Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1(=[O:12])(=[O:11])[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[C:13]([C:15](=[CH:21]OCC)[C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14].C(OCC)(=O)C>C(O)C>[C:13]([C:15](=[CH:21][NH:10][C:8]1[CH:7]=[CH:6][C:5]2[S:1](=[O:11])(=[O:12])[CH2:2][CH2:3][C:4]=2[CH:9]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: Nc1ccc2c(c1)CCS2(=O)=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C#N)=CNc1ccc2c(c1)CCS2(=O)=O
Yield: 82.1 %

Procedure:
5 g (27.3 mmol) of 2,3-dihydro-1-benzothiophen-5-amine 1,1-dioxide were suspended in 50 ml of ethanol under argon, 4.62 g (1 eq, 27.3 mmol) of ethyl 2-cyano-3-ethoxyacrylate were added, and the mixture was heated under reflux overnight. For working up, ethyl acetate was added to the mixture, and the precipitate which formed was filtered off with suction on a frit. The solid was dried in vacuo at 50° C. for 1.5 h. 6.87 g (81%) of the target compound were isolated and were employed without further purification in the next stage.
Reaction SMILES: [N:1]1([C@H:7]2[CH2:10][C@H:9]([C:11]3[S:12][C:13]4[CH:19]=[C:18]([C:20]5[CH:21]=[N:22][NH:23][CH:24]=5)[CH:17]=[CH:16][C:14]=4[N:15]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].I[CH3:28]>CN(C=O)C>[CH3:28][N:23]1[CH:24]=[C:20]([C:18]2[CH:17]=[CH:16][C:14]3[N:15]=[C:11]([C@H:9]4[CH2:8][C@H:7]([N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[CH2:10]4)[S:12][C:13]=3[CH:19]=2)[CH:21]=[N:22]1
Reactant: CI
Reactant: c1cc2nc([C@H]3C[C@H](N4CCCCC4)C3)sc2cc1-c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccc3nc([C@H]4C[C@H](N5CCCCC5)C4)sc3c2)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The product of Example 51B (34.0 mg, 0.10 mmole) was dissolved in DMF (2 ml) and then cooled to 0° C. NaH (60%, 44.0 mg, 1.1 mmol) was added under N2, and the reaction was stirred at 0° C. for 0.5 hours. Iodomethane (6.8 μl, 0.11 mmole) was added, and the reaction mixture was stirred at 0° C. for 1 hour, and then slowly raised to room temperature. The mixture was quenched with saturated aqueous sodium bicarbonate and extracted with dichloromethane (4×5 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give the crude product which was purified by column chromatography (10% methanol in dichloromethane) to give 23.8 mg (67.6%) of title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.94 (d, J=8.48 1H) 7.93 (d, J=2.03 1H) 7.80 (s, 1H) 7.66, (s, 1H) 7.56 (dd, J=8.48, 2.03 1H) 3.80 (s, 3H) 3.87 (m, 1H) 3.27 (m, 1H) 2.38-2.62 (m, 4H) 1.49-1.76 (m, 6H). MS: (M+H)+=353.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH:5]([C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18](Br)[N:17]=1)S(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].[CH3:33][O:34][C:35]([C:37]1[CH:38]=[N:39][CH:40]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:42]=1)=[O:36].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:33][O:34][C:35]([C:37]1[CH:42]=[C:41]([C:18]2[CH:19]=[CH:20][C:21]([N+:22]([O-:24])=[O:23])=[C:16]([CH:5]=[CH:4][C:3]([O:2][CH3:1])=[O:26])[N:17]=2)[CH:40]=[N:39][CH:38]=1)=[O:36]
Reactant: COC(=O)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COC(=O)CC(c1nc(Br)ccc1[N+](=O)[O-])S(=O)(=O)c1ccc(C)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C=Cc1nc(-c2cncc(C(=O)OC)c2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 99.9 %

