Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[O:21][C:22]3[CH:28]=[CH:27][C:26](Br)=[CH:25][C:23]=3[CH:24]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[CH3:30][S:31]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)(=[O:33])=[O:32]>O1CCOCC1.O>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[O:21][C:22]3[CH:28]=[CH:27][C:26]([C:37]4[CH:38]=[CH:39][C:34]([S:31]([CH3:30])(=[O:33])=[O:32])=[CH:35][CH:36]=4)=[CH:25][C:23]=3[CH:24]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(Br)ccc3o2)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4ccc(S(C)(=O)=O)cc4)ccc3o2)CC1
Temperature: 100 °C

Procedure:
An aqueous Na2CO3 solution (2 M, 0.68 mL) is added to a mixture of 4-(5-bromo-benzofuran-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (2.50 g) and 4-(methanesulfonyl)phenylboronic acid (1.97 g) in a mixture of dioxane/water (60:40). The mixture is sparged with argon for 10 min and PdCl2[1,1′-bis(diphenylphosphino)-ferrocene]*CH2Cl2 complex (500 mg) is added. The resulting mixture is heated to 100° C. for 2 h. After cooling to room temperature, ethyl acetate, brine, and activated charcoal are added. The mixture is filtered and the organic phase is separated, dried over Na2SO4, and the solvent is evaporated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 80:20→60:40) to give the title compound. LC (method 1): tR=1.80 min; Mass spectrum (ESI+): m/z=478 [M+Na]+.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[CH:10]=[C:9]([CH3:21])[N:8]=2)[CH:6]=1.[NH2:22][C:23]1[N:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1>>[Cl:20][C:15]1[CH:14]=[C:13]([C:11]2[CH:10]=[C:9]([CH3:21])[N:8]=[C:7]([N:5]3[CH:6]=[C:2]([C:26]4[CH:25]=[N:24][C:23]([NH2:22])=[N:28][CH:27]=4)[N:3]=[CH:4]3)[N:12]=2)[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(Br)c2)n1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(-c3cnc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-(3,4-dichloro-phenyl)-6-methyl-pyrimidine (example E.61) (0.16 g, 0.42 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.12 g, 0.54 mmol) according to the general procedure VI. Obtained as a yellow solid (0.043 g, 26%). MS (ISP) 398.1 [(M+H)+]; mp 255.5° C.
Reaction SMILES: CC1(C)CC(=O)C2C3C(C(OC)=O)=CC=CC=3NC=2C1.[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C[N:30]1[C:42]2[CH2:41][CH2:40][CH2:39][C:38]3=[N:43][NH:44][C:45](=[O:46])[C:35]4[C:36]([C:37]=23)=[C:31]1[CH:32]=[CH:33][CH:34]=4>>[CH2:21]([N:30]1[C:42]2[CH2:41][CH2:40][CH2:39][C:38]3=[N:43][NH:44][C:45](=[O:46])[C:35]4[C:36]([C:37]=23)=[C:31]1[CH:32]=[CH:33][CH:34]=4)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cn1c2c3c4c(cccc41)C(=O)NN=C3CCC2
Reactant: ClCc1ccccc1
Agent: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CC(C)(C)C3
Product: O=C1NN=C2CCCc3c2c2c1cccc2n3Cc1ccccc1

Procedure:
Compound 24 was prepared from methyl 2,2-dimethyl-4-oxo-2,3,4,9-tetrahydro-1H-carbazole-5-carboxylate and benzyl chloride according to the procedures for Compound 22 under appropriate conditions recognized by one of ordinary skill in the art. 1H NMR (DMSO-d6) δ 9.96 (s, 1H), 7.56 (d, 1H, J=8.4 Hz), 7.47 (d, 1H, J=7.8 Hz), 7.11-7.33 (m, 6H), 5.45 (s, 2H), 2.82-2.84 (m, 2H), 2.41-2.43 (m, 2H), and 1.97-2.00 (m, 2H). MS (ESI) m/e [M+1]+ 316.
Reaction SMILES: CN(C[C:5]1[N:6]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH2:19])[N:10]=[C:7]2[S:8][CH:9]=1)C.[N+](C1C=CC=CC=1C1N=[C:31]2[N:35]([CH:36]=1)[CH:34]=C(CO)S2)([O-])=O>>[CH3:34][N:35]([CH2:36][C:9]1[S:8][C:7]2=[N:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH2:19])=[CH:12][N:6]2[CH:5]=1)[CH3:31]
Reactant: CN(C)Cc1csc2nc(-c3ccccc3N)cn12
Reactant: O=[N+]([O-])c1ccccc1-c1cn2cc(CO)sc2n1
Product: CN(C)Cc1cn2cc(-c3ccccc3N)nc2s1

