Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([C:16]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:17])=[CH:6][C:5]=1[N:24]=[N:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:28][C:27]=1[N+:38]([O-])=O>O>[C:32]1([C:29]2[CH:30]=[CH:31][C:26]3=[N:25][N:24]([C:5]4[CH:6]=[C:7]([C:16]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:17])[CH:8]=[C:9]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=5)[C:4]=4[OH:3])[N:38]=[C:27]3[CH:28]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)CC(C)(C)c1cc(N=Nc2ccc(-c3ccccc3)cc2[N+](=O)[O-])c(O)c(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)CC(C)(C)c1cc(-c2ccccc2)c(O)c(-n2nc3ccc(-c4ccccc4)cc3n2)c1

Procedure:
To a solution of sodium hydroxide (6 g, 0.15 mol) in 8 mL of water is added 2-hydroxy-2′nitro3,4′-diphenyl-5-tert-octylazobenzene (6.56 g), prepared in (D) above. The reaction mixture is heated to reflux and then formadine sulfinic acid (10.8 g, 0.1 mol) is added portionwise over 20 minutes. The reaction mixture is heated at reflux for 1.5 hours. To the cooled reaction mixture is added 200 mL of water and the ethanol is removed under vacuum. The reaction mixture is adjusted to pH 4 with hydrochloric acid. The resultant mixture is extracted twice with methylene chloride and the combined organic phases are extracted with water. The organic phase is dried over anhydrous magnesium sulfate, and the solvent is then removed under vacuum. The residue is recrystallized sequentially from a mixture of water and methanol, and petroleum ether to give the title compound as a white solid melting at 123–125° C.
Reaction SMILES: [C:1]1([NH:7][C:8](=[NH:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:17]([CH2:23]C)[C:18](=O)[C:19]([O-:21])=[O:20].C([O-])(O)=O.[Na+].[CH3:30][CH:31](O)C>>[CH3:23][C:17]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:15][C:18]=1[C:19]([O:21][CH2:30][CH3:31])=[O:20]
Reactant: CC(C)O
Reactant: N=C(Nc1ccccc1)c1ccccc1
Reactant: CCC(Br)C(=O)C(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1nc(-c2ccccc2)n(-c2ccccc2)c1C
Temperature: 90 °C
Reaction time: 12 h
Yield: 55 %

Procedure:
A mixture of N-phenylbenzimidamide (compound 22, 1.0 g, 5.10 mmol), 3-bromo-2-oxovalerate (compound 23, 1.3 g, 6.12 mmol) and NaHCO3 in i-PrOH was stirred at 90° C. for 12 hrs. The reaction mixture was concentrated under reduced pressure, then the residue was diluted with EtOAc and washed with H2O. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (Biotage Isolera™ FLASH Purification System was used for normal phase column chromatography with EtOAc and hexane) to provide the title compound (0.86 g, 55%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[N:43]1([CH2:49][CH2:50][NH2:51])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:35]([NH:51][CH2:50][CH2:49][N:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)=[O:41]
Reactant: NCCN1CCCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc2ncnc(Oc3ccc(NC(=O)NCCN4CCCCC4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.6 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (134 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 2-piperidino-1-ethanamine (58 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (118 mg, yield 81%).
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]([C:6]1[CH:11]=[CH:10][C:9](I)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1OB(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C1(C)C=CC=CC=1.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>[CH2:1]([N:3]([CH2:13][CH3:14])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH3:15])=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: COc1ccccc1OB(O)O
Reactant: CCN(CC)C(=O)c1ccc(I)cc1
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: Cc1ccccc1
Solvent: O
Solvent: COCCOC
Product: CCN(CC)C(=O)c1ccc(-c2ccccc2OC)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.6 %

