Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[C:18]3[N:23]=[C:22]([CH2:24][N:25]4[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:27][CH2:26]4)[S:21][C:19]=3[N:20]=2)=[CH:11][N:10]=1)C)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[CH3:6][NH:7][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[C:18]3[N:23]=[C:22]([CH2:24][N:25]4[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:27][CH2:26]4)[S:21][C:19]=3[N:20]=2)=[CH:11][N:10]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(-c2nc(N3CCOCC3)c3nc(CN4CCN(S(C)(=O)=O)CC4)sc3n2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1ccc(-c2nc(N3CCOCC3)c3nc(CN4CCN(S(C)(=O)=O)CC4)sc3n2)cn1
Reaction time: 1 h
Yield: 64.5 %

Procedure:
Crude {5-[2-(4-methanesulfonyl-piperazin-1-ylmethyl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-5-yl]-pyridin-2-yl}-methyl-carbamic acid tert-butyl ester 75 (100 mg) was dissolved in a solution of 1 mL of trifluoroacetic acid and 1 mL of dichloromethane. The reaction mixture was stirred for 1 h. The mixture was concentrated. The product was purified by reverse phase HPLC to yield 53.8 mg of 101. MS (Q1) 505.2 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][NH:5][C:6]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7].C([O-])(=O)C.[Na+].CO>[Pd].CCOC(C)=O>[CH3:1][O:2][C:3](=[O:25])[CH2:4][NH:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7]
Reactant: COC(=O)CNC(=O)c1nc(Cl)c2ccccc2c1-c1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)CNC(=O)c1ncc2ccccc2c1-c1ccccc1
Reaction time: 2 h
Yield: 96.1 %

Procedure:
A mixture of [(1-chloro-4-phenyl-isoquinoline-3-carbonyl)-amino]-acetic acid methyl ester (177 mg, 0.5 mmol, Example D-74 b), Pd/C (50 mg, 10 wt % Pd), sodium acetate (49 mg, 0.6 mmol), MeOH (10 ml) and EtOAc (5 ml) was stirred under a H2-atmosphere at ambient pressure and temperature for 2 h. Then the mixture was filtered through a pad of celite. Celite and filter cake were washed thoroughly with EtOAc and the combined organic phases were concentrated in vacuo. To the residue was added concentrated aqueous NaHCO3 (10 ml) and the mixture was extracted with EtOAc (2×15 ml). The combined organic phases were dried over MgSO4 and concentrated in vacuo to give the title compound as a colorless gum (154 mg); MS-(+)-ion: M+1=321.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([C:20](=O)[CH3:21])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)[CH:2]=1.[CH:23]([NH2:25])=[O:24]>C(O)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]([NH:25][CH:23]=[O:24])[CH3:21])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)[CH:2]=1
Reactant: NC=O
Reactant: CC(=O)c1cccc(Nc2nccc(-c3cccnc3)n2)c1
Solvent: O=CO
Product: CC(NC=O)c1cccc(Nc2nccc(-c3cccnc3)n2)c1

Procedure:
A mixture of 2.9 g of 1-[3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]ethanone, 40 ml of formamide and 13 ml of concentrated formic acid was refluxed for 15 hours, then cooled and evaporated. The residue was partitioned between unsaturated aqueous potassium bicarbonate and chloroform. The organic phase was separated, dried, filtered and evaporated. The residue was chormatographed on silica gel, eluting 125 ml fractions, fractions 1-4 with chloroform and fractions 5-7 with 2% methanol in chloroform. Fractions 5-7 were combined and evaporated, giving 1.25 g of the desired product as a yellow foam.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:23]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1>C(Cl)Cl.C(Cl)(Cl)Cl>[C:23]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:24]=[CH:25][C:26]([C:29]([N:8]2[CH2:7][C:6]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]2=3)=[O:30])=[CH:27][CH:28]=1
Reactant: c1ccc2c(c1)CNc1ccccc1O2
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(c1ccc(-c2ccccc2)cc1)N1Cc2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.6 %