Procedure:
Essentially the same procedure used during the preparation of 2-(3-dimethylaminomethyl-imidazo [2,1-b]thiazol-6-yl)-phenylamine was employed, except that [6-(2-nitro-phenyl)-imidazo[2,1-b]thiazol-2-yl]-methanol was used as the starting material.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26]1[S:27][CH:28]([CH2:31][C:32]([OH:34])=O)[CH2:29][N:30]=1)=[CH:9]2.Cl.C[N:37](C)CCCN=C=NCC.CN(C)C=O>O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:17])=[O:18])[CH:14]=1)[NH:11][C:10]([C:26]1[S:27][CH:28]([CH2:31][C:32]([NH2:37])=[O:34])[CH2:29][N:30]=1)=[CH:9]2
Reactant: CCN=C=NCCCN(C)C
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CC(=O)O)S3)cc2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CC(N)=O)S3)cc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 40.1 %

Procedure:
A mixture of (2-{5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (200 mg), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (90 mg), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (120 mg) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-methanol (100:0-90:10, volume ratio) to give colorless crystals. The crystals were recrystallized from acetone-hexane to give the title compound (80 mg, yield 55%) as a colorless powder. melting point 100-102° C.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH2:26][C@H:27]([OH:31])[C:28]([OH:30])=[O:29].C[O-].[Na+].CO>>[OH:31][C@@H:27]([CH2:26][NH:25][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH:9]=2)=[O:4])[C:28]([OH:30])=[O:29]
Reactant: NC[C@H](O)C(=O)O
Reactant: COC(=O)c1ncc2cc(Oc3ccc(OC)cc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Oc2ccc3c(O)c(C(=O)NC[C@H](O)C(=O)O)ncc3c2)cc1
Yield: 45.2 %

Procedure:
A mixture of 4-hydroxy-7-(4-methoxy-phenoxy)-isoquinoline-3-carboxylic acid methyl ester (100 mg, 0.31 mmol) and 3-amino-2-(S)-hydroxy-propionic acid (97 mg, 0.92 mmol) in 0.5 M NaOMe/MeOH solution (1.23 mL, 0.62 mmol) was microwaved at 120° C. for 2 h. After cooled, solid precipitate was collected and rinsed with cold MeOH (1 mL). Solid was dissolved in water (40 mL), acidified by 1 N HCl to pH=3-4 and extracted with EtOAc. Organic layer was dried over MgSO4, filtered and concentrated to provide the title compound 54 mg (0.14 mmol) in 15% yield. LC-MS ESI−: 397.02 (M−1)−.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([C:19]([F:22])([F:21])[F:20])[CH:10]=2)=[O:7])=[C:4]([OH:25])[CH:3]=1.[N:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([C:19]([F:20])([F:21])[F:22])[CH:10]=2)=[O:7])=[C:4]([O:25][C:32]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:33])[CH:3]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(Cl)cc1O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(Cl)cc1OC(=O)N1CCOCC1
Yield: 84.1 %

Procedure:
Using 4-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide and morpholine-4-carbonyl chloride as the raw materials, the same operation as the Example 71 gave the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([CH3:16])[CH:4]=1.[C-:17]#[N:18].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[C:17]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([CH3:16])[CH:4]=1)#[N:18]
Reactant: [C-]#N
Reactant: Cc1cc(CCl)ccc1Sc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(CC#N)ccc1Sc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thus obtained 1-chloromethyl-3-methyl-4-phenylthiobenzene was dissolved in 56 ml of N,N-dimethylformamide, and 18.16 g of finely ground sodium cyanide was added, and the mixture was stirred overnight at room temperature. After adding 300 ml of saturated brine and 300 ml of ice water to the reaction mixture, it was extracted with ethyl acetate (300 ml×3). The extract was washed with saturated brine (200 ml×3), and dried with anhydrous sodium sulfate, concentrated in vacuo, and 1-cyanomethyl-3-methyl-4-phenylthiobenzene was obtained (45.95 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:43][C:44]([F:56])([F:55])[O:45][C:46]1[CH:47]=[C:48]([CH:52]=[CH:53][CH:54]=1)[C:49](O)=[O:50]>ClCCl.O>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:49](=[O:50])[C:48]2[CH:52]=[CH:53][CH:54]=[C:46]([O:45][C:44]([F:43])([F:55])[F:56])[CH:47]=2)[N:13]=1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Reactant: O=C(O)c1cccc(OC(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: O=C(NCCNc1nc(Cl)nc2c1ncn2C1CCCC1)c1cccc(OC(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
280 mg of the product obtained in Stage 1 of Example 7, 203 mg of 1-hydroxybenzotriazole hydrate, 287 mg of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride in 4 ml of dichloromethane are mixed together, 230 mg of 3-trifluoromethoxy benzoic acid is added and agitation is carried out for 4 hours and 30 minutes at ambient temperature. Water is added, followed by extracting with methylene chloride, drying, evaporating the solvents, recrystallizing from ether, separating, drying and 326 mg of expected product is collected.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH2:16][CH3:17])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][CH:20]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][CH:20]=[C:19]2[O:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH2:16][CH3:17])=[O:13])=[CH:10][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CCCOC(=O)c1cc2ccccc2cc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: CCCOC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 140 °C
Reaction time: 12.5 h
Yield: 44.5 %

