Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@@H:2]1[C:29]2[C@:24]([CH3:31])([CH:25]=[CH:26][C:27](=[O:30])[CH:28]=2)[C:23]2[C@@H:22]([OH:32])[CH2:21][C@@:20]3([CH3:33])[C@@H:5]([CH2:6][C@@H:7]([CH3:34])[C@@H:8]3[C:9](=[O:19])[CH2:10][O:11][C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:4]=2[CH2:3]1>[O-2].[Cr+6].[O-2].[O-2].CC(C)=O>[F:1][C@@H:2]1[C:29]2[C@:24]([CH3:31])([CH:25]=[CH:26][C:27](=[O:30])[CH:28]=2)[C:23]2[C:22](=[O:32])[CH2:21][C@@:20]3([CH3:33])[C@@H:5]([CH2:6][C@@H:7]([CH3:34])[C@@H:8]3[C:9](=[O:19])[CH2:10][O:11][C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:4]=2[CH2:3]1
Reactant: CCCCCC(=O)OCC(=O)[C@H]1[C@H](C)C[C@H]2C3=C([C@@H](O)C[C@@]21C)[C@@]1(C)C=CC(=O)C=C1[C@@H](F)C3
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(C)=O
Product: CCCCCC(=O)OCC(=O)[C@H]1[C@H](C)C[C@H]2C3=C(C(=O)C[C@@]21C)[C@@]1(C)C=CC(=O)C=C1[C@@H](F)C3
Temperature: 0 °C

Procedure:
300 mg. of 6α-fluoro-11β-hydroxy-21-hexanoyloxy-16α-methyl-1,4,8-pregnatriene-3,20-dione is dissolved in 7.5 ml. of acetone, combined with 0.36 ml. of a chromium (VI) oxide solution, and stirred for 1 hour at room temperature. The reaction solution is stirred into ice water; the thus-formed precipitate is vacuum-filtered and dissolved in methylene chloride. The methylene chloride solution is washed neutral, dried, and evaporated under vacuum. The crude product is purified by chromatography, and recrystallization from hexane-acetone yields 6α-fluoro-21-hexanoyloxy-16α-methyl-1,4,8-pregnatriene-3,11,20-trione, m.p. 159° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[C:23]([N:24]3[CH2:29][CH2:28][CH:27]([C:30]#N)[CH2:26][CH2:25]3)=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:13][CH2:12]1.CC(C[AlH]CC(C)C)C.C1C[O:44]CC1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[C:23]([N:24]3[CH2:29][CH2:28][CH:27]([CH:30]=[O:44])[CH2:26][CH2:25]3)=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:13][CH2:12]1
Reactant: N#CC1CCN(c2cccnc2OC2CCN(c3ccc4ccccc4n3)CC2)CC1
Reactant: C1CCOC1
Agent: CC(C)C[AlH]CC(C)C
Product: O=CC1CCN(c2cccnc2OC2CCN(c3ccc4ccccc4n3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 1-(2-((1-(quinolin-2-yl)piperidin-4-yl)oxy)pyridin-3-yl)piperidine-4-carbonitrile (290 mg, 0.70 mol) in 20 mL of THF was added DIBAL-H (1.4 mol, 1 M in toluene) dropwise at −65° C. The mixture was stirred for 1 hour at RT and then quenched with saturated aqueous NH4Cl. The resulting mixture was extracted with EtOAc (2×20 mL) and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give the product (0.232 g, 0.56 mmol, 80% yield). ESI-MS (M+1): 417 calc. for C25H28N4O2 416.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:12][CH2:13][O:14][CH3:15])[C:10]=1[Cl:11])=[O:5])C.[OH-].[Li+]>CO.O>[Cl:11][C:10]1[N:9]([CH2:12][CH2:13][O:14][CH3:15])[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnn(CCOC)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCCn1ncc(C(=O)O)c1Cl
Yield: 92.5 %

