Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:12]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: Cc1cc(Cl)cc(C(=O)O)c1N
Temperature: 100 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
To a solution of 2-amino-3-methylbenzoic acid (Aldrich, 15.0 g, 99.2 mmol) in N,N-dimethylformamide (50 mL) was added N-chlorosuccinimide (13.3 g, 99.2 mmol) and the reaction mixture was heated to 100° C. for 30 minutes. The heat was removed, the reaction was cooled to room temperature and let stand overnight. The reaction mixture was then slowly poured into ice-water (250 mL) to precipitate a white solid. The solid was filtered and washed four times with water and then taken up in ethyl acetate (900 mL). The ethyl acetate solution was dried over magnesium sulfate, evaporated under reduced pressure and the residual solid was washed with ether to afford the desired intermediate as a white solid (13.9 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Cl[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[N:13]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.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>[Cl:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: Clc1cccc(Cl)n1
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cccc(Cl)n2)cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 268.4 %

Procedure:
4-Methylphenylboronic acid (1.00 g), 2,6-dichloropyridine (3.27 g), tetrakis(triphenylphosphine)palladium(0) (0.255 g) and potassium phosphate (3.12 g) were dissolved in toluene (35 ml) and water (6.0 ml). The mixture was stirred at 80° C. for 15 hours under a nitrogen atmosphere. The organic layer was separated, washed with a saturated aqueous sodium hydrogen carbonate solution, and dried with anhydrous magnesium sulfate and the solvent was distilled off. The resultant was crudely purified through silica gel column chromatography (chloroform), thereby obtaining a mixture (4.02 g) containing the subject compound.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][CH2:10][C:11](NCOC)=[O:12])([CH3:4])[CH3:3].[CH3:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1>>[CH3:4][C:2]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][CH2:10][C:11]([C:23]1[N:19]([CH3:18])[N:20]=[CH:21][N:22]=1)=[O:12])([CH3:1])[CH3:3]
Reactant: COCNC(=O)CCCNC(=O)OC(C)(C)C
Reactant: Cn1cncn1
Product: Cn1ncnc1C(=O)CCCNC(=O)OC(C)(C)C

Procedure:
The subtitle compound was prepared according to the method of Example 43 step (b) using the product of Example 43 step (a) and 1-methyl-1H-1,2,4-triazole.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:3]=1[OH:4].Cl[O-]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:3](=[O:4])[CH:5]=[CH:6][C:7](=[O:9])[CH:8]=1
Reactant: Cc1cc(O)ccc1O
Agent: [O-]Cl
Solvent: ClC(Cl)Cl
Product: CC1=CC(=O)C=CC1=O

Procedure:
2-methyl hydroquinone (1b) of 3.0 g (24 mmol) is dissolved in 150 ml of chloroform, wherein 100 ml each of hypochloride solution which have been so prepared as mentioned above are added and each reaction is made in the same way as described in Example 1, and then 2-methyl benzoquinone (IIb) is obtained. Table below shows the yields of isolation corresponding to each case of the investigation:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH:12]1[CH2:20][CH2:19][CH:15]([C:16]([OH:18])=[O:17])[CH2:14][CH2:13]1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[C:2]([N:12]1[CH2:20][CH2:19][CH:15]([C:16]([OH:18])=[O:17])[CH2:14][CH2:13]1)([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 14 h
Yield: 85.8 %