Procedure:
3-(6-Bromo-3-nitro-pyridin-2-yl)-3-(toluene-4-sulfonyl)-propionic acid methyl ester (1.2 g, 2.7 mmol), Pd(PPh3)2Cl2 (190 mg, 0.27 mmol), Na2CO3 (572 mg, 5.4 mmol) and 3-(methoxycarbonyl)pyridine-5-boronic acid pinacol ester (926 mg, 3.5 mmol) were dissolved in 1,4-dioxane (4.0 mL) and the resulting reaction mixture was heated at 120° C. for 3 hours before it was poured into H2O (50 mL). After extraction with EtOAc, the organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give 6-(2-methoxycarbonyl-vinyl)-5-nitro-[2,3′]bipyridinyl-5′-carboxylic acid methyl ester (926 mg, quant.) as a light yellow solid. MS: 344.1 (M+H+).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O=C(C1C=CC=CN=1)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[C:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:13]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CCOC(=O)CC(=O)c1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Product: CCOC(=O)CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
N-Boc-4-(2-Ethoxycarbonyl-acetyl)-piperidine was prepared from N-Boc-piperidine-4-carboxylic acid in the same manner as ethyl 3-oxo-3-pyridin-2-yl-propionate (Example 94).
Reaction SMILES: C[Si](C)(C)[O:3][C@@H:4]1[C@@H:9]([O:10][Si](C)(C)C)[C@H:8]([O:15][Si](C)(C)C)[C@@H:7]([CH2:20][O:21][Si](C)(C)C)[O:6][C:5]1=[O:26]>CCCCCCC>[CH2:20]([OH:21])[C@H:7]1[O:6][C:5](=[O:26])[C@H:4]([OH:3])[C@@H:9]([OH:10])[C@@H:8]1[OH:15]
Reactant: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Solvent: CCCCCCC
Product: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 0.17 h

