Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:3]1[N:41]=[C:6]2[N:7]=[C:8]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]4[CH2:29][CH2:28][CH:27]([C:30]5[N:34]=[C:33]([C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=6)[NH:32][N:31]=5)[CH2:26][CH2:25]4)=[CH:19][CH:18]=3)[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:10][N:5]2[N:4]=1)#C.[CH3:42][O-:43].[Na+]>CO.O.ClCCl>[CH3:42][O:43][C:3]1[N:41]=[C:6]2[N:7]=[C:8]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]4[CH2:29][CH2:28][CH:27]([C:30]5[N:34]=[C:33]([C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=6)[NH:32][N:31]=5)[CH2:26][CH2:25]4)=[CH:19][CH:18]=3)[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:10][N:5]2[N:4]=1
Reactant: C#Cc1nc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)c(-c3ccccc3)cn2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COc1nc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)c(-c3ccccc3)cn2n1
Temperature: 55 °C

Procedure:
To 110 mg 2-bromo-6-phenyl-5-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)[1,2,4]triazolo[1,5-a]pyrimidine (prepared as described under example 53) in 5 ml methanol are added 1.11 ml of a sodium methoxide solution (25% in methanol). The reaction mixture is heated to 55° C. for 3.5 hours and diluted with water and dichloromethane. The phases are separated and the water layer is extracted with dichloromethane. The combined organic layers are dried over Na2SO4 and the solvent are removed by evaporation. The residue is purified by RP HPLC (water, 10 mM NH4COOH, pH 3.7/ACN) to yield the desired compound.
Reaction SMILES: C[CH:2]1[C@H:8]2[N:9]([CH3:10])[C@H:5]([CH2:6][CH2:7]2)[C:4](=[N:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:3]1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](Cl)=[O:29])=[CH:23][CH:22]=1.Cl[CH2:32]Cl>>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([N:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH3:32])=[CH:17][CH:18]=2)[C:4]2[C@H:5]3[N:9]([CH3:10])[C@H:8]([CH2:7][CH2:6]3)[CH2:2][CH:3]=2)=[O:29])=[CH:23][CH:22]=1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: ClCCl
Reactant: CC1CC(=NCc2ccccc2)[C@H]2CC[C@@H]1N2C
Product: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2=CC[C@H]3CC[C@@H]2N3C)cc1
Reaction time: 16 h
Yield: 18 %

Procedure:
47AKU-38 (242 mg, 1.0 mmol) was dissolved in 5 ml dichloromethane and placed in 50 ml flask. 4-Methoxyphenylacetyl chloride (185 mg, 1.2 mmol) in 10 ml dichloromethane was added. After 16 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40° C.). Crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 69 mg (18%) 47AKU-39. HCl-salt was prepared from 2M HCl/diethylether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0.4. HPLC-MS (Method A): M+=391.2 (UV/MS(%)=91/86).
