Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([NH:15][CH3:16])[C:12]([N+:17]([O-])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>CO.[Zn]>[NH2:17][C:12]1[C:13]([NH:15][CH3:16])=[N:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1
Reactant: CNc1nc(OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: CNc1nc(OCc2ccccc2)ccc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
21.4 g of zinc were added to a solution of 8.50 of 6-benzyloxy-2-methylamino-3-nitropyridine (prepared as described in Preparation 92) in 360 ml of methanol, and then 8.5 ml of acetic acid were added dropwise. The resuluting mixture was then stirred at room temperature for one hour. At the end of this time, the reaction mixture was filtered to remove insoluble material. The filtrate was freed from the solvent by distillation under reduced pressure, and the resulting residue was dissolved in ethyl acetate. The solution was washed with an aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure, to give 7.50 g of the title compound having Rf=0.63 (on silica gel thin layer chromatography using ethyl acetate as the developing solvent).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1.[CH:16]1([C:19](=[S:21])[NH2:20])[CH2:18][CH2:17]1>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:19]([CH:16]2[CH2:18][CH2:17]2)[S:21][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1)=[O:15]
Reactant: COC(=O)C(=O)C(Cl)c1cccc(F)c1
Reactant: NC(=S)C1CC1
Product: COC(=O)c1nc(C2CC2)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of 3-chloro-3-(3-fluoro-phenyl)-2-oxo-propionic acid methyl ester with cyclopropanecarbothioic acid amide.
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1)[CH3:2].[H-].[Na+].[F:13][C:14]([F:23])([F:22])[CH2:15][CH2:16][CH:17]([C:20]#[N:21])[C:18]#[N:19]>CN(C)C=O>[CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][C:17]([CH2:16][CH2:15][C:14]([F:13])([F:22])[F:23])([C:18]#[N:19])[C:20]#[N:21])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(CCl)cc1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1ccc(CC(C#N)(C#N)CCC(F)(F)F)cc1
Yield: 48.3 %

Procedure:
Using 0.16 g of 4-ethylbenzyl chloride, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.14 g of 2-(4-ethylbenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (31)).
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])C)[CH2:3]C1.F[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=1.C(=O)([O-])[O-].[Li+].[Li+]>>[CH2:9]([C@H:5]1[C@@:4]([CH2:1][CH3:3])([OH:12])[CH2:8][CH2:7][N:6]1[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:23])([F:25])[F:24])[CH:15]=1)[CH3:11]
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@@H]1N(c2ccc(C#N)c(C(F)(F)F)c2)CC[C@@]1(O)CC

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2,3-diethylpyrrolidin-3-ol 0.5 oxalate (193 mg), 4-fluoro-2-(trifluoromethyl)benzonitrile (364 mg) and lithium carbonate (221 mg), the title compound was obtained as pale-yellow oil (yield: 219 mg, yield: 82%).
Reaction SMILES: [C:1]([Si:5]([CH3:27])([CH3:26])[O:6][C@@H:7]([C@H:9]1[C:15](=[O:16])[N:14]2[C@@H:10]1[C@@H:11]([CH3:25])[C:12]([S:23][CH3:24])=[C:13]2[C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[CH3:8])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:36])C=1>ClCCl>[Si:5]([O:6][C@@H:7]([C@H:9]1[C:15](=[O:16])[N:14]2[C@@H:10]1[C@@H:11]([CH3:25])[C:12]([S:23]([CH3:24])=[O:36])=[C:13]2[C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[CH3:8])([C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:27])[CH3:26]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCOC(=O)C1=C(SC)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Solvent: ClCCl
Product: C=CCOC(=O)C1=C(S(C)=O)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Reaction time: 0.17 h
Yield: 93.3 %

Procedure:
To a solution of allyl (4R,5S,6S)-6-[(1R)-1-(tertbutyldimethylsilyloxy)ethyl]-4-methyl-3-methylthio-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (66 mg) in dichloromethane (1 ml) cooled to 0° C. was added meta-chloroperbenzoic acid (27.7 mg). The mixture was stirred for 10 minutes at the same temperature, washed with aqueous sodium bicarbonate solution and dried. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography to give allyl (4R,5S,6S)-6-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-methyl-3-methylsulfinyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (64 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][C:3]=1[N+:18]([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:18][C:3]1[CH:4]=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:7][C:2]=1[NH2:1]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(N)nc1C(=O)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc(N)c(N)nc1C(=O)OCC
Temperature: 0 °C
Yield: 94.5 %

