (m, 1H), 4.30 (s, 1H), 4.22 (s, 1H), 4.09 (m, 1H), 3.99 (m, 1H), 3.14 (m, 2H), 3.03 (m, 1H), 2.93 (m, 1H), 2.60 (m, 1H), 1.78 (m, 1H), 1.58 (m, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.Br.Br.[C:13]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>C(#N)C.O>[C:13]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Br
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Yield: 272.1 %

Procedure:
A solution of 800 mg (5.67 mmol) of 1-fluoro-4-nitrobenzene, 2.07 g (1.2 mmol) of 1-tert-butylpiperazine dihydrobromide and 3.2 mL (20.41 mmol) of triethylamine, in 22 mL of acetonitrile, was refluxed for 10 hours. The mixture was cooled to room temperature, diluted with water and extracted with dichloromethane. The organic layer was washed with water and brine, dried over Na2SO4 and evaporated. Purification by flash chromatography (eluant dichloromethane/methanol 7/3) yielded 860 mg of the title compound as yellow solid.
Reaction SMILES: [Br-].[CH3:2][O:3][CH:4]([O:31][CH3:32])[C:5]1[CH:6]=[C:7]([CH:28]=[CH:29][CH:30]=1)[CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.OCC1C=C(C=CC=1)C=O.P(Br)(Br)Br.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:77]1([C:82]2[CH:83]=[C:84]([CH:87]=[CH:88][CH:89]=2)[CH:85]=O)[CH:81]=[CH:80][CH:79]=[CH:78]1.C[O-].[Na+]>CO>[CH3:32][O:31][CH:4]([O:3][CH3:2])[C:5]1[CH:30]=[CH:29][CH:28]=[C:7]([CH:8]=[CH:85][C:84]2[CH:87]=[CH:88][CH:89]=[C:82]([N:77]3[CH:81]=[CH:80][CH:79]=[CH:78]3)[CH:83]=2)[CH:6]=1
Reactant: COC(OC)c1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: O=Cc1cccc(-n2cccc2)c1
Agent: BrP(Br)Br
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(OC)c1cccc(C=Cc2cccc(-n3cccc3)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
560 mg of 3-(dimethoxymethyl)benzyltriphenylphosphonium bromide synthesized by brominating 3-hydroxymethylbenzaldehyde with phosphorus tribromide, and then acetalizing the product in anhydrous methanol in the presence of p-toluenesulfonic acid, followed by reacting it with triphenylphosphine] and 180 mg of 3-(1-pyrrolyl)benzaldehyde [synthesized by oxidizing 3-(1-pyrrolyl)benzyl alcohol with pyridinium chlorochromate in chloroform]were dissolved in 20 ml of methanol. 110 mg of sodium methoxide was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and water were added to the residue to extract it. The organic layer was worked up in a customary manner, and purified by medium-pressure liquid chromatography [Lobar column, size B, Lichroprep Si 60 (E. Merck Co.); eluting solvent: hexane/ethyl acetate=10/1] to give 135 mg (yield 42%) of an E-form of 3-[2-[3-(1-pyrrolyl)phenyl]ethenyl]benzaldehyde dimethyl acetal and 127 mg of its Z-form.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]3=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=[C:20]3[NH:19][C:18]2=[O:27])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH:29]([CH3:31])[CH3:30].[Cl-].[Cl-].[Ca+2]>O>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]3=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=[C:20]3[N:19]([CH:29]([CH3:31])[CH3:30])[C:18]2=[O:27])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)I
Reactant: Cc1cnc2c(c1)[nH]c(=O)n2-c1ccc(OCc2ccccc2)cc1
Agent: [Ca+2]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Product: Cc1cnc2c(c1)n(C(C)C)c(=O)n2-c1ccc(OCc2ccccc2)cc1

