Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:13])[C@H:10]([OH:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([I:24])=[CH:19][N:18]=1.[Cl-].[Na+]>C(OCC)C.C(#N)C>[CH2:1]([O:8][C@H:9]([CH3:13])[C@@H:10]([CH3:11])[O:12][C:19]1[C:20]([I:24])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](O)[C@@H](C)OCc1ccccc1
Reactant: Clc1ncc(I)c(Cl)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: C[C@@H](OCc1ccccc1)[C@@H](C)Oc1nc(Cl)ncc1I
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41 %

Procedure:
8.55 g (47.4 mmol) of (2R,3R)-3-benzyloxybutan-2-ol in 56 ml of diethyl ether were admixed at 0° C. with stirring in portions with 2.07 g of sodium hydride (55%). After 10 minutes, the ice bath was removed and the mixture was stirred for a further 3 minutes at room temperature. The suspension formed was added at 0° C. to a solution of 6.52 g (23.7 mmol) of 2,4-dichloro-5-iodopyrimidine in 65 ml of acetonitrile. The mixture was stirred for 4 hours at 40° C. and then admixed with dilute sodium chloride solution. Extraction was carried out with ethyl acetate (2×). The combined organic phases were dried (Na2SO4), filtered and concentrated by evaporation. The resulting residue was purified chromatographically (hexane/ethyl acetate 4:1). This gave 4.12 g (9.8 mmol; yield: 41%) of the product.
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].[OH:5][CH:6]([CH3:17])[CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1.C(OCC)(=O)C>C(#N)C.CN(C)C1C=CN=CC=1>[CH3:17][CH:6]1[O:5][S:1](=[O:2])[N:9]([C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])[CH2:8][CH2:7]1
Reactant: CC(O)CCNC(=O)OC(C)(C)C
Reactant: O=S(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC1CCN(C(=O)OC(C)(C)C)S(=O)O1
Reaction time: 1.5 h
Yield: 95.6 %

Procedure:
To a stirred solution of thionyl chloride (2.0 mL, 27.9 mmol) in acetonitrile (15 mL) cooled to −45° C. is added a solution of tert-butyl (3-hydroxybutyl)carbamate (2.1 g, 11.2 mmol) in acetonitrile (20 mL) by syringe over 10 min, keeping the internal temperature below −40° C. 4-Dimethylaminopyridine (136 mg, 1.1 mmol) is added followed by the dropwise addition of pyridine (4.5 mL, 55.8 mmol, keeping the temperature below −40° C. The addition takes 90 min. Ethyl acetate (50 mL) is added to the suspension and the mixture is filtered at −35° C. to remove the solid and the solid which is washed with EtOAc before it is discarded. The filtrates are combined, and saturated Na2HPO4 solution (20 mL) is added. The mixture is stirred vigorously for 30 min and the organic layer is separated, washed with 1M NaHSO4 to remove residual pyridine, dried (MgSO4) and concentrated to afford the title compound (2.52 g, 96%) as an oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[Br:17]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:17][CH:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)Cc1ccc2ccccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(Br)c1ccc2ccccc2c1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
A solution consisting of ethyl 2-(2-naphthyl)acetate (1.07 grams, 5.0 mmol), N-bromosuccinimide (0.89 grams, 5.0 mmol), benzoyl peroxide (0.05 grams), and carbon tetrachloride (50 mL) was heated at reflux until complete as determined by hplc (3 hours). The reaction was cooled to ambient temperature, washed with water (2×25 mL), dried using sodium sulfate, and filtered. The filtrate was concentrated to dryness. The residue was purified using a Biotage Flash 40M system eluting with hexane:ethyl acetate (49:1) to give 1.20 grams (82%) of ethyl 2-bromo-2-(2-naphthyl)acetate, mp 80-82° C. MS (FIA) m/z 293.0 [(M+H)+]. Anal. calcd. for C14H13O2Br: C, 57.36; H, 4.47. Found: C, 57.62; H, 4.54. 1H nmr (CDCl3): δ 1.27-1.33 (t, 3H), 4.18-4.36 (m, 2H), 5.56 (s, 1H), 7.52-7.55 (m, 2H), 7.71-7.76 (m, 1H), 7.82-7.92 (m, 3H), 7.97 (s, 1H).
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.N([O-])=O.[Na+].N.[ClH:17]>[Cu]Cl>[Cl:17][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1
Reactant: Nc1cncc2ccccc12
Reactant: Cl
Agent: Cl[Cu]
Agent: N
Agent: O=N[O-]
Product: Clc1cncc2ccccc12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Intermediate 87 (1.27 g) was dissolved in 1 N aqueous hydrochloric acid (36 ml) and added dropwise with an aqueous solution (36 ml) of sodium nitrite (1.21 g, Wako Pure Chemical Industries) with ice cooling. The obtained suspension was added dropwise to a solution of copper(I) chloride (1.83 g, Wako Pure Chemical Industries) in 1 N aqueous hydrochloric acid (20 ml) with ice cooling, then warmed to room temperature and stirred for 15 hours. The reaction mixture was added with 28% aqueous ammonia (50 ml) and extracted twice with ethyl acetate (150 ml for each time). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to obtain the title compound (433 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12](O)=[O:13])[CH:11]=1)[NH:8][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:16]=1)[CH2:6][C:5]2([CH3:27])[CH3:26].[CH3:28][S:29]([NH2:32])(=[O:31])=[O:30]>CN(C)C1C=CN=CC=1.ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([NH:32][S:29]([CH3:28])(=[O:31])=[O:30])=[O:13])[CH:11]=1)[NH:8][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:16]=1)[CH2:6][C:5]2([CH3:27])[CH3:26]
Reactant: CC1(C)CC(c2cccc(N3CCCC3)c2)Nc2c(C(=O)O)cc(F)cc21
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc(N3CCCC3)c2)Nc2c(C(=O)NS(C)(=O)=O)cc(F)cc21
Yield: 25.2 %

