Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([OH:22])[N:11]=[C:10]([CH2:23][C:24]2[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=2Br)[N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O)CCC.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[C:1]([O:5][C:6]([C:8]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([OH:22])[N:11]=[C:10]([CH2:23][C:24]2[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(Br)c(Cc2nc(O)c(OCc3ccccc3)c(C(=O)OC(C)(C)C)n2)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCCCO
Solvent: O
Product: COc1ccc(-c2ccccc2)c(Cc2nc(O)c(OCc3ccccc3)c(C(=O)OC(C)(C)C)n2)c1
Yield: 56.9 %

Procedure:
To a stirred solution of 5-benzyloxy-2-(2-bromo-5-methoxybenzyl)-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (138) (3 g, 5.988 mmol) in n-butanol:water (3:1, 12 mL) were added phenyl boronic acid (1.096 g, 8.982 mmol), X-Phos (427 mg, 0.898 mmol), K3PO4 (4.44 g, 20.958 mmol) and Pd(dba)2 (275 mg, 0.479 mmol). The reaction mixture was refluxed for 10 h. After completion of the reaction, the mixture was evaporated to get a crude product which was purified by a normal silica column using 2% methanol in dichloromethane to afford 5-benzyloxy-6-hydroxy-2-(4-methoxybiphenyl-2-ylmethyl)-pyrimidine-4-carboxylic acid tert-butyl ester (139) (1.7 g, 56.94%) as an off-white solid.
Reaction SMILES: FC1C=CC([NH:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]3[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:22][C:21]=3[O:35][CH3:36])[N:10]=2)=C(C(=O)NC)C=1.ClC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(OCC)OCC)=CC=2OC)N=1.N[C:71]1[C:80]([F:81])=[CH:79][CH:78]=[CH:77][C:72]=1[C:73]([NH:75][CH3:76])=[O:74]>>[F:81][C:80]1[CH:79]=[CH:78][CH:77]=[C:72]([C:73](=[O:74])[NH:75][CH3:76])[C:71]=1[NH:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:22][C:21]=2[O:35][CH3:36])[N:10]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(F)cc3C(=O)NC)n2)c(OC)c1)OCC
Reactant: CNC(=O)c1cccc(F)c1N
Agent: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3c(F)cccc3C(=O)NC)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure from Example 102 (Diethyl (4-{[4-{[4-fluoro-2-(methylcarbamoyl)-phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate) using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and the commercially available 2-amino-3-fluoro-N-methylbenzamide. 1H NMR (CDCl3, 400 MHz): δ=1.26 (t, J=7.07 Hz, 6 H), 2.92 (d, J=4.80 Hz, 3 H), 3.03-3.12 (m, 2 H), 3.86 (s, 3 H), 3.95-4.07 (m, 4 H), 6.21 (q, J=4.97 Hz, 1 H), 6.57 (d, J=9.09 Hz, 1 H), 6.81 (t, J=1.89 Hz, 1 H), 7.28-7.36 (m, 3 H), 7.73 (br. s., 1 H), 7.85 (br. s., 1 H), 8.34 (s, 1 H), 8.89 (br. s., 1 H). MS (ES+): m/z 586.14 [MH+] (TOF, polar).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][C:7](=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=1)[C:6]2=[O:23]>CO.O1CCCC1.[Pd]>[NH2:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][CH:7]1[C:6](=[O:23])[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[O:9][CH2:8]1
Reactant: COc1ccc2c(c1)C(=O)C(=Cc1cccc([N+](=O)[O-])c1)CO2
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(=O)C(Cc1cccc(N)c1)CO2
Temperature: 25 °C
Yield: 107 %

