Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[Cl:7][C:8]1[CH:13]=[C:12]([S:14][CH2:15][CH:16]=[CH2:17])[CH:11]=[CH:10][C:9]=1[NH:18][C:19](=[O:27])[C@:20]([OH:26])([CH3:25])[C:21]([F:24])([F:23])[F:22].[OH2:28]>CO>[Cl:7][C:8]1[CH:13]=[C:12]([S:14]([CH2:15][CH:16]=[CH2:17])(=[O:1])=[O:28])[CH:11]=[CH:10][C:9]=1[NH:18][C:19](=[O:27])[C@:20]([OH:26])([CH3:25])[C:21]([F:24])([F:22])[F:23]
Reactant: O
Reactant: C=CCSc1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Product: C=CCS(=O)(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1
Reaction time: 1.5 h

Procedure:
A solution of Oxone (1.44 g) in water (15 ml) was added to a solution of (R)-N-{2-chloro-4-(2-propenylsulphanyl)phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 407) (0.389 g) in methanol (15 ml). The mixture was stirred for 1.5 hours. Water (50 ml) was added and the mixture extracted into ethyl acetate (100 ml) and dried. Volatile material was removed by evaporation and the residue purified on a silica gel Mega Bond Elut column eluting with 20-30% ethyl acetate/iso-hexane to give the title compound as a foam (0.180 g). NMR: 1.61 (s, 3H), 4.18 (d, 2H), 5.18-5.32 (m, 2H), 5.61-5.75 (m, 1H), 7.82-7.85 (m, 1H), 7.98 (s, 1H), 8.01 (s, 1H), 8.33 (d, 1H), 9.91 (s, 1H); MS (ESP−): 370.
Reaction SMILES: N.C1(S([N:11]2[C:19]3[CH:18]=[CH:17][N:16]=[C:15]([Cl:20])[C:14]=3[CH:13]=[C:12]2[CH2:21][N:22]2[CH2:26][CH2:25][C@H:24]([NH:27][S:28]([C:31]3[S:35][C:34]4[CH:36]=[C:37]([Cl:40])[CH:38]=[CH:39][C:33]=4[CH:32]=3)(=[O:30])=[O:29])[C:23]2=[O:41])(=O)=O)C=CC=CC=1>CO>[Cl:20][C:15]1[C:14]2[CH:13]=[C:12]([CH2:21][N:22]3[CH2:26][CH2:25][C@H:24]([NH:27][S:28]([C:31]4[S:35][C:34]5[CH:36]=[C:37]([Cl:40])[CH:38]=[CH:39][C:33]=5[CH:32]=4)(=[O:29])=[O:30])[C:23]3=[O:41])[NH:11][C:19]=2[CH:18]=[CH:17][N:16]=1
Reactant: O=C1[C@@H](NS(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1Cc1cc2c(Cl)nccc2n1S(=O)(=O)c1ccccc1
Agent: N
Solvent: CO
Product: O=C1[C@@H](NS(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1Cc1cc2c(Cl)nccc2[nH]1
Yield: 59.1 %

Procedure:
Ammonia gas is bubbled for 5 minutes into a solution of 6-chloro-benzo[b]thiophene-2-sulfonic acid[1-(1-benzenesulfonyl-4-chloro-1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide (0.14 g, 0.22 mmol) in MeOH (10 mL). The solution is refluxed overnight then concentrated to dryness. The crude product is purified by column chromatography eluting with 5% MeOH/CH2Cl2 to give the product (0.065 g, 0.13 mmol) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[CH2:18][C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O-:25])(=O)[CH3:23].[Na+].O.[C:28](OCC)(=O)C>C(OC(=O)C)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:22](=[O:25])[CH3:23])[N:13]=[C:12]2[CH2:18][C:19](=[O:21])[CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1n[nH]c2ccc(OCc3ccccc3)cc12
Reactant: CC(=O)[O-]
Reactant: CCOC(C)=O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Cc1nn(C(C)=O)c2ccc(OCc3ccccc3)cc12
Temperature: 130 °C
Reaction time: 3 h

