Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:11]([O:13]C)=[O:12])[C:10]2[CH:9]=[CH:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO.O>[C:1]1([C:11]([OH:13])=[O:12])[C:10]2[CH:9]=[CH:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc2c1C=CCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc2c1C=CCC2
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5,6-dihydronaphthalene-1-carboxylate (0.276 g, 1.466 mmol) in methanol (30 ml) was added 1N aqueous sodium hydroxide solution (8.80 ml, 8.80 mmol) and the mixture was stirred at 70° C. for 8 hrs. The reaction solution was diluted with water, acidified with dilute hydrochloric acid and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was crystallized from hexane to give the objective substance.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)[NH2:7])(=[O:3])[CH3:2].Cl[C:15]1[N:23]=[CH:22][N:21]=[C:20]2[C:16]=1[NH:17][CH:18]=[N:19]2.Cl.[OH-].[K+]>O>[C:1]([C:4]1[CH:5]=[C:6]([NH:7][C:15]2[N:23]=[CH:22][N:21]=[C:20]3[C:16]=2[NH:17][CH:18]=[N:19]3)[CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)(=[O:3])[CH3:2]
Reactant: Clc1ncnc2nc[nH]c12
Reactant: CC(=O)c1cc(N)cc(C(C)=O)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1cc(Nc2ncnc3nc[nH]c23)cc(C(C)=O)c1
Reaction time: 0.17 h
Yield: 90.4 %

Procedure:
A suspension of 3,5-diacetylaniline (0.531 g) in water (10 mL) was treated with 6-chloropurine (0.464 g) and concentrated HCl (0.25 mL) and heated at reflux for 30 min After cooling the mixture was treated with 6 mL of aqueous 1N KOH. The mixture was stirred for 10 min and the solid was filtered out, washed with water, and dried, to give 0.80 g of 6-[(3,5-diacetylphenyl)amino]purine, mp dec 340°-350° C.
Reaction SMILES: Cl[C:2]1[N:21]=[C:5]2[C:6]([O:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH2:22]([N:24]1[CH:28]=[C:27]([NH2:29])[CH:26]=[N:25]1)[CH3:23]>>[CH2:22]([N:24]1[CH:28]=[C:27]([NH:29][C:2]2[N:21]=[C:5]3[C:6]([O:10][C:11]4[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=4)=[CH:7][CH:8]=[CH:9][N:4]3[N:3]=2)[CH:26]=[N:25]1)[CH3:23]
Reactant: CS(=O)(=O)c1ccc(Oc2cccn3nc(Cl)nc23)cc1
Reactant: CCn1cc(N)cn1
Product: CCn1cc(Nc2nc3c(Oc4ccc(S(C)(=O)=O)cc4)cccn3n2)cn1

