Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]([OH:16])=O)[N:13]=1.[NH2:17][C:18]1[C:19]([N:27]2[CH2:32][CH2:31][CH2:30][C@H:29]([NH:33]C(=O)OC(C)(C)C)[CH2:28]2)=[C:20]2[CH2:26][CH2:25][O:24][C:21]2=[N:22][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:33][C@H:29]1[CH2:30][CH2:31][CH2:32][N:27]([C:19]2[C:18]([NH:17][C:14]([C:12]3[N:13]=[C:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[S:10][CH:11]=3)=[O:16])=[CH:23][N:22]=[C:21]3[O:24][CH2:25][CH2:26][C:20]=23)[CH2:28]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3c2CCO3)C1
Reactant: O=C(O)c1csc(-c2c(F)cccc2F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N[C@H]1CCCN(c2c(NC(=O)c3csc(-c4c(F)cccc4F)n3)cnc3c2CCO3)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.2 %

Procedure:
To a mixture of 2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (Example 2, Step 2, 14.5 mg, 0.0601 mmol), tert-butyl [(3S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate (19.2 mg, 0.0574 mmol) and HATU (72.5 mg, 0.191 mmol), DMF (1.50 mL) was added, followed by DIPEA (79.6 mg, 0.616 mmol). The reaction mixture was stirred at room temperature for 2 h, and then concentrated under reduced pressure. To the residue, DCM (2.0 mL) was added, followed by TFA (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.15% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (5.3 mg, 20%). LCMS calc. for C22H22F2N5O2S (M+H)+: m/z=458.1. found 458.1.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:27]C2CC2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=1.C[Si](Cl)(C)C>C(O)CCC>[NH2:27][C:4]1[C:5]2[C:10]([C:11]3[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=3)=[CH:9][NH:8][C:6]=2[N:7]=[C:2]([NH:31][C:32]2[CH:40]=[CH:39][C:35]([C:36]([O:38][CH2:4][CH2:5][CH2:10][CH3:9])=[O:37])=[CH:34][CH:33]=2)[N:3]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccncc3)c3c(NC4CC4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CCCCOC(=O)c1ccc(Nc2nc(N)c3c(-c4ccncc4)c[nH]c3n2)cc1
Temperature: 135 °C
Reaction time: 24 h
Yield: 122.2 %