Procedure:
A 100 mL flask was charged with (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one (6.54 g) and n-heptane (10.2 mL), and stirred for 10 min under argon sparging. The mixture was cooled to −20° C. to −30° C. under nitrogen atmosphere. The solution was added to a suitable cooled addition funnel and was kept ready for addition to the aryl magnesium.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:11])[CH2:9][CH3:10].[Br:12]Br>C(O)(=O)C>[Br:12][CH:9]([CH3:10])[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:11]
Reactant: BrBr
Reactant: CCC(=O)c1ccccc1F
Solvent: CC(=O)O
Product: CC(Br)C(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of 2′-fluoropropiophenone (25.0 g) in acetic acid (250 mL) was slowly added bromine (8.4 mL). The mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. Water (200 mL) was added to the residue, and the mixture was extracted with diisopropyl ether. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as a yellow oil (yield 36.8 g, 97%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][O:24][CH3:25]>C(#N)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][N:11]([CH2:22][CH2:23][O:24][CH3:25])[CH2:10]1
Reactant: OC1(c2cccc(F)c2F)CCNC1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCN1CCC(O)(c2cccc(F)c2F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Preparation according to Example 43: Enantiomer E2 of 3-(2,3-difluorophenyl)-pyrrolidin-3-ol (0.5 g, 2.5 mmol), acetonitrile (20 mL), potassium carbonate (0.69 g, 5 mmol), 1-bromo-2-methoxyethane (0.255 mL, 2.7 mmol). Stirred 1 h at ambient temperature. Addition of 1-bromo-2-methoxyethane (0.05 mL, 0.53 mmol), stirred at 40° C. for 2 min. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 4:1). Yield: 0.32 g. [α]D=−20.8° (methanol). The amine was converted to the oxalic acid salt and recrystallized from methanol/diisopropyl ether: M.p. 146.7° C.; MS m/z (relative intensity, 70 eV) 257 (M+, 2), 212 (bp), 182 (56), 141 (9), 127 (12).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[C:11]1[O:15][N:14]=[C:13]([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([C:28]([F:31])([F:30])[F:29])[C:22]([C:26]#[N:27])=[CH:23][CH:24]=3)[CH:19]=[C:18]2[CH2:32][CH2:33][CH3:34])[N:12]=1.[NH3:35]>CO>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:35])=[O:7])=[CH:4][C:3]=1[C:11]1[O:15][N:14]=[C:13]([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([C:28]([F:29])([F:30])[F:31])[C:22]([C:26]#[N:27])=[CH:23][CH:24]=3)[CH:19]=[C:18]2[CH2:32][CH2:33][CH3:34])[N:12]=1
Reactant: N
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(=O)Cl)ccc2Cl)n1
Solvent: CO
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(N)=O)ccc2Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
A round bottom flask was mixed with 4-chloro-3-(3-{[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]methyl}-1,2,4-oxadiazol-5-yl)benzoyl chloride (0.037 g, 0.07 mmol) and 2.0 M NH3 in MeOH (5.0 mL). The mixture was stirred at rt for 2 h and concentrated to dryness. The resulting solid was crystallized with Et2O, filtered in vacuo and dried under high vacuum to afford a pure solid (0.021 g, 58% yield): MS (ES) m/z 487(M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[NH:25][C:24](=[O:26])[C:23]([CH3:28])([CH3:27])[N:22]=3)[C:9]=2[CH2:29][CH3:30])=[CH:4][CH:3]=1.[CH3:31]I>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[N:25]([CH3:31])[C:24](=[O:26])[C:23]([CH3:27])([CH3:28])[N:22]=3)[C:9]=2[CH2:29][CH3:30])=[CH:4][CH:3]=1
Reactant: CI
Reactant: CCc1c(C2=NC(C)(C)C(=O)N2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Product: CCc1c(C2=NC(C)(C)C(=O)N2C)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
Compound 28 was synthesized from compound 24 (101 mg, 0.22 mmol) and methyl iodide (2 g, 14.08 mmol) as a white solid (70 mg, 68%) in a manner similar to that described in Example 57. 1H NMR (400 MHz, CDCl3) δ 7.42 (br s, 1H), 7.29 (d, 2H), 7.24 (d, 1H), 7.19 (d, 1H), 7.07 (d, 2H), 3.21 (s, 3H), 2.62 (q, 2H), 1.85 (s, 6H), 1.11 (t, 3H); ESMS m/z: 475.1 (M+1).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([S:18]([O-:21])(=O)=[O:19])[C:10]2[C:15]([C:16]=1[Br:17])=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:3])[CH3:2].[K+].CN(C)C=O.S(Cl)([Cl:30])=O>>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([S:18]([Cl:30])(=[O:21])=[O:19])[C:10]2[C:15]([C:16]=1[Br:17])=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1cc(S(=O)(=O)[O-])c2ccccc2c1Br
Reactant: O=S(Cl)Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCc1cc(S(=O)(=O)Cl)c2ccccc2c1Br
Reaction time: 0.17 h

Procedure:
Potassium 3-(2-acetoxy-ethyl)-4-bromo-naphthalene-1-sulfonate (17.75 g, 43.2 mmol) was added at room temperature to a stirred solution of N,N-dimethylformamide (0.334 mL, 4.31 mmol) in thionyl chloride (63 mL, 863 mmol). The resulting mixture was placed in an oil bath at 70° C. and stirred. After 10 minutes, additional thionyl chloride (20 mL) was added to facilitate stirring. After 40 minutes at 70°, the reaction flask was fitted with a distillation head and excess thionyl chloride was removed under vacuum. The residual brown solid was mixed with diethyl ether (300 mL) and added to an ice-cold, stirred mixture of water (100 mL) and ether (100 mL). The organic phase was separated, washed with water (200 mL) and brine (100 mL), dried over magnesium sulfate, filtered, and evaporated under vacuum to afford the title compound (14.63 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:18]([O:20][NH:21][C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)=S)[CH3:19].I([O-])(=O)(=O)=O.[Na+]>CN(C=O)C.O.O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:22](=[N:21][O:20][CH2:18][CH3:19])[NH:24][C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: CCONC(=S)Nc1ccc(F)cc1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CCON=C(Nc1ccc(F)cc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
7-Chloro-4-(piperazin-1-yl)quinoline (124 mg, 0.5 mmol), N-ethoxy-N′-(4-fluorophenyl)thiourea (105 mg, 0.49 mmol), and sodium periodate (118 mg, 0.55 mmol) in DMF-water 1:1 (20 mL) are heated at 85° C. for 1 h. The reaction mixture is diluted with water and extracted with ether. The organic phase is dried (MgSO4) and concentrated. The residue is purified by column chromatography with hexane-EtOAc yielding the title product as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]=[CH:14][CH:15]=[C:16]([SH:17])[C:9]2=[N:8][CH:7]=1)=[O:5])[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+]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]=[CH:14][CH:15]=[C:16]([S:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(S)cccn2c1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc2c(SCc3ccccc3)cccn2c1=O
Yield: 95.3 %

