Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:7][C@@H:6]2[C@H:4]1[CH2:5]2.C(N(CC)CC)C.Cl[C:27]1[O:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1>CN(C)C=O.CCOC(C)=O>[O:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[NH:1][CH2:2][C@H:3]1[N:8]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:7][C@@H:6]2[C@H:4]1[CH2:5]2
Reactant: NC[C@@H]1[C@@H]2C[C@@H]2CN1C(=O)OCc1ccccc1
Reactant: Clc1nc2ccccc2o1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1C[C@H]2C[C@H]2[C@H]1CNc1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of racemic 7-3 (6.3 g, 25.6 mmol) in dimethylformamide (100 mL) at 25° C. was added triethylamine (3.88 g, 38.4 mmol) followed by 2-chlorobenzoxazole (5.11 g, 33.3 mmol) and the reaction mixture was stirred at ambient temperature for 24 h. The mixture was diluted with EtOAc (400 mL) and washed with water (4×100 mL). The combined organic layers were dried over MgSO4 and concentrated to an oil. The oil was purified by normal phase silica gel chromatography (0 to 100% EtOAc in hexanes) to afford the racemic product as an oil. ESI+ MS: [M+H]+ 364.3. This material was then separated into its respective enantiomers by the following method: ChiralPak AD 2×25 cm, 10 uM (40:60 hexane:EtOH, 0.1% diethylamine; flow rate=8 mL/min). Enantiomer A Rt=7.3 min; Enantiomer B Rt=8.7 min. 1H NMR (500 MHz, CDCl3) δ 7.43-7.42 (m, 2H), 7.36-7.33 (m, 4H), 7.08-7.02 (m, 3H), 4.64 (m, 1H), 4.52 (m, 1H), 4.43 (m, 2H), 3.42 (m, 1H), 3.29 (m, 1H), 3.14 (m, 1H), 2.71 (s, 3H), 1.84 (m, 1H), 1.60 (m, 1H), 1.43 (m, 1H), 0.560 (m, 1H). HRMS [M+H] C24H23F1N2O2S1 calc'd 423.1537, found 423.1542.
Reaction SMILES: I[C:2]1[C:3]2[CH2:13][C:12]3[C:7](=[CH:8][C:9]([CH:14]=[O:15])=[CH:10][CH:11]=3)[C:4]=2[NH:5][N:6]=1.[S:16]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17]1.C(=O)(O)[O-].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:16]1[CH:20]=[CH:19][C:18]([C:2]2[C:3]3[CH2:13][C:12]4[C:7](=[CH:8][C:9]([CH:14]=[O:15])=[CH:10][CH:11]=4)[C:4]=3[NH:5][N:6]=2)=[CH:17]1
Reactant: OB(O)c1ccsc1
Reactant: O=Cc1ccc2c(c1)-c1[nH]nc(I)c1C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=Cc1ccc2c(c1)-c1[nH]nc(-c3ccsc3)c1C2
Yield: 30 %

Procedure:
A mixture of Example 319 (930 mg, 3.0 mmol), 3-thienylboronic acid (384 mg, 3.0 mmol), tetrakis(triphenylphosphine)palladium(0) (240 mg, 0.21 mmol) and sodium bicarbonate (630 mg, 7.5 mmol) in 1,2-dimethoxyethane (18 mL) and water (6 mL) was stirred under nitrogen in a heavy walled process vial in a microwave synthesizer at about 160° C. for about 10 minutes. The mixture was concentrated under vacuum and the residue was purified by flash chromatography on silica gel using hexane/ethyl acetate (3:1) as eluent to provide 240 mg (30%) of the desired product. MS (ESI): m/z 267 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH:19]([CH3:21])[CH3:20])[CH:17]=1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:51][C:52]1[N:56]([CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=2)[N:55]=[C:54]([NH2:64])[CH:53]=1>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH:19]([CH3:21])[CH3:20])[CH:17]=1)[C:12]([NH:64][C:54]1[CH:53]=[C:52]([CH3:51])[N:56]([CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=2)[N:55]=1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(N)nn1Cc1ccccn1
Reactant: CC(C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)c2cc(OCc3ccccc3)cc(OC(C)C)c2)nn1Cc1ccccn1
Temperature: 25 °C
Reaction time: 14 h
Yield: 31 %