Procedure:
To a solution of 5-chloro-1-(2-methoxyethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (8.51 g, 36.6 mmol) in methanol (37 mL) and water (37 mL) was added lithium hydroxide (1.21 g, 50.4 mmol). The reaction mixture was stirred at reflux for 3 h, and then the solution was concentrated under reduced pressure to remove the methanol. The residue was then acidified carefully with 6.0 N aqueous HCl. The resulting mixture was extracted with methylene chloride (3×50 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to provide 5-chloro-1-(2-methoxyethyl)-1H-pyrazole-4-carboxylic acid as a white solid (6.93 g, 92%). Mass spectrum: m/z: 205.3 (M+1).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][SiH:10]([Cl:12])[Cl:11]>[Pt].C1(C)C=CC=CC=1>[CH2:1]([CH2:9][SiH:10]([Cl:12])[Cl:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: C[SiH](Cl)Cl
Agent: [Pt]
Solvent: Cc1ccccc1
Product: Cl[SiH](Cl)CCCc1ccccc1
Yield: 22 %

Procedure:
Reaction between styrene and methyldichlorosilane with platinum catalyst (no substance acting as auxiliary catalyst). 624 mg Styrene and 732 mg methyldichlorosilane were introduced into a glass tube, and 0.9 mg of a toluene solution of a 0-valent platinum complex of divinylsiloxane (0.04 wt % platinum content) was added. The tube was sealed with Teflon tape and a rubber septum and placed in a 50° C. oil bath where it was heated for 30 minutes. After cooling, the tube contents were analyzed by gas chromatography revealing a styrene conversion of 75% and a phenethylmethyldichlorosilane yield of 22%. The ratio between the phenethylmethyldichlorosilane and the (α-methylbenzyl)methyldichlorosilane was 1.2:1.
Reaction SMILES: C(O[C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[N:15][N:14]3[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N:26]5[CH:30]=[CH:29][CH:28]=[N:27]5)[CH:21]=4)=[CH:18][N:19]=[C:13]3[CH:12]=2)=[CH:7][CH:6]=1)C.[CH2:32]([CH2:34][NH2:35])[OH:33].C([O-])([O-])=O.[K+].[K+]>CCO>[OH:33][CH2:32][CH2:34][NH:35][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[N:15][N:14]3[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N:26]5[CH:30]=[CH:29][CH:28]=[N:27]5)[CH:21]=4)=[CH:18][N:19]=[C:13]3[CH:12]=2)=[CH:7][CH:6]=1
Reactant: NCCO
Reactant: CCOC(=O)c1ccc(-c2cnn3c(-c4cccc(-n5cccn5)c4)cnc3c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(NCCO)c1ccc(-c2cnn3c(-c4cccc(-n5cccn5)c4)cnc3c2)cc1
Temperature: 55 °C
Reaction time: 5 h

Procedure:
4-[3-(3-Pyrazol-1-yl-phenyl)-imidazo[1,2-b]pyridazin-7-yl]-benzoic acid ethyl ester (Ex. 34) (1 eq, 0.073 mmol, 30 mg) and ethanol amine (10 eq, 0.73 mmol, 0.04 ml) are dissolved in EtOH (2 ml) and K2CO3 (1.5 eq, 0.11 mmol, 15.1 mg) is added. The reaction mixture is stirred for 5 h at 55° C. The solvent is then removed in vacuo and the reaction is purified by flash column chromatography eluting with 9:1 DCM/MeOH to yield N-(2-Hydroxy-ethyl)-4-[3-(3-pyrazol-1-yl-phenyl)-imidazo-[1,2-b]-pyridazin-7-yl]-benzamide as a yellow solid; [M+H]+=425
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:49]=[CH:48][C:11]([CH2:12][C:13]3[N:14]([C:26]4[CH:31]=[CH:30][C:29]([N:32]5[S:36](=[O:38])(=[O:37])[N:35]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:34](=[O:47])[CH2:33]5)=[CH:28][CH:27]=4)[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[N:17]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:50]1([CH2:56][CH2:57][OH:58])[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1>>[CH:50]1([CH2:56][CH2:57][O:58][C:2]2[N:7]=[N:6][C:5]([C:8]3[CH:9]=[CH:10][C:11]([CH2:12][C:13]4[N:14]([C:26]5[CH:31]=[CH:30][C:29]([N:32]6[S:36](=[O:38])(=[O:37])[N:35]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:44])([CH3:46])[CH3:45])[C:34](=[O:47])[CH2:33]6)=[CH:28][CH:27]=5)[CH:15]=[C:16]([C:18]5[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=5[Cl:25])[N:17]=4)=[CH:48][CH:49]=3)=[CH:4][CH:3]=2)[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Cl)nn4)cc3)cc2)S1(=O)=O
Reactant: OCCC1CCCCC1
Product: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(OCCC5CCCCC5)nn4)cc3)cc2)S1(=O)=O

