Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:9][CH2:10][N:11]([CH3:16])[CH2:12][CH2:13][CH2:14][NH2:15])=[CH:4][CH:3]=1.[C:23]([NH:25][C:26](=[N:34][CH2:35][CH2:36][S:37][CH2:38][C:39]1[N:40]=[C:41]([NH:44][C:45]([NH2:47])=[NH:46])[S:42][CH:43]=1)OC1C=CC=CC=1)#[N:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH2:14][NH:15][C:26]([NH:25][C:23]#[N:24])=[N:34][CH2:35][CH2:36][S:37][CH2:38][C:39]2[N:40]=[C:41]([NH:44][C:45]([NH2:47])=[NH:46])[S:42][CH:43]=2)[CH3:16])=[CH:4][CH:3]=1
Reactant: CN(CCCN)CCC(c1ccc(Cl)cc1)c1ccccn1
Reactant: N#CNC(=NCCSCc1csc(NC(=N)N)n1)Oc1ccccc1
Product: CN(CCCNC(=NCCSCc1csc(NC(=N)N)n1)NC#N)CCC(c1ccc(Cl)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.8 g (2.5 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,3-propanediamine and 0.94 g (2.5 mmol) of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a dry foam; MS (+FAB method): m/z (rel. int.[%])=599 ([M+H]+,7), 230 (100); IR (KBr): 2161 cm-1 (C≡N). For analytical purposes a sample is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from ether/isopropanol; m.p.: from 160° C. with decomposition.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[C:8]([CH3:20])=[CH:9][N:10]2[CH:14]([CH2:15][C:16](OC)=[O:17])[CH2:13][S:12][C:11]=12)=[O:6])([CH3:3])[CH3:2].[NH3:21]>CO>[CH:1]([O:4][C:5]([C:7]1[C:8]([CH3:20])=[CH:9][N:10]2[CH:14]([CH2:15][C:16]([NH2:21])=[O:17])[CH2:13][S:12][C:11]=12)=[O:6])([CH3:3])[CH3:2]
Reactant: N
Reactant: COC(=O)CC1CSc2c(C(=O)OC(C)C)c(C)cn21
Solvent: CO
Product: Cc1cn2c(c1C(=O)OC(C)C)SCC2CC(N)=O
Temperature: 25 °C
Reaction time: 144 h

Procedure:
1.0 g of methyl (7-isopropoxycarbonyl-6-methyl-2,3-dihydropyrrolo[2,1-b]thiazol-3-yl)acetate was dissolved in 30 ml of methanol and 30 ml of concentrated aqueous ammonia was added thereto. The obtained mixture was stirred at room temperature for 6 days. After distilling off the ammonia, the residue was extracted with chloroform. The chloroform layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After distilling off the solvent, the obtained oily residue was crystallized from ether/n-hexane. Thus 0.3 g of the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=O)[CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.Cl.[OH-].[Na+]>O1CCCC1>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][CH:21]=[C:20]2[O:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH2:10][NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:18][CH:17]=1
Reactant: COc1cccc(NC(=O)COc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cccc(NCCOc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)c1
Yield: 58.9 %