Procedure:
A mixture of 2-chloro-N-cyclopropyl-5-(pyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (245 mg, 0.557 mmol), 4-aminobenzoic acid (150 mg, 1.09 mmol) and trimethylsilyl chloride (0.300 mL, 2.37 mmol) in nBuOH (4 mL) was stirred at 135° C. for 24 h. It was concentrated in vacuo. The residue was purified by HPLC to give butyl 4-(4-amino-5-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzoate (137 mg).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:28])[NH:9][CH:10]([CH2:26][OH:27])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=2)=[CH:14][CH:13]=1)([CH3:6])([CH3:5])[CH3:4].[CH2:29]1COCC1>CCOC(C)=O>[C:3]([O:7][C:8](=[O:28])[NH:9][CH:10]([CH2:26][O:27][CH3:29])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=2)=[CH:14][CH:13]=1)([CH3:5])([CH3:4])[CH3:6]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)NC(CO)Cc1ccc(-c2ccc(F)c(Cl)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COCC(Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
NaH (55 mg, 1.31 mmol, 60% by wt suspension in mineral oil) was added at 0° C. to a solution of [2-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-1-hydroxymethyl-ethyl]-carbamic acid tert-butyl ester (0.5 g, 1.31 mmol) in 5 mL anhydrous THF and stirred for 20 min at 0° C. Mel (0.37 g, 2.63 mmol) was added to the reaction mixture and stirred for 6 h at room temperature. The reaction mixture was diluted with 5 mL EtOAc, and washed with water, brine and dried over Na2SO4. Solvent was removed under vacuum and silica gel chromatography (EtOAc: Hexanes) gave (R)-[[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-methoxymethyl-ethyl]-carbamic acid tert-butyl ester (0.38 g). The Boc protecting group was removed by stirring the compound in 4M HCl in dioxane (5 ml) for 30 min. Evaporation of the solvent under vacuo gave (R)-2-(3′-chloro4′-fluoro-biphenyl-4-yl)-1-methoxymethyl-ethylamine hydrochloride.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[O:9][C:8]2=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:1]1([N:7]2[C:11]([CH3:12])([C:10]([O:13][CH3:14])=[O:9])[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:23][C:8]2=[O:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccccc1
Reactant: COc1oc(=O)n(-c2ccccc2)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1(C)C(c2ccccc2)OC(=O)N1c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under argon atmosphere, in 3 ml of methylene chloride was dissolved 102.6 mg (0.5 mmol) of 3-phenyl-4-methyl-5-methoxy-2(3H)oxazolone, and after the solution was cooled to −78° C., 53.1 mg (0.5 mmol) of benzaldehyde and 0.5 ml (0.05 mmol) of a methylene chloride solution containing 0.1 M-trimethylsilyl triflate were added to the solution and the mixture was reacted under stirring for 1.0 hour. After the temperature of the mixture was raised up to the room temperature, 15 ml of a saturated aqueous sodium hydrogen carbonate solution was added to the resulting reaction mixture and the mixture was extracted with 15 ml of methylene chloride. The organic layer was washed twice with 15 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained concentrated residue was applied to silica gel column chromatography (eluent, hexane:ethyl acetate=10:1 (volume ratio)) to obtain 146.8 mg (0.47 mmol) of diastereomer mixture crude product of 3-phenyl-4-methyl-4-methoxycarbonyl-5-phenyl-2-oxazolidinone as pale yellowish liquid. A diastereomer ratio thereof was 72/28 according to 1H-NMR. Yield based on 3-phenyl-4-methyl-5-methoxy-2(3H)oxazolone was 94.3%.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:6]([NH:7][C:8](=[O:44])/[C:9](=[N:23]\[O:24][C:25]2([C:28]([O:30][CH:31]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])[CH2:27][CH2:26]2)/[C:10]2[N:11]=[C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[S:13][CH:14]=2)[C:5](=[O:45])[NH:4]1.O=[CH:47][CH2:48][NH:49][C:50](=[O:66])[O:51][CH2:52][CH:53]1[C:65]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:59]2[C:54]1=[CH:55][CH:56]=[CH:57][CH:58]=2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:55]1[C:54]2[CH:53]([CH2:52][O:51][C:50]([NH:49][CH2:48][CH2:47][NH:1][CH2:2][C@@H:3]3[C@H:6]([NH:7][C:8](=[O:44])/[C:9](=[N:23]\[O:24][C:25]4([C:28]([O:30][CH:31]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[O:29])[CH2:27][CH2:26]4)/[C:10]4[N:11]=[C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[S:13][CH:14]=4)[C:5](=[O:45])[NH:4]3)=[O:66])[C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[C:59]=2[CH:58]=[CH:57][CH:56]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2CN)cs1
Reactant: O=CCNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2CNCCNC(=O)OCC2c3ccccc3-c3ccccc32)cs1
Reaction time: 12 h
Yield: 57.5 %

Procedure:
To a solution of benzhydryl 1-(((Z)-(2-(((2R,3S)-2-(aminomethyl)-4-oxoazetidin-3-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylate (199 mg, 0.29 mmol) in DCE (2.9 mL) was added (9H-fluoren-9-yl)methyl (2-oxoethyl)carbamate (84 mg, 0.30 mmol) and sodium triacetoxyborohydride (181 mg, 0.86 mmol). After 12 h, the reaction mixture was quenched with saturated NaHCO3 (aq), diluted with EtOAc, and the layers were separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 0-100%) to afford the title compound (150 mg, 58%). LCMS: Rt=1.10 min, m/z=900.0 (M+1), Method 2m_acidic. 1H NMR (400 MHz, DMSO-d6): 9.16 (d, J=9.0 Hz, 1H), 8.35 (s, 1H), 7.87 (d, J=7.4 Hz, 2H), 7.66 (d, J=7.4 Hz, 2H), 7.45-7.18 (m, 16H), 6.83 (s, 1H), 5.24-5.17 (m, 1H), 4.28 (d, J=6.7 Hz, 2H), 4.19 (d, J=6.3 Hz, 1H), 3.79-3.67 (m, 1H), 3.03-2.95 (m, 2H), 2.73-2.63 (m, 1H), 1.54-1.37 (m, 13H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH:10](O)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[CH:10][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: O=CO
Product: Brc1cnc2[nH]cnc2c1
Temperature: 25 °C

