Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:19]([C:20]#[N:21])=[C:18]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[N:17]=[C:16](SC)[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=O)C=1.FC1C=CC(C2CCN(C3C(C#N)=C(OCC(F)(F)F)N=C(S(C)(=O)=O)N=3)CC2)=CC=1.[CH2:72]([CH2:74][NH2:75])[OH:73]>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:19]([C:20]#[N:21])=[C:18]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[N:17]=[C:16]([NH:75][CH2:74][CH2:72][OH:73])[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CSc1nc(OCC(F)(F)F)c(C#N)c(N2CCC(c3ccc(F)cc3)CC2)n1
Reactant: NCCO
Agent: CS(=O)(=O)c1nc(OCC(F)(F)F)c(C#N)c(N2CCC(c3ccc(F)cc3)CC2)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1COCCO1
Product: N#Cc1c(OCC(F)(F)F)nc(NCCO)nc1N1CCC(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 57c, 4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methylsulfanyl-6-(2,2,2-trifluoro-ethoxy)-pyrimidine-5-carbonitrile (example 61a) was oxidized by 3-chloro-perbenzoic acid to the 4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methanesulfonyl-6-(2,2,2-trifluoro-ethoxy)-pyrimidine-5-carbonitrile which was then treated with ethanolamine in dioxane at 40° C. during 4 hours to yield 4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-(2-hydroxy-ethylamino)-6-(2,2,2-trifluoro-ethoxy)-pyrimidine-5-carbonitrile as a clorless oil; MS: [M+H]+=440.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([OH:11])=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:23]I>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([O:11][CH3:23])=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CI
Reactant: COc1ccc(Cn2nc(O)c3cc(Br)cnc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(OC)c3cc(Br)cnc32)cc1
Reaction time: 0.17 h
Yield: 52.7 %

Procedure:
5-Bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-ol (0.200 g, 0.599 mmol) was dissolved in DMF. Sodium hydride (0.0287 g, 0.718 mmol) was added and stirred for 10 minutes. Methyl iodide (0.0448 mL, 0.718 mmol) was added, and the reaction mixture was stirred overnight. The solution was partitioned between water and EtOAc. The organic layer was washed with water (3×), brine, dried over Na2SO4 and concentrated to an oil, which was purified by column chromatography (2:1 hexanes/EtOAc) to give 5-bromo-3-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine (0.11 g, 52.3%) as an oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6](O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([OH:15])=[S:14].C1(C=CC(O)=CC=1)[OH:24].C(=O)(O)[O-].[Na+].S(=O)(=O)(O)O.[Cl-].[Na+]>C(OCC)(=O)C.C(O)=O.O.C(COC)OC>[OH:24][CH:3]1[CH2:4][C:5](=[O:1])[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]([OH:15])=[S:14])=[CH:2]1
Reactant: OC(=S)C(CCCCCC(O)c1ccco1)c1ccccc1
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: O
Solvent: COCCOC
Solvent: O=CO
Product: O=C1CC(O)C=C1CCCCCC(C(O)=S)c1ccccc1
Temperature: 50 °C

Procedure:
To a stirred solution of 54.4 g. of 8-(2-furyl)-8-hydroxy-2-phenylthiooctanoic acid in 815 ml. of glyme and 610 ml. of water is added successively 0.5 g. of hydroquinone, 12.0 g. of sodium bicarbonate and 122 ml. of 90% formic acid. The resulting solution is heated at reflux temperature for 24 hours, cooled to 50° C. to produce a mixture of the 3-hydroxy and 4-hydroxy isomers. This is then treated dropwise with 40 ml. of concentrated sulfuric acid during 15 minutes. The resulting solution is refluxed for 18 hours, cooled, diluted with ethyl acetate and then saturated with sodium chloride. The organic layer is separated, washed with brine, dried and concentrated. The residue is subjected to chromatography on silica gel with chloroform progressively enriched in ether, giving 13.0 g. of the product as an oil, identified by its PMRδ 4.94 (1, broad s, CHOH).
Reaction SMILES: Br[CH2:2][C:3]1[S:12][C:11]2[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8][C:7]3[CH:17]=[CH:18][CH:19]=[CH:20][C:6]=3[C:5]=2[CH:4]=1.[C-:21]#[N:22].[Na+]>C(O)C>[S:12]1[C:11]2[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8][C:7]3[CH:17]=[CH:18][CH:19]=[CH:20][C:6]=3[C:5]=2[CH:4]=[C:3]1[CH2:2][C:21]#[N:22]
Reactant: [C-]#N
Reactant: BrCc1cc2c(s1)-c1ccccc1Sc1ccccc1-2
Agent: [Na+]
Solvent: CCO
Product: N#CCc1cc2c(s1)-c1ccccc1Sc1ccccc1-2
Yield: 93.5 %