Procedure:
To a cooled (0° C.) solution of 1.0 g of 10,11-dihydrodibenz[b,f][1,4]oxazepine and 7 ml of triethylamine in 30 ml of CH2Cl2 under argon is added dropwise 2.0 g of [1,1'-biphenyl]-4-carbonyl chloride. The mixture is stirred at room temperature for 16 hours and diluted with 50 ml of CHCl3. The mixture is washed with 30 ml each of H2O, 2NHCl, H2O, saturated NaHCO3, H2O, and dried (Na2SO4). Solvent is removed under vacuum to give 1.6 g of a yellow solid, m.p. 93°-95° C; Mass spectrum (CI), 378(MH+).
Reaction SMILES: [CH:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].C[C:11](C)=[O:12].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O.CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([O:12][CH3:11])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8]
Reactant: CC(C)=O
Reactant: C=CCCCCCC=O
Agent: O=[Cr](=O)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Solvent: CO
Product: C=CCCCCCC(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
Crude 7-octenal (30.5 g) (90.0% in gas chromatography simple area %, net: 27.5 g, 0.22 mol; cis-6-octenal: 4.7% in gas chromatography simple area %, and trans-6-octenal: 4.5% in gas chromatography simple area %) was dissolved in 95% by mass acetone aqueous solution (300.0 g). After adding Jones reagent (3M chromic acid-sulfuric acid aqueous solution) (100.0 mL) and stirring at room temperature for 2 hours, isopropanol (20.0 g) was added thereto. After the precipitate was filtered off and acetone was distilled off from the filtrate, the filtrate was extracted with ethyl acetate. After the ethyl acetate layer was washed with water and saturated sodium chloride solution, the solvent was distilled off to obtain a crude product. Subsequently, this product was dissolved in methanol (300.0 g). After adding p-toluenesulfonic acid mono hydrate (3.0 g) thereto, the solution was heated at 60° C. for 2 hours. The solution was extracted with ethyl acetate, and the organic layer was washed with water and sodium carbonate aqueous solution. After that, the organic layer obtained by distilling off the solvent was distilled under a reduced pressure of 500 Pa. With this procedure, crude methyl 7-octenoate (34.3 g) (90.0% in gas chromatography simple area %, net: 30.9 g, net: 0.20 mol, yield: 91%; cis-6-octenonitrile: 4.7% in gas chromatography simple area %, and trans-6-octenonitrile: 4.5% in gas chromatography simple area %) was obtained as a distillate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][C:18]3[NH:17][C:16]([CH3:21])=[C:15]([N+:22]([O-])=O)[C:14]=3[C:13]=2[C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])[N:4]=1.Cl.[Sn]>CO>[NH2:22][C:15]1[C:14]2[C:13]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[C:12]([O:11][C:5]3[N:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[N:4]=3)[CH:20]=[CH:19][C:18]=2[NH:17][C:16]=1[CH3:21]
Reactant: C=CCOC(=O)c1c(Oc2nc(OC)cc(OC)n2)ccc2[nH]c(C)c([N+](=O)[O-])c12
Agent: Cl
Agent: [Sn]
Solvent: CO
Product: C=CCOC(=O)c1c(Oc2nc(OC)cc(OC)n2)ccc2[nH]c(C)c(N)c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.3 %

Procedure:
3.4 g of allyl 5-[(4,6-dimethoxypyrimidin-2-yl)oxy]-2-methyl-3-nitroindol-4-carboxylate was dissolved in 50 ml of methanol, and 5 ml of concentrated hydrochloric acid was added thereto. Then, 4.9 g of tin powder was gradually added at room temperature. Them, the mixture was stirred at room temperature for 12 hours. The solid was filtered off, and then residue was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure, was crystallized from isopropyl ether to obtain 2.5 g (yield: 79%) of the desired product. mp: 132°-135° C.
Reaction SMILES: O[CH:2]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.S(Cl)([Cl:17])=O>C1C=CC=CC=1>[Cl:17][CH:2]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: OC1c2ccccc2-c2ccccc21
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: ClC1c2ccccc2-c2ccccc21
Temperature: 25 °C