Procedure:
5-Bromo-2,3-diaminopyridine (1.69 g, 8.99 mmole) was taken up in 96% formic acid (50 mL) and heated to reflux. After 18 hr the mixture was cooled to RT and concentrated. The residue was taken up in H2O and the pH was adjusted to 7 with 2.0 M NaOH. The title compound (1.54 g, 87%) was collected as a solid by filtration, washed with H2O, and dried in vacuo: MS (ES) m/e 198/200 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C@@H:14]([CH3:15])[CH2:13][N:12](C(OC(C)(C)C)=O)[C@H:11]([CH3:23])[CH2:10]2)=[CH:5][C:4]=1[F:24])#[N:2].FC(F)(F)C(O)=O>ClCCl>[CH3:15][C@H:14]1[CH2:13][NH:12][C@H:11]([CH3:23])[CH2:10][N:9]1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:24])[CH:5]=1
Reactant: C[C@@H]1CN(c2ccc(C#N)c(F)c2)[C@@H](C)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc(C#N)c(F)c2)[C@@H](C)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.3 %

Procedure:
Into 150 ml of dichloromethane was dissolved 15.0 g of tert-butyl (2R,5S)-4-(4-cyano-3-fluorophenyl)-2,5-dimethylpiperazine-1-carboxylate, and then 30 ml of trifluoroacetic acid was added thereto, followed by stirring at room temperature overnight. After the reaction solution was removed by evaporation, 1M hydrochloric acid was added thereto, followed by washing with chloroform. The aqueous phase was made basic with a 5M sodium hydroxide aqueous solution, followed by extraction with chloroform. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed by evaporation to obtain 12.0 g of the title compound.
Reaction SMILES: O[CH:2]1[CH2:7][O:6][C:5]2[CH:8]=[CH:9][C:10]([C:13](=[O:15])[CH3:14])=[C:11]([OH:12])[C:4]=2[CH2:3]1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>N1C=CC=CC=1>[C:13]([C:10]1[CH:9]=[CH:8][C:5]2[O:6][CH2:7][CH:2]([S:17]([CH3:16])(=[O:19])=[O:18])[CH2:3][C:4]=2[C:11]=1[OH:12])(=[O:15])[CH3:14]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1ccc2c(c1O)CC(O)CO2
Solvent: c1ccncc1
Product: CC(=O)c1ccc2c(c1O)CC(S(C)(=O)=O)CO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The compound of Example 8 (250 mg) was dissolved in dry pyridine (5 ml) and cooled to 0°. Methanesulfonylchloride (100 μl) was added to the stirred solution, which warmed to room temperature and stirred for 16 hours. The pyridine was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was washed with dilute acid, water, dried and evaporated to afford the title compound, m.p. 158°-162°.
Reaction SMILES: C[N:2]([CH3:19])[CH:3]=[C:4]([CH2:17][CH3:18])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=O.N[C:21]1[C:25]([C:26]#[N:27])=C[NH:23][N:22]=1>C(O)(=O)C>[CH2:17]([C:4]1[CH:3]=[N:2][C:19]2[N:23]([N:22]=[CH:21][C:25]=2[C:26]#[N:27])[C:5]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=1)[CH3:18]
Reactant: N#Cc1c[nH]nc1N
Reactant: CCC(=CN(C)C)C(=O)c1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: CCc1cnc2c(C#N)cnn2c1-c1cccc(C(F)(F)F)c1