Procedure:
Diethyl 6-amino-5-nitro-2,3-pyridinedicarboxylate (5.00 g, 0.0176 mol) is suspended in 250 mL of absolute ethanol and the mixture cooled to 0° C. Palladium on carbon (50 g of 10% is added and the mixture is shaken under 50 psi hydrogen in a Parr apparatus for four hours. The catalyst is removed by filtration through a pad of Celite, and the filtrate is concentrated to yield 4.21 g (94.2%) of product as a yellow solid, melting point 143°-146.5° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]1([S:14]([C:17]2[C:18]([S:29][CH3:30])=[N:19][N:20]3[C:25]([OH:26])=[CH:24][C:23]([CH2:27]Cl)=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C=O)C>[C:8]1([S:14]([C:17]2[C:18]([S:29][CH3:30])=[N:19][N:20]3[C:25]([OH:26])=[CH:24][C:23]([CH2:27][N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN1CCNCC1
Reactant: CSc1nn2c(O)cc(CCl)nc2c1S(=O)(=O)c1ccccc1
Solvent: CN(C)C=O
Product: CSc1nn2c(O)cc(CN3CCN(C)CC3)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53 %

Procedure:
1.57 ml (15.70 mml) of 1-methyl-piperazine were added to a solution of 2.9 g (7.84 mmol) of 3-benzenesulphonyl-5-chloromethyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ol in 20 ml of DMF and stirred at RT for 4 hrs. The reaction solution was evaporated and the residue was partitioned between 0.5N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2. The combined organic phases were dried (MgSO4), filtered and evaporated. Chromatography (SiO2, CH2Cl2/MeOH 4:1) yielded 1.85 g (53%) of 3-benzenesulphonyl-5-(4-methyl-piperazin-1-ylmethyl)-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ol as a beige powder, m.p.>220°.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=1[C:22]1[C:31]2[N:30]=[CH:29][CH:28]=[N:27][C:26]=2[C:25]([C:32](O)=[O:33])=[CH:24][CH:23]=1>>[CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:32]([C:25]2[C:26]3[N:27]=[CH:28][CH:29]=[N:30][C:31]=3[C:22]([C:16]3[C:17]([CH3:21])=[CH:18][CH:19]=[CH:20][C:15]=3[CH3:14])=[CH:23][CH:24]=2)=[O:33])=[CH:8][CH:7]=1
Reactant: Cc1cccc(C)c1-c1ccc(C(=O)O)c2nccnc12
Reactant: CN(C)CCOc1ccc(N)cc1
Product: Cc1cccc(C)c1-c1ccc(C(=O)Nc2ccc(OCCN(C)C)cc2)c2nccnc12

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 4-(2-dimethylamino-ethoxy)-phenylamine (Step 5.1) and 8-(2,6-dimethyl-phenyl)-quinoxaline-5-carboxylic acid (Example 71). Title compound: ESI-MS: 441.1 [M+H]+; tR=3.52 min (System 3).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([Cl:7])=[C:4]([C:8]([OH:10])=O)[CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:17]1([O:23][CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[S:6][C:5]([Cl:7])=[C:4]([C:8]([C:20]2[CH:21]=[CH:22][C:17]([O:23][CH3:24])=[CH:18][CH:19]=2)=[O:10])[CH:3]=1
Reactant: O=C(O)c1cc(Br)sc1Cl
Reactant: COc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2cc(Br)sc2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.6 %