Procedure:
To a cold (0° C.) suspension of 9-hydroxyfluorene (49 g) in benzene (650 mL) was added thionylchloride (70 mL). This solution was allowed to stir while warming up to room temperature overnight. The benzene was distilled off and the product was recrystallized from isopropylether to give 41 g of the title compound as a white solid: m.p. 87°-89° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4](I)[CH:3]=1.C([Li])CCC.CCCCCC.[CH2:21]([O:24][CH2:25][C:26](N(OC)C)=[O:27])[CH:22]=[CH2:23]>O1CCCC1>[CH2:21]([O:24][CH2:25][C:26]([C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[F:8])=[O:27])[CH:22]=[CH2:23]
Reactant: Fc1ccc(Br)cc1I
Reactant: C=CCOCC(=O)N(C)OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCOCC(=O)c1cc(Br)ccc1F
Temperature: -72 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
To a stirred −72° C. solution of 4-bromo-1-fluoro-2-iodobenzene (130.4 g, 433.5 mmol) in tetrahydrofuran (722 mL) is added 2.5 M butyl lithium in hexane (173.4 mL, 433.5 mmol) under a nitrogen atmosphere over 40 min. The reaction is stirred for 30 minutes at −72° C. and 2-(allyloxy)-N-methoxy-N-methylacetamide (57.5 g, 361.2 mmol) in tetrahydrofuran (115 mL) is added dropwise for 35 minutes. After 45 min at −72° C., the cooling bath is removed and mixture is warmed to 25° C. The reaction is quenched with saturated aqueous NH4Cl (500 mL), diluted with water (300 mL) and extracted three times with ethyl acetate. Organics are combined, dried over magnesium sulfate, filtered, and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using a linear gradient of 5% to 10% ethyl acetate in hexanes to give the title compound (63 g, 64%). ES/MS m/e (79Br/81Br) 273/275 (M+1).
Reaction SMILES: CS[C:3]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]4[O:21][CH2:20][CH2:19][N:18]([C:22]5[C:31]6[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=6)[N:25]=[CH:24][CH:23]=5)[CH2:17][C:16]=4[CH:32]=3)[CH:10]=[CH:11][C:5]=2[N:4]=1.[CH2:33]([NH2:35])[CH3:34]>C(O)C>[CH2:33]([NH:35][C:3]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]4[O:21][CH2:20][CH2:19][N:18]([C:22]5[C:31]6[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=6)[N:25]=[CH:24][CH:23]=5)[CH2:17][C:16]=4[CH:32]=3)[CH:10]=[CH:11][C:5]=2[N:4]=1)[CH3:34]
Reactant: CCN
Reactant: CSc1nc2ccc(-c3ccc4c(c3)CN(c3ccnc5ccccc35)CCO4)cc2[nH]1
Solvent: CCO
Product: CCNc1nc2ccc(-c3ccc4c(c3)CN(c3ccnc5ccccc35)CCO4)cc2[nH]1
Temperature: 150 °C

Procedure:
A solution of 7-[2-(methylthio)-1H-benzimidazol-6-yl]-4-quinolin-4-yl-2,3,4,5-tetra-hydro-1,4-benzoxazepine (52 mg, 0.12 mmol, prepared according to the method of example 19) and ethylamine (1.5 mL) in ethanol (3 mL) heated with microwave irradiation at 150° C. for 8 h. Purification of the crude material by preparative reverse phase HPLC (0.1% aqueous ammonium acetate-acetonitrile) provided the title Compound as acetate salt (4 mg, 7% yield) as a colorless solid. 1H NMR (400 MHz, methanol-d4): 8.55 (d, 1H), 8.15 (d, 1H), 7.95 (d, 1H), 7.73 (m, 1H), 7.60-7.50 (m, 3H), 7.42 (m, 1H), 7.33 (dd, 1H), 7.29 (d, 1H), 7.09 (m, 2H), 4.69 (s, 2H), 4.41 (m, 2H), 3.92 (m, 2H), 3.44 (q, 2H), 1.94 (s, 3H), 1.31 (t, 3H); MS (EI) for C27H25N5O: 436 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][C:5]([NH:9][CH2:10][C:11]([O:13]C)=[O:12])=[C:4]([O:15][CH3:16])[CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[C:7]1[C:2]([Cl:1])=[CH:3][C:4]([O:15][CH3:16])=[C:5]([NH:9][CH2:10][C:11]([OH:13])=[O:12])[CH:6]=1
Reactant: COC(=O)CNc1cc(I)c(Cl)cc1OC
Reactant: OB(O)c1cc(Cl)ccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(Cl)c(-c2cc(Cl)ccc2Cl)cc1NCC(=O)O
Temperature: 25 °C
Yield: 59.1 %