Procedure:
A mixture of 10.20 g (32.8 mmol) of the product of Example 1 and 2 g of 10% Pd/C in 200 mL CH3OH and 200 mL tetrahydrofuran was shaken on a Parr (trademark) hydrogenation apparatus at 25 psi H2 at room temperature. After 30 minutes the reaction mixture was filtered through diatomaceous earth (Celite [trademark]), and the filtrate concentrated in vacuo to yield 9.94 g of a yellow solid. Silica gel chromatography eluting with 5% ethyl acetate-CH2Cl2 afforded 8.53 g of a yellow solid (92%). A small sample was recrystallized from ethyl acetate-hexane to obtain analytical data. M.p. 137°-139° C.; MS: 283M+, 107 Base; 1H NMR (AC 300, CDCl3): δ4.3 (1H, m); 4.15 (1H, m), 3.82 (3H, s); 3.7 (1H, m); 3.67 (1H, m); 2.9 (1H, m); 2.6 (1H, m); IR: 3430, 3250, 1660 cm-1. Analysis: calculated: C. 72.07, H 6.05, N 4.94%; found: C: 71.69, H 6.01, N 4.96%.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]2[N:14]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34]OS(C)(=O)=O)[CH:28]=3)[C:15](=[O:26])[N:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:40]([NH:42][CH2:43][CH3:44])[CH3:41]>C(O)C>[NH:1]([C:8]1[N:13]=[C:12]2[N:14]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][N:42]([CH2:43][CH3:44])[CH2:40][CH3:41])[CH:28]=3)[C:15](=[O:26])[N:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OCCc1cccc(N2C(=O)N(c3ccc(Cl)cc3Cl)Cc3cnc(Nc4ccccc4)nc32)c1
Reactant: CCNCC
Solvent: CCO
Product: CCN(CC)CCc1cccc(N2C(=O)N(c3ccc(Cl)cc3Cl)Cc3cnc(Nc4ccccc4)nc32)c1
Yield: 28 %

Procedure:
A solution of 58 mg (0.1 mmol) of 7-anilino-3-(2,4-dichlorophenyl)-3,4-dihydro-1-[3-(2-methanesulfonyloxyethyl)phenyl]-pyrimido[4,5-d]pyrimidin-2(1H)-one (prepared in Example 74) and 0.5 ml of diethylamine in 2 ml of ethanol was heated at 50° C. for 3 hours. The reaction mixture was evaporated and the crude material purified by flash chromatography on silica gel, eluting with 5% methanol in dichloromethane. Product containing fractions were combined and evaporated to give 16 mg (28%) of 7-anilino-3-(2,4-dichlorophenyl)-1-[3-[2-(diethylamino) ethyl]phenyl]-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one as an off-white solid of melting point 186° C. [Mass spectrum (ESI) MH+ =561].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C@H:21]([CH3:29])[CH2:22][CH:23]([CH3:28])[CH2:24][CH2:25][CH:26]=[CH2:27])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([OH:20])=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([O:41][CH2:42][CH3:43])=[CH:33][N:32]=1.CC([O-])(C)C.[K+]>CS(C)=O>[C:1]([O:5][C:6]([NH:8][CH:9]([C@H:21]([CH3:29])[CH2:22][CH:23]([CH3:28])[CH2:24][CH2:25][CH:26]=[CH2:27])[C:10]([N:12]1[CH2:16][C@H:15]([O:17][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]([O:41][CH2:42][CH3:43])=[CH:33][N:32]=2)[CH2:14][C@H:13]1[C:18]([OH:20])=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cnc(Cl)c2ccccc12
Reactant: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc2ncc(OCC)c3ccccc23)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.2 %