Procedure:
N1-(3-Methoxyphenyl)-2-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenoxy}acetamide (112 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A borane-tetrahydrofuran complex (1.0 M solution: 1.22 ml) was then added to the solution, and the mixture was heated under reflux for 5 hr. 1 N Hydrochloric acid was added thereto, and the mixture was further heated under reflux for 30 min. A 5% aqueous sodium hydroxide solution was added to the reaction solution, the mixture was extracted with chloroform, and the extract was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development to give the title compound (64 mg, yield 59%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[C:20]([NH:24][C:25](=[O:36])[C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=5)[CH:21]=[CH:22][CH:23]=4)=[N:13][N:12]3[CH:37]=2)[CH:5]=[CH:4][N:3]=1.[CH3:38][NH2:39].O1CCCC1.C(O)C>C(OCC)(=O)C>[CH3:38][NH:39][C:2]1[N:7]=[C:6]([NH:8][C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[C:20]([NH:24][C:25](=[O:36])[C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[CH:27]=5)[CH:21]=[CH:22][CH:23]=4)=[N:13][N:12]3[CH:37]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CN
Reactant: O=C(Nc1cccc(Oc2ccc3nc(Nc4ccnc(Cl)n4)cn3n2)c1)c1cccc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: CNc1nccc(Nc2cn3nc(Oc4cccc(NC(=O)c5cccc(C(F)(F)F)c5)c4)ccc3n2)n1
Temperature: 70 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A mixture of N-[3-({2-[(2-chloropyrimidin-4-yl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide (122 mg, 0.23 mmol), 2M methylamine-tetrahydrofuran solution (3.0 mL) and ethanol (6.0 mL) was heated to 70° C., and the mixture was stirred overnight. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous magnesium sulfate, and filtrated, and the residue was purified by silica gel column chromatography (ethyl acetate alone→ethyl acetate/methanol=4:1). The obtained residue was washed with ethyl acetate-hexane to give the title compound (60 mg, 50%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:44]=[CH:45][C:46]=1[O:47][CH3:48])[CH2:28][O:29][C:30]([NH:32][C:33]1[CH:38]=[CH:37][N:36]([CH2:39][C:40](O)=[O:41])[C:35](=[O:43])[N:34]=1)=[O:31]>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:40](=[O:41])[CH2:39][N:36]1[CH:37]=[CH:38][C:33]([NH:32][C:30]([O:29][CH2:28][C:27]2[CH:44]=[CH:45][C:46]([O:47][CH3:48])=[C:25]([O:24][CH3:23])[CH:26]=2)=[O:31])=[N:34][C:35]1=[O:43])[CH3:2]
Reactant: COc1ccc(COC(=O)Nc2ccn(CC(=O)O)c(=O)n2)cc1OC
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1ccc(NC(=O)OCc2ccc(OC)c(OC)c2)nc1=O
Yield: 85.4 %

Procedure:
The title compound (5.31 g, 81%) was synthesized by the reaction of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (3.26 g, 9.5 mmol) and [4-N-(3,4-dimethoxybenzyloxycarbonyl)-cytosin-1-yl]-acetic acid (3.28 g, 9.03 mmol) as per the procedure of Example 20. 1H NMR (500 MHz; DMSO-d6) δ 10.72 (s, 1H), 8.27 (dd, 1H), 8.17 (dd, 1H), 7.90 (d, 0.6H), 7.82 (d, 0.4H), 7.69˜7.62 (m, 2H), 7.02 (s, 1H), 7.00 (t, 1H), 6.94 (s, 2H), 5.09 (s, 2H), 4.80 (s, 1.2H), 4.61 (s, 0.8H), 4.34 (s, 0.8H), 4.13 (q, 0.8H), 4.05 (s, 1.2H), 4.03 (q, 1.2H), 3.75 (s, 3H), 3.74 (s, 3H), 3.58 (t, 1.2H), 3.42˜3.37 (m, 2H), 3.20 (t, 0.8H), 1.20 (t, 1.2H), 1.14 (t, 1.8H).
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]2([NH2:38])[CH2:37][CH2:36]2)=[CH:29][CH:28]=1.FC(F)(F)C([O-])=O>>[OH:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:24])[CH2:21][NH:38][C:35]2([CH2:34][CH2:33][C:30]3[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:32][CH:31]=3)[CH2:37][CH2:36]2)=[CH:11][CH:10]=1
Reactant: COc1ccc(CCC2(N)CC2)cc1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Agent: O=C([O-])C(F)(F)F
Product: COc1ccc(CCC2(NCC(O)c3ccc(O)c4c3OCC(=O)N4)CC2)cc1

