Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[N:19]=[C:18]([CH3:20])[C:17](/[CH:21]=[CH:22]/[C:23]([O:25]CC)=[O:24])=[CH:16][N:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[N:19]=[C:18]([CH3:20])[C:17](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:16][N:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C/c1cnc(NC2CCN(Cc3ccccc3)C2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(NC2CCN(Cc3ccccc3)C2)ncc1/C=C/C(=O)O
Yield: 100.1 %

Procedure:
A solution of ethyl (2E)-3-{2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl}acrylate (750 mg) and 1N NaOH solution (4.1 ml) in MeOH (10 ml) and THF (10 ml) was stirred at 80-85° C. for 2 hours. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture was AcOEt and H2O. The aqueous solution was adjusted to PH 5.4 with 5% HCl solution and resultant solution was evaporated in vacuo and the residue was dissolved in a MeOH and THF. The solvent was evaporated in vacuo and dried to give (2E)-3-{2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl}acrylic acid (693 mg).
Reaction SMILES: Cl.Cl.Cl.C[CH:5]([C:24](=[O:26])[OH:25])[CH2:6][C@H:7]([C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=[O:10])[NH2:8].[Cl:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32]([C:37](O)=[O:38])=[CH:31]2.[Li+].[OH-].Cl>>[ClH:27].[Cl:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32]([C:37]([NH:8][C@@H:7]([C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[CH2:15][CH2:16]1)=[O:10])[CH2:6][CH2:5][C:24](=[O:26])[OH:25])=[O:38])=[CH:31]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CC(C[C@@H](N)C(=O)N1CCC(C2CCN(C)CC2)CC1)C(=O)O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Product: CN1CCC(C2CCN(C(=O)[C@@H](CCC(=O)O)NC(=O)c3cc4cc(Cl)ccc4[nH]3)CC2)CC1

Procedure:
Prepared from 1-[(γ-methyl)-D-glutamyl]-4-(1-methylpiperidin-4-yl)piperidine dihydrochloride hydrochloride and 5-chloroindole-2-carboxylic acid using methods substantially equivalent to General Coupling Method 1. Ester deprotection with 2 eq LiOH and final purification and HCl salt formation via prep HPLC.
Reaction SMILES: N#N.[NH2:3][C:4]1[C:9]2=[C:10]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:33]=4[F:42])=[O:30])=[C:24]([F:43])[CH:23]=3)[C:11]([CH2:19][O:20][CH3:21])=[C:12]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:8]2[N:7]=[CH:6][N:5]=1.ClCCCl.[CH3:48][N:49]=[C:50]=[O:51]>O1CCCC1>[NH2:3][C:4]1[C:9]2=[C:10]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:30])[NH:31][C:32]4[CH:37]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:35]=[CH:34][C:33]=4[F:42])=[C:24]([F:43])[CH:23]=3)[C:11]([CH2:19][O:20][CH3:21])=[C:12]([CH:13]3[CH2:18][CH2:17][N:16]([C:50]([NH:49][CH3:48])=[O:51])[CH2:15][CH2:14]3)[N:8]2[N:7]=[CH:6][N:5]=1
Reactant: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)c(F)c2)c2c(N)ncnn2c1C1CCNCC1
Reactant: CN=C=O
Agent: N#N
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CNC(=O)N1CCC(c2c(COC)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)c3c(N)ncnn23)CC1
Temperature: 0 °C
Yield: 32.8 %