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=O.[C:7]([C:10]1[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:12][N:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=12)(=[O:9])[CH3:8]>C(Cl)Cl>[O:9]=[C:7]([C:10]1[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:12][N:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=12)/[CH:8]=[CH:3]/[C:2]([OH:6])=[O:5]
Reactant: CC(=O)c1c(-c2ccccc2)nn2ccccc12
Reactant: O=CC(=O)O
Solvent: O
Solvent: ClCCl
Product: O=C(O)/C=C/C(=O)c1c(-c2ccccc2)nn2ccccc12
Temperature: 100 °C
Yield: 7.4 %

Procedure:
A mixture of glyoxylic acid monohydrate (3.50 g) and 3-acetyl-2-phenylpyrazolo[1,5-a]pyridine (5.00 g) was stirred and heated at 100° C. for 4 hours. The warm reaction mixture was dissolved in methylene chloride (50 ml), and then extracted with 1N aqueous solution of sodium hydroxide (50 ml). The aqueous layer was washed with methylene chloride (total 200 ml) and then with ethyl acetate (total 200 ml). The aqueous solution was adjusted to pH 4~5 with 10% hydrochloric acid. The isolated oil was extracted with chloroform. The extract was evaporated in vacuo and crystallized from methylene chloride to give 4-oxo-4-(2phenylpyrazolo[1,5-a]pyridin-3-yl)crotonic acid (0.46 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:38][C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)[C@H:13]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH2:27][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)=[O:24])[CH2:19][CH2:18]2)[C:14](O)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:45]([O:49][NH2:50])([CH3:48])([CH3:47])[CH3:46].CN1CCOCC1.ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.C(OCC)(=O)C>[C:45]([O:49][NH:50][C:14](=[O:15])[C@H:13]([N:12]([S:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)(=[O:11])=[O:10])[CH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1)[CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)=[O:24])[CH2:19][CH2:18]1)([CH3:48])([CH3:47])[CH3:46]
Reactant: CC(C)(C)ON
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccncc2)[C@@H](C(=O)O)C2CCN(C(=O)OCCc3cccc4ccccc34)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(S(=O)(=O)N(Cc2ccncc2)[C@@H](C(=O)NOC(C)(C)C)C2CCN(C(=O)OCCc3cccc4ccccc34)CC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.3 %

Procedure:
To a solution of the crude 2-(R)-[(4-methoxybenzenesulfonyl)(4-picolyl)amino]-2-[(N-(2-(1-naphthyl)-ethoxycarbonyl))-4-piperidinyl] acetic acid (6.02 mmol) in methylene chloride (150 ml) is added O-t-butylhydroxylamine (2.27 g, 18.06 mmol), N-methylmorpholine (3.65 g, 36.12 mmol), 1-hydroxy-7-azabenzotriazole (819 mg, 6.02 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.5 g, 7.83 mmol). The reaction mixture is stirred at room temperature for 1.5 hours, diluted with ethyl acetate and washed with water. The aqueous layer is extracted with ethyl acetate, the combined organic layers are washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude product is purified by silica gel chromatography (2% methanol in methylene chloride) to provide N-(t-butyloxy)-2-(R)-[(4-methoxybenzenesulfonyl) (4-picolyl)amino]-2-[(N-(2-(1-naphthyl)-ethoxycarbonyl))-4-piperidinyl]acetamide (3 g).
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH2:7])=[CH:5][S:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[C:17]([NH2:20])[C:18]=2[NH2:19])=[CH:10][CH:9]=1.N[C:22](N)=[O:23].[CH2:25]([OH:30])CCCC>>[O:30]=[C:25]1[NH:20][C:17]2=[CH:16][S:15][C:14]([C:11]3[CH:10]=[CH:9][C:8]([C:3]4[S:4][CH:5]=[C:6]5[C:2]=4[NH:1][C:22](=[O:23])[NH:7]5)=[CH:13][CH:12]=3)=[C:18]2[NH:19]1
Reactant: NC(N)=O
Reactant: CCCCCO
Reactant: Nc1csc(-c2ccc(-c3scc(N)c3N)cc2)c1N
Product: O=c1[nH]c2csc(-c3ccc(-c4scc5[nH]c(=O)[nH]c45)cc3)c2[nH]1
Temperature: 130 °C

Procedure:
To the resulting 2-[4-(3,4-diaminothien-2-yl)phenyl]thiophene-3,4-diamine were added 2.2 equivalents of urea and amyl alcohol in an amount equivalent to 10 ml/mmol, and under argon gas atmosphere, a reaction was advanced by refluxing at 130° C. for 5 hours, then amyl alcohol was distilled off and the residue was purified by silica gel column chromatography using an ethyl acetate/hexane solvent, so that 4-[4-(2,3-dihydro-2-oxo-1H-thieno[3,4-d]imidazol-4-yl)phenyl]-2,3-dihydro-1H-thieno[3,4-d]imidazol-2-one was obtained. The yield based on 2-[4-(3,4-diaminothien-2-yl)phenyl]thiophene-3,4-diamine was 60%.