Procedure:
A mixture of (5-benzyloxy-1H-indazol-3-yl)-acetic acid (2 g, 7.08 mmol) and sodium acetate (0.99 g, 12 mmol) in acetic anhydride (6 ml) was stirred at 130° C. for 3 h. After cooling, water (15 ml) and ethyl acetate (15 ml) were added to the reaction mixture. The aqueous layer was separated and extracted with ethyl acetate (2×15 ml). The combined extracts were washed with saturated aqueous NaHCO3 (2×20 ml) and saturated aqueous NaCl (20 ml), dried (MgSO4), and evaporated to a residue which was purified by chromatography (silica, 15% ethyl acetate in hexane) to give a yellow solid (0.48 g): 1H NMR (CD3OD) δ 8.35–8.30 (m, 1H), 7.48–7.23 (m, 6H), 7.04–7.02 (m, 2H), 5.11 (s, 2H), 4.02 (s, 2H), 2.77 (s, 3H), 2.27 (s, 3H); 13C NMR (CDCl3)δ 203.64 (C), 170.47 (C), 156.20 (C), 145.04 (C), 136.52 (C), 128.64 (CH), 128.31 (CH), 127.60 (CH), 120.51 (CH), 116.74 (CH), 102.26 (CH), 70.68 (CH2), 42.76 (CH2), 29.59 (CH3), 22.77 (CH3), MS(APCl) m/z 323 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[C:18]([CH3:26])[CH:17]=2)=[CH:10][CH:9]=1)(C)(C)C.[ClH:28].C(OCC)C>C(OCC)(=O)C.O1CCOCC1>[ClH:28].[CH3:26][C:18]1[CH:17]=[C:16]([CH2:15][O:14][C:11]2[CH:10]=[CH:9][C:8]([NH2:7])=[CH:13][CH:12]=2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1
Reactant: Cc1cc(COc2ccc(NC(=O)OC(C)(C)C)cc2)c2ccccc2n1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(COc2ccc(N)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of [4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-carbamic acid tert-butyl ester (1.5 g, 4.1 mmol) in ethyl acetate (5 mL) was added 4 N HCl in dioxane (20 mL) and the mixture was stirred at room temperature for 3 h. Ethyl ether was then added and the precipitate was filtered and washed with ethyl ether to provide 1.3 g of the desired free amine as an HCl salt, which was used in the following reaction without further purification. MS (ESI): 265.0 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=2)[C:10]([C:22](O)=[O:23])=[C:9]1[CH:25]([CH3:27])[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.[F:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[F:41])[CH2:36][NH2:37]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=2)[C:10]([C:22](=[O:23])[NH:37][CH2:36][C:35]2[CH:38]=[CH:39][C:40]([F:41])=[C:33]([F:32])[CH:34]=2)=[C:9]1[CH:25]([CH3:26])[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccc(F)c(F)c1
Reactant: CCOC(=O)c1ccc2c(C(=O)O)c(C(C)C)n(Cc3ccccc3)c2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCOC(=O)c1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
General Procedure E. To a solution of 1-benzyl-6-(ethoxylcarbonyl)-2-isopropyl-1H-indole-3-carboxylic acid (Compound 39, 1.00 g, 2.74 mmol) in CH2Cl2 (10 ml) was added EDC (1.04 g, 5.84 mmol) and DMAP (500 mg, 4.11 mmol), followed by 3,4-difluorobenzylamine (589 mg, 4.11 mmol). The reaction was stirred at room temperature for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→35% EtOAc-hexanes) to yield the title compound as a yellow solid.
Reaction SMILES: [S:1]1[C:5]2[S:6](=[O:12])(=[O:11])[CH2:7][CH2:8][C:9](=[O:10])[C:4]=2[CH:3]=[CH:2]1.C1([C@]2(CO)CCCN2C2C=CC=CC=2)C=CC=CC=1.B.CSC.B>C1COCC1>[S:1]1[C:5]2[S:6](=[O:12])(=[O:11])[CH2:7][CH2:8][C@@H:9]([OH:10])[C:4]=2[CH:3]=[CH:2]1
Reactant: O=C1CCS(=O)(=O)c2sccc21
Agent: B
Agent: OC[C@@]1(c2ccccc2)CCCN1c1ccccc1
Solvent: CSC
Solvent: C1CCOC1
Product: O=S1(=O)CC[C@@H](O)c2ccsc21
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To a magnetically stirred solution of 5,6-Dihydro-4H-thieno[2,3-b]-thiopyran-4-one-7,7-dioxide (12) (1.00 g, 4.94 mmol) in dry THF (14 mL) was added (S)-diphenylprolinol-borane complex from Example 12 (132 mg, 0.494 mmol). The solution was cooled to -15° C. and a solution of borane-dimethyl sulfide (10M, 0.4 mL, 4.0 mmol) in dry THF (6.8 mL) was added at a rate to maintain the internal temperature at -151° C. The solution was stirred at -15° C. for 1 hour then at 22° C. for 6 hours. The product was isolated by the method decribed in Example 34 Step E. The enantiomeric ratio of the purified product was 95:5.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6]Br)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:14]([C:17]1[CH:18](C2C=CC(C#N)=CC=2)[NH:19][C:20](=[S:34])[N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:22]=1[CH3:23])(=[O:16])[CH3:15].C[N:44]([CH:46]=O)C>>[C:14]([C:17]1[CH2:18][N:19]=[C:20]([SH:34]([C:24]2[CH:29]=[CH:28][C:27]([C:46]#[N:44])=[CH:26][CH:25]=2)[CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])[N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=2)[C:22]=1[CH3:23])(=[O:16])[CH3:15]
Reactant: CC(=O)OCCBr
Reactant: CN(C)C=O
Reactant: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=S)NC1c1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)OCC[SH](C1=NCC(C(C)=O)=C(C)N1c1cccc(C(F)(F)F)c1)c1ccc(C#N)cc1
Reaction time: 15 h