Procedure:
3-Benzyloxy-5-isopropoxy-benzoic acid (0.35 mmol) is dissolved in acetonitrile, di-isopropyl ethyl amine (3 eq.), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium (1.2 eq.) and 5-methyl-1-pyridine-2-ylmethyl-1H-pyrazole-3-ylamine (1.0 eq., prepared similar to 1-pyridine-2-ylmethyl-1H-pyrazole-3-ylamine) is added and stirred at RT for 14 hours. The solvent is removed in vacuo. 3-Benzyloxy-5-isopropoxy-N-(5-methyl-1-pyridine-2-ylmethyl-1H-pyrazole-3-yl)-benzamide is obtained after column chromatography (chloroform (methanol) as a colourless powder in a yield of 31%; HPLC (Method B): 3.25 min; LC-MS: 2.350 min, 457.15 (M÷H+);
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([S:13][CH3:14])[NH:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([S:13][CH3:14])[N:10]([CH2:22][C:23]([N:25]3[CH2:26][CH2:27][N:28]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:29][CH2:30]3)=[O:24])[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: CSc1cc(-c2ccc(F)cc2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CSc1cc(-c2ccc(F)cc2)nn1CC(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 3-(4-Fluoro-phenyl)-5-methylsulfanyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3) afforded the title compound as white solid. 1H NMR (400 MHz, CDCl3): 7.7–7.76 (m, 2H), 6.96–7.1 (m, 4H), 6.88–6.92 (m, 2H), 6.64 (s, 1H), 5.3 (s, 2H), 3.7–3.84 (m, 4H), 3.04–3.2 (m, 4H), 2.5 (s, 3H). 13C NMR (400 MHz, CDCl3): 164.8, 152, 140, 127.4, 119, 118.4, 118.2, 116.2, 116, 108, 52.8, 52, 51.8, 45.4, 42.2, 20.
Reaction SMILES: [C:1]([P:6](Cl)[C:7]([CH2:10][CH3:11])([CH3:9])[CH3:8])([CH2:4][CH3:5])([CH3:3])[CH3:2].[CH:13]1(Cl)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[Mg].S(=O)(=O)(O)O>O1CCCC1.[Cu]Cl.C1(C)C=CC=CC=1>[C:1]([P:6]([C:7]([CH2:10][CH3:11])([CH3:9])[CH3:8])[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: ClC1CCCCC1
Reactant: CCC(C)(C)P(Cl)C(C)(C)CC
Agent: Cl[Cu]
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCC(C)(C)P(C1CCCCC1)C(C)(C)CC
Reaction time: 6 h
Yield: 96.7 %

Procedure:
In a 300 ml four-necked flask thoroughly purged with nitrogen, 10.4 g (0.05 mol) of di-tert-amylphosphinous chloride, 0.10 g (0.001 mol (corresponding to 2% by mol)) of copper(I) chloride and 30 ml of tetrahydrofuran were placed. To the contents of the flask, a Grignard reagent solution previously prepared from 8.3 g (0.060 mol) of cyclohexyl chloride and 2.0 g (0.08 mol) of metallic magnesium in 50 ml of tetrahydrofuran was dropwise added over a period of 1 hour with maintaining the temperature at 25° C. to 30° C. After the dropwise addition was completed, stirring was conducted at a temperature of 35° C. to 40° C. for 6 hours. After the temperature of the reaction solution was returned to room temperature, 20 ml of toluene and 20 ml of a 5% sulfuric acid aqueous solution were added to the reaction solution to perform liquid separation. Then, the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent and a low-boiling component were distilled off under reduced pressure to obtain 12.4 g (purity: 94.9%) of the aimed di-tert-amylcyclohexylphosphine as an oily substance. The yield was 90.2%.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:9]2=[CH:10][C:11]3[C:16]([N:8]2[CH2:7][CH2:6][C:5]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=[CH:13][CH:12]=3.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].O>CN(C=O)C>[CH2:20]([O:19][C:17]([C:5]1([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:6][CH2:7][N:8]2[C:16]3[C:11]([CH:10]=[C:9]2[C:4]1=[O:3])=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:18])[CH3:21]
Reactant: CCOC(=O)C1=C(O)c2cc3ccccc3n2CC1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC1(C(=O)OCC)CCn2c(cc3ccccc32)C1=O
Reaction time: 0.5 h
Yield: 95 %