Procedure:
To a solution of acid 1 (2.0 g, 8.28 mmol) in CH2Cl2 (50 mL) were added oxalyl chloride (0.87 mL, 9.94 mmol) and catalytic amounts of DMF at room temperature. The mixture was stirred at room temperature for 3 hours. The mixture was evaporated in vacuo and dried under high vacuum. The crude acid chloride was dissolved with CH2Cl2 (30 mL) and cooled to 0° C. To the mixture was added anisole (0.9 mL, 8.28 mmol) at 0° C. and stirred at 0° C. for 5 min. To the reaction mixture was added AlCl3 (1.2 g, 8.28 mmol) portionwise at 0° C. The mixture was stirred at 0° C. for 30 min, warmed up to room temperature and stirred at room temperature for 15 hours. The mixture was poured into ice-water and extracted with CH2Cl2 (50 mL×2). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (Biotage) to provide the title compound 2 (2.68 g, 98%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([N:7]2[CH2:12][CH2:11][NH:10][CH:9]([C:13]([F:16])([F:15])[F:14])[CH2:8]2)=[C:5]([NH2:17])[CH:4]=[N:3]1.[C:18]([O:22][C:23]([NH:25][C:26]1[S:30][C:29]([C:31]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=2[F:38])=[N:28][C:27]=1[C:39](O)=[O:40])=[O:24])([CH3:21])([CH3:20])[CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[F:38][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([F:37])[C:31]=1[C:29]1[S:30][C:26]([NH:25][C:23](=[O:24])[O:22][C:18]([CH3:20])([CH3:19])[CH3:21])=[C:27]([C:39](=[O:40])[NH:17][C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[N:7]2[CH2:12][CH2:11][NH:10][CH:9]([C:13]([F:16])([F:15])[F:14])[CH2:8]2)[N:28]=1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Cn1ncc(N)c1N1CCNC(C(F)(F)F)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCNC(C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 37.4 %

Procedure:
To a solution of (±)-1-methyl-5-(3-(trifluoromethyl)piperazin-1-yl)-1H-pyrazol-4-amine (300 mg, 2.05 mmol), 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 (516 mg, 1.73 mmol), HATU (0.54 g, 1.73 mmol) in DMF (15 mL) was added TEA (1.1 mL). The reaction mixture was stirred at 25° C. for 20 hours, poured into water (100 mL), and extracted with EtOAc (50 mL×2). The combined organic layers was washed with water (50 mL×2) and brine (30 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using DCM/MeOH (1:1) as eluting solvents to afford tert-butyl (±)-2-(2,6-difluorophenyl)-4-(1-methyl-5-(3-(trifluoromethyl)piperazin-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (380 mg, 52%) as white solid. MS (ESI) m/z: 588 (M+1+).
Reaction SMILES: C1(S[CH2:8][N:9]2[S:13](=[O:15])(=[O:14])[N:12]3[CH2:16][CH2:17][CH2:18][CH:11]3[C:10]2=[O:19])C=CC=CC=1.S(Cl)([Cl:23])(=O)=O>C(Cl)Cl>[Cl:23][CH2:8][N:9]1[S:13](=[O:15])(=[O:14])[N:12]2[CH2:16][CH2:17][CH2:18][CH:11]2[C:10]1=[O:19]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C1C2CCCN2S(=O)(=O)N1CSc1ccccc1
Solvent: ClCCl
Product: O=C1C2CCCN2S(=O)(=O)N1CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of 2-phenylthiomethyltetrahydropyrrolo[1,2-b]-1,2,5-thiadiazol-3 (2H) -one 1,1-dioxide (5 g) in 130 ml of methylene chloride was added sulfuryl chloride (2.02 ml) and the mixture was stirred for 2 hours at room temperature. The mixture was concentrated in vacuo, the residue triturated in hexane (2×, 150 ml, 75 ml) with stirring, the solvent decanted, and the resulting solid filtered and dried to afford 2.96 g (92%) of 2-chloromethyl-tetrahydropyrrolo [1,2-b]-1,2,5-thiadiazol-3 (2H) -one 1,1-dioxide (Formula II: X'=Cl; R1 =H; R2 and R3 together=--(CH2)3 --)as a solid, m.p. 46.5°-47.5° C.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.[N+:15]([O-])([OH:17])=[O:16]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16]
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Reactant: O=[N+]([O-])O
Product: O=C(O)CCC(=O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
A suspension of 3-(4-fluorobenzoyl)propionic acid (50 g) in nitric acid (d = 1.51, 500 ml) was stirred at -15°C for 30 minutes and poured into ice/water (2 1.). The precipitate was filtered off, washed with water and recrystallised from ethanol to give 3-(4-fluoro-3-nitrobenzoyl)-propionic acid (29.2g, 46%) as needles m.p. 136°C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@H:7]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:6][CH2:5]2.O.[Br:18][CH2:19][CH2:20][CH2:21]Br.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:18][CH2:19][CH2:20][CH2:21][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@H:7]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:6][CH2:5]2
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCBr)ccc21
Temperature: 25 °C
Reaction time: 13 h
Yield: 59.5 %