Procedure:
Benzyl chloroformate (16.4 mL, 115 mmol) in toluene (50 mL) was added dropwise to a stirred solution of 12.9 g (100 mmol) of isonipecotic acid (Aldrich) and 21.0 g (250 mmol) of sodium bicarbonate in 200 mL of water. After 14 h, the mixture was extracted with ether (3×50 ml) and the ether layers were discarded. The aqueous layer was acidified with conc. HCl to pH 2, causing the product to precipitate. The product was partitioned into ethyl acetate (3×50 mL) and the combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated in vacuo to yield 22.6 g (86%) of N-CBZ-isonipecotic acid as a viscous oil.
Reaction SMILES: NC1C=CN(CC2CC2)C(=O)N=1.ClCC(CCl)=O.[Cl:19][CH2:20][C:21]1[N:22]=[C:23]2[CH:28]=[CH:27][N:26]([C:29]3[CH:34]=[CH:33][C:32](F)=CC=3)[C:25](=[O:36])[N:24]2[CH:37]=1>>[Cl:19][CH2:20][C:21]1[N:22]=[C:23]2[CH:28]=[CH:27][N:26]([CH2:29][CH:34]3[CH2:33][CH2:32]3)[C:25](=[O:36])[N:24]2[CH:37]=1
Reactant: O=c1n(-c2ccc(F)cc2)ccc2nc(CCl)cn12
Agent: Nc1ccn(CC2CC2)c(=O)n1
Agent: O=C(CCl)CCl
Product: O=c1n(CC2CC2)ccc2nc(CCl)cn12

Procedure:
2-Chloromethyl-6-cyclopropylmethyl-6H-imidazo[1,2-c]pyrimidin-5-one was prepared from 4-amino-1-cyclopropylmethyl-1H-pyrimidin-2-one and 1,3-dichloroacetone using the methods described above for the preparation of 2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one.
Reaction SMILES: [C:1]([C:9]1[C:10]([NH:30][CH2:31][CH2:32][CH2:33][CH3:34])=[C:11]2[CH:23]=[N:22][N:21](CC3OC=CC=3)[C:12]2=[N:13][C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O>>[C:1]([C:9]1[C:10]([NH:30][CH2:31][CH2:32][CH2:33][CH3:34])=[C:11]2[CH:23]=[N:22][NH:21][C:12]2=[N:13][C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCNc1c(C(=O)c2ccccc2)c(-c2ccccc2)nc2c1cnn2Cc1ccco1
Agent: O=S(=O)(O)O
Product: CCCCNc1c(C(=O)c2ccccc2)c(-c2ccccc2)nc2[nH]ncc12