Procedure:
To an ethanol solution of 2-bromomethyl-1,8-dithia-dibenzo[e,h]azulene (0.5 g, 1,4 mmole in 8 ml of ethanol), sodium cyanide (0.105 g, 2.1 mmole) was added and the reaction mixture was heated under reflux for 8 hours. When all reactant had been reacted (the course of reaction was followed by thin layer chromatography), the solvent was evaporated and the dry residue was extracted in a system diethyl ether/water. 0.4 g of an oily product were isolated.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O.S(Cl)([Cl:14])=O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([Cl:14])=[O:11]
Reactant: O=C(O)CCCCCCCBr
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CCCCCCCBr
Reaction time: 1 h

Procedure:
8-Bromooctanoic acid (200 g) was added slowly to thionyl chloride (325 ml). The mixture was stirred at 60° for 1 hour. Excess thionyl chloride distilled off in vacuo. The dark oily residue was distilled to give 8-bromooctanoyl chloride as colorless oil, b.p. 112°-114°/0.1-0.3 mm Hg, (202.38, 93%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C.CCOC(C)=O>[CH3:12][N:10]1[CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[CH:9]1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cnc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-phenyl-1H-imidazole 41 (2.01 g, 13.9 mmol) in DMF (30 mL) containing cesium carbonate (6.05 g, 18.6 mmol) at room temperature was added iodomethane (0.950 mL, 15.3 mmol). The reaction mixture was stirred at room temperature for 5 h, diluted with EtOAc, washed with water (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (70% to 100% EtOAc in hexanes) gave 1-methyl-4-phenyl-1H-imidazole 42. Mass spectrum: calculated for C10H10N 158.1; found 159.2 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:11])=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=O)[CH2:13][CH3:14].[OH-].[K+]>C(O)C>[C:16]1([C:12]2[C:13]([CH3:14])=[CH:6][C:5]3[C:4](=[C:3]([O:2][CH3:1])[CH:10]=[CH:9][CH:8]=3)[N:11]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(C=O)c1N
Reactant: CCC(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc2cc(C)c(-c3ccccc3)nc12
Reaction time: 8 h
Yield: 0.1 %

Procedure:
15.3 g (101 mol) of 3-methoxy-2-aminobenzaldehyde and 14 ml (105 mol) of propiophenone are dissolved in 400 ml of ethanol. 1.4 g (25 mol) of potassium hydroxide are added to the reaction mixture and the latter is brought to 100° C. for 8 hours. After cooling the reaction medium, the latter is concentrated under vacuum and 200 ml of water are added. A yellow precipitate forms after a few minutes. The medium is filtered and the yellow precipitate is taken up in a mixture of 300 ml of ethyl ether and of 200 ml of a 1N hydrochloric acid solution. The aqueous phase is extracted with 2×100 ml of ethyl ether. Then, after addition of 300 ml of methylene chloride, 100 ml of a 3N sodium hydroxide solution are added to the aqueous phase. The latter is then extracted with 3×200 ml of methylene chloride. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under vacuum. 21.2 g of 2-phenyl-3-methyl-8-methoxyquinoline are obtained in the form of a pale yellow solid; M.p.=105° C. (Yield: 85%)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[NH2:12])=[CH:7][C:6]=1[N+:14]([O-])=O)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.C(OCC)(=O)C.CCCCCC>CO.C(OCC)(=O)C.[Zn]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[NH2:12])=[CH:7][C:6]=1[NH2:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C(N)=O)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCCCCC
Product: CC(C)(C)c1ccc(C(N)=O)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
38.98 g (596 mmol) of zinc dust were added to a solution of 13.24 g (59.6 mmol) of 2-t-butyl-5-carbamoyl-1-nitrobenzene [prepared as described in step (i) above] in 150 ml of methanol, and then 13 ml of acetic acid were added dropwise over a period of 10 minutes, whilst ice-cooling. The resulting mixture was then stirred at room temperature for 2 hours and then at 50° C. for 30 minutes. At the end of this time, the reaction mixture was diluted with ethyl acetate and filtered using a Celite (trade mark) filter aid. The filtrate was concentrated by evaporation under reduced pressure and the concentrate was dissolved in ethyl acetate. The resulting solution was washed with a saturated aqueous solution of ammonium chloride, with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was crystallized from a mixture of ethyl acetate and hexane, to give 8.94 g (yield 78%) of the title compound, melting at 140.5-142° C. (from ethyl acetate-hexane).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[C:12](=[N:16]O)[CH2:11][CH2:10]3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H][H]>[C].[Pd].C(O)C>[N:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[CH:12]([NH2:16])[CH2:11][CH2:10]3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: ON=C1CCc2cc(N3CCOCC3)ccc21
Agent: [Pd]
Solvent: CCO
Product: NC1CCc2cc(N3CCOCC3)ccc21
Yield: 63.2 %