Procedure:
To a flask charged with N2 was added 1-{4-[4-amino-6-(methoxymethyl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoro-methyl)phenyl]urea (Example 149) (30 mg, 0.052 mmol, 1.0 eq) and 1,2-dichloroethane (2 mL). Tetrahydrofuran was added dropwise until the reaction mixture was a complete solution. The solution was cooled to 0° C. and methyl isocyanate (5.2 μl, 1 eq) is added. The reaction mixture was allowed to gradually warm to rt over 17 hours. The reaction was concentrated and the residue dissolved in EtOAc. The organic phase was washed with saturated sodium bicarbonate solution (2×), brine (1×), separated and the organic layer dried (Na2SO4). The organic layer was filtered, concentrated and purified via flash column chromatography (tetrahydrofuran). The purified fractions were collected, concentrated, stirred in hexanes and filtered. The filtrate was placed under vacuum overnight to yield the title compound (18 mg, 32.8% yield). 1H-NMR (DMSO-d6) δ 9.44 (s, 1H), 9.29 (s, 1H), 8.65 (d, J=7.2 Hz, 1H), 8.29 (t, J=8.4 Hz, 1H), 7.88 (s, 1H), 7.51 (t, J=9.9 Hz, 1H), 7.41 (m, 1H), 7.2 (dd, J=12.1, 1.9 Hz, 1H), 7.1 (dd, J=8.5, 1.4 Hz, 1H), 4.22 (s, 2H), 4.06 (m, 2H), 3.42 (m, 1H), 3.15 (s, 3H), 2.73 (t, J=12.4 Hz, 2H), 2.57 (d, J=4.3 Hz, 3H) 2.17 (m, 2H), 1.59 (m, 2H); MS [M+H]+=633; LCMS RT=2.97 min.
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].[C:6]([CH2:9][C:10](=[O:12])[CH3:11])(=[O:8])[CH3:7].CN1C=CN=C1>>[CH3:3][Si:2]([CH3:5])([CH3:4])[O:12][C:10]([CH3:11])=[CH:9][C:6](=[O:8])[CH3:7]
Reactant: C[Si](C)(C)Cl
Reactant: CC(=O)CC(C)=O
Agent: Cn1ccnc1
Product: CC(=O)C=C(C)O[Si](C)(C)C
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 81.4 %

Procedure:
5.97 g (55.0 mmol) of chlorotrimethylsilane were added dropwise while stirring at 0° C. to a solution of 5.00 g (49.9 mmol) of acetylacetone and 4.50 g (55.0 mmol) of 1-methylimidazole. The reaction mixture was stirred at 0° C. for a further 1 h and at 80° C. for 5 min to form a liquid biphasic mixture. Removal of the upper phase gave 7.00 g (theory: 8.60 g) of 4-trimethylsilyloxypent-3-en-2-one as a bright yellow, cloudy oil having a purity of 84% (GC).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5](=O)/[CH:6]=[C:7](/[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)\[O-])[CH3:2].[Li+].Cl.[Cl:23][C:24]1[CH:25]=[C:26]([NH:30][NH2:31])[CH:27]=[CH:28][CH:29]=1>C(O)C>[Cl:23][C:24]1[CH:25]=[C:26]([N:30]2[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)=[CH:6][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:20])=[N:31]2)[CH:27]=[CH:28][CH:29]=1
Reactant: NNc1cccc(Cl)c1
Reactant: CCOC(=O)C(=O)/C=C(\[O-])c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Solvent: CCO
Product: CCOC(=O)c1cc(-c2cccc(C(F)(F)F)c2)n(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 62 %

Procedure:
631.5 mg (2.15 mmol) of lithium (1Z)-4-ethoxy-3,4-dioxo-1-[3-(trifluoromethyl)phenyl]but-1-en-1-olate from example 1A are suspended in 15 ml of ethanol, 522.7 mg (2.92 mmol) of 3-chlorophenylhydrazine hydrochloride are added and the mixture is stirred for 48 hours at room temperature. The reaction mixture is concentrated by evaporation to approx. 5 ml and the precipitated solid is collected by suction filtration. After drying the crystals, they are taken up in 15 ml of acetic acid and stirred for 12 hours under reflux. The mixture is added to ethyl acetate, and washed with water, a saturated sodium bicarbonate solution and a sodium chloride solution. The organic phase is dried over sodium sulfate and concentrated on a rotary evaporator. The residue obtained is purified on a silica gel flash (mobile phase: cyclohexane/ethyl acetate 3:1) and then crystallized from diethyl ether/pentane. 528 mg (1.5 mmol, 62% yield of theory) of product are obtained.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:14](Cl)(=[O:18])[C:15]([CH3:17])=[CH2:16]>>[CH3:16][CH:15]1[CH2:17][C:10]2[C:8]3[C:9]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[S:6][C:7]=3[CH:13]=[CH:12][C:11]=2[C:14]1=[O:18]
Reactant: c1ccc2c(c1)sc1ccccc12
Reactant: C=C(C)C(=O)Cl
Product: CC1Cc2c(ccc3sc4ccccc4c23)C1=O
Yield: 66 %