Procedure:
5-{4-[2-[4-(6-Chloro-pyridazin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one (38 mg, 0.05 mmol) was treated as described in general procedure L using 2-cyclohexyl ethanol (35 μL, 0.25 mmol) to give 5-{4-[2-{4-[6-(2-cyclohexyl-ethoxy)-pyridazin-3-yl]-benzyl}-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.[N:9]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14](OC)=[O:15].Cl>C1COCC1.O>[C:1]([CH2:2][C:14]([C@@H:10]1[CH2:11][CH2:12][CH2:13][N:9]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15])#[N:3]
Reactant: CC#N
Reactant: COC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)CC#N
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 97.2 %

Procedure:
To a solution of acetonitrile (1.5 mL, 29 mmol) in THF (60 mL) was added n-butyl lithium (2.5 M solution in hexane, 10.8 mL, 29 mmol) at −78° C. The solution was stirred at about −78° C. for about 10 min and a solution of 1-tert-butyl 2-methyl (2S)-pyrrolidine-1,2-dicarboxylate (5.64 g, 25 mmol, US2007197506) in 15 mL of THF was added. The mixture was stirred at about −78° C. for about 1 hr and was subsequently allowed to reach rt (overnight). Water was added and the mixture acidified to pH 3 with 1N aqueous hydrochloric acid. The layers were separated and the organic layer was washed with water (10 mL) and brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo to give tert-butyl (2S)-2-(2-cyanoacetyl)pyrrolidine-1-carboxylate (5.8 g, 24.3 mmol, 97%) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([Cl:24])[CH:3]=1.[C:25]([N:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33])(=[O:27])[CH3:26]>>[C:25]([N:28]1[CH2:32][CH2:31][N:30]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[C:4]([Cl:24])[CH:3]=2)[C:29]1=[O:33])(=[O:27])[CH3:26]
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3Cl)CC2)c(C)c1
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C)cc4C)CC3)c(Cl)c2)C1=O
Yield: 53 %

Procedure:
Using (4-bromo-2-chlorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (409 mg) described in Preparation Example 119 and 1-acetylimidazolidin-2-one (192 mg) and by the reaction and treatment in the same manner as in Example 511, the title compound (242 mg) was obtained.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[CH3:19][C:20]1[O:24][N:23]=[C:22]([C:25]2([NH2:29])[CH2:28][CH2:27][CH2:26]2)[N:21]=1>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([NH:29][C:25]3([C:22]4[N:21]=[C:20]([CH3:19])[O:24][N:23]=4)[CH2:28][CH2:27][CH2:26]3)=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: Cc1nc(C2(N)CCC2)no1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: Cc1nc(C2(NC(=O)c3ccc(C4CC4)c(OCC4CC4)n3)CCC2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and 1-(5-methyl-1,2,4-oxadiazol-3-yl)-cyclobutanamine hydrochloride (1:1) (CAN 1170897-28-5) as starting materials, LC-MS (UV peak area/ESI) 97.8%, 369.1914 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@H:9]([CH2:13]S(OC)(=O)=O)[C@H:8]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH2:7][CH2:6]2.[NH:27]1[CH:31]=[CH:30][N:29]=[CH:28]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:27]1([CH2:13][C@H:9]2[C:10]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=3)[CH2:6][CH2:7][C@H:8]2[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: COc1ccc([C@@H]2CCc3cc(OC)ccc3[C@@H]2CS(=O)(=O)OC)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc([C@@H]2CCc3cc(OC)ccc3[C@@H]2Cn2ccnc2)cc1