Procedure:
NaH (84 mg) was added to a solution of 3-[4-(benzyloxy)phenyl]-6-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (346 mg) and 2-iodopropane (0.208 mL) in DMF(dry) (4 mL) at room temperature. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) for 1 h. The mixture was poured into water, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, EtOAc/hexane) to give the title compound (283 mg) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[C:3]#[N:4].C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[CH3:5][C:2]([NH:1][S:15]([CH3:14])(=[O:17])=[O:16])([CH3:6])[C:3]#[N:4]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(N)C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C#N)NS(C)(=O)=O
Reaction time: 0.25 h
Yield: 54.9 %

Procedure:
To a stirred mixture of 8.4 g (0.1 mole) 2-amino-2-methylpropionitrile (the product of Example 1), and 10.1 g (0.1 mole) triethylamine in 125 ml methylene chloride, 11.5 g (0.1 mole) methanesulfonyl chloride in 25 ml methylene chloride were added dropwise over about 20 minutes in an exothermic addition reaction. The reaction mixture was stirred 15 minutes, then washed once with 100 ml water, washed twice with 50 ml water, dried over magnesium sulfate, and stripped to give 8.9 g of a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[CH3:11].Cl.[CH3:13][NH:14][O:15][CH3:16].N1C=CC=CC=1>S(Cl)(Cl)=O.ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:14]([O:15][CH3:16])[CH3:13])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: CNOC
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CON(C)C(=O)c1ccc(Br)c(C)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
A stirred suspension of 4-bromo-3-methylbenzoic acid (15 g, 69.0 mmol) in thionyl chloride (60 mL) was heated at reflux for 2 h and then concentrated under reduced pressure. The residual acyl chloride was dissolved in dichloromethane (300 mL) and added to a stirred solution of N,O-dimethylhydroxylamine hydrochloride (7.2 g, 72.0 mmol) and pyridine (16.8 mL, 207.0 mmol) in dichloromethane (450 mL) at −20° C. The reaction mixture was allowed to warm to room temperature overnight and then washed with 1 M aqueous potassium carbonate solution. The aqueous solution was extracted with dichloromethane. The organic extracts were concentrated under reduced pressure. The residue was purified by chromatography on silica gel using 50% ethyl acetate/hexanes as eluent to afford the title product as a pale yellow oil (17.81 g, 69.0 mmol, 100% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.C([Li])CCC.CCCCCC.[CH:23](=[N:26][S@:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28])[CH2:24][CH3:25].C(=NS(C(C)(C)C)=O)CC.[Cl-].[NH4+]>C(OCC)C.C1(C)C=CC=CC=1>[F:9][C:8]([F:11])([F:10])[C:5]1[N:4]=[CH:3][C:2]([C@H:23]([NH:26][S@:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28])[CH2:24][CH3:25])=[CH:7][N:6]=1
Reactant: FC(F)(F)c1ncc(Br)cn1
Reactant: CCC=N[S@@](=O)C(C)(C)C
Agent: CCC=NS(=O)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC[C@@H](N[S@@](=O)C(C)(C)C)c1cnc(C(F)(F)F)nc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-bromo-2-trifluoromethyl-pyrimidine (200 mg, 0.879 mmol) in dry diethyl ether (1.5 ml) at −78° C. was added a 2.5 M solution of n-butyllithium in hexane (0.32 ml, 0.811 mmol) and the mixture was stirred at −78° C. for 15 min. A solution of (S)-2-methyl-propane-2-sulfinic acid propylideneamide (Comp. No. 13b) (110 mg, 0.676 mmol) in dry toluene (1 ml) was added at −78° C., the mixture was stirred for 5 min at −78° C. and then poured into a saturated aqueous ammonium chloride solution. The mixture was extracted 3 times with dichloromethane, dried over sodium sulfate, and after evaporation of all solvents the crude product was purified by flash chromatography (silica gel, elution with heptane/ethyl acetate) to give 15 mg of (S)-2-methyl-propane-2-sulfinic acid ((R)-1-(2-trifluoromethyl-pyrimidin-5-yl)-propyl)amide (LC/MS (method 7): Rt=1.37 min; m/z=310.1 (M+H+)) and 20 mg of (S)-2-methyl-propane-2-sulfinic acid ((R)-1-(2-trifluoromethyl-pyrimidin-5-yl)-propyl)amide (LC/MS (method 7): Rt=1.37 min; m/z=310.1 (M+H+)).
Reaction SMILES: [NH:1]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[C@H:2]([C:4]([OH:6])=O)[CH3:3].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:40][C@H:41]([C:47]([OH:49])=[O:48])[CH2:42][CH2:43][C:44](=[O:46])[NH2:45].Cl>O1CCOCC1.C(=O)([O-])O.[Na+]>[C:7]([NH:1][C@H:2]([C:4]([NH:40][C@H:41]([C:47]([OH:49])=[O:48])[CH2:42][CH2:43][C:44](=[O:46])[NH2:45])=[O:6])[CH3:3])([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Reaction time: 5 h
Yield: 44.6 %