Procedure:
To a solution of (2S,4R)-1-((3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (700 mg, 1.6 mmole) in DMSO was added 1-chloro-4-ethoxyisoquinoline (420 mg, 2.0 mmole), prepared above, followed by t-BuOK (1M sol. in THF, 8 mL, 8 mmole) at room temperature under nitrogen atmosphere. The reaction mass was stirred at room temperature for 4 h. The reaction mass was quenched with aqueous citric acid solution and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get crude compound. The crude compound was purified by combiflash to get desired product (2S,4R)-1-((3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-((4-ethoxyisoquinolin-1-yl)oxy)pyrrolidine-2-carboxylic acid (600 mg, 64%) as off-white solid. MS: MS m/z 585.1 (M++1).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2OS(C)(=O)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[F:26][C:27]([F:36])([F:35])[C:28]1[CH:33]=[CH:32][C:31]([SH:34])=[CH:30][CH:29]=1>ClCCl.C(OCC)(=O)C>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[S:34][C:31]2[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:35])[F:36])=[CH:33][CH:32]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)OC1CCCc2ccc([N+](=O)[O-])cc21
Reactant: FC(F)(F)c1ccc(S)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2c(c1)C(Sc1ccc(C(F)(F)F)cc1)CCC2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Methanesulfonic acid 7-nitro-1,2,3,4-tetrahydronaphthalen-1-yl ester (1.3 g, 4.8 mmol), was dissolved in a solution of triethylamine (3.35 mL, 24 mmol) and dichloromethane (10 mL). 4-Trifluoromethylbenzenethiol (1.7 g, 9.6 mmol) was then added and the reaction mixture was stirred at room temperature for 6 hours. Next, the reaction mixture was diluted with ethyl acetate and washed with 1N HCl, saturated sodium bicarbonate, and brine. The organic solution was dried (Na2SO4), concentrated, and purified by column chromatography (EtOAc/hexanes) to give 7-nitro-1-(4-trifluoromethylphenylsulfanyl)-1,2,3,4-tetrahydronaphthalene. Yield 1.45 g (86%). LCMS (ESI): calc. C17H14F3NO2S=353; obs. low ionization.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:15][CH2:14]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][CH2:9][CH2:10][O:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:15][CH2:14]1
Reactant: CC(C)(C)[Si](C)(C)OCCOCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(COCCO)CC1
Yield: 78.2 %

Procedure:
The reaction was carried out in similar procedure to Example 75b using 237 mg (0.58 mmol) of benzyl 4-[(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)methyl]piperidine-1-carboxylate obtained in Example 77a and 0.87 mL (0.87 mmol) of a solution of 1M tetrabutylammonium fluoride in tetrahydrofuran to obtain 133 mg (yield: 78%) of the title compound as a brown oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][C:16]([O:22]C)=[CH:17][CH:18]=3)[N:13]=[C:12]2[C:24]2[CH:29]=[CH:28][C:27]([O:30]C)=[CH:26][CH:25]=2)=[CH:7][CH:6]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][C:16]([OH:22])=[CH:17][CH:18]=3)[N:13]=[C:12]2[C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(-c2nc3cc(OC)ccc3c(=O)n2-c2ccc(OCCCl)cc2)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1c2ccc(O)cc2nc(-c2ccc(O)cc2)n1-c1ccc(OCCCl)cc1
Temperature: -30 °C
Reaction time: 0.33 h

Procedure:
To a chilled (-30° C.) solution of 1.0 g (0.00229 mol) of 3-[4-(2-chloro-ethoxy)-phenyl]-7-methoxy-2-(4-methoxy-phenyl)-3H-quinazolin-4-one in 300 mL of dry methylene chloride was added 23 mL (0.0229 mol) of boron tribromide (1M solution in dichloromethane (Aldrich Chemicals)). The reaction mixture was stirred at -30° C. for 20 minutes, under nitrogen, and then at room temperature overnight. The crude reaction mixture was added to 700 mL of aqueous sodium bicarbonate. The solution was stirred vigorously for 40 minutes at room temperature. The precipitate which formed was collected by vacuum filtration. The crude product when subjected to HPLC gave pure product. (mp 285-287° C.)
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C([Li])CCC.[CH3:11][C:12]([CH3:20])=[CH:13][CH2:14][CH2:15][C:16]([CH:18]=[CH2:19])=[CH2:17].C(C(CC)/C(/C)=C/CC/C(/C)=C/CN)C.C(N)/C=C(/CCC=C(C)C)\C>CCCCCC>[CH2:1]([N:3]([CH2:19]/[CH:18]=[C:16](/[CH2:15][CH2:14][CH:13]=[C:12]([CH3:20])[CH3:11])\[CH3:17])[CH2:4][CH3:5])[CH3:2]
Reactant: CCNCC
Reactant: C=CC(=C)CCC=C(C)C
Agent: CC(C)=CCC/C(C)=C/CN
Agent: CCC(CC)/C(C)=C/CC/C(C)=C/CN
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CCN(CC)C/C=C(\C)CCC=C(C)C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Dry diethylamine (84 ml, 0.816 mole) was charged into a 500 ml 3 necked flask equipped with reflux condenser, thermometer, addition funnel and magnetic stirrer. The flask was swept out with dry nitrogen and maintained under a nitrogen blanket. Butyl lithium (16.6 ml, 2.2 M) in hexane was then added and the temperature raised to 50° C. After 15 minutes 200 ml 85% myrcene (1 mole) was added. The mixture exothermed and was cooled to 60°. After 4 hours at 60°, gas chromatography indicated that the amine had been converted to virtually a single product in high yield. Distillation gave a fraction boiling at 108° C./7 mm which was identified as diethylgeranylamine. The yield was 148.7 g (87% based on the amine used) of a product which was 96% "geranyl amine". (See Table I).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.O>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2cc[nH]c2c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc2c(c1)NCC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 50.6 %