Procedure:
A well stirred mixture of 2-amino-[1,2,4]triazolo[1,5-a]pyridine-8-ol (0.300 g, 2.00 mmol), 1-fluoro-4-methanesulfonyl-benzene (0.418 g, 2.40 mmol), N,N-dimethylacetamide (2 mL) and potassium tert-butoxide (0.448 g, 4.00 mmol) was heated at 130° C. for 18 h under an argon atmosphere. The reaction mixture was evaporated in vacuo and partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated in vacuo to furnish a crude product. The crude product was purified by preparative Gilson HPLC method to yield a pure product, which was triturated from a mixture of dichloromethane, methanol, ether and hexane. 8-(4-Methanesulfonyl-phenoxy)-[1,2,4-triazolo[1,5-a]pyridin-2-ylamine was isolated as a white solid (125 mg, 20%). MP=245-247° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.53 (d, J=6.56 Hz, 1H), 7.87 (d, J=8.77 Hz, 2H), 7.36 (d, J=7.73 Hz, 1H), 7.15 (d, J=8.76 Hz, 2H), 6.92 (t, J=7.28 Hz, 1H), 6.13 (s, 1H), 3.19 (s, 3H). MS=305 (MH)+. 211b) 2-Chloro-8-(4-methanesulfonyl-phenoxy)-[1,2,4]triazolo[1,5-a]pyridine was prepared in a manner analogous to Example 68a. Product was isolated as a yellow solid (0.455 g, 80%). MP=202-204° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.44 (d, J=6.77 Hz, 1H), 7.98 (d, J=8.08 Hz, 2H), 7.21 (t, J=7.76 Hz, 3H), 7.08 (t, J=7.52 Hz, 1H), 3.09 (s, 3H). MS=324 (MH)+. 211c) (1-Ethyl-1H-pyrazol-4-yl)-[8-(4-methanesulfonyl-phenoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was prepared from 2-chloro-8-(4-methanesulfonyl-phenoxy)-[1,2,4]triazolo[1,5-a]pyridine (0.065 g, 0.20 mmol) and 1-ethyl-1H-pyrazol-4-ylamine (0.029 g, 0.26 mmol) in a manner analogous to Example 2d. Product was isolated as a tan solid (45 mg, 56%). MP=183-185° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.27 (s, 1H), 8.67 (d, J=6.51 Hz, 1H), 7.89 (d, J=7.72 Hz, 2H), 7.68 (s, 1H), 7.45 (d, J=7.74 Hz, 1H), 7.35 (s, 1H), 7.22 (d, J=7.29 Hz, 2H), 7.00 (t, J=7.29 Hz, 1H), 4.055 (q, J=7.18 Hz, 2H), 3.20 (s, 3H), 1.32 (t, J=7.06 Hz, 3H). MS=399 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][C:10]=1[F:18].[NH2:19][C:20]1[C:21]([N:29]2[CH2:34][C@H:33]([C:35]([F:38])([F:37])[F:36])[CH2:32][C@H:31]([NH:39]C(=O)OC(C)(C)C)[CH2:30]2)=[C:22]2[CH2:28][CH2:27][O:26][C:23]2=[N:24][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:39][C@H:31]1[CH2:32][C@@H:33]([C:35]([F:37])([F:38])[F:36])[CH2:34][N:29]([C:21]2[C:20]([NH:19][C:15]([C:13]3[CH:12]=[CH:11][C:10]([F:18])=[C:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[N:14]=3)=[O:17])=[CH:25][N:24]=[C:23]3[O:26][CH2:27][CH2:28][C:22]=23)[CH2:30]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2c(N)cnc3c2CCO3)C1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N[C@H]1C[C@@H](C(F)(F)F)CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCO3)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.6 %

Procedure:
To a mixture of 6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (38.7 mg, 0.153 mmol), tert-butyl [(3S,5R)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate (51.4 mg, 0.128 mmol) and HATU (178.7 mg, 0.4700 mmol) was added DMF (2.0 mL) followed by DIPEA (159.5 mg, 1.234 mmol). The reaction mixture was stirred at room temperature for 3 h, and then concentrated under reduced pressure. To the resulting residue was added DCM (2.0 mL), followed by TFA (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (13.5 mg, 20%). LCMS calc. for C25H22F6N5O2 (M+H)+: m/z=538.2. found 538.2.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:27]([O:29]C)=O)=[N:4][C:5]([C:8]2[CH:9]=[C:10]3[CH:16]=[CH:15][N:14]([Si](C(C)C)(C(C)C)C(C)C)[C:11]3=[N:12][CH:13]=2)=[CH:6][CH:7]=1.O.[CH:32]([NH2:34])=O>>[NH:14]1[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]4[N:1]=[CH:32][NH:34][C:27](=[O:29])[C:3]=4[N:4]=3)[CH:9]=[C:10]2[CH:16]=[CH:15]1
Reactant: COC(=O)c1nc(-c2cnc3c(ccn3[Si](C(C)C)(C(C)C)C(C)C)c2)ccc1N
Reactant: NC=O
Solvent: O
Product: O=c1[nH]cnc2ccc(-c3cnc4[nH]ccc4c3)nc12
Yield: 83 %