Procedure:
Into a 300 mol round bottom flask were charged 10 g (44.8 mmol) of Z-L-Ala and 5.2 g (45.2 mmol) of N-hydroxysuccinimide, and the contents were dissolved in 100 ml of dioxane. Then, a solution of 9.2 g (44.7 mmol) of dicyclohexylcarbodiimide in 40 ml of dioxane was added dropwise, while the temperature of the reaction mixture wa maintained at 25° to 20° C. After the reaction had been allowed to proceed for 5 hours, precipitated dicyclohexylurea was filtered off. On the other hand, 7.2 g (50 mmol) of L-Gln was dissolved in 70 ml of aqueous 10% sodium hydrogencarbonate solution, and the resulting solution was cooled to 15° to 10° C. The dioxane solution prepared above was then added dropwise to the cooled solution, and the reaction was allowed to proceed for 5 hours. After the completion of the reaction, the pH of the reaction mixture was adjusted to 6.8 with lN HCl, and the dioxane was distilled off. After insoluble substances were filtered off, its pH was adjusted to 3 to 3.5 with 1N HCl. Crystals precipitated within 1 to 2 minutes, and the crystals were collected by filtration, washed with water and dried under reduced pressure to give 7 g (20 mmol) of Z-L-Ala-L-Gln. The pH of the above mother liquor was adjusted to 2.0 with lN HCl, so as to precipitate an additional 5 g of Z-L-Ala-L-Gln.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[S:7]1(=[O:17])=[O:16].C(N(C(C)C)C(C)C)C.[CH2:27]([NH:34][CH2:35][CH:36]1[CH2:45][CH:44]([O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48])[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[O:37]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN1CCCC1=O>[CH2:27]([N:34]([CH2:35][CH:36]1[CH2:45][CH:44]([O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:48])[CH3:49])[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[O:37]1)[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[S:7]1(=[O:17])=[O:16])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CC(CNCc2ccccc2)Oc2ccccc21
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCBr
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CC(CN(CCCCN2C(=O)c3ccccc3S2(=O)=O)Cc2ccccc2)Oc2ccccc21
Temperature: 120 °C
Reaction time: 3 h

Procedure:
380 mg (1.19 mmol) of 2-(4-bromobutyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[d]isothiazol-3-one and 263 μl (1.51 mmol) of N-ethyldiisopropylamine are added to a solution of 224 mg (0.58 mmol) of benzyl-[4-(tert-butyldimethylsilanyloxy)chroman-2-ylmethyl]amine in 1.25 ml of dry N-methylpyrrolidinone. The reaction mixture is stirred at 120° C. for 3 hours. After cooling to room temperature, 2 ml of water are added, resulting in the precipitation of a dark, viscous product. The supernatant is decanted and the residue is washed twice with in each case 1.5 ml of water. The product is then dissolved in 3 ml of dichloromethane, the residue water is removed by drying and the solution is evaporated to dryness. The crude product is purified by HPLC chromatography under the following conditions: column Nucleosil® 100 C-18, 125×16 mm (particle size 7 μm), column temperature room temperature, mobile phase 85% acetonitrile/15% water (v/v), flow rate 6 ml/min, UV detection at 230 nm. The product-containing fractions are combined and evaporated to dryness. The residue is dissolved in 2.5 ml of ethanol and 6 ml of acetone and again evaporated to dryness. The product is dried in a desiccator over blue gel.