Procedure:
A mixture of methyl 2-(4-chloro-5-iodo-2-methoxyphenylamino)acetate (5.0 g, 14.08 mmol), 2,5-dichlorophenylboronic acid (4.03 g, 21.12 mmol), Pd(PPh3)4 (1.626 g, 1.04 mmol), Na2CO3 (4.477 g, 42.24 mmol) in 1,4-dioxane (100 mL) and water (20 mL) was stirred at reflux under argon for 6 h. Then reaction mixture was allowed to cool to room temperature, quenched with water and acidified with HCl (10% in water) to adjust the pH to 3-4. The mixture was extracted with ethyl acetate, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (50% petroleum ether/ethyl acetate) to afford the desired product (3 g, 59% yield) as an off-white solid. ESI-MS m/z: 360.2 [M−H]−.
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]([NH:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([Br:14])=[C:9]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[C:22]([OH:29])[C:21]=2[CH2:30][CH2:31][CH3:32])[CH:8]=1)=[O:5].[OH-].[Na+]>CO>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:18][CH2:17][CH2:16][O:15][C:9]2[CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]([OH:33])=[O:2])[C:12]([CH3:13])=[CH:11][C:10]=2[Br:14])=[C:21]([CH2:30][CH2:31][CH3:32])[C:22]=1[OH:29])(=[O:28])[CH3:27]
Reactant: CCCc1c(OCCCOc2cc(NC(=O)C(=O)OC)c(C)cc2Br)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCCOc2cc(NC(=O)C(=O)O)c(C)cc2Br)ccc(C(C)=O)c1O

Procedure:
A suspension of 15.1 g (29 mmol) of N-{3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-4-bromo-6-methylphenyl}-oxamic acid methyl ester in 120 ml of methanol and 30.4 ml of N sodium hydroxide solution is heated under reflux for 90 minutes. The reaction mixture is concentrated under reduced pressure, dissolved in acetone and dilute sodium hydroxide solution and acidified with dilute hydrochloric acid. The product that has formed is filtered off, washed with acetone/water and recrystallised from isopropanol. N-{3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-4-bromo-6-methylphenyl}-oxamic acid having a melting point of 191°-192° is obtained. 10.9 g (21.5 mmol) of this product are dissolved in 450 ml of isopropanol under reflux, and a solution of 3.20 g (21.5 mmol) of triethanolamine in 30 ml of isopropanol is then added thereto. The solution is cooled and concentrated to approximately one third under reduced pressure. After the addition of ether, crystallisation begins. The product that has formed is filtered off and washed with ether. The triethanolammonium salt of N-{3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-4-bromo-6-methylphenyl}-oxamic acid having a melting point of 85°-86° is obtained.
Reaction SMILES: [F:1][C:2]1[CH:46]=[CH:45][C:5]([CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[C:21]4[C:16](=[N:17][CH:18]=[C:19]([C:22]5[CH:23]=[CH:24][C:25]([O:33][CH3:34])=[C:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:27]=5)[CH:20]=4)[N:15](S(C4C=CC(C)=CC=4)(=O)=O)[CH:14]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:46]=[CH:45][C:5]([CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[C:21]4[C:16](=[N:17][CH:18]=[C:19]([C:22]5[CH:23]=[CH:24][C:25]([O:33][CH3:34])=[C:26]([NH:28][S:29]([CH3:32])(=[O:30])=[O:31])[CH:27]=5)[CH:20]=4)[NH:15][CH:14]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2cnc3c(c2)c(-c2cnn(CCc4ccc(F)cc4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2cnc3[nH]cc(-c4cnn(CCc5ccc(F)cc5)c4)c3c2)cc1NS(C)(=O)=O
Yield: 41.8 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(5-(3-(1-(4-fluorophenethyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxyphenyl) methanesulfonamide (25 mg, 0.0379 mmol) was hydrolyzed by lithium hydroxide (15 mg, 0.379 mmol) in THF/methanol/water (2/2/1 ml) to yield 8 mg (40.0% yield) of the titled compound. 1H NMR (DMSO-d6, 300 MHz): δ 11.7 (s, 1H), 9.034-9.035 (d, 1H), 8.43-8.42 (d, 1H), 8.20 (s, 1H), 8.14 (s, 1H), 7.87 (s, 1H), 7.69-7.68 (d, 2H), 7.58-7.56 (m, 2H), 7.26-7.18 (m, 3H), 7.11-7.05 (m, 2H), 4.39-4.35 (t, 2H), 3.89 (s, 3H), 3.18-3.13 (t, 2H), 3.00 (s, 3H). MS: m/z=506.5 (M+1), HPLC: 96.65% in method B.
Reaction SMILES: [CH:1]12[C:9](=[O:10])[NH:8][C:7](=[O:11])[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[H-].[Na+].[CH2:14](Br)[CH2:15][CH2:16][CH2:17][Br:18].O>CN(C)C=O>[Br:18][CH2:17][CH2:16][CH2:15][CH2:14][N:8]1[C:7](=[O:11])[CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]2[C:9]1=[O:10]
Reactant: O=C1NC(=O)C2CCCCC12
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1C2CCCCC2C(=O)N1CCCCBr
Reaction time: 3 h