Procedure:
5-Benzoyl-1-(2-furanyl)methyl-4-n-butylamino-6-phenyl-1H-pyrazolo[3,4-b]pyridine is treated with concentrated sulfuric acid according to the procedure of Example 4 to obtain 5-benzoyl-4-n-butylamino-6-phenyl-1H-pyrazolo[3,4-b]pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:26][C@H:25]([CH2:27][O:28]C(=O)C)[C@@H:20]([O:21]C(=O)C)[C@H:15]([O:16]C(=O)C)[C@H:10]2[O:11]C(=O)C)[OH:9])=[CH:4][C:3]=1[CH2:32]Br.[F:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[C:39]([F:43])[C:40]=1[O:41][CH3:42].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O.[Pd](Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:26][C@H:25]([CH2:27][OH:28])[C@@H:20]([OH:21])[C@H:15]([OH:16])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:32][C:37]1[CH:36]=[C:35]([F:34])[C:40]([O:41][CH3:42])=[C:39]([F:43])[CH:38]=1
Reactant: COc1c(F)cc(B(O)O)cc1F
Reactant: CC(=O)OC[C@H]1OC(O)(c2ccc(Cl)c(CBr)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1c(F)cc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred mixture of 1-chloro-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-2-bromomethyl-benzene (0.30 g), 3,5-difluoro-4-methoxy-phenylboronic acid (0.21 g) and potassium carbonate (0.31 g) in acetone (3 mL) and water (1 mL) under argon is cooled in an ice-bath. Then palladium dichloride (5 mg) is added and the cooling bath is removed. The reaction mixture is stirred at ambient temperature overnight. Then brine is added and the resulting mixture is extracted with ethyl acetate. The combined extracts are dried over sodium sulfate, and the solvent is removed in vacuo. The residue is taken up in methanol (5 mL) aqueous potassium hydroxide solution (1 mL, 4 mol/L) is added. The solution is stirred at ambient temperature for 0.5 h and then neutralized with 1 M hydrochloric acid. The methanol is evaporated, and the residue is diluted with brine and extracted with ethyl acetate. The organic extracts are dried over sodium sulfate, and the solvent is removed. The residue is chromatographed on silica gel (dichloromethane/methanol 1:0->9:1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21]([OH:23])=O)[O:5][C:6]=1[CH:7]=[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[N:48]1([CH2:53][CH2:54][NH2:55])[CH2:52][CH2:51][CH2:50][CH2:49]1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21]([NH:55][CH2:54][CH2:53][N:48]2[CH2:52][CH2:51][CH2:50][CH2:49]2)=[O:23])[O:5][C:6]=1[CH:7]=[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:17]
Reactant: Cc1cc(-c2cccc(C(=O)O)c2)oc1C=C1C(=O)Nc2ccccc21
Reactant: NCCN1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2cccc(C(=O)NCCN3CCCC3)c2)oc1C=C1C(=O)Nc2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-(4-methyl-5-((2-oxoindolin-3-ylidene)methyl)furan-2-yl)benzoic acid (40 mg, 0.12 mol) and HOBt (32 mg, 0.24 mol) in DMF (0.5 mL) was added EDCI (46 mg, 0.24 mmol). The reaction was stirred at rt for 10 min and then added 2-(pyrrolidin-1-yl)ethanamine (0.05 mL) followed by DIEA (0.05 mL). The reaction mixture was stirred at rt for 1 h and diluted with H2O (10 mL). The mixture was extracted with EtOAc (3×20 mL), dried over Na2SO4 and concentrated. The crude was purified by prep TLC (5%/MeOH, 1% TEA/DCM) to give 3-(4-methyl-5-((2-oxoindolin-3-ylidene)methyl)furan-2-yl)-N-(2-(pyrrolidin-1-yl)ethyl)benzamide (25 mg) LCMS (ES): m/z 442 [M+1]+.
Reaction SMILES: [P:1]([O:13][CH2:14][C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:34][C:35]3[S:36][C:37]([CH2:40][C:41]([NH:43][C:44]4[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[C:45]=4[F:51])=[O:42])=[CH:38][N:39]=3)=[N:29][CH:30]=[N:31]2)=[CH:26][C:25]=1[O:52][CH3:53])([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[P:1]([OH:3])([OH:8])([O:13][CH2:14][C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:34][C:35]3[S:36][C:37]([CH2:40][C:41]([NH:43][C:44]4[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[C:45]=4[F:51])=[O:42])=[CH:38][N:39]=3)=[N:29][CH:30]=[N:31]2)=[CH:26][C:25]=1[O:52][CH3:53])=[O:2]
Reactant: COc1cc2c(Nc3ncc(CC(=O)Nc4cccc(F)c4F)s3)ncnc2cc1OCCCN1CCC[C@H]1COP(=O)(OC(C)(C)C)OC(C)(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: COc1cc2c(Nc3ncc(CC(=O)Nc4cccc(F)c4F)s3)ncnc2cc1OCCCN1CCC[C@H]1COP(=O)(O)O
Yield: 102.4 %

Procedure:
An analogous reaction to that described in example 32, but starting with di(tert-butyl) ((2S)-1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl phosphate (202 mg, 0.26 mmol) yielded the title compound (177 mg, 88% yield) as a yellow dihydrochloride salt:
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]([C:13]3[S:14][C:15]4[N:16]=[CH:17][N:18]=[C:19](SC)[C:20]=4[N:21]=3)=[C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:10]=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([N:32]1C(C2SC3N=CN=C(SC)C=3C=2)=C(C2C=CC=CC=2)N=C1)C.N>>[CH:1]1([CH2:7][N:8]2[C:12]([C:13]3[S:14][C:15]4[N:16]=[CH:17][N:18]=[C:19]([NH2:32])[C:20]=4[N:21]=3)=[C:11]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:10]=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSc1ncnc2sc(-c3c(-c4ccccc4)ncn3CC3CCCCC3)nc12
Reactant: CCn1cnc(-c2ccccc2)c1-c1cc2c(SC)ncnc2s1
Agent: N
Product: Nc1ncnc2sc(-c3c(-c4ccccc4)ncn3CC3CCCCC3)nc12