Procedure:
3.80 g of methyl 3-amino-6-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-pyridine-2-carboxylate in 60 ml of formamide are heated at 120° C. under nitrogen in a flask until the reaction is complete (HPLC check, about 52 hours). The cooled reaction solution is added to about 50 ml of water, during which a precipitate precipitates out. This is filtered off with suction and dried, giving 2.00 g of 6-(1H-pyrrolo[2,3-b]pyridin-5-yl)-3H-pyrido[3,2-d]pyrimidin-4-one as orange solid (yield 83%, content 98%); MS-FAB (M+H+)=264.1; Rf (polar method): 1.28 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Br:9])=[CH:4][C:3]=1[F:10].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(=O)CC>[CH2:17]([O:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Br:9])=[CH:4][C:3]=1[F:10])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cc(F)c(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Fc1cc(OCc2ccccc2)c(F)cc1Br
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 21 g of 1-hydroxy-4-bromo-2,5-difluoro-benzene in 2-butanone (300 ml) and was added potassium carbonate (20.8 g) and benzylbromide (24 mL). The reaction mixture was boiled while stirring for 1.5 hours. After cooling to room temperature the mixture was partitioned between ethyl acetate and water. Organic phases were pooled, dried with MgSO4 and concentrated in vacuo. The residue was then purified by column chromatography (heptane/silica gel) to give 25.3 g of the title compound.
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:15]([O-])=O)=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11].CCO.CC(O)=O>CCOC(C)=O.[Pd]>[NH2:15][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH:2]([F:1])[F:18])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cc(OCC(F)F)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1cc(OCC(F)F)ccc1N
Reaction time: 24 h

Procedure:
21 g of methyl 5-(2,2-difluoroethoxy)-2-nitrobenzoate obtained in stage 3.1 and 1 g of Pd/C (10%) in a mixture of 300 ml of AcOEt, 50 ml of EtOH and 5 ml of AcOH are stirred at AT under a hydrogen atmosphere for 24 h 00.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([C@H:10]2[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11]2)=[O:9])[CH:5]=[CH:4][CH:3]=1.[F:17][C:18]1[CH:39]=[CH:38][C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][CH:24]=2)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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.Cl[Pd]Cl.[Fe+2]>[CH3:15][C:12]1([CH3:16])[O:11][C@@H:10]([C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:26]3[CH:25]=[CH:24][C:23]([O:22][C:21]4[CH:20]=[CH:19][C:18]([F:17])=[CH:39][CH:38]=4)=[CH:28][CH:27]=3)[N:7]=2)=[O:9])[CH2:14][O:13]1
Reactant: CC1(C)OC[C@H](C(=O)c2cccc(Br)n2)O1
Reactant: CC1(C)OB(c2ccc(Oc3ccc(F)cc3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC1(C)OC[C@H](C(=O)c2cccc(-c3ccc(Oc4ccc(F)cc4)cc3)n2)O1
Temperature: 100 °C
Yield: 79 %

Procedure:
To a mixture of (R)-(6-bromopyridin-2-yl)(2,2-dimethyl-1,3-dioxolan-4-yl)methanone (0.574, g, 2.01, mmol) in dioxane (10, mL) was added 2-(4-(4-fluorophenoxyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.691, g, 2.20 mmol), 2M aqueous Na2CO3, (2.0, mL, 4.0, mmol), and PdCl2(dppf) (0.086, g, 0.11 mmol). The reaction vessel was flushed with argon, sealed, and heated at 100° C. for 3, hours. After cooling, the reaction mixture was evaporated in vacuo and the residue chromatographed over silica gel with 5-40% EtOAc in hexanes. The product fractions were evaporated in vacuo to give (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)(6-(4-(4-fluorophenoxy)phenyl)pyridin-2-yl)methanone as a very pale tan thick oil (0.621, g, 1.58, mmol, 79% yield). LC/MS: m/z=394.2, [M+H]+, .
Reaction SMILES: Cl.O1CCCCC1[O:8][CH2:9][CH2:10][C:11]1([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:15][CH2:14][NH:13][CH2:12]1>CCOCC.CO.C(OC(C)C)(C)C.CCOCC>[OH:8][CH2:9][CH2:10][C:11]1([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:15][CH2:14][NH:13][CH2:12]1
Reactant: Clc1ccc(C2(CCOC3CCCCO3)CCNC2)cc1Cl
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)OC(C)C
Solvent: CO
Product: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Temperature: 25 °C
Yield: 101.2 %