Procedure:
A mixture of 6-fluoro-4,4-dimethyl-2-(3-pyrrolidin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (150 mg, 0.32 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (91 mg, 0.48 mmol), 4-dimethylaminopyridine (59 mg, 0.48 mmol), methane sulfonamide (91.2 mg, 0.96 mmol) in dichloromethane (10 mL) was refluxed for 12 h. Removal of the solvent to afford the oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-[6-fluoro-4,4-dimethyl-2-(3-pyrrolidin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carbonyl]-methanesulfonamide (36 mg, 20%) as a light yellow solid: MS (ESI) M+1=446.3.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[N:4][N:5]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[N:15][N:16]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:17]=3[CH:18]([CH3:20])[CH3:19])[C:9]2=[O:28])[C:6]=1[CH3:7].[CH3:30][N:31](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[Cl:1][C:2]1[C:3]([C:30]#[N:31])=[N:4][N:5]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[N:15][N:16]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:17]=3[CH:18]([CH3:20])[CH3:19])[C:9]2=[O:28])[C:6]=1[CH3:7]
Reactant: Cc1c(Cl)c(I)nn1C1CCN(c2cnn(-c3ccc(F)cc3)c2C(C)C)C1=O
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1c(Cl)c(C#N)nn1C1CCN(c2cnn(-c3ccc(F)cc3)c2C(C)C)C1=O
Temperature: 85 °C
Yield: 92 %

Procedure:
A mixture of 3-(4-chloro-3-iodo-5-methylpyrazol-1-yl)-1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-yl]pyrrolidin-2-one (0.057 g, 0.11 mmol), Zn(CN)2 (0.025 g, 0.21 mmol), Pd2(dba)3 (0.010 g, 0.011 mmol) and dppf (0.009 g, 0.016 mmol) in DMF (2 mL) was heated at 85° C. for 1 h under a N2 atmosphere. The mixture was then cooled to room temperature, quenched with sat. NaHCO3 (30 mL,) and extracted with EtOAc (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by flash chromatography (SiO2, 0˜100% EtOAc/CH2Cl2 gradient elution) to give 4-chloro-1-[1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-yl]-2-oxo-pyrrolidin-3-yl]-5-methylpyrazole-3-carbonitrile (0.042 g, 92%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([OH:14])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:18]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([OH:14])=[CH:10][N:9]=2)=[CH:4][CH:3]=1)=[CH:19][CH2:20][CH2:21][CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Oc1cnc(-c2ccc(Br)cc2)nc1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCC=Cc1ccc(-c2ncc(O)cn2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 75 %