Procedure:
An ethanol (20 mL) suspension of 5-morpholin-4-yl-indan-1-on-oxime (2.76 g) and 10% palladium carbon (48% water content, 1.0 g) was agitated at room temperature under 0.4 MPa hydrogen atmosphere for 6 hours. After filtering the reaction solution and condensing the filtrate under reduced pressure, 1.64 g of the title compound was obtained by purifying the obtained residue by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system→ethyl acetate-methanol system). The physical properties of the compound are as follows.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].[H-].[Na+].I[CH3:25]>CN(C)C=O>[CH3:25][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21]
Reactant: CI
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Reaction time: 0.25 h
Yield: 102.3 %

Procedure:
To a stirred solution of 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.06 g, 0.20 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added sodium hydride (60% in mineral oil, 0.20 g, 0.50 mmol) at ambient temperature. The mixture was stirred for 15 min, and iodomethane (0.14 g, 1.0 mmol) was added in one portion. The reaction mixture was stirred at ambient temperature for 1 h, and then concentrated to dryness. The residue was purified by flash chromatography with ethyl acetate in hexanes (0% to 30% gradient) to afford 1′-methyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.06 g, 88%): mp 187-190° C.; 1H NMR (300 MHz, CDCl3) δ7.32 (dd, J=7.4, 7.4 Hz, 1H), 7.17 (d, J=7.4 Hz, 1H), 7.06 (t, J=7.4 Hz, 1H), 6.91 (d, J=7.4 Hz, 1H), 6.49 (s, 1H), 6.40 (s, 1H), 4.79 (ABq, 2H), 4.52 (t, J=8.5 Hz, 2H), 3.28 (s, 3H), 2.98 (t, J=8.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 177.7, 161.6, 161.1, 142.9, 132.7, 128.6, 123.6, 123.2, 120.0, 119.7, 118.8, 108.1, 93.0, 80.4, 72.2, 57.6, 28.9, 26.6; MS (ES+) m/z 294.1 (M+1).
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]([F:20])=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(OC)(O[CH3:25])(=O)=O.[OH-].[K+]>C(#N)C>[F:20][C:11]1[C:10]([N:9]([CH3:25])[C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cccc(NC(=O)c2ccccc2)c1F
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: COC(=O)c1cccc(N(C)C(=O)c2ccccc2)c1F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
Methyl 3-benzamido-2-fluorobenzoate (8.75 g, 32.0 mmol) was dissolved in acetonitrile (200 ml). Dimethyl sulfate (4.3 g, 34.1 mmol) and potassium hydroxide (2.63 g, 39.8 mmol) were sequentially added thereto, and the reaction mixture was agitated for 30 minutes at 60° C. The mixture was cooled to room temperature, and then was concentrated. Ethyl acetate was added to the concentration residue, and the mixture was washed with water and dried over anhydrous sodium sulfate. The sodium sulfate was filtered away, and the filtrate was concentrated under reduced pressure. n-hexane was added to the concentration residue, as a result of which 8.00 g (yield: 87%) of the indicated compound was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]1[C:19](=[O:38])[CH2:20][NH:21][C:22](=[O:37])[NH:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:25][C:26]([O:28]CC)=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>CO.O>[C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]1[C:19](=[O:38])[CH2:20][NH:21][C:22](=[O:37])[NH:23][CH:24]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:25][C:26]([OH:28])=[O:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(NC(=O)NCC(=O)N1C(C(=O)OC(C)(C)C)CCC1c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)C1CCC(c2ccccc2)N1C(=O)CNC(=O)NC(CC(=O)O)c1ccccc1
Yield: 56.9 %