Procedure:
For the synthesis of the compounds according to the invention, the operation started with 2-methyl indan-1-one and, in a three-step method, the desired 2-methyl indene was obtained in a yield of over 60%. As emerges from the diagram, m-xylene (1) is converted in a first step with methacryloyl chloride. The purified indanone (2) is obtained after cleaning by distillation and Friedel-Crafts alkylation in a yield of 66%. The reduction of the indanone (2) is implemented with NaBH4. The indene (3) is obtained as a viscous fluid. By reaction of the compound (4), which is produced by addition of 1,2-dibromoethane and fluorenyl lithium, the two isomers (5) and (6) are obtained in a subsequent reaction in a yield of 45%. The desired isomer 5 can then be isolated by crystallisation from toluene/hexane in a ratio of 1:2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[NH:16][C:15]([CH:19]([F:21])[F:20])=[N:14]1.[C:22](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[N:16]([CH3:22])[C:15]([CH:19]([F:20])[F:21])=[N:14]1
Reactant: CC(C)Oc1cc(-n2nc(C(F)F)[nH]c2=O)c(Cl)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CC(C)Oc1cc(-n2nc(C(F)F)n(C)c2=O)c(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
A stirred mixture of 4.0 g (0.012 mole) of 1-[2,4-dichloro-5-(1-methylethoxy)phenyl]-3-difluoromethyl-4,5-dihydro-1,2,4-triazol-5(1H)-one and 4.1 g (0.03 mole) of potassium carbonate in 160 mL of acetone was heated at reflux for 0.5 hours then cooled to about 50° C. Methyl iodide, 8.4 g (0.06 mole), was added and the mixture stirred at 45° for one hour then at reflux for one hour. The mixture was cooled to room temperature and evaporated under reduced pressure to leave an oil. This oil was partitioned between methylene chloride and water. The organic phase was washed with a 10% aqueous sodium hydroxide solution and then dried over anhydrous magnesium sulfate. The mixture was filtered and the filtrate evaporated under reduced pressure to leave an oil. This oil solidified when stirred with petroleum ether and upon filtration provided 2.6 g of 1-[2,4-dichloro-5-(1-methylethoxy)phenyl]-3-difluoromethyl-4,5-dihydro-4-methyl-1,2,4 -triazol-5-(1H)-one (mp 95°-97° C).
Reaction SMILES: Cl.[CH2:2]([O:12][CH2:13][CH2:14][CH2:15][C:16]1([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)OCC[O:17]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].CCOCC>C1COCC1>[CH2:2]([O:12][CH2:13][CH2:14][CH2:15][C:16]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)=[O:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCOCCCC1(c2ccc(OC)cc2)OCCO1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCCCOCCCC(=O)c1ccc(OC)cc1
Temperature: 25 °C