Procedure:
1.3 g of sodium hydride were added over 0.5 hour to a stirred, ice-cold solution of 12.85 g of ethyl 6,7-dihydro-9-hydroxypyrido[1,2-a]indole-8-carboxylate in 200 ml of DMF and the mixture was stirred for a further 0.5 hour. A solution of 9.2 g of ethyl bromoacetate in 50 ml of DMF was added dropwise to the cooled mixture. After a further 3 hours at room temperature the mixture was poured into 1.5 l of water and extracted with diethyl ether. The ethereal extracts were washed with water, dried and concentrated to give 16.3 g of ethyl 8-(ethoxycarbonyl)-6,7,8,9-tetrahydro-9-oxopyrido[1,2-a]indole-8-acetate.
Reaction SMILES: CN(C=O)C.CO[C:8](=[O:43])[N:9]=[C:10](SC)[C:11]([C:28]1[CH:37]=[C:36]([O:38][CH3:39])[C:31]2[O:32][CH2:33][CH2:34][O:35][C:30]=2[C:29]=1[F:40])=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[O:21][N:20]=2)=[CH:15][CH:14]=1.[CH2:44]([O:46][C:47]([C:49]1[S:53][CH:52]=[N:51][C:50]=1[NH:54][NH2:55])=[O:48])[CH3:45]>C(N(CC)CC)C>[CH2:44]([O:46][C:47]([C:49]1[S:53][CH:52]=[N:51][C:50]=1[N:54]1[C:8](=[O:43])[NH:9][C:10]([CH:11]([C:28]2[CH:37]=[C:36]([O:38][CH3:39])[C:31]3[O:32][CH2:33][CH2:34][O:35][C:30]=3[C:29]=2[F:40])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[O:21][N:20]=3)=[CH:15][CH:14]=2)=[N:55]1)=[O:48])[CH3:45]
Reactant: CCOC(=O)c1scnc1NN
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C(F)(F)F)n2)cc1)c1cc(OC)c2c(c1F)OCCO2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1scnc1-n1nc(C(Nc2ccc(-c3noc(C(F)(F)F)n3)cc2)c2cc(OC)c3c(c2F)OCCO3)[nH]c1=O
Temperature: 85 °C
Reaction time: 16 h
Yield: 42.1 %

Procedure:
To 5 ml of a DMF solution containing 113 mg of [2-(5-fluoro-8-methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-[4-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester, 40 mg of 4-hydrazinothiazole-5-carboxylic acid ethyl ester (Example (185c)) and 0.030 ml of triethylamine were added. The resulting mixture was stirred at 85° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in 5 ml of methanol and 0.035 ml of acetic acid, and 103 mg of sodium cyanotrihydroborate was added thereto. The mixture was stirred at room temperature for 15 hours, and then 100 ml of ethyl acetate and 50 ml of water were added thereto. The organic layer was washed with 50 ml of water and then with 50 ml of saturated brine and was dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol-ethyl acetate) to give the title compound (57 mg).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:23])([F:22])[F:21])[C:12]2=[O:24])[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:31][C:32]1[CH:36]=[CH:35][N:34]([CH2:37][C@@H:38]([OH:41])[CH2:39][OH:40])[N:33]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:21])([F:22])[F:23])[C:12]2=[O:24])[C:8]([NH:31][C:32]2[CH:36]=[CH:35][N:34]([CH2:37][C@@H:38]([OH:41])[CH2:39][OH:40])[N:33]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Reactant: Nc1ccn(C[C@@H](O)CO)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1ccn(C[C@@H](O)CO)n1)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.3 %