Procedure:
To a solution of 2-bromoethyl acetate (37.6 mg, 0.23 mmol) in 500 μl DMF are added potassium carbonate (82.9 mg, 0.6 mmol) and 4-{5-acetyl-6-methyl-2-thioxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-4-pyrimidinyl}benzonitrile (Example 1; 62.3 mg, 0.15 mmol). The reaction mixture is shaken for 15 hours, filtered and purified by preparative HPLC (column: Nucleosil 100-5 C 18 Nautilus 20 mm×50 mm, 5 μm; solvent A: acetonitrile, solvent B: water+0.1% formic acid; flow rate: 25 ml/min; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 min 10% A, 8 nm 10% A; wavelength: 220 um; injection volume: approx. 550 μl; number of injections: 1). The product containing fractions are combined and concentrated in vacuo.
Reaction SMILES: [F:1][C:2]1[C:10]([I:11])=[C:9]([CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([CH3:12])=[C:10]([I:11])[C:2]=1[F:1]
Reactant: CO
Reactant: Cc1ccc(C(=O)O)c(F)c1I
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C)c(I)c1F
Temperature: 90 °C

Procedure:
In a 500 ml one-neck flask equipped with a magnetic stir-bar and condenser was added 2-fluoro-3-Iodo-4-methyl-benzoic acid (31.5 g, 112.5 mmol), 250 ml of methanol and 10 ml of sulfuric acid. The reaction was heated at 90° C. overnight.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH:4]([CH2:9][C:10](=O)[CH3:11])[CH2:3]1.[NH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1>>[CH3:11][C:10]1[N:13]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)[C:5]2[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][C:4]=2[CH:9]=1
Reactant: CC(=O)CC1CC(C)CCC1=O
Reactant: Nc1ccc(C(=O)O)cc1
Product: Cc1cc2c(n1-c1ccc(C(=O)O)cc1)CCC(C)C2
Yield: 66 %

Procedure:
Following the general methods as outlined under Intermediate 7, starting from 4-methyl-2-(2-oxopropyl)cyclohexanone and 4-aminobenzoic acid, the title compound was isolated, in 66% yield (98% purity by HPLC). MS(ESI+): 270.5; MS(ESI−): 268.4.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[CH3:8][N:9]([C+:11]([N:13]([CH3:15])[CH3:14])Cl)[CH3:10].[CH3:16][N-:17][CH3:18].[Li+]>C(#N)C>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[CH3:8][N:9]([CH3:10])[C:11](=[N+:17]([CH3:18])[CH3:16])[N:13]([CH3:15])[CH3:14]
Reactant: CN(C)[C+](Cl)N(C)C
Reactant: C[N-]C
Agent: O=C([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Product: CN(C)C(N(C)C)=[N+](C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.6 %