Procedure:
6-Methyl indole (0.50 g, 3.8 mmol) was dissolved in glacial acetic acid (19.1 mL) and cooled to 0° C. Sodium cyanoborohydride (0.48 g, 7.6 mmol) was added portionwise and the mixture warmed to ambient temperature and stirred for 2 h. The reaction was diluted with water (8.0 mL), made alkaline with 40% aqueous NaOH and extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine (3×30 mL), dried over sodium sulfate, filtered and concentrated. Purification by column chromatography on silica gel (gradient elution, 0-100% EtOAc/petrol), gave the title compound (0.256 g, 51%) as a purple oil. 1H NMR (Me-d3-OD): 6.96 (1H, d), 6.53 (2H, d), 3.44 (2H, t), 2.94 (2H, t), 2.23 (3H, s).
Reaction SMILES: [C:1]([CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([NH:6][NH2:7])=[O:5])#[N:2].[CH3:14][C:15](=O)[CH2:16][C:17](=O)[CH3:18]>>[CH3:14][C:15]1[CH:16]=[C:17]([CH3:18])[N:7]2[N:6]=[C:4]([OH:5])[C:3]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:1]2[N:2]=1
Reactant: N#CC(C(=O)NN)c1ccccc1
Reactant: CC(=O)CC(C)=O
Product: Cc1cc(C)n2nc(O)c(-c3ccccc3)c2n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 27.4 %