Procedure:
By proceeding in a fashion similar to that described in Example 9, but starting from 3.9 g of ethyl (2RS,5SR)-3-{3-[2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}-3-phenylpropionate in solution in 60 cm3 of methanol and 0.45 g of potassium hydroxide dissolved in 20 cm3 of water and after treatment, 2.1 g of (2RS,5SR)-3-{3-[2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2oxoethyl]ureido}-3-phenylpropionic acid are obtained [proton NMR (250 MHz, DMSO D6, δ in ppm), 2 rotamers at room temperature, peak coalescence at 120° C.; 15. (bs, 9H, (CH3)3); 2.5 (t, 2H, CH2); 2.8 (t, 2H, CH2); 6.8 to 7.60 (m, 9H, aromatic). Infrared spectrum (KBr), characteristic bands in cm-1 : 3380, 3700 to 2250 with a maximum at 2625, 3160, 3060, 3030, 2980, 2930, 2880, 1735, 1635, 1610, 1595, 1560, 1495, 1450, 1440, 1395, 1370, 1310, 1225, 1155, 905, 890, 865, 840, 790, 760, 705].
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[N:6][CH:7]=[C:8]([C:10]([CH3:12])=[CH2:11])[CH:9]=1.C(O)(C(F)(F)F)=O>>[CH2:11]=[C:10]([C:8]1[CH:7]=[N:6][CH:5]=[C:4]([CH:9]=1)[CH:3]=[O:2])[CH3:12]
Reactant: C=C(C)c1cncc(C(OC)OC)c1
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)c1cncc(C=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3-(dimethoxymethyl)-5-(prop-1-en-2-yl)pyridine (2.2 g, 11.3 mmol), TFA (5.2 ml, 67.8 mmol) was added at 0° C., and the reaction mixture was stirred at rt for 16 h. Then volatiles were removed under vacuum and the reaction mixture was diluted with ether. Ether layer was washed with aqueous sodium bicarbonate solution, water, brine and dried. The organic layer was dried and evaporated to provide 5-(prop-1-en-2-yl)nicotinaldehyde.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])(C)(C)C.Cl>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1ccccc1O
Agent: Cl
Solvent: ClCCl
Product: NCCNC(=O)c1ccccc1O
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
To a stirring solution of [2-(2-hydroxy-benzoylamino)-ethyl]-carbamic acid tert-butyl ester (1.0 g, 3.57 mmol) in CH2Cl2 (20 mL) was added 2 M HCl (10.71 mL, 21.42 mmol). The reaction was stirred for 30 min and then conc in vacuo to yield a white solid. The solid was rinsed with Et2O and dissolved in 20 mL of MeOH. To the solution was added DiaionWaz21 J resin (5 g, Supelco). The solution was stirred for 30 min and then filtered. The filtrate was conc in vacuo to yield 629 mg (98%) of the product as a colorless oil. MS (ESI): 181 (M+H).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18]C)=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][C:21]([OH:23])=O)[C:8]=2[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[CH2:33][N:34](C(C)C)[CH:35](C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CNC.[OH-].[K+]>C(Cl)Cl.CCOC(C)=O>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][C:21]([N:34]([CH3:35])[CH3:33])=[O:23])[C:8]=2[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OC)cc3)n(CC(=O)O)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2CC(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91 %

Procedure:
A solution (0.04 M) of [3-cyclohexyl-6-(methoxycarbonyl)-2-(4-methoxyphenyl)-1H-indol-1-yl]acetic acid (from Step 3) in CH2Cl2 was treated with DIPEA (4 eq.), HATU (2 eq.) and dimethylamine hydrochloride (1.5 eq.). The solution was stirred at 25° C. for 12 h. The mixture was diluted with EtOAc and then washed sequentially with aqueous HCl (1 N), NaOH (2 N) and brine. The dried organic layer was concentrated and the residue dissolved in a 1:1 mixture of THF/H2O. The resulting solution (0.05 M) was treated with aqueous KOH (1 N, 4 eq.), then stirred at 70° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was treated with aqueous HCl (1 N) and extracted with EtOAc. The dried organic phase was washed with brine, dried and then concentrated to give the title compound (91%) as a solid. 1H NMR (300 MHz, DMSO-d6, 300K) δ 1.14-1.35 (m, 3H), 1.63-1.98 (m, 7H), 2.54-2.65 (m, 1H), 2.83 (s, 3H), 2.94 (s, 3H), 3.85 (s, 3H), 4.86 (s, 2H), 7.09 (d, J 8.6, 2H), 7.25 (d, J 8.6, 2H), 7.66 (d, J 8.4, 1H), 7.82 (d, J 8.4, 1H), 7.92 (s, 1H), 12.45 (br s, 1H); MS (ES+) m/z 435 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[N:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[NH2:15][C:16]1[CH:17]=[C:18]([C:22]([C:24]2[C:28]3[CH:29]=[N:30][CH:31]=[C:32]([F:33])[C:27]=3[N:26]([CH:34]([CH3:37])[CH2:35][OH:36])[CH:25]=2)=[O:23])[CH:19]=[N:20][CH:21]=1>>[F:33][C:32]1[C:27]2[N:26]([CH:34]([CH3:37])[CH2:35][OH:36])[CH:25]=[C:24]([C:22]([C:18]3[CH:17]=[C:16]([NH:15][C:8](=[O:10])[CH2:7][N:6]4[C:2]([CH3:1])=[CH:3][C:4]([C:11]([F:14])([F:13])[F:12])=[N:5]4)[CH:21]=[N:20][CH:19]=3)=[O:23])[C:28]=2[CH:29]=[N:30][CH:31]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Reactant: CC(CO)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Product: Cc1cc(C(F)(F)F)nn1CC(=O)Nc1cncc(C(=O)c2cn(C(C)CO)c3c(F)cncc23)c1