Procedure:
A solution of (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid (100 mg, 0.29 mmol, prepared as in Example 1) in methylene chloride (5 mL) and N,N-dimethylformamide (5 drops) was treated with a solution of oxalyl chloride in methylene chloride (2.0 M, 200 μL, 0.40 mmol) and stirred for 15 min at room temperature. After this time, the reaction mixture was then concentrated in vacuo and the resulting residue was dissolved in methylene chloride (5 mL) and then added dropwise to a separate reaction flask containing a mixture of (R)-3-(3-amino-pyrazol-1-yl)-propane-1,2-diol (prepared as in US 20080021032, Example 35, 70 mg, 0.45 mmol) and 2,6-lutidine (250 μL) in methylene chloride (3 mL) at room temperature. The resulting reaction mixture was then stirred room temperature for 2 h. The reaction mixture was quenched by the addition of methanol and then diluted with methylene chloride. The organic layer was then washed with a 1 N aqueous hydrochloric acid solution. The organic layer was then concentrated in vacuo with silica gel (2.0 g). The silica gel with absorbed material was placed in a SIM and purified via Biotage flash column chromatography (40 S silica gel column, 100% ethyl acetate to 10% methanol/ethyl acetate) to afford (S)-3-cyclopentyl-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide (98 mg, 69%) as a white foam: [α]29D=+12.0°, (c=0.15, methanol); HR-ES(+) m/e calcd for C23H27N4O4F3 [M+H]+ 481.2057, observed 481.2055; 1H NMR (400 MHz, DMSO-d6) δ ppm 10.91 (s, 1H), 7.94-8.05 (m, 2H), 7.71-7.79 (m, 1H), 7.53 (d, J=2.34 Hz, 1H), 6.40 (d, J=2.13 Hz, 1H), 4.99-5.11 (m, 2H), 4.93 (d, J=5.33 Hz, 1H), 4.67-4.76 (m, 2H), 4.09 (dd, J=3.84, 13.85 Hz, 1H), 3.81-3.91 (m, 1H), 3.76 (br. s., 1H), 3.23-3.31 (m, 2H), 1.05-2.13 (m, 11H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=O)[CH3:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1(C)C=CC=CC=1>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[S:27])[CH3:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)Nc1ccc(Oc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=S)Nc1ccc(Oc2ccccc2)cc1
Temperature: 120 °C
Yield: 86.6 %

Procedure:
To a solution of N-(4-phenoxy-phenyl)-acetamide (1.20 g, 5.28 mmol) in 10 ml of toluene was added Lawesson's reagent (1.50 g, 3.70 mmol). The reaction mixture was heated at 120° C. for 2 h. After the completion of the reaction (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (5:95) as the eluent to provide the title compound (0.78 g, 60.7%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(C)=O.C(OCC)(=O)C>[CH2:15]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Brc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
4-Bromophenol (2 g, 0.0116 mol) in acetone (40 mL) was treated with potassium carbonate anhydrous (1.91 g, 1.2 equivalents) and benzyl bromide (1.44 mL, 1.05 equivalents). The reaction was refluxed under a nitrogen atmosphere. After 5-6 hours reflux, the reaction was cooled to room temperature and diluted with an equal volume of ethyl acetate. This solution was washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness. A white fluffy solid was obtained. Yield=2.36 g (73%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][O:18][CH3:19])=[CH:12][N:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCCCCC.C([Li])CCC.[F:31]N(S(C1C=CC=CC=1)(=O)=O)S(C1C=CC=CC=1)(=O)=O>C1COCC1.[Cl-].[Na+].O>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([F:31])[C:13]([O:16][CH2:17][O:18][CH3:19])=[CH:12][N:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COCOc1ccc(CO[Si](C)(C)C(C)(C)C)nc1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOc1cnc(CO[Si](C)(C)C(C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
To a solution of 2-(((tert-butyl(dimethyl)silyl)oxy)methyl)-5-(methoxymethoxy)pyridine (13.5 g) in THF (100 mL) was added 1.6 M n-butyllithium hexane solution (38.6 mL) at −78° C., and the mixture was stirred at the same temperature for 1 hr. To the reaction mixture was added N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (19.5 g) at −78° C., and the mixture was allowed to warm to room temperature, and stirred for 30 min. To the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (7.49 g).
Reaction SMILES: C(OC([N:8]([C:22]1[N:23]=[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]2[C:30]=1[CH3:31])[S:9]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10])=O)(C)(C)C.Cl>O1CCOCC1.CCOCC>[CH3:31][C:30]1[N:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]2=[N:23][C:22]=1[NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: COC(=O)c1ccc(S(=O)(=O)N(C(=O)OC(C)(C)C)c2nc3ccccn3c2C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)c1ccc(S(=O)(=O)Nc2nc3ccccn3c2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.4 %