Procedure:
1.85 g (7.44 mmol) of bis(dimethylamino)chlorocarbenium trifluoroacetate and 0.38 g (7.45 mmol) of lithium dimethylamide are dissolved in 15 ml of acetonitrile under a protective-gas atmosphere (argon). The reaction mixture is stirred for 5 hours at room temperature, and LiCl is subsequently filtered off. The salt LiCl is washed with 5 ml of acetonitrile, and the organic phases are combined. The solvent is distilled off, and the residue is dried under reduced pressure at 7 Pa and 50° C., giving 1.81 g of hexamethylguanidinium trifluoroacetate as a viscous oil, corresponding to a yield of 99.2%.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1CC[C:8]2=[O:13])([O-:3])=[O:2].[Se](=O)=[O:15].[O:17]1[CH2:22][CH2:21][O:20]CC1>C(O)(=O)C>[OH:15][C:21]1([OH:20])[C:22](=[O:17])[C:5]2[C:9](=[CH:10][CH:11]=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])[C:8]1=[O:13]
Reactant: O=C1CCc2c1cccc2[N+](=O)[O-]
Reactant: O=[Se]=O
Reactant: C1COCCO1
Solvent: CC(=O)O
Product: O=C1c2cccc([N+](=O)[O-])c2C(=O)C1(O)O
Yield: 100 %

Procedure:
A solution of 4-nitro-2,3-dihydro-1H-inden-1-one (4.00 g, 20.9 mmol) in 1,4-dioxane (40 ml) and glacial acetic acid (4 ml) was added with selenium dioxide (5.10 g, 46.03 mmol), and refluxed for 3 hrs. After filtration at high temperature, the filtrate was concentrated to afford 2,2-dihydroxy-4-nitro-2H-inden-1,3-dione (4.67 g, 100%). To a solution of 2,2-dihydoxy-4-nitro-2H-inden-1,3-dione (4.67 g, 20.9 mmol) in TFA (10 ml) was added isopropyl anisole (3.14 g, 20.9 mmol), followed by stirring at 60° C. for 6 hrs. The reaction mixture was concentrated in a vacuum, and extracted with aq. sodium bicarbonate and ethylacetate. The concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:4) to afford the title compound (1.19 mg, 16%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].C(OC1C=CC(/C=C2/C(=O)N(CCC)C(=O)S/2)=CC=1)C>>[CH2:18]([N:11]1[C:10](=[O:15])/[C:9](=[CH:8]/[C:7]2[CH:16]=[CH:17][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)/[S:13][C:12]1=[O:14])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOc1ccc(/C=C2\SC(=O)NC2=O)cc1
Reactant: BrCc1ccccc1
Agent: CCCN1C(=O)S/C(=C\c2ccc(OCC)cc2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1ccc(/C=C2\SC(=O)N(Cc3ccccc3)C2=O)cc1

Procedure:
The title compound 28i was prepared from compound 2 (75 mg, 0.30 mmol), benzyl bromide (39 μL, 0.33 mmol) and potassium carbonate (83 mg, 0.60 mmol) in a manner similar to that described for 28d in 99.6% (101 mg) yield as a white solid.
Reaction SMILES: [F:1][S:2]([O:5][CH3:6])(=[O:4])=[O:3].[C:7]([C@@H:10]1[CH2:14][C@H:13]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH2:12][N:11]1[CH2:25][CH2:26][F:27])(=[O:9])[NH2:8]>C(Cl)Cl>[F:1][S:2]([O-:5])(=[O:4])=[O:3].[C:7]([C@@H:10]1[CH2:14][C@H:13]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH2:12][N+:11]1([CH2:25][CH2:26][F:27])[CH3:6])(=[O:9])[NH2:8]
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(N)=O)N(CCF)C2)cc1
Reactant: COS(=O)(=O)F
Solvent: ClCCl
Product: COc1ccc(CS[C@H]2C[C@@H](C(N)=O)[N+](C)(CCF)C2)cc1
Product: O=S(=O)([O-])F
Reaction time: 0.5 h