Procedure:
To a suspension of 0.3 g of 3-ethoxycarbonyl-9-mercapto-4H-pyrido[1,2-a]pyrimidin-4-one II-1 in 4 ml of anhydrous DMF are added 0.3 g of benzyl bromide VI-1 and 0.5 g of K2CO3, and the resultant mixture is stirred at room temperature for 5 hours. The reaction mixture is diluted with water. The crystal precipitated is filtered and dissolved in CHCl3. The chloroform solution is dried over Na2SO4 and evaporated to give 0.389 g of the titled compound Ic-21.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1>ClCCl>[Br:1][C:8]1[CH:9]=[C:4]([F:3])[CH:5]=[CH:6][C:7]=1[OH:10]
Reactant: Oc1ccc(F)cc1
Reactant: BrBr
Solvent: ClCCl
Product: Oc1ccc(F)cc1Br
Reaction time: 24 h

Procedure:
At -20° C., 15.3 ml of bromine is dripped into 33.6 g of 4-fluorophenol in 300 ml of dichloromethane. After the solution has stood for 24 hours it is colorless. Distillation gives 46 g of 2-bromo-4-fluorophenol of boiling point 70° C./13.3 mbars.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[C:21]2[C:7]([CH2:8][C@@H:9]3[C:17]4[CH:16]=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][C:12]=4[NH:11][C@@H:10]32)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:23](OC(=O)C)(=[O:25])[CH3:24]>O>[C:23]([N:11]1[C:12]2[CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:16][C:17]=2[C@H:9]2[CH2:8][C:7]3[C:21]([C@@H:10]12)=[CH:22][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1ccc2c(c1)N[C@@H]1c3cc([N+](=O)[O-])ccc3C[C@H]21
Solvent: O
Product: CC(=O)N1c2cc([N+](=O)[O-])ccc2[C@H]2Cc3ccc([N+](=O)[O-])cc3[C@H]21
Reaction time: 0.5 h

Procedure:
cis-4b,5,9b,10-Tetrahydro-3,7-dinitroindeno[1,2-b]indole (0.40 g, 1.35 mM) and acetic anhydride (1.5 cm3 ) were heated at 90° C. for 1 hour, cooled and poured into water (7 cm3) ice and the mixture was stirred for 30 minutes. The colourless solid which deposited was collected and taken up into hot ethanol. The after hot filtration, the title compound separated from the cold filtrate as prisms. Yield: 0.42 g, 92% M.p. 264°-266° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][CH3:13])[CH2:9][C:8](=[O:14])[NH:7][C:6]=2[CH:15]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[C:22]([Cl:38])=[CH:21][N:20]=1>CO.C(Cl)Cl>[Cl:38][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[N:24][C:19]([NH:1][C:2]2[C:3]([O:16][CH3:17])=[CH:4][C:5]3[CH2:11][N:10]([CH2:12][CH3:13])[CH2:9][C:8](=[O:14])[NH:7][C:6]=3[CH:15]=2)=[N:20][CH:21]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CC(=O)Nc2cc(N)c(OC)cc2C1
Solvent: ClCCl
Solvent: CO
Product: CCN1CC(=O)Nc2cc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)C(C)C)n3)c(OC)cc2C1
Yield: 14.1 %