Procedure:
4-Diethylcarbamoyl-1-iodobenzene (100 mg) was dissolved in dimethoxyethane (1 ml), added with tetrakis(triphenylphosphine)palladium (19.1 mg) under argon atmosphere, and stirred at room temperature for 10 minutes. The reaction mixture was added with the solution of (2-methoxyphenyl)boric acid (100 mg) dissolved in toluene (0.5 ml) prepared above and a solution of sodium carbonate (105 mg) dissolved in water (0.5 ml) and stirred at 90° C. for 5.5 hours. The reaction mixture was added with water (2 ml) and extracted twice with dichloromethane (4 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=3:1) to obtain 81.9 mg of the title compound. Yield: 88%.
Reaction SMILES: [CH2:1]1[CH2:22][O:21][C:3]2([C:12]3[C:7](=[C:8]([O:15][CH3:16])[CH:9]=[CH:10][C:11]=3[O:13][CH3:14])[CH2:6][CH:5]([C:17]([O:19][CH3:20])=[O:18])[CH2:4]2)[O:2]1.C([O:25]P(OCC)OCC)C.O=O>O1CCCC1.CCOCC>[CH2:22]1[CH2:1][O:2][C:3]2([C:12]3[C:7](=[C:8]([O:15][CH3:16])[CH:9]=[CH:10][C:11]=3[O:13][CH3:14])[CH2:6][CH:5]([C:17]([O:19][CH3:20])=[O:18])[CH2:4]2)[O:21]1.[CH2:22]1[CH2:1][O:2][C:3]2([C:12]3[C:7](=[C:8]([O:15][CH3:16])[CH:9]=[CH:10][C:11]=3[O:13][CH3:14])[CH2:6][C:5]([OH:25])([C:17]([O:19][CH3:20])=[O:18])[CH2:4]2)[O:21]1
Reactant: CCOP(OCC)OCC
Agent: COC(=O)C1Cc2c(OC)ccc(OC)c2C2(C1)OCCO2
Agent: O=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C1(O)Cc2c(OC)ccc(OC)c2C2(C1)OCCO2
Reaction time: 0.33 h
Yield: 66 %

Procedure:
(b) A solution of the lithium enolate of methyl rac-4,4-ethylenedioxy-1,2,3,4-tetrahydro-5,8-dimethoxynaphthalene-2-carboxylate was prepared in tetrahydrofuran as described in part (ii) (a) hereinbefore from 9.84 g of methyl rac-4,4-ethylenedioxy-1,2,3,4-tetrahydro-5,8-dimethoxynaphthalene-2-carboxylate. The enolate was added over a period of 5 minutes at -78° C. to a stirred solution of 11.2 ml of dry triethylphosphite in 60 ml of tetrahydrofuran through which a rapid stream of oxygen was passing. The passage of oxygen was maintained for 50 minutes and the temperature was held at -78° C. The reaction was then quenched by the addition of 8.8 ml of acetic acid. The cooling bath was removed and, after 5 minutes, 200 ml of water were added. After a further 20 minutes, most of the tetrahydrofuran was evaporated and the product was extracted into four 100 ml portions of ethyl acetate. The combined ethyl acetate extracts were washed with 200 ml of 10% aqueous potassium hydrogen carbonate, dried over magnesium sulphate, filtered and evaporated to give a yellow oil which was dissolved in 130 ml of ether and left to crystallise. There were obtained 6.86 g (66%) of methyl rac-4,4-ethylenedioxy-1,2,3,4-tetrahydro-2-hydroxy-5,8-dimethoxynaphthalene-2-carboxylate in the form of colourless crystals of melting point 74°-75° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C@H:14]([N+:15]([O-])=O)[CH2:13][C:12]([CH2:18][O:19][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)=[C:11]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:10]1>CO.C(O)(=O)C.[Zn]>[NH2:15][C@@H:14]1[CH2:13][C:12]([CH2:18][O:19][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)=[C:11]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:10][C@H:9]1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: N#Cc1ccc(OCC2=C(c3ccccc3)C[C@@H](c3ccc(Cl)cc3Cl)[C@H]([N+](=O)[O-])C2)cc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1ccc(OCC2=C(c3ccccc3)C[C@@H](c3ccc(Cl)cc3Cl)[C@H](N)C2)cc1
Yield: 75.9 %