Procedure:
A mixture of methyl (1R*,2R*)-1,2,3,4-tetrahydro-6-methoxy-2-(4-methoxyphenyl)-1-naphthylmethanesulphonate (1 g), imidazole (1.2 g) and potassium carbonate (1.2 g) in acetonitrile (75 ml) was stirred and heated under reflux for 24 h. The acetonitrile was evaporated under reduced pressure, and the residue was dissolved in a mixture of ethyl acetate (50 ml) and water (50 ml). The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate (50 ml). The combined ethyl acetate extracts were dried and evaporated to dryness, and the residue was purified by flash column chromatography on silica (K60), using ethyl acetate: toluene (1:4 by volume), then ethyl acetate as the eluting solvent, to give (1R*,2R*)-1,2,3,4-tetrahydro-1-(1H-imidazol-1-ylmethyl)-6-methoxy-2-(4-methoxyphenyl)naphthalene as a colourless gum, which crystallised on standing, m.p. 114°.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]([O-:10])=[O:9])[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])=[CH:15][CH:14]=2)=[N:3]1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[C:4]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[O:25][C:26]=3[CH3:27])=[CH:17][CH:18]=2)=[N:3]1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(COc2nn(C)cc2CC(=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(COc2nn(C)cc2CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
A mixture of methyl [1-methyl-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyloxy]-1H-pyrazol-4-ylacetate (379 mg), 1N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 2 hrs. 1N Hydrochloric acid (2 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give [1-methyl-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyloxy]-1H-pyrazol-4-yl]acetic acid (333 mg, yield 91%), which was then recrystallized from ethanol-hexane. melting point: 148–149° C.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:10]=[C:9]([NH:11][C:12]([C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:13])[O:8][N:7]=1)([CH3:5])[CH:3]=O.Cl.[NH2:26][OH:27].N1C=CC=CC=1>CO>[OH:27][N:26]=[CH:3][C:2]([C:6]1[CH:10]=[C:9]([NH:11][C:12]([C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:13])[O:8][N:7]=1)([CH3:1])[CH3:5]
Reactant: NO
Reactant: CC(C)(C=O)c1cc(NC(=O)[C@@H]2CCCN2C2CCOCC2)on1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CC(C)(C=NO)c1cc(NC(=O)[C@@H]2CCCN2C2CCOCC2)on1
Temperature: 60 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
To 90.0 mg (0.27 mmol) of (S)-1-(tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylic acid [3-(1,1-dimethyl-2-oxo-ethyl)-isoxazol-5-yl]-amide in MeOH (3.00 mL) are added 22.4 mg (0.32 mmol) hydroxylamine hydrochloride and 58.5 μL (0.72 mmol) pyridine. The reaction is stirred at 60° C. for 3 h. The solvent is removed under reduced pressure and the residue is purified by HPLC-MS to afford 79.0 mg of (S)-1-(tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylic acid [3-(2-hydroxyimino-1,1-dimethyl-ethyl)-isoxazol-5-yl]-amide. Yield: 84%; ESI-MS: 351 [M+H]+; HPLC (Rt): 1.04 min (method E)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10](SC)[N:11]=1.[CH3:20][C:21]1([CH3:27])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][C:21]1([CH3:27])[CH2:26][CH2:25][N:24]([C:10]2[N:11]=[C:6]([CH2:5][C:4]3[CH:17]=[CH:18][CH:19]=[C:2]([Cl:1])[CH:3]=3)[NH:7][C:8](=[O:16])[C:9]=2[C:14]#[N:15])[CH2:23][CH2:22]1
Reactant: CC1(C)CCNCC1
Reactant: CSc1nc(Cc2cccc(Cl)c2)[nH]c(=O)c1C#N
Product: CC1(C)CCN(c2nc(Cc3cccc(Cl)c3)[nH]c(=O)c2C#N)CC1