Procedure:
After replacing inner atmosphere of a four-necked flask equipped with a stirring device and a thermometer with nitrogen gas, the flask was charged with 1.26 g (5 mmol) of 2-(4-bromophenyl)-5-hydroxypyrimidine, 0.01 g (0.008 mmol) of tetrakis-triphenylphosphine-palladium, 0.6 g (15 mmol) of sodium hydroxide and 20 ml of tetrahydrofuran. Then, 19.5 ml of a solution prepared by dissolving 7.5 mmol of E-1-nonenylcatecholborane, prepared in the same manner as in Example 2, in tetrahydrofuran was dropwise added at room temperature. The resulting mixture was heated under reflux with stirring for 7 hours. After cooling the mixture to room temperature, the mixture was extracted with 30 ml of toluene, and the organic layer was twice washed with each 10 ml portion of saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent, purification of the residue by silica gel column chromatography gave 1.16 g (yield 75%) of 2-{4-(1-decenyl)-phenyl}-5-hydroxypyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([CH3:13])([CH3:12])[C:10]#[CH:11]>O1CCOCC1.CCCCCC.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[C:6]2[C:7]=1[NH:8][C:9]([CH3:12])([CH3:13])[CH:10]=[CH:11]2
Reactant: C#CC(C)(C)Nc1ccc(C(C)C(=O)OCC)cc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1COCCO1
Solvent: CCCCCC
Product: CCOC(=O)C(C)c1cc(Cl)c2c(c1)C=CC(C)(C)N2
Yield: 93.8 %

Procedure:
6.5 g of Ethyl 2-[3-chloro-4-(1,1-dimethyl-2-propynylamino)phenyl]propionate (Compound 1) was dissolved in 70 ml of dioxane, and 10.0 g of zinc chloride were added thereto. The mixture was reacted at 95° C. for 15 hours under nitrogen atmosphere. After the reaction, the mixture was diluted with 100 ml of hexane, and subjected to column chromatography on silica gel. The solvent was distilled off to give 6.1 g of Ethyl 2-(8-chloro-1,2-dihydro-2,2-dimethylquinolin-6-yl)propionate (Compound 6).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([N:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23]2)[CH:17]=1)=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@@H:8]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([N:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23]2)[CH:17]=1)=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ccnc(N2CCc3ccccc32)c1)C1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](C(=O)N1CCC[C@H]1c1ccnc(N2CCc3ccccc32)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of ((S)-1-Cyclohexyl-2-{(S)-2-[2-(2,3-dihydro-indol-1-yl)-pyridin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-carbamic acid tert-butyl ester (120 mg, 0.24 mmol) in DCM (5 mL) is added TFA (6 mL). After stirring at room temperature for 1 h, the reaction mixture is concentrated down to give crude (S)-2-Amino-2-cyclohexyl-1-{(S)-2-[2-(2,3-dihydro-indol-1-yl)-pyridin-4-yl]-pyrrolidin-1-yl}-ethanone, which is used in next step without further purification.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[F:6][CH:7]([F:17])[O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O.C(O)C>O>[F:6][CH:7]([F:17])[O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[N:2][OH:3]
Reactant: O=Cc1cccc(OC(F)F)c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=Cc1cccc(OC(F)F)c1

Procedure:
A 2.0 g portion of hydroxylamine hydrochloride was dissolved in 12 ml of water and 8 ml of 5N sodium hydroxide was added. A 1.0 g portion of 3-(difluoromethoxy)benzaldehyde was added followed by enough ethanol to give a solution. After 10 minutes of reflux, the reaction mixture was concentrated in vacuo and the residue taken up in 10 ml of water. The pH was adjusted to 4 with hydrochloric acid, then the mixture was extracted with chloroform. The organic phase was dried over sodium sulfate and concentrated, giving the desired compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:16][CH2:17][CH3:18])[CH2:10][NH:11][NH:12][C:13](=O)C.C(OCC)C.[OH-].[Na+].[Cl-].[CH3:27][N:28](C)C=NC=[N+](C)C>C(O)C.Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:16][CH2:17][CH3:18])[CH2:10][N:11]1[CH:27]=[N:28][CH:13]=[N:12]1
Reactant: CCCC(CNNC(C)=O)c1ccc(Cl)cc1Cl
Reactant: CN(C)C=NC=[N+](C)C
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CCCC(Cn1cncn1)c1ccc(Cl)cc1Cl
Temperature: 170 °C
Yield: 86.9 %