Procedure:
To a solution of Example 7E (42 mg, 0.088 mmol) in a mixture of methanol/acetic acid (0.75 mL/0.75 mL), Zn powder (57 mg, 0.88 mmol) was added at room temperature. The reaction mixture was stirred for thirty minutes, filtered, concentrated under reduced pressure and purified by high-pressure liquid chromatography (eluting with 0-70% acetonitrile/water and 0.1% trifluoroacetic acid to provide the title compound (30 mg, 76%)). 1H NMR (400 MHz, CDCl3) δ ppm 7.44-7.53 (m, 2H), 7.24-7.39 (m, 4H), 7.12-7.23 (m, 4H), 6.68-6.82 (m, 2H), 4.40-4.51 (m, 1H), 4.27-4.40 (m, 1H), 2.68-2.88 (m, 2H), 2.45-2.64 (m, 2H). MS (ESI) m/z 449 (M+H)+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:17][C:16]2[N:12]([N:13]=[N:14][CH:15]=2)[C:11]2[CH:18]=[CH:19][CH:20]=[CH:21][C:10]=2[CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.[C:29]([O:33][C:34]([NH:36][C@H:37]([CH2:42][C:43]1[CH:48]=[C:47]([F:49])[C:46]([F:50])=[CH:45][C:44]=1[F:51])[CH2:38]C(O)=O)=[O:35])([CH3:32])([CH3:31])[CH3:30].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)CCl>[C:29]([O:33][C:34](=[O:35])[NH:36][CH:37]([CH2:42][C:43]1[CH:48]=[C:47]([F:49])[C:46]([F:50])=[CH:45][C:44]=1[F:51])[CH2:38][C:6](=[O:7])[N:8]1[CH2:17][C:16]2[N:12]([N:13]=[N:14][CH:15]=2)[C:11]2[CH:18]=[CH:19][CH:20]=[CH:21][C:10]=2[CH2:9]1)([CH3:30])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2-n2nncc2C1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC(CC(=O)N1Cc2ccccc2-n2nncc2C1)Cc1cc(F)c(F)cc1F

Procedure:
4H,6H-1,2,5,10b-Tetraaza-benzo[e]azulene-5-carboxylic acid tert-butyl ester was deprotected using trifluoroacetic acid and the resulting salt was coupled with (R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid using HOBt, EDC and DIPEA. The desired compound was obtained as viscous oil.
Reaction SMILES: [Cl:1][C:2]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:3]=1[CH2:4][NH:5][C:6](=[O:29])[N:7]([CH:9]([CH2:25][CH2:26][CH:27]=O)[CH2:10][O:11][C:12](=[O:24])[NH:13][C:14]1[N:15]=[CH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:8].[C:35]([O:39][C:40](=[O:45])[NH:41][CH2:42][CH2:43][NH2:44])([CH3:38])([CH3:37])[CH3:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CC(O)=O>[C:35]([O:39][C:40]([NH:41][CH2:42][CH2:43][NH:44][CH2:27][CH2:26][CH2:25][CH:9]([N:7]([CH3:8])[C:6]([NH:5][CH2:4][C:3]1[CH:30]=[CH:31][CH:32]=[C:33]([F:34])[C:2]=1[Cl:1])=[O:29])[CH2:10][O:11][C:12](=[O:24])[NH:13][C:14]1[N:15]=[CH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:45])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)C(CCC=O)COC(=O)Nc1cc2ccccc2cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(C(=O)NCc1cccc(F)c1Cl)C(CCCNCCNC(=O)OC(C)(C)C)COC(=O)Nc1cc2ccccc2cn1
Temperature: 24 °C
Reaction time: 10 h
Yield: 25 %