Procedure:
3 ml of HCl (1N) were added to a solution of 2.64 g (6.9 mmol) of 2-[3-(decyloxy)propyl]-2-(4-methoxyphenyl)-1,3-dioxolane obtained under b) in 50 ml of THF. The reaction mixture was heated at 40° for 2 h. After cooling down to room temperature, ether was added and the reaction mixture washed with a saturated solution of NaCl (3×). The organic phase was dried (Na2SO4) and concentrated to give 2.29 g (99%) of a slightly red oil that solidifies at 4°.
Reaction SMILES: [N+](=[CH2:3])=[N-].[F:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([CH2:15][O:16][C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:34])[CH2:25][C:26]([CH2:32][CH3:33])([CH2:30][CH3:31])[C:27]([OH:29])=[O:28])[CH:20]=[CH:21][CH:22]=3)=[N:12]2)=[CH:7][CH:6]=1>C(OCC)C.O1CCCC1>[CH3:3][O:28][C:27](=[O:29])[C:26]([CH2:32][CH3:33])([CH2:30][CH3:31])[CH2:25][C:24]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([O:16][CH2:15][C:11]2[CH:10]=[CH:9][C:8]3[C:13](=[CH:14][C:5]([F:4])=[CH:6][CH:7]=3)[N:12]=2)[CH:18]=1)=[O:34]
Reactant: CCC(CC)(CC(=O)Nc1cccc(OCc2ccc3ccc(F)cc3n2)c1)C(=O)O
Reactant: C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(CC)(CC(=O)Nc1cccc(OCc2ccc3ccc(F)cc3n2)c1)C(=O)OC

Procedure:
A solution of diazomethane in diethyl ether is added at 0° to a solution of 1.9 g of 4-[3-(7-fluoro-2-quinolinylmethoxy)phenylamino]-2,2-diethyl-4-oxobutanoic acid (Example 3) in 150 ml of tetrahydrofuran until a yellow colour remains established. The yellow solution is immediately concentrated by evaporation to give the title compound in the form of a colourless oil which crystallises on being left to stand in a refrigerator, m.p. 92°-93°; IR (methylene chloride): 1735 cm-1 (C=O).
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[CH:6]=[C:7]([C:12](=[O:32])[CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[N:27][C:26]([CH3:29])=[N:25]3)=[C:20]([O:30][CH3:31])[CH:19]=2)[CH:8]=[CH:9][C:10]=1[Cl:11].[Cl-].[NH4+]>C1COCC1>[Cl:4][C:5]1[CH:6]=[C:7]([C:12]([OH:32])([CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[N:27][C:26]([CH3:29])=[N:25]3)=[C:20]([O:30][CH3:31])[CH:19]=2)[CH3:1])[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: C[Mg]Br
Reactant: COc1cc(C#CCCCC(=O)c2ccc(Cl)c(Cl)c2)ccc1-n1cnc(C)n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(C#CCCCC(C)(O)c2ccc(Cl)c(Cl)c2)ccc1-n1cnc(C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methylmagnesium bromide (12% THF solution, 550 μL) was added to a mixture of 1-(3,4-dichlorophenyl)-6-[3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]hex-5-yn-1-one (198 mg) in THF (5 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 min. Methylmagnesium bromide (12% THF solution, 550 μL) was added to the reaction mixture under ice-cooling, and the mixture was stirred for 15 min under ice-cooling. Saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (177 mg).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][CH2:9][C:10](Cl)=[O:11].[NH2:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][C:18]([C:24]#[N:25])=[C:17]2[NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Br:33])[CH:28]=1>O1CCCC1>[Br:33][C:29]1[CH:28]=[C:27]([NH:26][C:17]2[C:16]3[C:21](=[CH:22][CH:23]=[C:14]([NH:13][C:10](=[O:11])[CH2:9][Cl:8])[CH:15]=3)[N:20]=[CH:19][C:18]=2[C:24]#[N:25])[CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)CCl
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1cnc2ccc(NC(=O)CCl)cc2c1Nc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.9 %