Procedure:
0.17 ml of methyl fluorosulfonate was added, whilst ice-cooling, to a solution of 630 mg of (2S, 4S)-2-carbamoyl-4-(4-methoxybenzylthio)-1-(2-fluoroethyl)-pyrrolidine [prepared as described in step (1) above] dissolved in 12 ml of dry methylene chloride. The mixture was stirred at the same temperature for 30 minutes and then at room temperature for 5 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was washed repeatedly by decantation with diethyl ether and dried under reduced pressure to afford 850 mg of the title compound as an oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O[CH2:25][C:26]2([OH:43])[C:30](=[O:31])[O:29][C@H:28]3[C:32]4[C@@:37]([CH3:40])([CH2:38][CH2:39][C:27]23[OH:42])[CH2:36][CH2:35][CH2:34][C:33]=4[CH3:41])(=O)=O)=CC=1>C(O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:25][C:26]2([OH:43])[C:30](=[O:31])[O:29][C@H:28]3[C:32]4[C@@:37]([CH3:40])([CH2:38][CH2:39][C:27]23[OH:42])[CH2:36][CH2:35][CH2:34][C:33]=4[CH3:41])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CC1=C2[C@@H]3OC(=O)C(O)(COS(=O)(=O)c4ccc(C)cc4)C3(O)CC[C@@]2(C)CCC1
Solvent: CCO
Product: CC1=C2[C@@H]3OC(=O)C(O)(CN4CCN(Cc5ccccc5)CC4)C3(O)CC[C@@]2(C)CCC1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
Benzyl piperazine (190 mg, 1.078 mmol) was added to the solution of compound of example 5 (470 mg, 1.078 mmol) in ethanol (15 mL), and stirred at 50° C. under nitrogen atmosphere for 6 hours. The reaction mixture was concentrated, and dissolved in water (25 mL) and was extracted using ethyl acetate (3×50 mL). Ethyl acetate layer was washed with water and brine, dried over sodium sulfate. Solvent was removed and crude product was purified by column chromatography (silica gel, using 12.5% ethyl acetate in petroleum ether). Semi-pure product was crystallized using ethyl acetate/petroleum ether to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:18]=[C:17]([Cl:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH3:20][NH2:21]>C(O)C>[ClH:19].[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:18]=[C:17]([NH:21][CH3:20])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: Cc1ccccc1Nc1nc(Cl)c2ccccc2n1
Reactant: CN
Solvent: CCO
Product: CNc1nc(Nc2ccccc2C)nc2ccccc12
Product: Cl
Yield: 8.9 %

Procedure:
2-(2-methylphenylamino)-4-chloroquinazoline (2 g, 0.0065 mol) and methylamine in ethanol (33%, 30 ml) were placed in a pressure vessel and heated for 4 hours at 140°. After cooling, the reaction mixture was evaporated to dryness. The residue afforded crystals of 2-(2-methylphenylamino)-4-methylaminoquinazoline hydrochloride (0.29 g, 8.9%) from ethanolic hydrogen chloride, m.p. 275°-279°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C([O-])([O-])=O.[K+].[K+].O>CC#N>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:8])[CH:7]=1)[O:9][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Cc1cc(C)cc(O)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)COc1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Referring to FIG. 37, to a solution of 3,5-dimethylphenol (10 g, 82 mmol) in CH3CN (150 mL) were added ethyl 2-bromoacetate (14.9 g, 90 mmol) and K2CO3 (16.9 g, 123 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was poured into water (200 mL) and the resulting mixture was extracted with ethyl acetate (150 mL×2). The combined extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give product as a yellow oil, which was used in the next step without further purification (19 g); 1H NMR (CDCl3, 300 MHz): δ 6.13 (s, 1H), 6.11 (s, 2H), 4.59 (s, 2H), 4.30 (q, J=7.2 Hz, 2H), 3.77 (s, 6H), 1.31 (1, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([CH3:11])[C:3]=1[O:12][CH3:13].[CH3:14]N(C(OC)OC)C.N1CCCC1>CN(C=O)C>[CH3:13][O:12][C:3]1[C:4]([CH3:11])=[CH:5][CH:6]=[C:7]2[C:2]=1[CH:1]=[CH:14][NH:8]2
Reactant: COc1c(C)ccc([N+](=O)[O-])c1C
Reactant: COC(OC)N(C)C
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: COc1c(C)ccc2[nH]ccc12
Temperature: 125 °C
Reaction time: 3 h
Yield: 16.5 %