Reaction SMILES: [Br:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[N:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C(Cl)(=O)C(Cl)=O.ClC1N(CC([N:30]2[CH2:35][CH2:34][CH:33]([C:36]3[S:37][CH:38]=[C:39]([C:41]4[CH2:45][CH:44]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)[O:43][N:42]=4)[N:40]=3)[CH2:32][CH2:31]2)=O)N=C(C(F)(F)F)C=1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[Br:1][C:2]1[N:6]([CH2:7][C:8]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]3[S:37][CH:38]=[C:39]([C:41]4[CH2:45][CH:44]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)[O:43][N:42]=4)[N:40]=3)[CH2:32][CH2:31]2)=[O:10])[N:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1
Reactant: O=C(O)Cn1nc(C(F)(F)F)cc1Br
Reactant: O=C(Cn1nc(C(F)(F)F)cc1Cl)N1CCC(c2nc(C3=NOC(c4ccccc4)C3)cs2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cn1nc(C(F)(F)F)cc1Br)N1CCC(c2nc(C3=NOC(c4ccccc4)C3)cs2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-3-(trifluoromethyl)-1H-pyrazole-1-acetic acid (i.e. the product of Example 11, Step D) (0.12 g, 0.61 mmol) in dichloromethane (5 mL) was added N,N-dimethylformamide (1 drop) followed by oxalyl chloride (0.25 mL, 2.86 mmol). The reaction mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The residue containing crude acid chloride was taken up in dichloromethane (5 mL), and the solution was added dropwise to a mixture of 4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]-1-piperidine hydrochloride (i.e. the intermediate product of Example 10, Step F) (0.15 g, 0.43 mmol) and triethylamine (0.25 mL, 1.8 mmol) in dichloromethane (5 mL) at 0° C. The reaction mixture was allowed to warm to room temperature, and then stirred overnight at room temperature. The mixture was then partitioned between 1.0 N aqueous hydrochloric acid solution and dichloromethane. The organic layer was washed with water, dried (MgSO4), concentrated under reduced pressure, and purified by medium-pressure liquid chromatography using ethyl acetate in hexanes as eluant to give 90 mg of the title product, a compound of the present invention, as an amorphous solid.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[Cl:25][C:26]1[CH2:33][C:32](=[S:34])[CH:31]=[CH:30][C:27]=1[CH:28]=O.CCCCCC>ClCCl>[Br:21][C:20]([Br:24])=[CH:28][C:27]1[CH:30]=[CH:31][C:32]([S:34][CH3:1])=[CH:33][C:26]=1[Cl:25]
Reactant: O=CC1=C(Cl)CC(=S)C=C1
Reactant: BrC(Br)(Br)Br
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CSc1ccc(C=C(Br)Br)c(Cl)c1
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
Triphenyl phosphine (2.5 g) was added to a stirred solution of carbon tetrabromide (1.48 g) in dichloromethane maintaining the temperature at 0° C. The mixture was stirred for 0.5 hours and 2-chloro-4-(sulphenyl)-benzaldehyde (1.0 g) was added. The resultant mixture was stirred for 0.5 hours and poured into hexane. The resulting solid was filtered off and washed with ether. The combined filtrates were evaporated to dryness and the residue was purified by chromatrography eluted with hexane to give 1,1-dibromo-2-[2-chloro-4-(methylsulphenyl)phenyl]ethene (0.96 g) as a white solid, NMR (CDCl3) 2.45 (s,3H), 7.15(d,1H), 7.25(s,1H), 7.55(s,1H), 7.6(d,1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][CH2:9][NH:10][CH:11]1[CH:15]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:14][N:13]([C:24](=[O:32])[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH2:12]1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Cl:43][CH2:44][C:45](Cl)=[O:46]>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][CH2:9][N:10]([CH:11]1[CH:15]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19])[CH2:14][N:13]([C:24](=[O:32])[C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[CH2:12]1)[C:45](=[O:46])[CH2:44][Cl:43])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)NCCNC1CN(C(=O)c2ccc(Cl)cc2)CC1O[Si](C)(C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCN(C(=O)CCl)C1CN(C(=O)c2ccc(Cl)cc2)CC1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of {2-[4-(tert-butyl-dimethyl-silanyloxy)-1-(4-chloro-benzoyl)-pyrrolidin-3-ylamino]-ethyl}-carbamic acid tert-butyl ester (389 mg, 0.78 mmol) at 0° C., was added DIPEA (0.150 mL, 0.85 mmol) and chloroacetyl chloride (62 uL, 0.78 mmol). The reaction mixture was stirred at RT for overnight. The organic phase was washed with Sat. NaHCO3, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (Ethyl acetate:Hexane: 1:2) to give the desired product (260 mg, 58% yield) as a colorless oil. MS: (ESI), M/Z, 574 (M+1). Retention time: 2.78 min (FA-polar).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[CH:10]1>CC(C)=O>[I-:1].[CH3:8][N+:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:10]=1
Reactant: Cn1cnc2ccccc21
Reactant: Ic1ccccn1
Solvent: CC(C)=O
Product: C[n+]1cn(-c2ccccn2)c2ccccc21
Product: [I-]
Reaction time: 72 h

Procedure:
A mixture of 2-iodopyridine (2.0 g, 9.8 mmol) and 1-methylbenzimidazole (1.29 g, 9.8 mmol) was kept neat at 140° C. for 72 h. After cooling to ca 50° C., acetone was added and the resulting solid was filtered and washed with acetone and ether. Yield: 826 mg (25%). 1H NMR (DMSO-d6): δ 10.48 (s, 1H, NCHN), 8.79 (d, 1H), 8.47-8.49 (m, 1H), 8.27-8.32 (dt, 1H), 8.14-8.16 (m, 1H), 8.04 (d, 1H), 7.77-7.82 (m, 2H), 7.71-7.74 (dd, 1H), 4.20 (s, 3H, CH3). This ligand was pure by 1H-NMR and was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C1C(=O)N([Br:23])C(=O)C1.O>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:12][C:5]1[C:4]([N+:13]([O-:15])=[O:14])=[CH:3][C:2]([Cl:1])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1CBr
Yield: 86.6 %

Procedure:
A mixture of methyl 5-chloro-2-methyl-3-nitrobenzoate (6 g, 26.2 mmol), NBS (5.1 g, 28.8 mmol), and BPO (0.63 g, 2.6 mmol) in CCl4 (50 mL) was heated to reflux overnight. Water (200 mL) was added and CCl4 was removed under reduced pressure. The residue was extracted with DCM (200 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give crude title compound (7 g, yield 87%) as a brown oil which was used in the next step without purification.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][C@@H:7]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH2:6][N:5]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:15])(=[O:3])[CH3:2].C1C=C[NH+]=CC=1.[Br:33][Br-]Br.O.C(OCC)(=O)C>O1CCCC1>[Br:33][CH2:2][C:1]([C@@H:4]1[CH2:8][C@@H:7]([O:9][S:10]([CH3:13])(=[O:11])=[O:12])[CH2:6][N:5]1[C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1)=[O:15])=[O:3]
Reactant: CC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)CBr)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a solution of (2S,4R)-2-acetyl-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.5 g) in tetrahydrofuran (80 ml) was added pyridinium bromide perbromide (2.59 g) at 5°-10° C. After stirring at room temperature for 3 hours, the mixture was poured into water (80 ml) and ethyl acetate (160 ml). The separated organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate and brine successively, dried over magnesium sulfate, and evaporated in vacuo. The oily residue was subjected to a column chromatography on silica gel (60 g) eluting with a mixture of acetone and dichloromethane (1:20 V/V) to give (2S,4R)-2-bromoacetyl-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.98 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([Br:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[C:16]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C.O>[C:1]([C:5]1[CH:10]=[C:9]([Br:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=1[O:15][CH3:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(Br)c([N+](=O)[O-])cc1O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])c(Br)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.4 %