Procedure:
Propyl 2-hydroxy-3-naphthoate (400 mg), 4-chloro-6,7-dimethoxyquinoline (130 mg), and 4-dimethylaminopyridine (213 mg) were suspended in o-dichlorobenzene (4 ml), and the suspension was stirred at 140° C. for 12.5 hr. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (108 mg, yield 44%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][N:3]=1.[C:16](Cl)(=[O:26])[C:17]1[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:19](Cl)=[O:20]>N1C=CC=CC=1.CCOC(C)=O>[C:12]([O:11][C:9]([NH:8][C:5]1[CH:6]=[N:7][C:2]([N:1]2[C:19](=[O:20])[C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[C:16]2=[O:26])=[N:3][CH:4]=1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)Nc1cnc(N)nc1
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cnc(N2C(=O)c3ccccc3C2=O)nc1
Temperature: 45 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To a solution of N-(2-aminopyrimidin-5-yl)(tert-butoxy)carboxamide (0.237 g, 1.0 mmol) in pyridine (1 mL) was added phthaloyl dichloride (0.144 mL, 1.0 mmol). The resulting suspension was stirred at 45° C. for 2 hr, diluted with EtOAc, washed with water and brine, dried and concentrated in vacuo to give crude (tert-butoxy)-N-[2-(1,3-dioxobenzo[c]azolidin-2-yl)pyrimidin-5-yl]carboxamide (0.31 g). ES-MS (M+H)+=341; (M+H−tBu)+=285.
Reaction SMILES: [H-].[Na+].CCCCCC.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[OH:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH:14][CH:15]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C(Cc1ccc(O)cc1)OCc1ccccc1
Temperature: 4 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (50% w/w dispersion in mineral oil, 3.7 g) was treated under argon with repeated washes of hexane. The oil-free residue was suspended in dry DMF (100 ml) and 4-hydroxyphenylacetic acid (13.0 g) was added portionwise to the stirred cooled (4° C.) mixture. After 30 minutes, benzyl bromide (9.2 ml) was added dropwise and, after a further 1 hour at 4° C., stirring was continued overnight at ambient temperature. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate and water. The aqueous phase was re-extracted with further ethyl acetate and the combined organic extracts washed with water and brine, then dried (MgSO4) and evaporated. The crystalline residue gave benzyl 4-hydroxyphenylacetate, 17.8 g, as off-white crystals: m.p. 70°-72° C.; NMR (CDCl3) δ 7.32(5H, m), 7.14(2H, d), 6.76(2H, d), 5.12(2H, s), 3.59(2H, s); m/e 242 (M.)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.CS(C)=[O:20]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:20])=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(F)cc1)c1ccc(F)cc1
Reactant: CS(C)=O
Product: O=C(C(=O)c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
SeO2 (191 mg, 1.72 mmol, 4.00 equiv) was added in batches to a solution of 1,2-bis(4-fluorophenyl)ethanone (100 mg, 0.43 mmol, 1.00 equiv) in DMSO (4.5 mL). The resulting solution was allowed to react, with stirring, for 2 hrs while the temperature was maintained at 100° C. in an oil bath. The solids were filtered out and discarded.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]#[N:9])=[CH:4][N:3]=[CH:2]1.C([O-])([O-])=[O:15].[K+].[K+].OO>CS(C)=O>[NH:3]1[CH:4]=[C:5]([C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]([NH2:9])=[O:15])[N:1]=[CH:2]1
Reactant: N#Cc1ccccc1-c1cnc[nH]1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccccc1-c1c[nH]cn1
Reaction time: 16 h
Yield: 74.5 %