Procedure:
Prepared according to Method M (Example 206) using [5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid and (5-aminopyridin-3-yl)[7-fluoro-1-(2-hydroxy-1-methylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]methanone (Enantiomer 2, Preparation 26). The residue was purified using preparative TLC eluting with 5% MeOH in EtOAc.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:28][C:27]([CH3:30])([CH3:29])[O:26][C:25](=[O:31])[C:24]=2[CH:32]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][NH:19][C:20]3[CH:21]=[CH:22][C:23]4[O:28][C:27]([CH3:29])([CH3:30])[O:26][C:25](=[O:31])[C:24]=4[CH:32]=3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C#Cc2ccc(C=O)cc2)cc1
Reactant: CC1(C)OC(=O)c2cc(N)ccc2O1
Product: COc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Yield: 53.8 %

Procedure:
The title compound was prepared following procedure described in Example 1, step c) from 4-[(4-methoxyphenyl)ethynyl]benzaldehyde (1.31 g; 5.53 mmol, intermediate which may be obtained according to methods disclosed in EP03103780.7) and 6-amino-2,2-dimethyl-benzo[1,3]dioxin-4-one (1.07 g; 5.53 mmol). The crude (1.7 g) was purified by recrystallisation from MeOH/EtOAc to give 1.23 g (54%) of the title compound as a yellow powder. HPLC, Rt: 4.77 min (purity: 77%). 1H NMR (CDCl3) δ: 7.46 (m, 4H), 7.31 (d, J=7.9 Hz, 2H), 7.15 (d, J=2.6 Hz, 1H), 6.85 (d, J=8.5 Hz, 2H), 6.78 (m, 2H), 4.30 (s, 2H), 3.81 (s, 3H), 1.68 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5](I)=[CH:4][N:3]=1.[CH3:10][CH:11]([CH3:14])[C:12]#[CH:13]>CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([C:13]#[C:12][CH:11]([CH3:14])[CH3:10])=[CH:4][N:3]=1
Reactant: Nc1cc(Cl)ncc1I
Reactant: C#CC(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)C#Cc1cnc(Cl)cc1N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-chloro-5-iodopyridin-4-amine (Compound 11, 2.55 g, 10.0 mmol) in Et3N (35 ml) was added Pd(PPh3)2Cl2 (70 mg, 0.10 mmol), Cul (19 mg, 0.10 mmol), and 3-methyl-1-butyne (1.2 ml, 12 mmol). The reaction was stirred at room temperature for 20 h and was quenched with H2O, extracted with EtOAc (×2). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) to yield the title compound as an off-white solid.
Reaction SMILES: CS(O)(=O)=O.[Cl:6][C:7]1[C:15]2[N:14]([CH2:16][CH2:17][CH2:18]O)[C:13](=[O:20])[NH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.[C:21]1([N:27]2[C:31]3([CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[C:30](=[O:37])[NH:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[Cl:6][C:7]1[C:15]2[N:14]([CH2:16][CH2:17][CH2:18][N:34]3[CH2:33][CH2:32][C:31]4([N:27]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH2:28][NH:29][C:30]4=[O:37])[CH2:36][CH2:35]3)[C:13](=[O:20])[NH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: O=c1[nH]c2cccc(Cl)c2n1CCCO
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=C1NCN(c2ccccc2)C12CCN(CCCn1c(=O)[nH]c3cccc(Cl)c31)CC2
Yield: 17 %

Procedure:
A mixture of 4.2 parts of 4-chloro-1,3-dihydro-3-(3-hydroxypropyl)-2H-benzimidazol-2-one methane sulfonate, 2.5 parts of 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one, 10 parts of sodium carbonate and 80 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. The reaction mixture is cooled and water is added. The precipitated product is filtered off and crystallized twice from a mixture of N,N-dimethylformamide and water, yielding 0.8 parts (17%) of 8-[3-(7-chloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one; mp. 258.4° C.