Procedure:
A mixture of 4.0 g of 3-dimethylamino-2-ethyl-3'-trifluoromethylacrylophenone and 1.5 g of 3-amino-4-cyanopyrazole in 75 ml of glacial acetic acid was refluxed for two hours to give 6-ethyl-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile, m.p. 135°-137° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12](OCC(F)(F)F)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:41])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[CH:29]=1)(C)(C)C.[C:43](O)([C:45]([F:48])([F:47])[F:46])=[O:44]>C(Cl)Cl>[N:36]1[CH:37]=[CH:38][CH:39]=[C:34]([C:30]2[CH:29]=[C:28]([C:27]3[CH2:26][C:25](=[O:41])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:23])([F:22])[F:21])[C:12]([O:44][CH2:43][C:45]([F:48])([F:47])[F:46])=[CH:13][C:8]=4[N:7]=3)[CH:33]=[CH:32][CH:31]=2)[CH:35]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3cccnc3)c2)=Nc2cc(OCC(F)(F)F)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from [2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M27) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (173 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=2[N:4]=[C:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19].[C:21]([O-:24])(O)=O.[Na+].C(Cl)(Cl)Cl>C(O)(=O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]3[C:9]([CH:21]=[O:24])=[CH:10][CH:5]=[CH:6][CH:7]=3)[C:5]=2[N:4]=[C:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19]
Reactant: Cc1cccc2c1nc(-c1ccccc1[N+](=O)[O-])n2C
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cn1c(-c2ccccc2[N+](=O)[O-])nc2c(-c3ccccc3C=O)cccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 42 %

Procedure:
A solution of ceric ammonium nitrate (2.19 g, 4.0 mmol) in acetic acid (10 mL, 50%) was added to a stirred solution of N-methyl-4-methyl-2-(2-nitrophenyl)-benzimidazole (0.27 g, 1.0 mmol) in same acid (5.0 mL, 50%) dropwise at 90° C. and the mixture was stirred for 6 hours. The mixture was then cooled to room temperature, neutralized with saturated NaHCO3 to PH=7-8,extracted with CHCl3 and the extract dried over Na2SO4. Concentration using a rotary evaporator and subsequent column chromatography on silica gel using hexane/ethyl acetate (1:3) as the eluent to give N-methyl-2-(2-nitrophenyl)-benzimidazole-4-benzaldehyde (115 mg, 42%) as a light-yellow solid. Rf=0.28 (hexane/ethyl acetate=1:3); 1H NMR (250 MHz, CDCl3) δ 3.68 (s, 3H), 7.47 (t, J=7.8 Hz, 1H), 7.66-7.74 (m, 2H), 7.77-7.86 (m, 2H), 7.90 (d, J=7.6 Hz, 1H), 8.28 (dd, J,=7.9 Hz, J2 =1.5 Hz, 1H), 10.81 (s, 1H). HRMS: Calcd for C15H11N3O3 281.0800, found 281.0814.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1.C1(C)C=CC=CC=1>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:28])[C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=C(NCCCCl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccccc1N1CCN(CCCNC(=O)c2ccc(F)cc2)CC1
Reaction time: 5 h

Procedure:
A mixture of 1.92 g (0.01 mol) of 1-(2-methoxyphenyl)-piperazine and 2.15 g (0.01 mol) of N-(3-chloropropyl)-4-fluorobenzamide was added to a mixture of toluene (20 ml) and triethylamine (2 ml) under agitation. The resulting mixture was gradually heated to the refluxing temperature at which the mixture was held for 5 hours. After completion of the reaction, the mixture was cooled and the precipitating salt was filtered off. The filtrate was extracted with 20 ml of benzene, and the extract was washed first with saturated aqueous sodium bicarbonate, then washed with water twice. By drying with anhydrous magnesium sulfate and subsequent concentration, 1-(2-methoxyphenyl)-4-[3-(4-fluorobenzoyl)aminopropyl]piperazine was produced as an oily substance. The oil was dissolved in methanol (30 ml) and the solution was saturated with hydrogen chloride gas. Upon concentration of the saturated solution, a crystal of the piperazine in hydrochloride form was obtained (2.9 g). m.p. 231.7° C. (recrystallized from ethanol).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:5](=[O:16])[C:6]2[CH:11]=[C:10]([S:12](=[O:15])(=[O:14])[NH2:13])[S:9][C:7]=2[N:8]=1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:4]1[C:5](=[O:16])[C:6]2[CH:11]=[C:10]([S:12](=[O:15])(=[O:14])[NH2:13])[S:9][C:7]=2[N:8]=[C:3]1[CH2:2][N:28]1[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]1
Reactant: NS(=O)(=O)c1cc2c(=O)n(-c3ccccc3Cl)c(CBr)nc2s1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCN(Cc2nc3sc(S(N)(=O)=O)cc3c(=O)n2-c2ccccc2Cl)CC1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 36.4 %