Procedure:
2-cyano-2-phenylacetohydrazide [Int-1A] (3.27 g, 18.3 mmol, 1.0 eq) and pentane-2,4-dione (1.89 mL, 18.3 mmol, 1.0 eq) were dissolved in 59 mL acidic acid and stirred for 3 h at 60° C. The resulting yellow suspension was cooled to rt and the precipitate was isolated by filtration. The solid was washed with hexane and dried to give 1.20 g (27% yield) of the title compound.
Reaction SMILES: Cl[Si:2]([O:9][CH2:10][CH3:11])([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5].[C:12](=[C:15]([Li])[F:16])([F:14])[F:13]>CCOCC>[F:16][C:15]([Si:2]([O:9][CH2:10][CH3:11])([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5])=[C:12]([F:14])[F:13]
Reactant: CCO[Si](Cl)(OCC)OCC
Reactant: [Li]C(F)=C(F)F
Solvent: CCOCC
Product: CCO[Si](OCC)(OCC)C(F)=C(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
30.80 g (0.155 mol) ClSi(OEt)3 in Et2O is slowly added to solution of CF2═CF—Li (0.155 mol 13.633 g, prepared in situ) in Et2O at −78° C. Reaction mixture is stirred overnight while it will slowly warm to room temperature. LiCl is removed by filtration and the product, trifluorovinyltriethoxysilane, is isolated by distillation.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][C:24]([C:35]1[C:43]2[NH:42][C:41](=[O:44])[NH:40][C:39]=2[CH:38]=[C:37]([C:45]2[C:46]([CH3:51])=[N:47][O:48][C:49]=2[CH3:50])[CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[CH:25]([OH:28])[CH2:26][CH3:27]>ClCCl.C1COCC1>[CH3:51][C:46]1[C:45]([C:37]2[CH:36]=[C:35]([C:24]([OH:23])([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:25](=[O:28])[CH2:26][CH3:27])[C:43]3[NH:42][C:41](=[O:44])[NH:40][C:39]=3[CH:38]=2)=[C:49]([CH3:50])[O:48][N:47]=1
Reactant: CCC(O)C(O)(c1ccccn1)c1cc(-c2c(C)noc2C)cc2[nH]c(=O)[nH]c12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCC(=O)C(O)(c1ccccn1)c1cc(-c2c(C)noc2C)cc2[nH]c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Dess-Martin Periodinane (90 mg, 0.24 mmol) was added to a solution of 4-(1,2-dihydroxy-1-(pyridin-2-yl)butyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one (50 mg, 0.12 mmol) in a mixture of dichlormethane and THF. The reaction was stirred for 72 h at room temperature, concentrated and purified by reverse-phase HPLC. A portion of this product was dissolved in concentrated HCl (0.1 mL) and ethanol (1 mL), heated at 80° C. for 3 h and concentrated to give 6-(3,5-dimethylisoxazol-4-yl)-4-(1-hydroxy-2-oxo-1-(pyridin-2-yl)butyl)-1H-benzo[d]imidazol-2(3H)-one.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH3:22])=[C:18]([CH2:23][CH3:24])[NH:17][C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].S(OC)(O[CH3:30])(=O)=O>CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH3:22])=[C:18]([CH2:23][CH3:24])[N:17]([CH3:30])[C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: CCc1[nH]c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)c1C
Solvent: CN(C)C=O
Product: CCc1c(C)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C

Procedure:
using isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-4-ethyl-5-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate and dimethyl sulphate in dimethylformamide there is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-4-ethyl-3,5-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, 1H--NMR (CDCl3, 400 MHz) 7.82 ppm (d, 1H), 7.33 ppm (d, 1H), 5.23 ppm (m, 1H), 3.51 ppm (s, 3H), 2.71 ppm (m, 2H), 2.04 ppm (s, 3H), 1.35 ppm (d, 6H), 1.28 ppm (t, 3H),
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:9]=1[C:10]([C:12]1[CH:13]=[N:14][N:15]([CH3:18])[C:16]=1[OH:17])=[O:11]>CN(C)C=O>[Cl:23][C:21]1[CH:20]=[CH:19][C:9]2[C:10](=[O:11])[C:12]3[CH:13]=[N:14][N:15]([CH3:18])[C:16]=3[O:17][C:8]=2[CH:22]=1
Reactant: Cn1ncc(C(=O)c2ccc(Cl)cc2Cl)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ncc2c(=O)c3ccc(Cl)cc3oc21
Temperature: 0 °C
Reaction time: 5 h
Yield: 91.6 %

Procedure:
1.38 g (0.01 mol) of potassium carbonate was added to 2.71 g (0.01 mol) of 4-(2,4-dichlorobenzoyl)-1-methyl-5-hydroxypyrazole dissolved in 20 ml of N,N-dimethylformamide, and the reaction mixture was stirred at 100°-120° C. for 5 hours. After cooling, the reaction mixture was poured into ice water, and extracted with chloroform. The chloroform layer was dried and the solvent was distilled off under reduced pressure to obtain a solid product. It was recrystallized from methanol to obtain 2.15 g of the title compound as colorless needle crystals (yield: 92%).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[NH2:11][C@H:12]([C:18]([O-:20])=[O:19])[CH2:13][CH2:14][C:15]([O-:17])=[O:16].C(O)(=O)/C=C/C(O)=O.[I:29]I>O>[NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[I+2:29].[NH2:11][C@H:12]([C:18]([O-:20])=[O:19])[CH2:13][CH2:14][C:15]([O-:17])=[O:16]
Reactant: II
Agent: NCCCC[C@H](N)C(=O)O
Agent: N[C@@H](CCC(=O)[O-])C(=O)[O-]
Agent: O=C(O)/C=C/C(=O)O
Solvent: O
Product: [I+2]
Temperature: 65 °C