Procedure:
Prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 191 mg (1 mmol) 1-[2-(4-methoxy-phenyl)-ethyl]-cyclopropylamine. Yield: 55 mg (11%, trifluoroacetate); mass spectroscopy: [M+H]+=399.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18]>C(O)C>[CH2:18]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH2:17][CH2:16][CH:15]=[CH2:14]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C=CCCCBr
Agent: [Na]
Solvent: CCO
Product: C=CCCCC(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 300 ml of ethanol are added 5 g of sodium spheres and after a clear solution is obtained, 32.1 g of diethyl malonate is added in one portion. After 1 h at room temperature, 15 g of 5-bromopent-1-ene is added and the reaction mixture is stirred at room temperature for 16 h. The reaction mixture is evaporated to dryness and the residue is distilled under high vacuum to obtain diethyl pent-4-enylmalonate.
Reaction SMILES: ClC1C=C(CCC[N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)C=CC=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42][C:43](O)=O)=[CH:36][CH:35]=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:32][O:33][C:34]1[CH:35]=[CH:36][C:37]([CH2:40][CH2:41][CH2:42][CH2:43][N:11]([CH:25]2[CH2:26][CH2:27][CH:28]([CH3:31])[CH2:29][CH2:30]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)=[CH:38][CH:39]=1
Reactant: COc1ccc(CCCC(=O)O)cc1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: COc1ccc(CCCCN(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCC(C)CC2)cc1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 4-(4-methoxy-phenyl)-butyric-acid and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH:12]([CH3:14])[CH3:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH:15](O)=[O:16]>C1(C)C=CC=CC=1>[CH:15]([NH:1][CH2:2][C:3]([N:5]([CH:12]([CH3:14])[CH3:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4])=[O:16]
Reactant: O=CO
Reactant: CC(C)N(C(=O)CN)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)N(C(=O)CNC=O)c1ccccc1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
α-amino-N-isopropylacetanilide (76.8 g.) was mixed with 97% formic acid, boiling chips added and the mixture refluxed for 2 hours. After cooling to 110° C. and adding toluene, the temperature was again raised to reflux and held for 24 hours. The solvent was then removed and the residue recrystallized from benzene to give α-formamido-N-isopropylacetanilide. To a flask equipped with drying tube was added 55 g. of α-formamido-N-isopropylacetanilide. Triethylamine (126.0 g.) and 400 ml. methylene chloride were then added. The resulting clear solution was cooled to -10° and dropwise addition of POCl3 started (57.5 g.). The temperature was lowered to -10° and continuous addition of sodium carbonate solution (1.0 mole, 106 g.) was commenced, keeping the temperature at 0° or lower. After addition, more water was added and the mixture allowed to stir at room temperature for 30 minutes. The organic layer was separated off, and filtered through MgSO4. The organic layer was then washed with salt water, and again filtered through MgSO4. The material was dried over MgSO4, filtered, and vacuum treated to remove methylene chloride. The residue was recrystallized from ether to give α-isocyano-N-isopropylacetanilide melting at 80°-82° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH2:8])=[CH:6][CH:5]=[N:4]1)[CH3:2].[CH2:9]([O:11][C:12](=[O:23])[C:13](=[CH:19]OCC)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:10]>C(O)C>[CH2:9]([O:11][C:12](=[O:23])[C:13](=[CH:19][NH:8][C:7]1[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][CH:6]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:10]
Reactant: CCn1nccc1N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccnn1CC)C(=O)OCC

Procedure:
245 g of 1-ethyl-5-aminopyrazole (2.2mol) and 476 g of ethoxymethylene malonic acid diethyl ester (2.2 mol) are heated to 120° (bath temperature) for 2 hours with stirring. The ethanol formed by this reaction is removed by means of a water aspirator. Vacuum distillation (b.p.0.1 154°-160°) yields 520 g (84% of theory) of a quickly crystallizing oil of [[(1-ethyl-5-pyrazolyl)amino]methylene]malonic acid diethyl ester, m.p. 50°-53°. The compound is recrystallized from N-hexane, and has a melting point of 55°-57°.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C:15]1[CH:16]=[N:17][C:18]([Cl:23])=[C:19]([Br:22])[C:20]=1[I:21])(C)(C)C>C(Cl)Cl>[Br:22][C:19]1[C:20]([I:21])=[C:15]([NH2:14])[CH:16]=[N:17][C:18]=1[Cl:23]
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)c(Br)c1I
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cnc(Cl)c(Br)c1I
Yield: 78.4 %