Procedure:
To a solution of cyclohexane-1,2-dicarboximide (10 g; 65.3 mmol) in anhydrous dimethylformamide (50 ml), there was added 60% sodium hydride (2.6 g; 68.5 mmol) under nitrogen at room temperature, and the resultant mixture was stirred at the same temperature for 3 hours. Tetramethylene bromide (70.5 g; 0.327 mol) was added thereto, and the mixture was stirred for 3 hours. After completion of the reaction, the resultant mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water twice and with a saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent and excessive tetramethylene bromide were removed by evaporation to give N-(4-bromobutyl)cyclohexane-1,2-dicarboximide. IR νmaxFilm (cm-1): 1770, 1700.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=O)=[CH:9][N:8]=1.[CH:19]1([C:22]2[CH:27]=[C:26]([CH:28]3[CH2:30][CH2:29]3)[CH:25]=[CH:24][C:23]=2[N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:21][CH2:20]1>>[CH:19]1([C:22]2[CH:27]=[C:26]([CH:28]3[CH2:30][CH2:29]3)[CH:25]=[CH:24][C:23]=2[N:31]2[CH2:32][CH2:33][N:34]([C:11]([C:10]3[CH:9]=[N:8][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:18])=[CH:17][CH:16]=3)=[O:13])[CH2:35][CH2:36]2)[CH2:20][CH2:21]1
Reactant: CCOC(=O)c1ccc(N2CCCS2(=O)=O)nc1
Reactant: c1cc(N2CCNCC2)c(C2CC2)cc1C1CC1
Product: O=C(c1ccc(N2CCCS2(=O)=O)nc1)N1CCN(c2ccc(C3CC3)cc2C2CC2)CC1
Yield: 72.4 %

Procedure:
Using ethyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)nicotinate (300 mg) described in Preparation Example 25 and 1-(2,4-dicyclopropylphenyl)piperazine (296 mg) described in Preparation Example 101 and by the reaction and treatment in the same manner as in Example 109, the title compound (375 mg) was obtained.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][C:4]([C:6]1[CH:18]=[CH:17][C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:8][CH:7]=1)=O.C([O-])(=O)C.[NH4+].C([BH3-])#[N:26].[Na+].Cl>CO>[NH2:26][CH:4]([C:6]1[CH:18]=[CH:17][C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:8][CH:7]=1)[CH2:3][CH:2]([CH3:19])[CH3:1]
Reactant: [BH3-]C#N
Reactant: CC(C)CC(=O)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: CC(C)CC(N)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-(3-methylbutanoyl)benzoate (500 mg, 1.91 mmol) and ammonium acetate (1.50 g, 19.1 mmol) in methanol (9.5 mL) was added sodium cyanoborohydride (189 mg, 2.86 mmol). The mixture was heated to 60° C. for 21 hours, then cooled to room temperature. 1 N hydrochloric acid (7 mL) was added dropwise. After 1 hour, the mixture was concentrated under reduced pressure to remove methanol. 1 N sodium hydroxide (10 mL) was added, and the mixture was extracted with dichloromethane (3×25 mL). The combined organics were washed with sat. aq sodium chloride (15 mL), dried over anhydrous Na2SO4, and filtered, and the filtrate was concentrated. Purification by silica gel flash chromatography (methanol/dichloromethane) gave tert-butyl(+/−)-4-(1-amino-3-methylbutyl)benzoate as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.99-7.94 (m, 2H), 7.41-7.37 (m, 2H), 4.08-4.01 (m, 1H), 1.60 (s, 9H), 1.59-1.43 (m, 3H), 0.92 (d, J=6.5 Hz, 3H), 0.90 (d, J=6.3 Hz, 3H).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].[OH:14][C:15]1[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:16]=1[CH:17]=[O:18]>CC(C)=O>[CH:17]([C:16]1[CH:19]=[C:20]([CH3:24])[C:21]([CH3:23])=[CH:22][C:15]=1[O:14][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:18]
Reactant: Cc1cc(O)c(C=O)cc1C
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(C)c(C)cc1C=O