Procedure:
In analogy to the preparation of Example 1, 150 mg (0.51 mmol) of 2-(3-chlorobenzyl)-4-(methylsulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are reacted with 582 mg (5.14 mmol) of 4,4-dimethylpiperidine to give 96 mg (52% of theory) of the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.[CH2:13]([O:15][C:16](=[O:19])[NH:17][NH2:18])[CH3:14]>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[N:18][NH:17][C:16]([O:15][CH2:13][CH3:14])=[O:19])=[CH:3][CH:2]=1
Reactant: O=Cc1ccnc2ccccc12
Reactant: CCOC(=O)NN
Solvent: CCO
Product: CCOC(=O)NN=Cc1ccnc2ccccc12
Yield: 52.3 %

Procedure:
A mixture of 4.72 gm (0.03 mole) of 4-quinolinecarboxaldehyde, 3.12 gm (0.03 mole) of ethylcarbazate and 100 ml of absolute ethanol is refluxed 9 hr. The solvent is evaporated. The solid is crystallized from ethyl acetate/Skellysolve B to give 3.82 gm (53%) of the title compound having a melting point of 161.2° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[CH3:10][O:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19]Br)[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:10][O:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:9])[CH:14]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(COc2ccc(Br)cc2F)c1
Temperature: 25 °C