Procedure:
Trifluoroacetic acid (30 mL) was added to a solution of (5-bromo-6-chloro-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester (19.0 g, 44 mmol) in DCM (120 mL) and the resultant solution was stirred at ambient temperature for 2 h then concentrated in vacuo. The resultant residue was loaded onto an SCX-2 cartridge (70 g) eluting with acetonitrile (100 mL) then 2N ammonia in methanol (100 mL). The basic fraction was concentrated in vacuo to afford the title compound (11.5 g, 78%). 1H NMR (DMSO-D6, 400 MHz): 7.23 (s, 1H), 5.92 (s, 2H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]([C@@H:27]2[C@:44]3([CH3:45])[C@H:30]([C@H:31]4[C@H:41]([CH2:42][CH2:43]3)[C@:39]3([CH3:40])[C:34]([CH2:35][C@@H:36]([O:53][CH:54]5[CH2:59][CH2:58][CH2:57][CH2:56][O:55]5)[CH2:37][C@@H:38]3[O:46][CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][O:48]3)=[CH:33][CH2:32]4)[CH2:29][CH2:28]2)[CH2:14][CH2:15][C@H:16]([F:26])[C:17]([O:20][CH:21]([O:23][CH2:24][CH3:25])[CH3:22])([CH3:19])[CH3:18])(=O)=O)=CC=1.[I-:60].[Na+].O.C(Cl)Cl>CC(C)=O>[O:48]1[CH2:49][CH2:50][CH2:51][CH2:52][CH:47]1[O:46][C@@H:38]1[C@@:39]2([CH3:40])[C:34](=[CH:33][CH2:32][C@@H:31]3[C@@H:41]2[CH2:42][CH2:43][C@@:44]2([CH3:45])[C@H:30]3[CH2:29][CH2:28][C@@H:27]2[C@H:13]([CH2:12][I:60])[CH2:14][CH2:15][C@H:16]([F:26])[C:17]([O:20][CH:21]([O:23][CH2:24][CH3:25])[CH3:22])([CH3:19])[CH3:18])[CH2:35][C@@H:36]([O:53][CH:54]2[CH2:59][CH2:58][CH2:57][CH2:56][O:55]2)[CH2:37]1
Reactant: [I-]
Reactant: CCOC(C)OC(C)(C)[C@@H](F)CC[C@@H](COS(=O)(=O)c1ccc(C)cc1)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCOC(C)OC(C)(C)[C@@H](F)CC[C@@H](CI)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A mixture of 0.220 g. (0.00026 mole) of [1α,3β,24S]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluorocholest-5-en-21-ol 21-(4-methylbenzenesulfonate), and 0.165 g. (0.0011 mole) of sodium iodide in 2 ml of acetone was heated at 50° for 18 hr and cooled. The mixture was poured into water and the product was isolated with methylene chloride. The organic layers were washed with aqueous sodium sulfite solution, and saturated aqueous sodium bicarbonate solution. The organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to yield [1α,3β,24S]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluoro-21-iodocholest-5-ene.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15](/[C:18](/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:19](\[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)/[CH2:20][CH2:21]O)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:54]C(Cl)(Cl)Cl>C(#N)C>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15](/[C:18](/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:19](\[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)/[CH2:20][CH2:21][Cl:54])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC/C(=C(\c1ccccc1)c1ccc(OCCOCc2ccccc2)cc1)c1ccccc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: ClCC/C(=C(\c1ccccc1)c1ccc(OCCOCc2ccccc2)cc1)c1ccccc1

Procedure:
Z-4-[4-(2-benzyloxyethoxy)-phenyl]-3,4-diphenyl-but-3-en-1-ol prepared in the previous stage was dissolved in acetonitrile (400 ml). Triphenyl phosphine (103.5 g, 0.4 mol) and tetrachloromethane (120 g, 0.79 mol) were added and the mixture was refluxed for 2 hours. Then the mixture was evaporated to dryness under reduced pressure. The residue was dissolved in methanol (160 ml) and water (40 ml) and extracted three times with petroleum ether (3×200 ml) at boiling point. Petroleum ether layers were combined and evaporated to dryness under reduced pressure. The residue was crystallized twice from ethanol (700 ml). Yield 36 g.
Reaction SMILES: [CH2:1](I)[CH2:2][CH3:3].[OH:5][C:6]1[CH:11]=[C:10]([OH:12])[N:9]=[C:8]([SH:13])[N:7]=1.[OH-].[Na+]>O>[OH:5][C:6]1[CH:11]=[C:10]([OH:12])[N:9]=[C:8]([S:13][CH2:1][CH2:2][CH3:3])[N:7]=1
Reactant: CCCI
Reactant: Oc1cc(O)nc(S)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCSc1nc(O)cc(O)n1