Procedure:
Following a method similar to example 1, 110 ml of water was added, raised the temperature up to 65° C. with stirring, added 25 g of lysine-glutamate, when dissolved completely, 3.0 g of fumaric acid was added, and 9.7 g of iodine was then introduced gradually, and the mixture was stirred for about 220 minutes, then filtrated, the filtrate was concentrated and dried to afford 33.4 g title compound.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[C:18]([C:20]3[C:21]4[CH:28]=[CH:27][N:26](COCC[Si](C)(C)C)[C:22]=4[N:23]=[CH:24][N:25]=3)[CH:17]=[N:16]2)[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].C(Cl)Cl.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[N:23]1[C:22]2[NH:26][CH:27]=[CH:28][C:21]=2[C:20]([C:18]2[CH:17]=[N:16][N:15]([C:4]3([CH2:3][C:1]#[N:2])[CH2:7][NH:6][CH2:5]3)[CH:19]=2)=[N:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CNC1
Reaction time: 8 h
Yield: 88 %

Procedure:
A solution of tert-butyl 3-(cyanomethyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate, as prepared in Example 1, Step 2 (0.60 g, 1.2 mmol) in trifluoroacetic acid (10 mL) and methylene chloride (40 mL) was stirred for 5 hours. The solvents were removed in vacuo and the residue stirred in a solution of methanol (40 mL) and 14.50 M of ammonium hydroxide in water (10 mL) overnight. The solvent was evaporated, the residue reconstituted in methanol and purified by preparative-HPLC/MS (SunFire C18 column, eluting with a gradient of MeCN/H2O containing 0.1% TFA) to afford the product as the trifluoroacetic acid salt (526 mg, 88%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:8]=1)([O-])=O>O1CCOCC1>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([N:7]2[CH:8]=[C:4]([NH2:1])[CH:5]=[N:6]2)[CH:10]=1
Reactant: O=[N+]([O-])c1cnn(-c2cccnc2)c1
Solvent: C1COCCO1
Product: Nc1cnn(-c2cccnc2)c1
Reaction time: 8 h

Procedure:
98.9 g (520 mmol) of 3-(4-nitro-1H-pyrazol-1-yl)pyridine were dissolved in 1.3 l of warm dioxane, and twice evacuated and filled with argon. 500 ml of ammonia in methanol (˜7 mol/l) were added and the mixture was again twice evacuated and filled with argon. 27.5 g of Raney nickel (water-moist slurry) were added and the mixture was twice evacuated and filled with argon, and three times more evacuated and filled with hydrogen. The suspension was stirred under a hydrogen balloon overnight. A further 32 g of Raney nickel were added and the mixture was stirred under a hydrogen atmosphere for a further 24 hours. The hydrogen atmosphere was exchanged for argon, and the reaction mixture was filtered through Hyflo and washed with 500 ml of dioxane. The filtrate was concentrated on a rotary evaporator and dried under HV (high vacuum). The brown oil obtained crystallized in a refrigerator. The crude product was dissolved in 750 ml of ethyl acetate, 20 g of activated carbon were added and the mixture was stirred at 50° C. for 30 minutes. After filtration, activated carbon was added again and the mixture was again stirred at 50° C. for 30 minutes. Filtration through Hyflo was followed by concentration to approx. 250 g. 350 ml of diisopropyl ether were added and the mixture was stirred at room temperature. The solid was filtered off and washed with diisopropyl ether and heptane. Drying on a rotary evaporator gave a beige solid.