Procedure:
To a solution of isoquinolin-3-yl-carbamic acid 2-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-5-oxo-pentyl ester (0.8 g crude mixture, 1.64 mmol) in anhydrous DCE (3 mL) and AcOH (0.1 mL) was added (2-Amino-ethyl)-carbamic acid tert-butyl ester at 24° C. After 10 h of stirring at 24° C., sodium triacetoxyborohydride (1.05 g, 4.92 mmol) was added in one portion. The slurry was stirred for 2 h at 24° C., quenched with methanol and concentrated. The resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give isoquinolin-3-yl-carbamic acid 5-(2-tert-butoxycarbonylamino-ethylamino)-2-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-pentyl ester (0.25 g, 25%) LRMS (M+H+) m/z 631.2.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.Br[CH:13]([CH2:16]Br)[CH2:14][OH:15]>>[OH:15][CH2:14][CH:13]([O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7])[CH2:16][O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: OCC(Br)CBr
Reactant: COc1cc(C=O)ccc1O
Product: COc1cc(C=O)ccc1OCC(CO)Oc1ccc(C=O)cc1OC
Yield: 71.8 %

Procedure:
Vanillin (30.4 g, 0.2 m) is reacted with 2,3-dibromopropanol (21.8 g, 0.1 mol) according to the procedure employed in Example 41 to obtain 25.86 g of 4,4'-[[1-(hydroxymethyl)-1,2-ethanediyl]bis(oxy)]bis[3-methoxybenzaldehyde]. This intermediate (3.60 g, 0.01 m) is reacted with ethyl cyanoacetate as described in Example 41 to yield 4.3 g of product which mas spectroscopy indicated had the structure: ##STR32## When dissolved in methylene chloride, the product has an absorption maximum (λmax) at 361 nm.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:3]=1.[C:20]([N:24]1[C:28]([NH2:29])=[CH:27][C:26]([CH3:30])=[N:25]1)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1>[C:20]([N:24]1[C:28]([NH:29][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[N:4]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:3]=2)=[CH:27][C:26]([CH3:30])=[N:25]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: Cc1cc(N)n(C(C)(C)C)n1
Reactant: O=c1c2ccccc2c(Br)nn1-c1ccc(Cl)cc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1cc(Nc2nn(-c3ccc(Cl)cc3)c(=O)c3ccccc23)n(C(C)(C)C)n1

Procedure:
200 mg 4-Bromo-2-(4-chloro-phenyl)-2H-phthalazin-1-one (prepared as described in Method R), 91 mg 1-tert.-butyl-3-methyl-1H-pyrazol-5-ylamine, 310 mg cesium carbonate, 21 mg 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and 16.4 mg tris-(di-benzylideneacetone)-dipalladium in 2 ml dry dioxane were stirred under nitrogen at 100° C. for 18 hrs. The solvent was removed under vacuum and the residue stirred with 50 ml water. The crude product was isolated by filtration, washed with water and purified by chromatography on silica, eluting sequentially with heptane, DCM and finally DCM/MeOH 60:1. Yield 180 mg (74%) of the title product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[C:4]([Br:11])[N:3]=1.[K].[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1)([O-:15])=[O:14]>CN(C)C=O>[Br:11][C:4]1[CH:5]=[C:6]([S:22][C:19]2[CH:20]=[CH:21][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=2)[CH:7]=[C:2]([Br:1])[N:3]=1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: O=[N+]([O-])c1cc(Br)nc(Br)c1
Agent: [K]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Sc2cc(Br)nc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.9 %