Procedure:
Propyl iodide (136 ml) was added to a suspension of 4,6-dihydroxy-2-mercaptopyrimidine (200 g) in water (800 ml), containing sodium hydroxide (55.6 g). The reaction mixture was stirred for 2 weeks then concentrated to half volume, 2N hydrochloric acid was added and the subtitle compound was isolated by filtration (167 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH2:37][C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Brc1cccc(OCCc2ccccc2)n1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(OCCc5ccccc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 134, Step 3, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-phenethyloxy-pyridine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][CH3:31])=[CH:4][C:5]([O:28][CH3:29])=[C:6]([NH:8][C:9]([CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]([CH2:23][C:24](O)=[O:25])[C:13]2=[O:27])=[O:10])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:56][N:57]([CH3:63])[C@H:58]1[CH2:62][CH2:61][NH:60][CH2:59]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([O:30][CH3:31])=[CH:4][C:5]([O:28][CH3:29])=[C:6]([NH:8][C:9](=[O:10])[CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]([CH2:23][C:24]([N:60]3[CH2:61][CH2:62][C@H:58]([N:57]([CH3:63])[CH3:56])[CH2:59]3)=[O:25])[C:13]2=[O:27])[CH:7]=1
Reactant: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)O)c(=O)c3ccccc32)cc1Cl
Reactant: CN(C)[C@H]1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)N3CC[C@H](N(C)C)C3)c(=O)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a vial charged with {1-[(5-chloro-2,4-dimethoxy-phenylcarbamoyl)-methyl]-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-acetic acid (50 mg, 0.11 mmol), HATU (46.6 mg, 0.12 mmol), and dimethyl-(S)-pyrrolidin-3-yl-amine (14.0 mg, 0.12 mmol) DCM (2 ml) is added. The mixture is treated with DIPEA (48.6 μL, 2.79 mmol) and stirred at RT for 1 hour. DCM (5 ml) is added to the mixture and washed with 1M HCl. The acidic aqueous phase is treated with 1M NaOH until the pH is adjusted to pH of 7-8. The product is extracted from the aqueous phase with EtOAc (3×10 ml). The organic portions are combined, washed with water (10 ml), dried (MgSO4), filtered and concentrated to afford the title compound, [M+H]+ 544
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([I:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[O:21]1[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]1.CC(C)([O-])C.[Na+]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:27][CH:24]2[CH2:25][CH2:26][O:21][CH2:22][CH2:23]2)[C:5]2[C:10]([I:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: OC1CCOCC1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)nc(Cl)nc21
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1cc(I)c2c(OC3CCOCC3)nc(Cl)nc21
Temperature: 70 °C
Yield: 86 %

Procedure:
2,4-Dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), tetrahydro-2H-pyran-4-ol (1.05 equiv), sodium tert-butoxide (1.05 equiv) and 1,4-dioxane (0.56 M) were combined and heated at 70° C. for 5 h. The reaction mixture was concentrated and extracted with EtOAc/H2O. The organic layers were combined, evaporated under reduced pressure and purified by silica-gel chromatography (0-50% Hex:EtOAc over 800 mL) followed by 5-15% (DCM:MeOH over 800 mL). Pure fractions were combined, evaporated under reduced pressure and dried under high vacuum to give the title compound (86% yield) as a yellow oil. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.57 (s, 1 H), 5.62-5.70 (m, 1 H), 5.59 (s, 2 H), 4.11-4.19 (m, 2 H), 3.74-3.82 (m, 2 H), 3.62 (d, J=8.20 Hz, 2 H), 2.15-2.24 (m, 2 H), 1.91-2.01 (m, 2 H), 0.90-0.98 (m, 2 H), 0.00 (s, 9 H); MS (ESI) m/z 510.2 [M+1]+.
Reaction SMILES: [OH:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]4)[CH:15]=3)[CH:9]=2)[CH:4]=[CH:3]1.Br[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=1>>[NH:19]1[CH2:18][CH2:17][CH:16]([N:14]2[CH:15]=[C:11]([C:8]3[CH:9]=[C:10]4[N:2]([O:1][CH2:30][C:31]5[CH:36]=[CH:35][C:34]([O:37][C:38]([F:39])([F:40])[F:41])=[CH:33][CH:32]=5)[CH:3]=[CH:4][C:5]4=[N:6][CH:7]=3)[CH:12]=[N:13]2)[CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc4ccn(O)c4c3)cn2)CC1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Product: FC(F)(F)Oc1ccc(COn2ccc3ncc(-c4cnn(C5CCNCC5)c4)cc32)cc1

Procedure:
The entitled compound is prepared from tert-butyl 4-[4-(1-hydroxy-1H-pyrrolo[3,2-b]pyridin-6-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate and 1-(bromomethyl)-4-(trifluoromethoxy)benzene as described in the last 2 steps of Example 18.