Procedure:
A solution of hydrogen chloride in ether is added to a solution of 3.4 g of 3-tetrahydropyranyloxyethyl-3-(3,4-dichlorophenyl)pyrrolidine in 20 ml of methanol until the pH is 1. The mixture is stirred for half an hour at room temperature and concentrated to dryness, the residue is taken up in water, rendered basic with a solution of sodium hydroxide and extracted with dichloromethane and the extract is washed with a saturated solution of NaCl, dried over Na2SO4 and evaporated to dryness to give an oil. This oil is taken up in 20 ml of an isopropyl ether/ether mixture (50/50 v/v). After stirring and filtration, the product is washed with ethyl ether and dried under vacuum over P2O5. 2.6 g of the expected product are isolated.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH:14]2[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]2)[CH2:10][C@H:9]1[C:22]([O:24][CH3:25])=[O:23])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>ClCCCl.CN(C1C=CN=CC=1)C>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH:14]2[CH2:19][CH2:18][C:17]([F:20])([F:21])[CH2:16][CH2:15]2)[C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:10][C@H:9]1[C:22]([O:24][CH3:25])=[O:23])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)[C@@H]1C[C@H](NC2CCC(F)(F)CC2)CN1C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: COC(=O)[C@@H]1C[C@H](N(C(=O)C(C)(C)C)C2CCC(F)(F)CC2)CN1C(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
Methyl (2S,4S)-1-BOC-4-[(4,4-difluorocyclohexyl)amino]pyrrolidine-2-carboxylate (1.03 g, 2.84 mmol) obtained in Step A was dissolved in DCE (5 mL) and TEA (5 mL) and DMAP (0.36 g, 2.84 mmol) were added thereto. Commercially available pivaloyl chloride (1.03 g, 8.52 mmol) was also added thereto. The reaction solution was heated to 90° C. and stirred for 24 hours. After the reaction was completed, the solvent was removed in vacuo and saturated NaHCO3 aqueous solution was added. The solution was extracted with EtOAc. The extracted organic solution was washed with 1N HCl solution, dried over MgSO4, concentrated in vacuo and purified by column chromatography (eluent: EtOAc/Hex=1/4) to give the title compound (1.04 g, 82%).
Reaction SMILES: [CH2:1](/[C:3](=[CH:6]\[CH2:7][C@H:8]1[CH2:12][CH:11]=[C:10]([CH3:13])[C:9]1([CH3:15])[CH3:14])/[CH:4]=[O:5])[CH3:2].CC1[C@H]2C(C)(C)[C@H](C2)CC=1>>[CH2:1](/[C:3](=[CH:6]\[CH2:7][C@H:8]1[CH2:12][CH:11]=[C:10]([CH3:13])[C:9]1([CH3:14])[CH3:15])/[CH2:4][OH:5])[CH3:2]
Reactant: CC/C(C=O)=C\C[C@H]1CC=C(C)C1(C)C
Agent: CC1=CC[C@H]2C[C@@H]1C2(C)C
Product: CC/C(=C\C[C@H]1CC=C(C)C1(C)C)CO