Procedure:
The title compound was prepared by a similar process to that described for Example 56 but using 2-[1-(cyclohexylmethyl)-4-phenyl-1H-imidazol-5-yl]-7-(methylthio)[1,3]-thiazolo[5,4-d]pyrimidine (Intermediate 79) in place of 6-(1-ethyl-4-phenyl-1H-imidazol-5-yl)-4-(methylthio)thieno[2,3-d]pyrimidine (Intermediate 70) and using NH3 gas in place of NH3 solution (0.5 M in dioxane). Solid (160 mg, 25%);
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)=[C:2]=[S:3].[CH3:14][C:15]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:16]=1[NH2:17]>CO>[C:15]1([CH3:14])[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:16]=1[NH:17][C:2]([NH:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)=[S:3]
Reactant: Cc1ccc(N=C=S)cc1[N+](=O)[O-]
Reactant: Cc1cc(C)c(N)c(C)c1
Solvent: CO
Product: Cc1cc(C)c(NC(=S)Nc2ccc(C)c([N+](=O)[O-])c2)c(C)c1
Yield: 71.4 %

Procedure:
A mixture of 4-isothiocyanato-1-methyl-2-nitrobenzene (500 mg, 2.58 mmol) and 2,4,6-trimethylaniline (0.329 ml, 2.34 mmol) in methanol (10 ml) was refluxed for 4 h. The solvent was evaporated under vacuum. The residue was triturated with ether. The resulting solid was collected by filtration to afford 550 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[O:19]C(=O)[NH:17][CH:16]3[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:34])([F:33])[CH:30]([F:32])[F:31])[CH:23]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[CH2:35][CH3:36].[OH-].[Na+]>C(O)C>[NH2:17][CH:16]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:34])([F:33])[CH:30]([F:32])[F:31])[CH:23]=1)[CH:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:35][CH3:36])[CH:4]=2)=[CH:10][CH:11]=1)[OH:19]
Reactant: CCc1cc(Oc2ccc(C3OC(=O)NC3Cc3cccc(OC(F)(F)C(F)F)c3)cc2)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc(Oc2ccc(C(O)C(N)Cc3cccc(OC(F)(F)C(F)F)c3)cc2)ccc1Cl
Yield: 89 %

Procedure:
To a solution of (4RS,5SR)-5-(4-((4-chloro-3-ethylphenyl)oxy)phenyl)-4-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)-1,3-oxazolidin-2-one (4.3 g, 8.21 mmol) in ethanol (20 ml) was added 8N aqueous sodium hydroxide solution (5.13 ml, 41.1 mmol), and the mixture was heated under reflux for 4 hrs. The reaction solution was concentrated, diluted with water (100 ml), and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give (1RS,2SR)-2-amino-1-(4-((4-chloro-3-ethylphenyl)oxy)phenyl)-3-(3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)-1-propanol (3.64 g, 89%) as a colorless oil.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH:10]([CH2:15][F:16])[CH2:9]1)C1C=CC=CC=1>[Pd].CO>[F:16][CH2:15][CH:10]1[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[CH3:14]
Reactant: CN1CCN(Cc2ccccc2)CC1CF
Agent: [Pd]
Solvent: CO
Product: CN1CCNCC1CF
Reaction time: 15 h
Yield: 89.7 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 111c (3 g, 13.5 mmol) and MeOH (80 mL), and the resulting mixture was added Pd/C (10%) (300 mg). The reaction mixture was stirred under hydrogen gas (H2) for 15 h. After the reaction was finished, it was filtered and concentrated to afford 111d as a yellow oil (1.6 g, yield 90%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12](=[O:20])[CH2:13][CH2:14][C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)[CH2:6][CH2:5]2.[CH3:21][C:22]([CH3:27])([CH3:26])[C:23](Cl)=[O:24]>FC(F)(F)C(O)=O>[CH3:21][C:22]([CH3:27])([CH3:26])[C:23]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12](=[O:20])[CH2:13][CH2:14][C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)[CH2:6][CH2:5]2)=[O:24]
Reactant: O=C(CCc1cccs1)N1CCc2cc(O)ccc2C1
Reactant: CC(C)(C)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)Oc1ccc2c(c1)CCN(C(=O)CCc1cccs1)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the product of Example 14 (2.83 g) in trifluoroacetic acid (30 mL) at 0° C. was added dropwise trimethylacetyl chloride (1.4 mL) and the reaction allowed to warm to room temperature. After 4 hours, the reaction was quenched with water and concentrated, the residue was dissolved in CH2Cl2, washed with brine, dried (MgSO4), filtered and concentrated. Chromatography of the residue on silica gel (elution with 50% ethyl acetate/hexanes) provided 3.8 g of desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[C:19](=[O:20])[CH:14]2[CH2:15][O:16][CH2:17][CH2:18][N:13]2[C:12]1=[O:21].[Sn](Cl)Cl>C(O)C>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[C:19](=[O:20])[CH:14]3[CH2:15][O:16][CH2:17][CH2:18][N:13]3[C:12]2=[O:21])=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C1C2COCCN2C(=O)N1c1ccc([N+](=O)[O-])cc1Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccc(N2C(=O)C3COCCN3C2=O)c(Cl)c1
Temperature: 80 °C
Yield: 87.4 %