Procedure:
A mixture of 4-bromo-2-fluorophenol (10 g, 52.36 mmol), 3-bromomethylbenzoic acid methyl ester (10.9 g, 47.6 mmol), potassium carbonate (9.9 g, 71.4 mmol), and DMF (100 mL) was stirred at room temperature over the weekend, followed by treatment with water. The precipitate was collected by filtration and washed with water and cold MeOH to give 3-(4-bromo-2-fluoro-phenoxymethyl)-benzoic acid methyl ester. LC-MS (ES) calculated for C15H12BrFO3, 338; found m/z 338 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:20])[C:5]2[N:6]=[CH:7][N:8]([C@H]3[C@@H](O)[C@@H](O)[C@H](CO)O3)[C:9]=2[N:10]=1.[CH2:21](Br)[CH:22]=[CH2:23].Cl.[OH-].[Na+]>CS(C)=O.O>[CH2:23]([N:6]1[C:5]2[C:4](=[O:20])[NH:3][C:2]([NH2:1])=[N:10][C:9]=2[N:8]=[CH:7]1)[CH:22]=[CH2:21]
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@@H](CO)[C@H](O)[C@@H]2O)c(=O)[nH]1
Reactant: C=CCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: C=CCn1cnc2nc(N)[nH]c(=O)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
To a solution of 2-amino-9-((2R,3S,4R,5S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H-purin-6(9H)-one (50 g, 176.7 mmol) in DMSO (150 mL) was added allyl bromide (36 mL, 420 mmol), the mixture was stirred at room temperature overnight under nitrogen atmosphere. The reaction was chilled to 0° C. concentrated HCl (100 mL) was added and the reaction was stirred at 70° C. for 4 h. The reaction was cooled to room temperature, poured into water (800 mL), and neutralized with 6N sodium hydroxide to pH 7-8. The solids that formed were collected and the filter cake was washed with water and ethanol, then dried under vacuum to give 7-allyl-2-amino-1H-purin-6(7H)-one (20 g, 59.2% yield) as yellow solid. LCMS retention time 0.330 min; LCMS MH+ 192.
Reaction SMILES: [NH2:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[C:15](Cl)(Cl)=[S:16]>C1COCC1.O>[F:10][C:9]1[C:2]([N:1]=[C:15]=[S:16])=[CH:3][C:4]([C:11]([F:14])([F:12])[F:13])=[C:5]([CH:8]=1)[C:6]#[N:7]
Reactant: N#Cc1cc(F)c(N)cc1C(F)(F)F
Reactant: S=C(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(F)c(N=C=S)cc1C(F)(F)F
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a solution of the compound 25 (660 mg, 3.25 mmol) in THF (6 mL) was added a solution of thiophosgene (1 mL, 13 mmol) in water (1 mL) slowly at room temperature. The reaction mixture was stirred for 1 h, then concentrated in vacuo. The residue was diluted with H2O. The aqueous solution was extracted with ethyl acetate. The organic layers were combined and washed with aq.NaHCO3 and brine, dried over Na2SO4, filtered and concentrated to provide the title compound 3d (700 mg, 88%) as a light yellow solid, which was used directly in next step without further purification. 1H NMR (400 MHz, CDCl3) δ7.63 (d, 1H, J=8.5 Hz), 7.57 (d, 1H, J=6.9 Hz).
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:17][CH:18]([N:20]1[C:24]([NH2:25])=[CH:23][CH:22]=[N:21]1)[CH3:19]>C1C=CC=CC=1>[CH3:17][CH:18]([N:20]1[C:24]2[N:25]=[C:9]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[CH:8]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:23]=2[CH:22]=[N:21]1)[CH3:19]
Reactant: CC(C)n1nccc1N
Reactant: CCOC(=O)C(=O)CC(=O)c1ccncc1
Solvent: c1ccccc1
Product: CCOC(=O)c1cc(-c2ccncc2)nc2c1cnn2C(C)C
Temperature: 62 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
To a suspension of ethyl 2,4-dioxo-4-(4-pyridinyl)butanoate (442 mg, 1.997 mmol) in benzene (5 mL) was added 1-(1-methylethyl)-1H-pyrazol-5-amine (250 mg, 1.997 mmol), and the reaction mixture was stirred at 62° C. overnight. The reaction mixture was concentrated in vacuo and the residue was purified using column chromatography (Silica gel, 0 to 100% EtOAc/hexanes) to give 270 mg (43%) of product. LCMS E-S (M+H)=311.3 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.54 (t, J=7.2 Hz, 3H), 1.68 (d, J=6.6 Hz, 6H), 4.58 (q, J=7.1 Hz, 2H), 5.41-5.60 (m, 1H), 8.04-8.19 (m, 2H), 8.29 (s, 1H), 8.44-8.55 (m, 2H), 8.76-8.91 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([N:10]1[N:14]=[N:13][C:12]([C:15]2[CH:20]=[C:19](C=O)[CH:18]=[CH:17][C:16]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:11]1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[BH4-].[Na+].O.[CH2:32]([OH:34])C>>[CH3:3][C:2]([N:10]1[N:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:23]2[CH:28]=[CH:27][C:26]([CH2:32][OH:34])=[CH:25][CH:24]=2)=[N:11]1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:1]
Reactant: CCO
Reactant: CC(C)(c1ccccc1)n1nnc(-c2cc(C=O)ccc2-c2ccccc2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CC(C)(c1ccccc1)n1nnc(-c2ccccc2-c2ccc(CO)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2,-[2-(1-methyl-1-phenylethyl)-2H-tetrazol-5-yl]biphenyl-4-carbaldehyde (0.62 g, 1.7 mmol), prepared as in Example 8 or 9, and sodium borohydride in 30 mL of absolute ethanol was stirred at room temperature for 1 hour. The mixture poured into 150 mL of water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate and then concentrated. The residue was dissolved in approximately 10 mL of absolute diethyl ether and the solution was cooled in an ice bath giving a precipitate. The precipitate was isolated by filtration and drying gave 2'-[2-(1-methyl-1-phenylethyl)-2H-tetrazol-5-yl]biphenyl-4-methanol (0.37 g, 1.0 mmol), m.p. 119°-120° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(=O)=O.[I-:17].[Na+]>CC(C)=O>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][CH2:6][I:17])=[CH:10][CH:11]=1
Reactant: COc1ccc(CCCOS(C)(=O)=O)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(CCCI)cc1
Yield: 93 %

Procedure:
A solution of 6.30 g of 3-(4-methoxyphenyl)propyl methanesulfonate and 11.1 g of sodium iodide in 100 ml of acetone was refluxed for 15 hours. The reaction mixture was concentrated under reduced pressure and, after addition of water, the residue was extracted with ether. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 6.62 g of 3-(4-methoxyphenyl)propyl iodide.