Procedure:
0.48 g (0.0025 mol) of 2,6-dibromo-4-nitropyridine and 0.70 g (0.0024 mol) of 4nitrothiophenol potassium salt were dissolved in 12.5 ml of dimethylformamide and stirred at room temperature for 3 hrs. The solvent was removed and the residue was partitioned in water and ethyl acetate. The combined organic phases were washed with sat. sodium chloride solution and dried over MgSO4. After filtration and removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane 1:19 and subsequently dried in a high vacuum. There was obtained 0.785 g (81%) of 2,6-dibromo-4-(4-nitrophenylsulphanyl)-pyridine as yellow crystals; m.p. 166-168° C.
Reaction SMILES: [C:1]1([CH:7]([CH3:10])[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]1COC[CH2:12]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(I)C>CS(C)=O.O>[CH3:10][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:11][CH3:12])[C:8]#[N:9]
Reactant: C1CCOC1
Reactant: CC(C#N)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCI
Product: CCC(C)(C#N)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-phenylpropionitrile (5 g, 38 mmol) in 50 mL of DMSO was added 42 mL of 1 M THF solution of sodium bis(trimethylsilyl)amide (NaHMDS). After 15 minutes, the reaction was cooled to 0° C. and 4.6 mL of ethyl iodide was added. The reaction was then stirred for 30 minutes. As TLC showed the reaction was complete, the reaction mixture was poured into water and extracted with diethyl ether. The organics were combined, washed four times with water, washed with brine, dried over magnesium sulfate, and concentrated in vacuo to give 6.1 g of 2-methyl-2-phenylbutyronitrile as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:42])[N:12]([C:17]4[CH:22]=[CH:21][C:20]([N:23]5[CH2:28][CH2:27][CH:26]([O:29][Si](C(C)C)(C(C)C)C(C)C)[CH2:25][CH2:24]5)=[C:19]([O:40][CH3:41])[CH:18]=4)[CH2:13][CH2:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1.[F-].C([NH3+])(C)(C)C>C1COCC1.CCOC(C)=O>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:42])[N:12]([C:17]4[CH:22]=[CH:21][C:20]([N:23]5[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]5)=[C:19]([O:40][CH3:41])[CH:18]=4)[CH2:13][CH2:14][C:15]=3[N:16]=2)=[CH:6][CH:7]=1
Reactant: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1N1CCC(O[Si](C(C)C)(C(C)C)C(C)C)CC1
Agent: CC(C)(C)[NH3+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1N1CCC(O)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dissolve 2-(4-chloro-phenyl)-5-[3-methoxy-4-(4-triisopropylsilanyloxy-piperidin-1-yl)-phenyl]-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one (681 mg, 1.09 mmol) in THF (10 mL) then add tert-butylammonium fluoride (1.0 M solution in THF, 1.30 mL, 1.30 mmol). Stir the solution at room temperature for 2 h, then dilute with EtOAc (50 mL) and wash with 2N NH4Cl (20 mL). Concentrate the organic solution and purify the crude material by flash chromatography, using 8% MeOH (2N NH3)/CHCl3 as eluent, to give semi-pure material. Triturate the solids with ether to give the title compound as the free base (265 mg, 52%). Mix 2-(4-chloro-phenyl)-5-[4-(4-hydroxy-piperidin-1-yl)-3-methoxy-phenyl]-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one (53 mg, 0.11 mmol) in MeOH (1 mL) and add 1N HCl (2.0 mL, 2.0 mmol). Stir the mixture at room temperature until all the solids dissolve and then cool to −20° C. overnight. Collect the precipitate by filtration, wash with ether, and dry under vacuum to give the title compound (40 mg, 70%). MS (ES+) 470.0 (M+1)+. 1H NMR (400 MHz, DMSO-d6): δ 11.69 (s, 1H), 8.06 (d, 2H, J=8.4 Hz), 7.70 (s, 1H), 7.63 (d, 2H, J=8.4 Hz), 7.34 (s, 1H), 7.14 (s, 1H), 4.65 (s, 4H), 4.16 (t, 2H, J=6.8 Hz), 3.95 (s, 3H), 3.64-3.32 (m, 2H), 3.29 (t, 2H, J=7.0 Hz), 2.11-1.76 (m, 4H),
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH2:5]=O.[CH2:7](N)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].N[C:27]([NH2:29])=S.C=O>O1CCOCC1>[CH3:7][CH:8]([N:29]1[CH2:27][NH:4][C:2](=[S:3])[N:1]=[CH:5]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: C=O
Reactant: NC(N)=S
Reactant: CCCCCCCCCCCCCCCCCCN
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCCCC(C)N1C=NC(=S)NC1