Procedure:
To 5.0 g of 3,4-dihydro-2-bromomethyl-3-(2-chlorophenyl)-4-oxo-6-sulfamoylthieno[2,3-d]pyrimidine were added 50 ml of dimethylformamide, 1.5 g of N-methylpiperazine and 3.2 g of potassium carbonate, and the mixture was stirred at 40° C. for 1.5 hours. The reaction mixture was poured onto water, and the mixture was extracted with ethyl acetate. The concentrated residue of the extract was crystallized from ethanol, followed by recrystallization of the obtained crystals from methanol-chloroform to afford 1.9 g of the title compound, m.p. 233.5°-234° C. (decomposition). The hydrochloric thereof showed m.p. of 246°-247° C. (decomposition).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[NH:21]1[C:29]2[C:24](=[CH:25][C:26](B(O)O)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1>>[CH:13]1([C:9]2[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6](=[O:20])[N:5]3[C:10]=2[C:11]([CH3:12])=[C:2]([C:26]2[CH:25]=[C:24]4[C:29](=[CH:28][CH:27]=2)[NH:21][CH:22]=[CH:23]4)[CH:3]=[CH:4]3)[CH2:15][CH2:14]1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: OB(O)c1ccc2[nH]ccc2c1
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc4[nH]ccc4c3)ccn2c1=O
Yield: 47.4 %

Procedure:
Methyl 8-(1H-indol-5-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 1H-indol-5-yl-boronic acid (83 mg, 0.51 mmol) to afford the title compound as a yellow solid (60 mg, 47%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][CH:8]=[CH2:9])(=[O:3])[CH3:2].[C:10](O)(=[O:14])[C:11](C)=C.N1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:14][CH:10]=[CH2:11])(=[O:3])[CH3:2]
Reactant: C=C(C)C(=O)O
Reactant: C=COCCOC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=COCCOCCOC(C)=O
Yield: 93 %

Procedure:
The thus obtained acetoxyethylvinylether by 19.5 grams (0.15 mols) and methacrylic acid by 15.5 grams (0.18 mols) were dissolved into methylene chloride. Then, 0.38 grams (0.0015 mols) of p-toluenesulfonic acid pyridine salt was added into the mixture, and stirred for complete dissolution. The resultant mixture is stood at room temperature for 6 hours. Then, the mixture was washed three times with 2.5% aqueous sodium hydroxide, and six times with water. Then, the resultant mixture was dehydrated with magnesium sulfate. After filtering magnesium sulfate out, solvent was removed by means of an evaporator. Then, the resultant residue was distilled under reduced pressure, thereby there was obtained 29.6 grams of acetoxyethoxyethylvinylether (b.p. 100-105° C./0.07 mmHg). The yield was 93%.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:15]2[C:16]([F:33])=[C:17]([C@H:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:23][CH3:24])[CH:18]=[CH:19][C:20]=2[Cl:21])=[O:14])=[CH:9][C:8]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(CC)CC)C>ClCCl>[CH2:35]([O:34][C:8]1[CH:9]=[C:10]([C:13]([C:15]2[C:16]([F:33])=[C:17]([C@H:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:23][CH3:24])[CH:18]=[CH:19][C:20]=2[Cl:21])=[O:14])[CH:11]=[CH:12][C:7]=1[NH:6][C:3](=[O:4])[CH2:2][Cl:1])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2ccc(N)c(OCc3ccccc3)c2)c1F
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2ccc(NC(=O)CCl)c(OCc3ccccc3)c2)c1F
Yield: 95.4 %