Procedure:
Triethylamine(0.359 g, 3.55 mmol) and chloroacetyl chloride (0.402 g, 3.55 mmol) were added to an ice cold solution of 1.00 g (2.96 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 12 mL of tetrahydrofuran under N2. After stirring overnight at 25° C., volatile material was removed and the residue was slurried in water and collected. Recrystallization from methanol gave 0.540 g of tan solid: mass spectrum (electrospray, m/e): M+H 415, 417.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]([O:17]CCCC)=[O:16])=[CH:7][C:6]1=[O:22])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O>O1CCOCC1>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]1=[O:22])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1cc(=O)n(CCCC)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCCn1c(=O)cc(C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
A mixture of 2.04 g (6.77 mmols) of Compound b, 0.54 g of sodium hydroxide, 40 ml of water and 40 mt of dioxane was stirred at room temperature for 30 minutes. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluting solvent: chloroform/methanol=5/1) to give 1.44 g (yield: 87%) of Compound a.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([Li])CCC.[CH2:23]1[O:26][CH:24]1[CH3:25]>C1COCC1>[O:11]([C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH2:1][CH2:23][CH:24]([OH:26])[CH3:25])(=[O:3])=[O:4])=[CH:10][CH:9]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC1CO1
Reactant: CS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)CCS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
A solution of 4-phenoxyphenyl methyl sulfone (1.0 g, 4.0 mmol) in 40 mL of THF at −78° C. was treated with n-butyllithium (1.6 mL, 2.5 M in hexanes), stirred 15 minutes at −78° C., treated with propylene oxide (257 μL), stirred from −78° C. to 23° C. over 16 hours, quenched with H2O, extracted with ethyl acetate, washed with brine, dried over Na2SO4, filtered, and concentrated. Purification on silica gel with 1:1 hexanes/ethyl acetate provided 1.1 g (100%) of the desired product.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[NH2:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[C:4]([C:3]1[C:2]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)=[N:10][C:9]([Cl:11])=[CH:8][CH:7]=1)(=[O:5])[NH2:6]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Nc2nc(Cl)ccc2C(N)=O)cc1
Reaction time: 0.17 h
Yield: 106.1 %

Procedure:
To a solution of 2,6-dichloronicotinamide (1 g, 5.24 mmol) and methyl 4-aminobenzoate (0.950 g, 6.28 mmol) in THF (30 mL) was added lithium bis(trimethylsilyl)amide (18.32 mL, 18.32 mmol) at −78° C. The reaction mixture was stirred for 10 min. The dry ice bath was removed and the reaction mixture was stirred at rt for 3.5 h. The reaction mixture was diluted with water and the resulting yellow precipitate was filtered to give 1.7 g of methyl 4-(3-carbamoyl-6-chloropyridin-2-ylamino)benzoate as a yellow solid.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[N:16](S(C3C=CC(C)=CC=3)(=O)=O)[C:17]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=4)[N:21]([CH3:32])[CH:20]=3)=[CH:18][C:11]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>>[CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][C:17]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=4)[N:21]([CH3:32])[CH:20]=3)=[CH:18][C:11]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(-c3cc4c(CNCc5ccccc5)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(-c3cc4c(CNCc5ccccc5)ccnc4[nH]3)cn(C)c2cc1OC
Yield: 73.9 %

Procedure:
Benzyl [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amine is prepared as described in Example 179a starting with 0.070 g of benzyl [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amine instead of the [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]-pyrid-4-ylmethyl] (4-trifluoromethylsulfanylbenzyl)amine used in Example 179a and 0.54 cm3 of 5N potassium hydroxide. 0.038 g of benzyl [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amine is obtained, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[C:21]([C:23]#[N:24])[C:20]3[N:25]=[CH:26][N:27]([CH3:28])[C:19]=3[CH:18]=2)=[CH:13][C:12]=1[C:29]([F:32])([F:31])[F:30].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:23]([C:21]1[C:20]2[N:25]=[CH:26][N:27]([CH3:28])[C:19]=2[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[C:12]([C:29]([F:32])([F:30])[F:31])[CH:13]=2)[N:22]=1)#[N:24]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1cnc2c(C#N)nc(-c3ccc(OCCCN)c(C(F)(F)F)c3)cc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1cnc2c(C#N)nc(-c3ccc(OCCCNS(C)(=O)=O)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methanesulphonyl chloride (31 mg) was added to the solution of 6-[4-(3-Aminopropoxy)-3-(trifluoromethyl)-phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (20 mg) in DCM (1 ml) containing DIPEA (44 uL). The mixture was stirred at rt for 1 hour, then solvent removed under vacuum and residue dissolved in NMP (1 ml) and purified by HPLC to give expected product, N-(3-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)propyl)methanesulfonamide.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[O-]CC.[Na+].C([O:13][C:14](=O)[C:15]([C:24]#[N:25])=[C:16]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH3:17])C>C(O)C>[CH3:17][C:16]1([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:3]([C:1]#[N:2])[C:4](=[O:5])[NH:6][C:14](=[O:13])[CH:15]1[C:24]#[N:25]
Reactant: N#CCC(N)=O
Reactant: CCOC(=O)C(C#N)=C(C)c1cccnc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC1(c2cccnc2)C(C#N)C(=O)NC(=O)C1C#N
Reaction time: 16 h