Procedure:
Thiourea (0.5 mole), formaldehyde (1 mole of 37% aqueous solution) and 200 ml. dioxane were placed in a 1 l. round bottom flask equipped with a stirrer. Octadecylamine (0.5 mole) was dissolved in 500 ml. dioxane and added to the thiourea/formaldehyde solution. The mixture was warmed slowly until it formed a waxy mass. It was cooled, filtered and extracted with methanol to afford the title compound as a white, fluffy material.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([OH:26])=O)=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.C(N(CC)CC)C.[Si:46]([O:63][CH2:64][CH2:65][N:66]1[C:70]([NH2:71])=[CH:69][CH:68]=[N:67]1)([C:59]([CH3:62])([CH3:61])[CH3:60])([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C=O)C>[Si:46]([O:63][CH2:64][CH2:65][N:66]1[C:70]([NH:71][C:24]([C:23]2[CH:22]=[N:21][N:18]3[CH:19]=[CH:20][C:15]([N:11]4[CH2:12][CH2:13][CH2:14][C@@H:10]4[C:4]4[C:5]([O:8][CH3:9])=[N:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[N:16][C:17]=23)=[O:26])=[CH:69][CH:68]=[N:67]1)([C:59]([CH3:60])([CH3:61])[CH3:62])([C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Reactant: CC(C)(C)[Si](OCCn1nccc1N)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)Nc3ccnn3CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 46.3 %

Procedure:
To a suspension of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (220 mg, 0.616 mmol) in DMF (5 mL) was added dropwise 2,4,6-trichlorobenzoyl chloride (106 μL, 0.677 mmol) and triethylamine (81.0 mg, 0.800 mmol). The reaction was stirred for 2 hours, and 1-(2-(tert-butyldiphenylsilyloxy)ethyl)-1H-pyrazol-5-amine (338 mg, 0.923 mmol) was added to the reaction mixture. The reaction was heated to 60° C. for 3 hours and then cooled to ambient temperature. The solvent was removed under reduced pressure and the residue was purified by silica column chromatography to afford the desired product (201 mg, 46.3% yield). MS (apci) m/z=705.1 (M+H).
Reaction SMILES: Cl[CH2:2][N:3]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.[Cl:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[NH:22][CH:23]=1.CCOCC>ClCCl>[CH2:9]([N:3]([CH2:2][N:22]1[CH:23]=[C:18]([Cl:17])[CH:19]=[N:20][C:21]1=[O:24])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: CCOC(=O)N(CCl)Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)N(Cc1ccccc1)Cn1cc(Cl)cnc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
N-Chloromethyl-N-ethoxycarbonylbenzylamine (see German Offenlegungsschrift No. 2,119,518) (10 mmol) in dichloromethane (20 ml) was added dropwise with stirring to a solution of 5-chloropyrimidin-2-one hydrochloride (20 mmol) in dichloromethane (80 ml). The reaction mixture was stirred at room temperature for 2 hours, extracted with water, the solution dried (MgSO4) and evaporated. The residual crude product (yield 80%, 2.57 g) was triturated with ether to leave the title compound in 53% yield (1.70 g), m.p. 143° C. 1H NMR (CDCl3): δ1.31 and 4.22 (EtO), 4.73 (CH2Ph), 5.23 (CH2N), 7.20 (Ph), 8.03 and 8.38 (H-4, H-6, J 4 Hz). IR(KBr): 1670 cm-1 (CO), 1720 (CO-carbamate).