Procedure:
To a stirred solution of 2-(2-chloro-4-nitrophenyl)tetrahydro-1H-imidazo[5,1-c][1,4]oxazine-1,3(2H)-dione (0.106 g, 0.341 mmol) in ethanol (5 mL) was added tin (II) chloride (0.323 g, 1.70 mmol) and the reaction mixture was heated at 80° C. for 15 h. The reaction was cooled to room temperature, quenched with sat. NaHCO3, and the white precipitate was filtered. The filtrate was partitioned between ethyl acetate (20 mL) and brine (15 mL). The organic phase was separated, dried (MgSO4), filtered and concentrated to give the crude product. The residue was purified by column chromatography eluting with ethyl acetate/hexanes 0 to 70% to give 84 mg of 2-(4-amino-2-chlorophenyl)tetrahydro-1H-imidazo[5,1-c][1,4]oxazine-1,3(2H)-dione, 1.2.21, (88%).
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([OH:21])=O)[N:13]2[CH3:18])C1C=CC=CC=1.[C:22]1([CH2:28][CH2:29][CH2:30][CH2:31][NH2:32])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:19]([C:12]2[N:13]([CH3:18])[C:14]3[C:10]([CH:11]=2)=[C:9]([OH:8])[CH:17]=[CH:16][CH:15]=3)=[O:21])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cn1c(C(=O)O)cc2c(OCc3ccccc3)cccc21
Reactant: NCCCCc1ccccc1
Product: Cn1c(C(=O)NCCCCc2ccccc2)cc2c(O)cccc21

Procedure:
From 4-benzyloxy-1-methyl-1H-indole-2-carboxylic acid and 4-phenylbutylamine the title compound was prepared by a method analogous to that described in Example 11. MS ES (M++H)=323.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:18][N:19]([CH3:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([O-])=[O:25])=[CH:22][CH:21]=1>>[CH3:18][N:19]([CH3:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([NH:1][C:24](=[O:25])[C:23]5[CH:27]=[CH:28][C:20]([N:19]([CH3:29])[CH3:18])=[CH:21][CH:22]=5)=[CH:3][CH:4]=4)[NH:8][CH:7]=3)=[CH:12][CH:13]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: Nc1ccc(-c2c[nH]c3cc(N)ccc23)cc1
Reactant: CN(C)c1ccc(C(=O)[O-])cc1
Product: CN(C)c1ccc(C(=O)Nc2ccc(-c3c[nH]c4cc(NC(=O)c5ccc(N(C)C)cc5)ccc34)cc2)cc1

Procedure:
Compound 626 was prepared according to the procedure described in Scheme IV from 6-amino-3-(4-aminophenyl)-1H-indole and 4-dimethylaminobenzoate. [M+H]+ calcd for C32H31N5O2: 518.15; found: 518.09.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([SH:13])[S:11][CH:12]=2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].C(=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]1[CH:25]=[C:26]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:27][N:28]1[CH2:33][CH2:32][CH:31]([NH:34][C:35](=[O:38])[CH2:36]Cl)[CH2:30][CH2:29]1.C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([S:13][CH2:36][C:35]([NH:34][CH:31]3[CH2:30][CH2:29][N:28]([CH2:27][C:26]4[CH:39]=[CH:40][C:41]([Cl:42])=[C:24]([Cl:23])[CH:25]=4)[CH2:33][CH2:32]3)=[O:38])[S:11][CH:12]=2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1cc(-c2csc(S)n2)ccc1Cl
Reactant: O=C(CCl)NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CSc1nc(-c2ccc(Cl)c([N+](=O)[O-])c2)cs1)NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.5 %