Procedure:
Step 4 Chloroacetyl chloride (0.323 ml, 4.05 mmol) was added to a mixture of tert-butyl N-[(1R)-1-(3-{[4-amino-3-(benzyloxy)phenyl]carbonyl}-4-chloro-2-fluorophenyl)propyl]carbamate (1.6 g, 3.12 mmol), triethylamine (0.651 ml, 4.68 mmol) and dichloromethane (30 ml) at room temperature. After 30 minutes a small additional portion of chloroacetyl chloride was added and in 60 minutes the reaction was complete. The reaction mixture was washed with dilute citric acid solution and dilute sodium bicarbonate and then concentrated. The residue was purified on silica eluting with 30-70% ethyl acetate/petrol to furnish tert-butyl N-[(1R)-1-(3-{[3-(benzyloxy)-4-(2-chloroacetamido)-phenyl]-carbonyl}-4-chloro-2-fluorophenyl)propyl]carbamate as a yellow oil (1.754 g). [M−H]−=587
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3[NH:16][C:17]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([C:28]6[CH:33]=[C:32]([F:34])[C:31]([OH:35])=[CH:30][C:29]=6[CH2:36][CH3:37])=[CH:25][CH:26]=5)[NH:21][N:20]=4)=[N:18][C:12]=3[CH2:11]2)=[O:9])=[N:6][CH:7]=1.[N:38]1([CH2:43][CH2:44][NH2:45])[CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH2:36]([C:29]1[CH:30]=[C:31]([OH:35])[C:32]([F:34])=[CH:33][C:28]=1[C:24]1[CH:23]=[C:22]2[C:27]([C:19]([C:17]3[NH:16][C:13]4[CH2:14][CH2:15][N:10]([C:8]([C:5]5[CH:4]=[N:3][C:2]([NH:45][CH2:44][CH2:43][N:38]6[CH2:42][CH2:41][CH2:40][CH2:39]6)=[CH:7][N:6]=5)=[O:9])[CH2:11][C:12]=4[N:18]=3)=[N:20][NH:21]2)=[CH:26][CH:25]=1)[CH3:37]
Reactant: NCCN1CCCC1
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(Cl)cn3)C4)n[nH]c2c1
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(NCCN5CCCC5)cn3)C4)n[nH]c2c1
Yield: 52 %

Procedure:
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (50 mg, 96 μmol) and (2-(pyrrolidin-1-yl)ethanamine, 50 mg, 132 μmol) using the method of Example 32. The crude material was purified by HPLC Method E to afford (30 mg, 52%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])(=[O:8])=[O:7])[CH3:3].C1C(=O)N([Br:32])C(=O)C1>ClC1C=CC=CC=1.C1(C)C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:32][CH2:24][C:21]1[CH:20]=[CH:19][C:18]([S:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:6]([N:5]=[CH:4][N:2]([CH3:1])[CH3:3])(=[O:7])=[O:8])(=[O:16])=[O:17])=[CH:23][CH:22]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)(=O)c2ccccc2S(=O)(=O)N=CN(C)C)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: Clc1ccccc1
Product: CN(C)C=NS(=O)(=O)c1ccccc1S(=O)(=O)c1ccc(CBr)cc1
Yield: 87.8 %

Procedure:
1.5 g of N-dimethylaminomethylene-2-(toluene-4-sulfonyl)benzenesulfonamide, 0.74 g of NBS and 20 mg of benzoyl peroxide are refluxed for 2 h in 15 ml of chlorobenzene. The reaction mixture is allowed to cool and is diluted with 100 ml of toluene, and washed once each with 20 ml of a saturated aqueous Na2SO3 solution and twice with 50 ml of a saturated aqueous Na2CO3 solution. It is dried over MgSO4 and the solvent is removed in vacuo. 1.6 g of an amorphous solid are obtained, which is further reacted without further purification.