Procedure:
To a stirred solution of 2,6-dimethyl-3-nitroanisole (3.26 g, 18 mmol) in dry DMF (36 ml) were added DMF dimethyl acetal (2.51 g, 19.8 mmol, 2.8 ml) and pyrrolidine (1.8 ml). The reaction mixture was stirred under N2 at 125° C. for 3 h, cooled to rt and concentrated in vacuo. The oily residue was dissolved in a mixture of toluene-acetic acid (5:3, 36 ml) and added to a stirred mixture of iron powder (18 g) and silica gel (70-230 mesh, 45 g) in a mixture of toluene-acetic acid (5:3, 234 ml). The mixture was then heated at reflux under N2 for 1 h, cooled to rt, diluted with CH2Cl2 and filtered. The filter cake was washed thoroughly with CH2Cl2 and the combined filtrates were washed successively with Na2S2O5 solution, saturated aq. NaHCO3 and brine, dried and evaporated. The residue was flash chromatographed [(CH2Cl2-hexanes (3:2)] to give 27 as a colourless viscous oil (0.48 g, 16%) which was used without further purification; δH (90 MHz) 8.10 (1 H, br s, NH), 6.88-7.08 (3 H, m, 2-, 6-, and 7-H), 6.50-6.64 (1 H, m, 3-H), 3.98 (3 H, s, OMe) and 2.32 (3 H, s, Me).
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1B(O)O.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.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>[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2cccs2)C1
Yield: 79.8 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of 2-thiopheneboronic acid (117 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (160 mg, 79.6%) as an oil.
Reaction SMILES: [Br:1][C:2]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=[C:7]([Br:16])[C:3]=1[C:4]([OH:6])=[O:5].[C:17]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[C:10]([O:11][CH3:17])=[C:9]([C:12]([CH3:13])([CH3:15])[CH3:14])[CH:8]=[C:7]([Br:16])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1cc(Br)c(C(=O)O)c(Br)c1O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(C(C)(C)C)cc(Br)c(C(=O)O)c1Br
Temperature: 60 °C
Yield: 34.8 %

Procedure:
step 4—To a solution of 122 (1.0 eq, 2.18 mmol, 767 mg) in acetone (15 mL) was added K2CO3 (3.0 eq, 6.54 mmol, 903 mg) and MeI (5.0 eq, 10.89 mmol, 680 μL). The mixture was heated at 60° C. for 2 h before it was cooled to RT and the organic volatiles were removed under reduced pressure. The residue was partitioned between in EtOAc and water. The organic layer was separated, washed with brine, dried and concentrated. The crude was purified by SiO2 chromatography eluting with a EtOAc/hexane gradient (5 to 30% EtOAc) to afford 278 mg of 2,6-dibromo-4-tert-butyl-3-methoxybenzoic acid (124).
Reaction SMILES: C([O:4][C:5]1[C:13]2[S:12][C:11]([CH3:14])=[CH:10][C:9]=2[CH:8]=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C.ClCCl>[OH:4][C:5]1[C:13]2[S:12][C:11]([CH3:14])=[CH:10][C:9]=2[CH:8]=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=1
Reactant: CCOC(=O)c1cc(OC(C)=O)c2sc(C)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1cc(O)c2sc(C)cc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
Ethyl 7-(acetyloxy)-2-methyl-1-benzothiophene-5-carboxylate was dissolved in absolute ethanol (500 mL). Potassium carbonate (18 g, 0.13 mol) was added. The reaction mixture was stirred for 3 h at 60° C. and diluted with 200 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 100 mL of dichloromethane. The combined solutions were washed by 200 mL of a 10% aqueous solution of citric acid and evaporated in vacuum to dryness. The residue was crystallized from ether/hexane mixture (1:5) to give the desired product 10 g (42 mmol, 84%) as a cream solid. 1H NMR (DMSO-d6): δ ppm 1.30 (t, 3H), 2.50 (s, 3H), 4.30 (qt, 2H), 7.20 (s, 1H), 7.95(s, 1H), 7.85 (s, 1H); MS(APCl, pos): 237.1.