Procedure:
0.808 ml of ethyl bromoacetate and 1 g of potassium carbonate were added to a solution of 838 mg of 2-hydroxy-4,5-dimethylbenzaldehyde (J.Chem.Soc. (1953) 820) in 150 ml of acetone. The suspension obtained was heated to reflux overnight and then filtered. The filtrate was concentrated. The crude product was isolated by extraction and purified by chromatography on silica gel and yielded 952 mg of ethyl (2-formyl-4,5-dimethyl-phenoxy)-acetate as a pale yellow solid.
Reaction SMILES: [Cl-].C([N+](C)(C)C)CCCCCCCCCCCCCCCCC.[Cl:24][C:25]1[CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=[CH:29][C:30]=1[Cl:31].[F-:35].[K+]>>[Cl:24][C:25]1[CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=[CH:29][C:30]=1[F:35].[Cl:24][C:25]1[CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: [F-]
Agent: CCCCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Agent: [Cl-]
Product: O=[N+]([O-])c1ccc(F)c(Cl)c1
Temperature: 180 °C
Yield: 90.6 %

Procedure:
70 g (0.2 mol) of octadecyltrimethylammonium chloride were dissolved in a melt of 2020 g (10.5 mol) of 3,4-dichloronitrobenzene at 50° C. with stirring, 580 g (10.0 mol) of potassium fluoride were suspended at 100° C. and this suspension was heated to 180° C. for 9 h. After cooling to about 60° C., the reaction suspension was filtered with suction, the liquid adhering to the residue was distilled off at 150° C./70 torr and the combined organic phases were fractionated with the addition of an auxiliary base as an acid scavenger. 1445 g (90.6%, relative to 3,4-dichloronitrobenzene converted) of 3-chloro-4-fluoronitrobenzene and 324 g (13.6%, relative to 3,4-dichioronitrobenzene employed) of unreacted 3,4-dichloronitrobenzene were obtained.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl.[CH3:5][NH:6]C.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].Cl.[C-]#N.[K+]>CO.O>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18]([C:5]#[N:6])([N:2]([CH3:3])[CH3:1])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CNC
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Solvent: O
Product: CN(C)C1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 5 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
500 ml (10 eq.) dimethylamine solution and 109.9 g (5 eq.) dimethylamine hydrochloride were added to a solution of 50 g (1 eq.) tert-butyloxycarbonyl-4-oxopiperidine in 100 ml methanol and the mixture was cooled to 5° C. 5 ml (0.1 eq.) hydrochloric acid were then added dropwise to the reaction mixture over a period of 10 min and the mixture was stirred for 60 min at room temperature. 48.9 g (3 eq.) potassium cyanide were added in portions to this reaction mixture and the mixture was stirred for 24 h at room temperature. Once the conversion was complete, 150 ml water were added to the reaction mixture and it was extracted 3 times with 100 ml ethyl acetate. The combined organic phases were dried with Na2SO4. Following removal of the solvent under reduced pressure, crude product was obtained which was recrystallized out of hexane. 57 g (90%) of product were obtained in the form of a colorless solid.