Procedure:
To a solution of ethyl [(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (0.166 g, 0.754 mmol) (Example 6) in DMF (0.5 mL, containing 1% v/v of water), were added 1,3-dibromopropane (0.27 mL, 2.64 mmol) and Cs2CO3 (0.295 g, 0.905 mmol). The mixture was stirred at rt for 13 h and then at 80° C. for 1 h. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure. The residue was suspended in EtOAc, filtered, and the filter cake was washed with EtOAc. The combined filtrate was dried, concentrated and purified by silica gel chromatography (100% hexanes to EtOAc/hexane (v/v) 1:19 gradient) to give 153 mg (60%) of the title compound containing minor impurities. This material was used in later steps without further purification. 1H NMR (300 MHz, CDCl3): δ 7.08 (d, 1H), 6.78 (s, 1H), 6.70 (dd, 1H), 4.19 (q, 2H), 4.08 (t, 2H), 3.60 (t, 2), 3.58-3.44 (m, 1H), 2.96-2.64 (m, 3H), 2.50-2.21 (m, 4H), 1.93-1.68 (m, 1H), 1.28 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[NH:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[CH:15]=[O:16].[CH2:17](Br)[CH3:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH2:17][CH3:18])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[CH:15]=[O:16]
Reactant: CCBr
Reactant: Nc1c(C=O)c(-c2ccccc2)n[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(-c2ccccc2)c(C=O)c(N)c1=O
Temperature: 85 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 5-amino-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carbaldehyde (Dal Piaz, V., Ciciani, G, Giovannoni, M. P., Heterocycles, 1991, 32, 1173-9) (258 mg, 1.2 mmol), ethyl bromide (294 mg, 2.7 mmol) and anhydrous potassium carbonate (240 mg, 2.4 mmol) in anhydrous DMF (5 mL) was stirred at 85° C. for 2 h. Cold water (25 mL) was added and the precipitate was collected by filtration to yield the title product (90%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]([OH:25])=O)[CH:21]=3)[C:16]([S:26]([CH3:28])=[O:27])=[CH:15]2)=[N:12][CH:13]=1.Cl.[CH3:30][NH:31][C:32]1([CH2:35][OH:36])[CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]([N:31]([C:32]4([CH2:35][OH:36])[CH2:34][CH2:33]4)[CH3:30])=[O:25])[CH:21]=3)[C:16]([S:26]([CH3:28])=[O:27])=[CH:15]2)=[N:12][CH:13]=1
Reactant: CNC1(CO)CC1
Reactant: CS(=O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)O)ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: CN(C(=O)c1ccc2c(S(C)=O)cn(-c3ncc(-c4ccccc4F)cn3)c2c1)C1(CO)CC1

Procedure:
Prepared from 1-(5-(2-fluorophenyl)pyrimidin-2-yl)-3-(methylsulfinyl)-1H-indole-6-carboxylic acid and (1-(methylamino)cyclopropyl)methanol hydrochloride under use of HATU as reagent. White solid. Yield: 42 mg
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:22][CH2:23][CH2:24][O:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:22][CH2:23][CH2:24][O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCN1
Reactant: BrCCCOC1CCCCO1
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCCOC2CCCCO2)CC1