Procedure:
5.1 g (0.017 mol) of 1-[2-(2,4-dichlorophenyl)pentyl]-2acetylhydrazine in 10 ml of ethanol and 10 ml of concentrated hydrochloric acid are stirred at 50° C. overnight. The reaction mixture is then distributed between diethyl ether and 2 N sodium hydroxide solution; and the residue after concentration by evaporation is refluxed in 50 ml of absolute ethanol with 5.75 g (0.035 mol) of [3-(dimethylamino)-2-aza-prop-2-en-1-ylidene]-dimethylammonium chloride for 3.5 hours. The reaction solution is then concentrated by evaporation; 50 ml of formamide are added, and the mixture is heated at 170° C. for 1.5 hours. The reaction mixture, to which water has been added, is extracted with diethyl ether, and the residue obtained after concentration by evaporation is chromatographed to yield 4.2 g (84% of theory) of 1-[2-(2,4-dichlorophenyl)-pentyl]-1H-1,2,4-triazole.
Reaction SMILES: B(Br)(Br)Br.[CH:5]([C:8]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25]C)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH3:17])[C:9]1=[O:18])([CH3:7])[CH3:6]>C(Cl)Cl>[OH:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:8]1([CH:5]([CH3:7])[CH3:6])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH3:17])[C:9]1=[O:18]
Reactant: COc1ccccc1C1(C(C)C)C(=O)N(C)c2ccccc21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)C1(c2ccccc2O)C(=O)N(C)c2ccccc21
Reaction time: 0.5 h

Procedure:
A solution of 1.92 ml (0.02 mol) of boron tribromide in 20 ml of methylene chloride is added dropwise over the course of 1 hour to 5.9 g (0.02 mol) of 3-isopropyl-3-(2-methoxyphenyl)-1-methylindolin-2-one in 75 ml of methylene chloride at 0° C. After 30 minutes, the mixture is poured onto ice-water, and the organic phase is washed with water, dried and evaporated. The residue is triturated with cold toluene and is filtered off with suction. 4.8 g, melting point 172°-174° C.
Reaction SMILES: [CH3:1][S:2]([CH2:5][N:6]1[C:14]2[CH:13]=[C:12]([C:15]([O:17]C(C)(C)C)=[O:16])[N:11]=[CH:10][C:9]=2[CH:8]=[CH:7]1)(=[O:4])=[O:3]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][S:2]([CH2:5][N:6]1[C:14]2[CH:13]=[C:12]([C:15]([OH:17])=[O:16])[N:11]=[CH:10][C:9]=2[CH:8]=[CH:7]1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)c1cc2c(ccn2CS(C)(=O)=O)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Cn1ccc2cnc(C(=O)O)cc21
Temperature: 50 °C
Reaction time: 15 h
Yield: 96.3 %

Procedure:
A mixture of tert-butyl 1-(methylsulfonylmethyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (8B, 820 mg, 2.7 mmol) in DCM (5 ml) and TFA (5 ml) was stirred at 50° C. for 15 h. The mixture was concentrated in vacuo to give 1-(methylsulfonylmethyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylic acid (8C, 650 mg, 2.6 mmol, 97% yield) as a brown oil. The material was used for next reaction without further purifications. ESI-MS: m/z 255.1 (M+H)+.
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:18]([O:21][C:22]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:23]=1[C:24](O)=[O:25])([CH3:20])[CH3:19]>C(#N)C.C(OCC)C>[CH:18]([O:21][C:22]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:23]=1[C:24]([N:5]1[CH2:4][CH2:3][N:2]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:7][CH2:6]1)=[O:25])([CH3:20])[CH3:19]
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Solvent: CCOCC
Solvent: CC#N
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc3ccccc3n2)CC1