Procedure:
To a solution of 2-(1H-imidazol-5-yl)benzonitrile (85 mg, 0.502 mmol) in DMSO (3 mL) at room temperature was added K2CO3 (69 mg, 0.502 mmol) followed by H2O2 (30%, 1.1 mL, 10.04 mmol). After stirring for 16 h, the reaction was concentrated and the crude product was purified by flash column chromatography (silica gel, 10% MeOH/DCM followed by 10% MeOH/EtOAc) to yield the desired amide as a white solid (70 mg, 0.374 mmol, 75%). 1H NMR (DMSO-d6): 7.20-7.35 (m, 5H), 7.66 (s, 1H), 7.75 (s, 1H), 7.83 (s, 1H), 12.01 (br s, 1H).
Reaction SMILES: C([Mg]Cl)(C)C.[C:6]([NH2:10])([CH3:9])([CH3:8])[CH3:7].CCC.[CH3:14][Si:15](OC)([O:18][CH3:19])[O:16][CH3:17]>O1CCCC1>[CH3:14][Si:15]([NH:10][C:6]([CH3:9])([CH3:8])[CH3:7])([O:18][CH3:19])[O:16][CH3:17]
Reactant: CO[Si](C)(OC)OC
Reactant: CC(C)(C)N
Agent: CC(C)[Mg]Cl
Solvent: CCC
Solvent: C1CCOC1
Product: CO[Si](C)(NC(C)(C)C)OC
Temperature: 25 °C

Procedure:
A thermometer an addition funnel and a condenser were fitted to a stirrer-equipped one liter, four-necked flask. The flask was charged with one mol of isopropylmagnesium chloride in 500 ml of tetrahydrofuran (THF). The addition funnel was charged with 1.02 mol (75 g) of tert-butylamine which was slowly added to the stirred isopropylmagnesium chloride. The reaction was mildly exothermic and there was immediate evolution of propane gas. After completion of the addition (2 hours), the contents were refluxed for 30 minutes to complete the evolution of the gas. The reaction mixture was cooled to room temperature and one mol (135 g) of methyltrimethoxysilane was added to the stirred reaction mixture over a period of one hour. The reaction was mildly exothermic and the contents were refluxed at a pot temperature of 75° C. for 30 minutes to complete the reaction. The methyl(t-butylamino)dimethoxysilane was filtered under nitrogen atmosphere from the magnesium methoxychloride. The salt cake was washed with diethyl ether (2×200 ml) to obtain the residual methyl(t-butylamino)dimethoxysilane. The solvent was distilled to a pot temperature of 90° C. and the residue was distilled under reduced pressure to yield 138 g of methyl(t-butylamino)dimethoxysilane as a colorless oil (purity>98%); bp 107° C./135 mm. The yield was 82% of theoretical.
Reaction SMILES: N1C=CC=CC=1.[S:7]([O:11][S:12]([OH:15])(=[O:14])=[O:13])([OH:10])(=[O:9])=[O:8].[OH:16][CH2:17]/[C:18](/[CH2:27][CH2:28]/[CH:29]=[C:30](\[CH3:37])/[CH2:31][CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35])=[CH:19]/[CH2:20][CH2:21]/[C:22](/[CH3:26])=[CH:23]/[CH2:24][OH:25].C(C(CCCC)C([O-])=O)C.[Na+:48]>C(OCC)(=O)C>[Na+:48].[S:7]([O:11][S:12]([O-:15])(=[O:14])=[O:13])([O-:10])(=[O:9])=[O:8].[OH:16][CH2:17]/[C:18](/[CH2:27][CH2:28]/[CH:29]=[C:30](\[CH3:37])/[CH2:31][CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35])=[CH:19]/[CH2:20][CH2:21]/[C:22](/[CH3:26])=[CH:23]/[CH2:24][OH:25].[Na+:48]
Reactant: O=S(=O)(O)OS(=O)(=O)O
Agent: CC(C)=CCC/C(C)=C/CC/C(=C\CC/C(C)=C/CO)CO
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=S(=O)([O-])OS(=O)(=O)[O-]