Procedure:
In an analogous manner to procedure 1656g, 8-amino-4-ethyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (60 mg, 0.26 mmol) and (2,5-dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine (88 mg, 0.26 mmol) were coupled to provide 8-{5-chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-4-ethyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (20 mg, 14%) as a mustard yellow solid following preparative tlc (10% MeOH-DCM); NMR (400 MHz, CDCl3) δ 9.56 (s, 1H), 8.49 (d, J=8 Hz, 1H), 8.20 (s, 1H), 8.08 (s, 1H), 7.97 (d, J=8 Hz, 1H), 7.68 (m, 2H), 7.39 (m, 1H), 7.16 (s, 1H), 6.82 (s, 1H), 3.94 (s, 3H), 3.75 (s, 2H), 3.42 (s, 2H), 3.24 (t, J=7 Hz, 1H), 2.76 (t, J=7 Hz, 2H), 1.33 (d, J=7 Hz, 6H), 1.20 (t, J=7 Hz, 3H); MS (m/e) 546 (M+1); mp 175° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[NH:9][C:10]([S:12][CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[CH:17]=[CH:16][N:15]=3)=[N:11][C:6]2=[CH:5][C:4]=1[CH3:23].ClC1C=CC=C(C(OO)=[O:32])C=1.C(=O)(O)[O-].[Na+]>CO.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[NH:9][C:10]([S:12]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[CH:17]=[CH:16][N:15]=3)=[O:32])=[N:11][C:6]2=[CH:5][C:4]=1[CH3:23]
Reactant: COc1ccnc(CSc2nc3cc(C)c(OC)nc3[nH]2)c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccnc(CS(=O)c2nc3cc(C)c(OC)nc3[nH]2)c1C
Temperature: -30 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
5-Methoxy-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)thio)-6-methyl-3H-imidazo[4,5-b]pyridine (784 mg, 2.37 mmol) was dissolved in a mixture of methanol (6 ml) and toluene (54 ml). Metachloroperbenzoic acid (566 mg) in a mixture solution of methanol (3 ml) and toluene (3 ml) were added thereto at −40° C. under nitrogen flow, and the reaction mixture was stirred at −20 to −40° C. for 2 hours. After the reaction was completed, a sodium bicarbonate solution was added, and the organic layer was separated. The aqueous layer was extracted with chloroform (40 ml), combined with the organic layer and dried over sodium sulfate, the solvent was evaporated and the residue was obtained which was then precipitated as a solid from a mixture of chloroform and ether, thereby yielding the title compound (654 mg, 1.89 mmol, 80%) as a purple gray solid.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[CH2:12](O)[C:13]([Cl:16])([Cl:15])[Cl:14].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:14][C:13]([Cl:16])([Cl:15])[CH2:12][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=1[CH2:2][Br:1]
Reactant: OCC(Cl)(Cl)Cl
Reactant: O=C(O)c1ccccc1CBr
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=C(OCC(Cl)(Cl)Cl)c1ccccc1CBr
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.7 %

Procedure:
To a suspension of 2-(bromomethyl)benzoic acid (1.0 g, 4.65 mmol), β-trichloroethanol (0.54 mL, 5.58 mmol) and DMAP (0.057 g, 0.465 mmol) in DCM (20 mL) was added EDCxHCl (1.34 g, 6.98 mmol) at 0° C. The solution was stirred at 0° C. for 0.5 h and thereafter allowed to reach rt and stirred overnight. Water was added and the phases were separated through a phase separator. The organic portion was concentrated and the crude was submitted to flash chromatography using heptane and EtOAc (90/10) as eluent to yield the titled compound (0.80 g, 50%) as an oil; 1H NMR (400 MHz, CDCl3): δ 4.99 (s, 2H), 5.08 (s, 2H), 7.46 (m, 1H), 7.60 (m, 2H), 8.13 (d, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([NH:22][C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=3)[CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[C:11]([CH3:33])[CH:10]=2)=[N:7][CH:8]=1)[CH3:2].[OH-].[Na+].C1COCC1.Cl>CO>[CH2:1]([C:3]1[CH:8]=[N:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=3)[CH2:16][CH2:17][C:18]([F:20])([F:21])[F:19])=[C:11]([CH3:33])[CH:10]=2)=[N:5][CH:4]=1)[CH3:2]
Reactant: CCc1cnc(-c2ccc(C(CCC(F)(F)F)Nc3ccc(C(=O)OC)cc3)c(C)c2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cnc(-c2ccc(C(CCC(F)(F)F)Nc3ccc(C(=O)O)cc3)c(C)c2)nc1
Temperature: 70 °C
Reaction time: 7 h