Procedure:
To a mixture of 2-tert-butyl-4-bromo-5-nitrophenol (C-14-a) (1.5 g, 5.5 mmol) and Cs2CO3 (2.2 g, 6.6 mmol) in DMF (6 mL) was added methyl iodide (5150 μL, 8.3 mmol). The mixture was stirred at room temperature for 4 h, diluted with H2O and extracted twice with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. After removal of solvent, the residue was washed with hexane to yield 1-tert-butyl-2-methoxy-5-bromo-4-nitrobenzene (1.1 g, 69%). 1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.44 (s, 1H), 3.92 (s, 3H), 1.39 (s, 9H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=O)[C:7]2=[O:14].[Cl:15][C:16]1[CH:27]=[C:20]2[C:21](OC(=O)[NH:25][C:19]2=[CH:18][CH:17]=1)=[O:22].CO>CN(C=O)C.C(Cl)(Cl)Cl>[Cl:15][C:16]1[CH:27]=[C:20]2[C:19](=[CH:18][CH:17]=1)[N:25]=[C:8]1[C:7](=[O:14])[C:6]3[C:10]([N:9]1[C:21]2=[O:22])=[CH:11][CH:12]=[C:4]([F:3])[CH:5]=3
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: O=C1Nc2ccc(F)cc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C1c2cc(F)ccc2-n2c1nc1ccc(Cl)cc1c2=O
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (10 mmol, 40 mg 60%) in 4 mL of DMF was added 10 mmol of 5-fluoroisatin in 2 mL of DMF. After 15 min, a solution of 5-chloroisatoic anhydride in 3 mL of DMF was added. The reaction mixture was stirred for 18 h, methanol (0.5 mL) and 20 mL of chloroform was added and the organic solution was washed with water, dried (MgSO4) and concentrated to give a residue that was purified by silica gel chromatography (CHCl3:CH3OH). Yield 77%: mp 280-282° C.
Reaction SMILES: BrC[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9](C)[C:8](=O)[CH:7]=[CH:6]2.[H][H]>O=[Pt]=O>[NH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:12][CH:11]=2)[CH2:6][CH2:7][CH2:8]1
Reactant: [H][H]
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Agent: O=[Pt]=O
Product: c1ccc2c(c1)CCCN2

Procedure:
The alkylation step was carried out using 6-bromomethyl-1-methyl-2-oxo-1,2-dihydroquinoline, as in Example 1, and the intermediate was reduced with hydrogen over an Adam's catalyst to give 1,2,3,4-tetrahydroquinoline intermediate which was then deprotected as in Example 13. This provided the title compound as a white solid.
Reaction SMILES: [Cl:1][CH2:2][SiH2:3][CH:4](OCC)OCC.[C:11]1([Li])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:18](OCC)(=[O:20])[CH3:19]>CCOCC>[Cl:1][CH2:2][Si:3]([O:20][CH2:18][CH3:19])([CH3:4])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [Li]c1ccccc1
Reactant: CCOC(C)=O
Reactant: CCOC(OCC)[SiH2]CCl
Solvent: CCOCC
Product: CCO[Si](C)(CCl)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 18.2 ml (18.2 g, 0.10 mol) of chloromethyl(diethoxy)methylsilane in 200 ml of dry ether was stirred vigorously under N2 and chilled while 56 ml (0.10 mol) of 1.8 molar phenyllithium in 70:30 cyclohexane-ether was added at a rate that held the mixture below -50°. The resulting slurry was allowed to warm to room temperature, treated cautiously with 10 ml of ethyl acetate, washed with water and brine, dried over magnesium sulfate, and evaporated to leave 16.8 g of a golden yellow liquid. Distillation provided 9.5 g (44%) of the title compound as a colorless liquid: bp 80°-84° (0.1 mm); nD20 1.5144; nmr (CDCl3) 0.5 (3H, s), 1.2 (3H, t, J=7), 3.0 (2H, s), 3.8 (2H, q, J=7), 7.2-7.8 (5H, m).