Procedure:
In the same manner as in Example 2, the title compound was prepared by hydrogenating (E)-(R)-2-ethyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)-2-buten-1-al which was synthesized from (1S,5S)-α-pinene having an optical purity varying from 50% e.e. to 92% e.e.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[N:29][CH:30]=3)=[CH:21][CH:20]=1)[C:13]([CH2:33][C:34]([CH3:39])([CH3:38])[C:35]([OH:37])=[O:36])=[C:12]2[S:40][C:41]([CH3:44])([CH3:43])[CH3:42].[OH-].[Na+:46]>C(O)C.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[N:29][CH:30]=3)=[CH:23][CH:24]=1)[C:13]([CH2:33][C:34]([CH3:39])([CH3:38])[C:35]([O-:37])=[O:36])=[C:12]2[S:40][C:41]([CH3:44])([CH3:43])[CH3:42].[Na+:46]
Reactant: COc1ccc(-c2ccc(Cn3c(CC(C)(C)C(=O)O)c(SC(C)(C)C)c4cc(OCc5ccccn5)ccc43)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2ccc(Cn3c(CC(C)(C)C(=O)[O-])c(SC(C)(C)C)c4cc(OCc5ccccn5)ccc43)cc2)cn1

Procedure:
3-[5-(Pyrid-2-ylmethoxy)-3-(2-methyl-2-propylthio)-1-[4-(2-methoxypyrid-5-yl)benzyl]indol-2-yl]-2,2-dimethylpropionic acid (14.2 g) was dissolved in ethanol (233 ml) and 1N NaOH in water (23.75 ml) was added. After removal of the solvent, 15.7 g of sodium 3-[5-(pyrid-2-ylmethoxy)-3-(2-methyl-2-propylthio)-1-[4-(2-methoxypyrid-5-yl)benzyl]indol-2-yl]-2,2-dimethylpropionate was obtained.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)=[C:2]=[O:3].[CH:27]([C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][C:31]=1[NH:37][C:38]([NH2:40])=[S:39])([CH3:29])[CH3:28]>>[CH:27]([C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][C:31]=1[NH:37][C:38]([NH:40][C:2]([NH:1][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:25])([F:24])[F:26])=[CH:18][CH:17]=3)[N:12]=2)[CH:6]=1)=[O:3])=[S:39])([CH3:29])[CH3:28]
Reactant: O=C=NCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Reactant: Cc1ccc(C(C)C)c(NC(N)=S)c1
Product: Cc1ccc(C(C)C)c(NC(=S)NC(=O)NCc2cccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)c2)c1

Procedure:
The title compound was prepared as described in Example 75 using 3-(3-(isocyanatomethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CB34) and 1-(2-isopropyl-5-methylphenyl)thiourea and isolated as an off-white solid (0.181 g, 42%).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][CH2:5][CH2:6][CH2:7][OH:8].C(S[C:13]1[N:14]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[CH:27][CH:26]=2)[C:15](=[O:24])[C:16]2[CH:22]=[CH:21][C:20](=[O:23])[NH:19][C:17]=2[N:18]=1)CC.O>O1CCCC1>[CH3:3][S:4][CH2:5][CH2:6][CH2:7][O:8][C:13]1[N:14]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[CH:29][CH:30]=2)[C:15](=[O:24])[C:16]2[CH:22]=[CH:21][C:20](=[O:23])[NH:19][C:17]=2[N:18]=1
Reactant: CCCSc1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reactant: CSCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CSCCCOc1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of sodium hydride (60% in oil, 48 mg) in tetrahydrofuran (5 ml) was added 3-(methylsulfanyl)propan-1-ol (0.206 ml) at room temperature, and the mixture was stirred at room temperature for 10 min. To the reaction mixture was added 2-(propylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (165 mg), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (acetic acid ethyl/hexane) to give the title compound (96 mg).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:41]=[CH:40][C:16]([CH2:17][N:18]([C:27]3[CH:28]=[CH:29][C:30]4[C:35](=[O:36])[O:34]C(C)(C)[O:32][C:31]=4[CH:39]=3)[C:19]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]>C1COCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:41]=[CH:40][C:16]([CH2:17][N:18]([C:19]([CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)=[O:20])[C:27]3[CH:28]=[CH:29][C:30]([C:35]([OH:36])=[O:34])=[C:31]([OH:32])[CH:39]=3)=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(C(=O)C3CCCCC3)c3ccc4c(c3)OC(C)(C)OC4=O)cc2)cc1
Solvent: C1CCOC1
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)C3CCCCC3)c3ccc(C(=O)O)c(O)c3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure C using N-{4-[(4-butylphenyl)ethynyl]benzyl}-N-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-7-yl)cyclohexanecarboxamide in the presence of THF as a brown powder (78%). 1H NMR (CDCl3, 300 MHz) δ 10.64 (s, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.41 (m, 4H), 7.14 (m, 4H), 6.68 (m, 1H), 6.52 (d, J=8.7 Hz, 1H), 4.87 (s, 2H), 2.60 (t, J=7.1 Hz, 2H), 2.25 (m, 1H), 1.80-1.50 (m, 8H), 1.41-0.95 (m, 6H), 0.91 (t, J=7.3 Hz, 3H). M− (ESI): 507.9. M+ (ESI): 510.0. HPLC, Rt: 5.92 min (Purity: 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][NH2:9])=[CH:5][CH:4]=1>CO>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH:7]([NH:9][CH2:8][CH2:7][C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:8]#[N:9])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCN)cc1
Solvent: CO
Product: COc1ccc(CCNC(C#N)c2ccc(OC)cc2)cc1
Temperature: 125 °C