Procedure:
A reaction mixture of methyl 4-((1-(4-(5-ethylpyrimidin-2-yl)-2-methylphenyl)-4,4,4-trifluorobutyl)amino)benzoate (12.6 g), 1M aqueous sodium hydroxide solution (82 mL), THF (40 mL) and methanol (40 mL) was stirred at 70° C. for 7 hr. The reaction mixture was neutralized with 1M hydrochloric acid at 0° C., and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a crudely purified product. This compound was used in step C without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH3:24])[CH:18]=2)([CH3:16])[CH2:9][CH2:10][C:11](OCC)=[O:12])=[CH:4][C:3]=1[CH3:25].[OH-].[NH4+:27]>O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH3:24])[CH:18]=2)([CH3:16])[CH2:9][CH2:10][C:11]([NH2:27])=[O:12])=[CH:4][C:3]=1[CH3:25]
Reactant: [NH4+]
Reactant: CCOC(=O)CCC(C)(c1ccc(O)c(C)c1)c1ccc(O)c(C)c1
Agent: [OH-]
Solvent: O
Product: Cc1cc(C(C)(CCC(N)=O)c2ccc(O)c(C)c2)ccc1O

Procedure:
A solution of ethyl 4,4-bis(4-hydroxy-3-methylphenyl)pentanoate (69.00 grams, 0.201 mole) and 29% aqueous ammonium hydroxide (1500 milliliters) was stirred at room temperature for 144 hours. The resulting slightly cloudy, emerald green solution was diluted with water and extracted with ethyl acetate (4×500 milliliters). The combined organic fractions were washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over magnesium sulfate, the solvent was removed in vacuo leaving the amide, 4,4-bis(4-hydroxy-3-methylphenyl)pentanamide, as a tan powder (45.1 grams, 72% yield).
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)[CH:10]=2)[CH2:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH3:27]I>>[CH3:27][O:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)[CH:10]=2)[CH2:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: OC1(c2cccc(OCc3ccc4ccccc4c3)c2)CCCOCC1
Reactant: CI
Product: COC1(c2cccc(OCc3ccc4ccccc4c3)c2)CCCOCC1
Yield: 36 %

Procedure:
Using the procedure described in Example 1, 4-hydroxy-4-[3-(naphth-2-ylmethoxy)phenyl]oxepane was reacted with methyl iodide to give 4-methoxy-4-[3-(naphth-2-ylmethoxy)phenyl]oxepane (36%), m.p. 69°-70° C.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:6][CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>C(Cl)Cl>[CH:3]1([CH2:2][N:26]2[CH2:25][CH2:24][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:28][CH2:27]2)[CH2:6][CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: BrCC1CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CC2CCC2)CC1
Temperature: 35 °C
Reaction time: 2 h
Yield: 8.8 %

Procedure:
Bromomethylcyclobutane (0.200 g, 1.34 mmol, 1 eq) was suspended in DCM (2 mL). DIPEA (0.59 mL, 3.35 mmol, 2.5 eq) was added dropwise, followed by N-Boc-piperazine (0.550 g, 2.95 mmol, 2.2. eq), and the reaction mixture was stirred at 35° C. for 2 h. The crude product was purified by column chromatography on a Biotage SP1 system (DCM/EtOAc; v/v 1:1) to give the title compound (0.030 g, 8.8%); 1H-NMR (500 MHz, CDCl3): δ 1.46 (s, 9H, C(CH3)3), 1.64-1.74 (m, 2H), 1.76-1.96 (m, 2H), 2.02-2.12 (m, 2H), 2.37 (t, J=5.0 Hz, 4H, piperazine N(CH2)2), 2.43 (d, J=7.0 Hz, 2H, NCH2), 2.55 (m, 1H, cyclobutyl CH), 3.43 (t, J=5.0 Hz, 4H, piperazine N(CH2)2); GC-MS (Cl, m/z): Rt=3.77 min—255 [(M+H)+, 100%].