Procedure:
Prepared in analogy to example 1.1(b) from 2-piperazin-1-yl-quinoline hydrochloride and 2-isopropoxy-5-methanesulfonyl-benzoic acid (example 2.2) in acetonitrile. Trituration in diethyl ether yields the title compound as a yellowish foam.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:13][OH:14].C([O-])([O-])=O.[K+].[K+].C(O)C>O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8](=[N:13][OH:14])[NH2:9])=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: NO
Reactant: N#Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: NC(=NO)c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 29.6 g. (0.20 mole) of p-nitrobenzonitrile, 13.9 g. (0.20 mole) of hydroxylamine HCl, 13.8 g. (0.10 mole) of K2CO3 in 700 ml. of ethanol and 70 ml. of water is refluxed for 20 hours, cooled and diluted with 200 ml. of water. After removal of the ethanol by distillation in vacuo, the product is collected by filtration, washed with water and dried to yield 21.6 g. (60%).
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH:7]([CH2:9]OS(C)(=O)=O)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[C:4]2[CH:19]=[CH:20][CH:21]=[CH:22][C:3]1=2.[Na+].[I-:24]>CC(C)=O>[I:24][CH2:9][CH:7]1[NH:8][C:2](=[O:1])[C:3]2[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=2[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]1=2
Reactant: CS(=O)(=O)OCC1NC(=O)c2ccccc2-c2ccccc21
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C1NC(CI)c2ccccc2-c2ccccc21
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of methanesulfonic acid 7-oxo-6,7-dihydro-5H-dibenzo[c,e]azepin-5-ylmethyl ester in acetone (5 mL) is added NaI and the mixture is stirred at 50° C. for 18 h. The solvent is removed under reduced pressure and EtOAc is added. The solution is washed sequentially with sodium bisulfite solution, water and brine and is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue purified by flash chromatography using a gradient of 0-100% EtOAc/hexane as eluent to give the title compound as a yellow solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[C:15]3[N:16]=[C:17]([N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)[N:18]=[C:19]([C:20]4[CH:21]=[N:22][C:23]([N:26]([CH2:36][C:37]5[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=5)[CH2:27][C:28]5[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=5)=[N:24][CH:25]=4)[C:14]=3[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[N:51]1[CH:56]=[CH:55][CH:54]=[C:53](B(O)O)[CH:52]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[N:51]1[CH:56]=[CH:55][CH:54]=[C:53]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]3[C:15]4[N:16]=[C:17]([N:45]5[CH2:50][CH2:49][O:48][CH2:47][CH2:46]5)[N:18]=[C:19]([C:20]5[CH:25]=[N:24][C:23]([N:26]([CH2:36][C:37]6[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=6)[CH2:27][C:28]6[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=6)=[N:22][CH:21]=5)[C:14]=4[CH2:13][CH2:12]3)=[O:10])=[CH:4][CH:3]=2)[CH:52]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)Nc3ccc(I)cc3)cn2)cc1
Reactant: OB(O)c1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)Nc3ccc(-c4cccnc4)cc3)cn2)cc1

Procedure:
4-{2-[Bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid (4-iodo-phenyl)-amide (35 mg) obtained in Step A, pyridin-3-boronic acid (11 mg), palladium acetate (1.0 mg), S-Phos (3.7 mg) and potassium phosphate (9.5 mg) were stirred at 100° C. for 3 hours in DMF (4.5 ml). To this, water was added, and the solid was filtered, followed by purification by silica gel column chromatography (dichloromethane/methanol=100/1 to 50/1), to obtain 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid (4-pyridin-3-yl-phenyl)-amide as a crude product. To this, N-Acetylcysteine (11 mg) was added, followed by refluxing for 4 hours in TFA (1 ml). TFA was distilled off, followed by purification by silica gel column chromatography (dichloromethane/methanol=100/1 to 50/1), to obtain the desired compound (D-65) as a colorless solid (5.0 mg, 23%, deprotection method according to the above Deprotection method 3).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][CH:41]([NH:44][C:45](=[O:47])[CH3:46])[CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:38]3[CH2:43][CH2:42][CH:41]([NH:44][C:45](=[O:47])[CH3:46])[CH2:40][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(=O)NC1CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(NC(C)=O)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with N-piperidin-4-yl-acetamide (TCI) to give the title compound. HR-MS (ES, m/z) calculated for C36H44Cl2N5O3 [(M+H)+] 664.2816, observed 664.2813.