Procedure:
To compound 1-F (0.188 g, 0.422 mmol) was added 4N HCl in dioxane (6 mL) and the reaction mixture was stirred at room temperature for 18 h. The reaction was diluted with ether, filtered, and the solid washed with ether and dried in vacuo to afford compound 1-G as a white solid (0.104 g, 65%). 1H-NMR (CD3OD): δ 8.53-8.55 (d, 1H), 8.21-8.23 (d, 2H), 7.99-8.03 (m, 1H), 7.84-7.86 (d, 2H), 7.51-7.55 (m, 1H), 3.97 (s, 3H), 2.07 (s, 9H); MS: m/z 346.0 (MH+).
Reaction SMILES: [C:1]1(=[CH:10][C:11]([O:13]CC)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C1(=O)C2C(=CC=CC=2)CC1.P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]1([CH2:10][C:11]([OH:13])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]=1
Reactant: CCOC(=O)C=C1CCc2ccccc21
Agent: O=C1CCc2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(O)CC1=CCc2ccccc21
Yield: 90 %

Procedure:
2-(ind-1-en-1-yl)-acetic acid was prepared according to the method of H. Ahmed and N. Campbell J.C.S. (1960), 4115-4120, in a yield of 90%, from ethyl 2-(indan-1-ylidene)-acetate, which was itself prepared in a yield of 48% from indan-1-one and (C6H5)3P=CH--COOC2H5 in toluene.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:17])[N:5]([CH3:16])[C:6](=[O:15])[N:7]([CH3:14])[C:8]=1[N:9]=[CH:10][N:11](C)C)#[N:2].Cl.ON.C(N(CC)CC)C.C([OH:30])C>O>[NH2:2][C:1]1[N+:11]([O-:30])=[CH:10][N:9]=[C:8]2[N:7]([CH3:14])[C:6](=[O:15])[N:5]([CH3:16])[C:4](=[O:17])[C:3]=12
Reactant: CN(C)C=Nc1c(C#N)c(=O)n(C)c(=O)n1C
Reactant: CCO
Agent: Cl
Agent: NO
Solvent: CCN(CC)CC
Solvent: O
Product: Cn1c(=O)c2c(N)[n+]([O-])cnc2n(C)c1=O
Yield: 85 %

Procedure:
0.235 g (1 mmol) of the compound 15, 0.138 g (2 mmol) of hydroxyamine hydrochloride and 0.243 g (2.4 mmol) of triethylamine were added to 3 ml of ethanol, and then the reaction mixture was refluxed for 3 hours. After cooling, 5 ml of water was added thereto, and the crystalline precipitate was filtered off and recrystallized from ethanol to give 0.223 g of 5-amino-1,3-dimethylpyrimido[4,5-d]pyrimidine-2,4-dione-6-oxide in a 85% yield.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[NH:24][C:25](=[O:53])[NH:26][CH:27]2[C:33](=[O:34])[N:32]([CH2:35][C:36]([N:38]([CH:45]([CH3:47])[CH3:46])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:37])[C:31]3[CH:48]=[CH:49][CH:50]=[CH:51][C:30]=3[C:29]([CH3:52])=[N:28]2)[CH:17]=[N:16]1)=O)(C)(C)C>>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[NH:24][C:25](=[O:53])[NH:26][CH:27]2[C:33](=[O:34])[N:32]([CH2:35][C:36]([N:38]([CH:45]([CH3:47])[CH3:46])[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[O:37])[C:31]3[CH:48]=[CH:49][CH:50]=[CH:51][C:30]=3[C:29]([CH3:52])=[N:28]2)[CH:17]=[N:16]1
Reactant: CC1=NC(NC(=O)Nc2cccc3cnn(C(=O)OC(C)(C)C)c23)C(=O)N(CC(=O)N(c2ccccc2)C(C)C)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Product: CC1=NC(NC(=O)Nc2cccc3cn[nH]c23)C(=O)N(CC(=O)N(c2ccccc2)C(C)C)c2ccccc21
Reaction time: 0.25 h
Yield: 97.5 %