Procedure:
Following the procedures of Example 27, a solution of 2.2 g of (E,Z,E) and (E,E,E)-7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraen-1-ol disulfate pyridine salt prepared in Example 28 in 20 ml of ethyl acetate was treated with 6.0 ml (2 mM/ml) of sodium 2-ethylhexanoate to afford 1.4 g of the end product as a white powder.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]([F:31])[C:16]([C:19]#[C:20][C:21]3[CH:30]=[CH:29][C:24]([O:25][CH2:26][CH2:27][OH:28])=[CH:23][CH:22]=3)=[N:17][CH:18]=2)=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:28][CH2:27][CH2:26][O:25][C:24]1[CH:23]=[CH:22][C:21]([C:20]#[C:19][C:16]2[C:15]([F:31])=[CH:14][C:13]([C:10]3[CH:9]=[CH:8][C:7]([Cl:6])=[CH:12][CH:11]=3)=[CH:18][N:17]=2)=[CH:30][CH:29]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOc1ccc(C#Cc2ncc(-c3ccc(Cl)cc3)cc2F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOc1ccc(C#Cc2ncc(-c3ccc(Cl)cc3)cc2F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
At 0° C., 63 μL (0.816 mmol) of methanesulfonyl chloride was added dropwise to a solution of 0.20 g (0.544 mmol) of 2-{4-[5-(4-chlorophenyl)-3-fluoropyridin-2-ylethynyl]phenoxy}ethanol and 0.11 mL (0.816 mmol) of triethylamine in 10 mL of DCM and the mixture was stirred for 16 hours at RT. A further 0.11 mL (0.816 mmol) of triethylamine and 63 μL (0.816 mmol) of methanesulfonyl chloride were added and the mixture was stirred for 8 hours. The reaction mixture was diluted with DCM, and the organic phase was washed with water and dilute aqueous sodium bicarbonate solution, dried over magnesium sulfate, and evaporated down in vacuo. Yield: 0.24 g (99% of theoretical); C22H17ClFNO4S (M=445.892); calc.: molpeak (M+H)+: 446/448 (Cl); found: molpeak (M+H)+: 446/448 (Cl); HPLC-MS: 6.19 minutes (method B).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH:16]([N:19]([CH:30]([CH3:32])[CH3:31])[CH2:20][CH2:21][NH:22][C:23](N1C=CN=C1)=[O:24])([CH3:18])[CH3:17].C(N(CC)CC)C>ClCCl>[CH:30]([N:19]([CH:16]([CH3:18])[CH3:17])[CH2:20][CH2:21][NH:22][C:23]([NH:2][CH2:3][CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:24])([CH3:32])[CH3:31]
Reactant: CC(C)N(CCNC(=O)n1ccnc1)C(C)C
Reactant: NCCNC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N(CCNC(=O)NCCNC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Yield: 109.6 %

Procedure:
A solution of benzyl 2-aminoethylcarbamate hydrochloride (4.33 g, 18.8 mmol), N-[2-(diisopropylamino)ethyl]-1H-imidazole-1-carboxamide (Preparation 19) (3.73 g, 15.64 mmol) and triethylamine (2.62 ml, 18.8 mmol) in dichloromethane (100 ml) was heated under reflux for 14 hours. The solution was allowed to cool to room temperature and then washed with water (20 ml). The aqueous layer was separated and extracted with more dichloromethane (20 ml). The combined organic layers were dried over anhydrous magnesium sulfate and solvent evaporated under reduced pressure to give the title compound as a yellow oil (6.25 g).
Reaction SMILES: [N:1]#[N:2].[CH2:3]([O:10][C:11]([C@@:13]1([C:23]([NH2:25])=[O:24])[CH2:17][C@H:16]([OH:18])[CH2:15][N:14]1[C:19]([CH3:22])([CH3:21])[CH3:20])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>N1C=CC=CC=1>[N:1]#[N:2].[CH2:3]([O:10][C:11]([C@@:13]1([C:23]([NH2:25])=[O:24])[CH2:17][C@H:16]([O:18][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:15][N:14]1[C:19]([CH3:21])([CH3:22])[CH3:20])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)N1C[C@@H](O)C[C@]1(C(N)=O)C(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: N#N
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)N1C[C@@H](OS(C)(=O)=O)C[C@]1(C(N)=O)C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
0.32 g of N2 -(benzyloxycarbonyl)-N1 -tert.butyl-4(S)-hydroxy-L-prolinamide was dissolved in 5 ml of dry pyridine while stirring, cooled to 0° C. and treated dropwise with 0.82 ml of methanesulphonyl chloride. The solution was stirred at 0° C. for a further 2 hours. The mixture was poured into a mixture of ice and water which was then extracted with ethyl acetate. The combined organic extracts were washed with 2M hydrochloric acid and then with saturated sodium bicarbonate solution and subsequently dried over anhydrous sodium sulphate. After evaporation there was obtained 0.5 g of N2 -(benzyloxycarbonyl)-N1 -tert.butyl-4(S)-(methanesulphonyloxy)-L-prolinamide as an oil which was used without further purification.