Procedure:
4-Methoxyphenethylamine (1.2 mL, 8.2 mmol) and methanol (0.5 mL) are added to the crude material obtained above. The solution is heated to 125° C. for 15 minutes in a microwave reaction vessel after which the solution is concentrated in vacuo and the crude product obtained is used without further purification.
Reaction SMILES: [CH:1]1([N:4]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:5](=[O:22])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)=[N:8][CH:7]=2)[CH2:3][CH2:2]1.[CH2:29]([N:31](C(C)C)C(C)C)C.O.C(OCC)(=O)C>ClCCl.O1CCCC1>[C:29]([N:26]1[CH2:27][CH2:28][CH:23]([N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5](=[O:22])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]=[CH:14][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[CH:16][CH:17]=3)=[N:8][CH:7]=2)[CH2:24][CH2:25]1)#[N:31]
Reactant: CCN(C(C)C)C(C)C
Reactant: CS(=O)(=O)c1ccc(-c2ccc(C(=O)N(C3CCNCC3)C3CC3)cn2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2ccc(C(=O)N(C3CC3)C3CCN(C#N)CC3)cn2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Bromonitrile (44 mg) is added to a solution of N-cyclopropyl-6-(4-methanesulfonyl-phenyl)-N-piperidin-4-yl-nicotinamide (111 mg) and ethyldiisopropylamine (238 μL) in dichloromethane (2.5 mL) and tetrahydrofuran (2.5 mL). The reaction mixture is stirred for two days at room temperature prior to the addition of water and ethyl acetate. The organic phase is separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The crude product is used without further purification for the next reaction step. LC (method 7): tR=0.87 min; Mass spectrum (ESI+): m/z=425 [M+H]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([N:26]1[C:30]2[C:31]([C:35](OC)=[O:36])=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+].C(OCC)(=O)C>O1CCCC1>[C:7]([N:26]1[C:30]2[C:31]([CH2:35][OH:36])=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1cccc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c12
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1cccc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of 0.210 g of lithium aluminium hydride in 15 ml of anhydrous tetrahydrofuran is cooled under argon to 0° C. A solution of 2.300 g of methyl 3-trityl-3H-benzimidazole-4-carboxylate in 25 ml of anhydrous tetrahydrofuran is added dropwise to the suspension over 5 minutes and the reaction mixture is subsequently stirred at 0° C. over one hour. The reaction mixture is subsequently poured slowly onto 80 ml of 1M sodium potassium tartrate solution and admixed with ethyl acetate (100 ml). The phases are separated and the aqueous phase is extracted with (100 ml) of ethyl acetate. The combined organic phases are washed with 100 ml of water, dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a reddish foam and is used for the next stage without further purification. Rt=4.04.