Procedure:
Trifluoroacetic acid (2.0 mL) and 2-(3-{3-[1-(tert-Butoxycarbonyl)-indazol-7-yl]-ureido}-5-methyl-2-oxo-2,3-dihydro-benzo[e][1,4]diazepin-1yl)-N-isopropyl-N-phenyl-acetamide (75 mg, 0.120 mmol), prepared as in Example 4A, are combined, cooled to 0-5--C. with an ice water bath, and stirred under nitrogen for 15 min. The reaction mixture is concentrated in vacuo to an oil, triturated with a mixture of diethyl ether and n-hexane and then concentrated again. This process is repeated several times until a solid is obtained on concentration. The product is dried under high vacuum overnight at room temperature and then at 65--C. overnight to give the title compound as a crystalline solid (61 mg, 0.117 mmol). The pure material is then lyophilized from acetonitrile/water. 1H NMR (300 MHz, CDCl3) δ=1.08-1.12 (m, 6H); 2.73 (s, 3H); 4.11 (d, J=16.8 Hz,1H); 4.24 (d, J=16.6 Hz, 1H); 4.93-5.08 (m, 1H); 5.76 (b, 1H); 6.99-7.75 (m, 14H); 8.00 (b, 1H); 8.83 (b, 1H). MS(FAB): [M+H]+ =524.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=3)=[O:26])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1nc(C(=O)O)c(-c2cccc(C(F)(F)F)c2)o1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3nc(C)oc3-c3cccc(C(F)(F)F)c3)n2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 2-methyl-5-(3-trifluoromethyl-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.15 min; [M+H]+=459.09.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][OH:10])[CH:6]=[N:7][CH:8]=1.I(O)(=O)(=O)=O>C(#N)C.CC(CC(C)=O)=O.CC(CC(C)=O)=O.CC(CC(C)=O)=O.[Cr].[Cr].[Cr].[Cr].[Cr].[Cr+6]>[CH3:1][O:2][C:3]1[CH:8]=[N:7][CH:6]=[C:5]([CH:4]=1)[CH:9]=[O:10]
Reactant: COc1cncc(CO)c1
Agent: [Cr+6]
Agent: [Cr]
Agent: [O-][I+3]([O-])([O-])O
Solvent: CC(=O)CC(C)=O
Solvent: CC#N
Product: COc1cncc(C=O)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To an cooled solution (−78° C. internal temp) of 0.2 g of methyl 3-methoxypyrazine-2-carboxylate in 25 mL of toluene was added 3 mL of 1 M diisobutyl aluminum hydride in toluene. After stirring 10 min the reaction was quenched with 5 mL of water, allowed to warm to room temperature and dried with 5 g of MgSO4. Concentration under reduced pressure gave 0.2 g of (5-methoxypyridin-3-yl)methanol as an resin (MS (m+1)=140.1). The (5-methoxypyridin-3-yl)methanol (0.2 g) was taken up 10 mL of anhydrous acetonitrile and added to a stirred mixture of 0.5 g of periodic acid and 0.05 g of chromium (III) acetylacetonate in 10 mL of acetonitrile. After stirring for 5 hrs at room temperature, the mixture was concentrated on the rotovap and partitioned between 20 mL of saturated sodium carbonate and 3×50 mL of ethyl acetate. The combined extracts were dried over MgSO4 and concentrated under reduced pressure. The product was obtained as an orange-brown oil and was used without further purification: MS (m+1)=138.1.