Procedure:
4-(4-Chloro-3-nitrophenyl)-2-mercaptothiazole (0.5 g) was dissolved in dimethylformamide (20 mL), and potassium carbonate (0.7 g) was added to the solution. Then, N-[1-(3,4-dichlorobenzyl)piperidin-4-yl]chloroacetamide (0.6 g) was added, and the mixture was stirred at room temperature for 3 hrs. Ethyl acetate was added to the reaction mixture, washed with water and saturated brine, and dried. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to give the title compound (0.7 g) as a yellow solid.
Reaction SMILES: B(F)(F)F.CCOCC.[CH3:10][O:11][C:12](=[O:35])[C@H:13]1[O:22][C@@H:17](OC(=O)C)[C@H:16]([O:23][C:24](=[O:26])[CH3:25])[C@@H:15]([O:27][C:28](=[O:30])[CH3:29])[C@@H:14]1[O:31][C:32](=[O:34])[CH3:33].[Cl:36][C:37]([Cl:41])([Cl:40])[CH2:38][OH:39]>ClCCl>[CH3:10][O:11][C:12](=[O:35])[C@H:13]1[O:22][C@H:17]([O:39][CH2:38][C:37]([Cl:41])([Cl:40])[Cl:36])[C@H:16]([O:23][C:24](=[O:26])[CH3:25])[C@@H:15]([O:27][C:28](=[O:30])[CH3:29])[C@@H:14]1[O:31][C:32](=[O:34])[CH3:33]
Reactant: OCC(Cl)(Cl)Cl
Reactant: COC(=O)[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)[C@H]1O[C@H](OCC(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
BF3-Et2O (15 ml) was added dropwise to a cooled solution at 0° C. of 1,2,3,4-tetra-O-acetyl-β-D-glucopyranuronic acid methyl ester (11.23 g, 0.03 mol) and 2,2,2-trichloroethanol (20 ml) in anhydrous dichloromethane (250 ml) under inert atmosphere. The mixture was stirred at room temperature overnight and then washed with 1N HCl (100 ml), water (100 ml) and brine (100 ml). The organic phase was dried over sodium sulphate, filtered and concentrated to dryness. 1-O-trichloroethyl-2,3,4-tri-O-acetyl-α-D-glucopyranuronic acid methyl ester 1 (8.95 g) was obtained after recrystallization of the crude product from ether.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][C:8]2([CH3:18])[CH3:17])(=O)[CH3:2].C(C1C=C2C(CCC2(C)C)=C(C=C)C=1)(C)(C)C.C([N-]C(C)C)(C)C.[Li+].P(Cl)(OCC)(OCC)=O.P([O-])([O-])([O-])=O>>[C:13]([C:11]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH3:18])[CH3:17])=[C:4]([C:1]#[CH:2])[CH:12]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(=O)c1cc(C(C)(C)C)cc2c1CCC2(C)C
Agent: C=Cc1cc(C(C)(C)C)cc2c1CCC2(C)C
Agent: CC(C)[N-]C(C)C
Agent: CCOP(=O)(Cl)OCC
Product: C#Cc1cc(C(C)(C)C)cc2c1CCC2(C)C

Procedure:
With reference to Table A, 4-acetyl-6-tert-butyl-1,1-dimethylindane (1) is converted into the intermediate 6-tert-butyl-4-ethenyl-1,1-dimethylindane by treatment with lithium diisopropylamide (LDA) and is then treated with an alkyl chlorophosphate, such as diethyl chlorophosphate. The resulting mixed phosphate intermediate is subsequently again treated with LDA and thus results in the 6-tert-butyl-4-ethynyl-1,1-dimethylindane (2).