Procedure:
Cyanoacetamide was stirred with sodium ethoxide in ethanol for 30 minutes. 2-Cyano-3-pyridin-3-yl-but-2-enoic acid ethyl ester was added and allowed to sit for 16 hours. The solution was acidified to pH 4 and partially concentrated under reduced pressure, causing precipitation of product. The product was filtered and allowed to dry. MS (ESI+) for C13H10N4O2 mz 255.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([NH:14][CH3:15])[CH3:13]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:14]([CH2:12][CH3:13])[CH3:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCNC
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Product: CCN(C)S(=O)(=O)c1ccc(Br)cc1
Yield: 27.7 %

Procedure:
According to general procedure C, 4-Bromobenzene sulfonyl chloride (0.40 g, 1.56 mmol) and N-Ethyl-N-methylamine (0.33 mL, 3.90 mmol) were stirred together in dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-ethyl-N-methylbenzenesulfonamide (0.12 g, 28%) was provided after purification. MS (ESI) m/z 278. HPLC purity 99.2% at 210-370 nm, 8.9 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 mm.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[C:6]([N+:15]([O-:17])=[O:16])=[CH:7][C:8]([CH3:14])=[C:9]([CH:13]=1)[C:10](O)=[O:11].P(Cl)(Cl)(Cl)(Cl)[Cl:24]>C1C=CC=CC=1>[F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[C:6]([N+:15]([O-:17])=[O:16])=[CH:7][C:8]([CH3:14])=[C:9]([CH:13]=1)[C:10]([Cl:24])=[O:11]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1cc([N+](=O)[O-])c(Oc2ccc(F)cc2F)cc1C(=O)O
Solvent: c1ccccc1
Product: Cc1cc([N+](=O)[O-])c(Oc2ccc(F)cc2F)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.9 %

Procedure:
A mixture of 5-(2,4-difluorophenoxy)-2-methyl-4-nitrobenzoic acid (1.4 g) and phosphorus pentachloride (1 g) in benzene (10 ml) was stirred for 1 hour at room temperature. The mixture was concentrated under reduced pressure to give an oil of 5-(2,4-difluorophenoxy)-2-methyl-4-nitrobenzoyl chloride (1.6 g). A solution of diethyl malonate (0.88 g) and ethanol (0.5 ml) in ether (5 ml) was added dropwise to a stirred solution of magnesium (132 mg), ethanol (0.2 ml), and carbon tetrachloride (0.3 ml) in ether (5 ml) at room temperature. The mixture was stirred for 1 hour at room temperature and refluxed for 30 minutes. To the resulting mixture was added dropwise a solution of 5-(2,4-difluorophenoxy)-2-methyl-4-nitrobenzoyl chloride (1.6 g) in ether (3 ml) at 5° C. The mixture was stirred for 2 hours at room temperature and refluxed for 1 hour. The reaction mixture was poured into 10% sulfuric acid (40 ml) and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated to give an oil of diethyl 5-(2,4-difluorophenoxy)-2-methyl-4-nitrobenzoylmalonate (2.1 g).