Procedure:
In analogy to the procedure described in example 5A, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 1A]) and 2-(3-bromo-propoxy)-tetrahydro-pyran gave the title compound as white solid. MS: 455.3 (MH+, 2Cl).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:14]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C(=O)([O-])O.[Na+]>>[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([C:2]2[C:11]3[N:12]=[C:13]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:14]([CH2:15][CH2:16][CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19][CH2:18]4)[C:10]=3[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=2)[CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCn2c(-c3ccccc3)nc3c(Cl)nc4ccccc4c32)CC1
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Product: CN1CCN(c2nc3ccccc3c3c2nc(-c2ccccc2)n3CCC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of 0.80 g of tert-butyl 4-[2-(4-chloro-2-phenyl-1H-imidazo-[4,5-c]quinolin-1-yl)ethyl]-1-piperidinecarboxylate and 1 ml of N-methylpiperazine was stirred at 80° C. for 6 hours. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was dried, and the solvent was evaporated. The residue was purified by alumina column chromatography using ethyl acetate—n-heptane (1:3 to 1:1) as eluting solvents, and washed with a mixture of diisopropyl ether and n-heptane to give 0.74 g of colorless crystals. Recrystallization from ethyl acetate gave colorless needles having the melting point of from 140 to 141° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:14])[CH:8]=2)[N:3]=1.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].N1C=CC=CC=1>ClCCl>[CH3:13][O:12][C:11]1[C:2]([NH:1][C:16](=[O:17])[O:18][CH2:19][CH3:20])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([CH3:14])=[CH:6][CH:5]=2
Reactant: COc1nc2cc(C)ccc2nc1N
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.1 %

Procedure:
2-Amino-3-methoxy-6-methylquinoxaline (1.15 g, 6.08 mmol) and ethyl chloroformate (1.32 g, 12.2 mmol) were dissolved in dichloromethane (30 ml) at room temperature and thereto pyridine (0.96 g, 12.2 mmol) was added. The resulting mixture was stirred at room temperature for 24 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (3:1) mixture and concentration gave 1.59 g of the titled compound (yield, 100%).
Reaction SMILES: [C:1]1([CH:7]([NH:9][C:10]2[CH:11]=[C:12]([N:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[CH:13]=[CH:14][C:15]=2[C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:35]>ClCCl.C(OCC)C>[ClH:35].[C:1]1([C@H:7]([NH:9][C:10]2[CH:11]=[C:12]([N:22]3[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]3)[CH:13]=[CH:14][C:15]=2[C:16](=[O:21])[C:17]([F:20])([F:18])[F:19])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)C(F)(F)F)c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@@H](Nc1cc(N2CCNCC2)ccc1C(=O)C(F)(F)F)c1ccccc1
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of t-butyl 4-(3-(1-phenylethylamino)-4-(2,2,2-trifluoroacetyl)phenyl)piperazine-1-carboxylate (50 mg, 0.1 mmol) in dry dichloromethane (1.0 mL) was added a saturated solution of HCl in diethyl ether (20 mL). The reaction mixture was stirred for 2 h. The solvent was removed by rotary evaporation to afford the title compound (31 mg, 72% yield). 1H NMR (400 MHz, CD3OD): δ 7.63 (d, 1H), 7.36 (m, 5H), 6.36 (d, 1H), 5.86 (s, 1H), 4.75 (m, 1H), 3.52 (m, 2H), 3.45 (m, 2H), 3.17 (m, 4H), 1.60 (d, 3H); MS (ESI) m/z: Calculated for C20H23F3N3O: 378.18; Observed: 378.5 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([CH2:12]Br)[CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(CC)CC>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:8])[N:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:12]2
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: Nc1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C1c2ccc(Br)cc2CN1c1ccccc1
Temperature: 85 °C
Yield: 72.3 %

Procedure:
To a suspension of methyl 4-bromo-2-(bromomethyl)benzoate (0.204 g, 0.662 mmol) in MeOH (5.5 mL) were added aniline (0.063 mL, 0.696 mmol) and Et3N (0.144 mL, 1.027 mmol). The mixture was heated to reflux (85° C.) for 24 hours and subsequently cooled. A white solid that formed was collected by vacuum filtration, rinsed with MeOH, and dried under vacuum to give the title compound as a white solid (0.138 g, 72% yield). 1H NMR (500 MHz, CDCl3) δ ppm 3.89 (s, 2 H), 4.85 (s, 2 H), 7.15-7.24 (m, 1 H), 7.40-7.52 (m, 2 H), 7.62-7.96 (m, 5 H); ESI-MS m/z/[M+H]+ 288.3.