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][C:14]=3[C:21]([F:24])([F:23])[F:22])[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][C:16]([CH2:17][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:15][C:14]=3[C:21]([F:24])([F:23])[F:22])[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: O=Cc1ccc(N2CCC(CN3CCCC3)CC2)c(C(F)(F)F)c1
Product: FC(F)(F)c1cc(CN2CCCCC2)ccc1N1CCC(CN2CCCC2)CC1

Procedure:
Prepared from the product of Example 63 and piperidine.
Reaction SMILES: [O:1]=[C:2]([C:6]1[N:14]2[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]2)=[CH:8][C:7]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3](Cl)=[O:4].[O:21]=[S:22]1(=[O:35])[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.C(N(CC)CC)C>C1COCC1>[O:35]=[S:22]1(=[O:21])[CH2:23][CH2:24][N:25]([C:28]2[CH:29]=[CH:30][C:31]([NH:34][C:3](=[O:4])[C:2](=[O:1])[C:6]3[N:14]4[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]4)=[CH:8][C:7]=3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:32][CH:33]=2)[CH2:26][CH2:27]1
Reactant: Nc1ccc(N2CCS(=O)(=O)CC2)cc1
Reactant: O=C(Cl)C(=O)c1c(-c2ccccc2)cc2ccccn12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(N2CCS(=O)(=O)CC2)cc1)C(=O)c1c(-c2ccccc2)cc2ccccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
A solution of oxo-(2-phenyl-indolizin-3-yl)-acetyl chloride (0.12 g, 0.42 mmol) in THF was added to a solution of 4-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-phenylamine (70 mg, 0.31 mmol) and triethylamine (85 mg, 0.85 mmol) in THF (10 mL) at 0° C., then the mixture was stirred for 8 h at r.t. The mixture was concentrated to dryness and washed with water to give a crude product which was triturated with methanol to afford the title compound (70 mg, 48%) as a solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.CN(C)CCN(C)C.C([Li])CCC.[Cl:22][C:23]1[CH:37]=[CH:36][C:26]([C:27]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[O:28])=[CH:25][CH:24]=1>CCCCCC.O.O1CCCC1>[Cl:22][C:23]1[CH:37]=[CH:36][C:26]([C:27]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)([C:5]2[N:4]([CH2:3][O:2][CH3:1])[CH:8]=[CH:7][N:6]=2)[OH:28])=[CH:25][CH:24]=1
Reactant: COCn1ccnc1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCn1ccnc1C(O)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
To a solution of 11.2 g. (0.1 mol) of 1-(methoxymethyl)-imidazole and 13.9 g. (0.12 mol) of N,N,N',N'-tetramethylethylenediamine in 150 ml. of anhydrous tetrahydrofuran 51 ml. (0.12 mol) of n-butyllithium solution in hexane was added with stirring over a period of about one hour and at a temperature of -60° C. Stirring was continued for another 2 hours at -60° C. Cooling was discontinued and 25.1 g. (0.1 mol) of 4,4'-dichlorobenzophenone in 150 ml. of anhydrous tetrahydrofuran was added drop-wise. The mixture was stirred for 6 hours at room temperature and decomposed by addition of 15 ml. of water. Lithium hydroxide was removed by filtration and the filtrate was concentrated. A 2 N hydrochloric acid solution was added and the mixture was extracted with liberal amounts of diethyl ether. The acidic aqueous solution was made alkaline by addition of potassium carbonate and extracted with diethyl ether, toluene and ethyl acetate. The organic solvent solutions were combined, dried and concentrated. The solid was purified by crystallisation from toluene; its melting point was 145°-146° C.