Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.N#N.Cl[C:18](Cl)(Cl)[C:19](Cl)=[O:20].[NH4+].[Cl-]>COCCOC.C(OC)(C)(C)C>[O:20]=[C:19]1[CH2:18][C:2]2([CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH2:1]1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: COC(C)(C)C
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)C2
Temperature: 15 °C
Yield: 15 %

Procedure:
To a flame-dried RB flask with tert-butyl 4-methylenepiperidine-1-carboxylate (2.96 g, 15 mmol, 1.0 equiv) and Zn/Cu couple (6.54 g, 172.5 mmol, 11.5 equiv) under vacuum, t-BuOMe (60 mL) was charged and refilled the flask with N2 balloon. To the mixture thus obtained stirred at 15° C., a solution of 2,2,2-trichloroacetyl chloride in DME (20 mL) was added dropwise. The mixture was stirred at room temperature overnight after addition. To the reaction mixture stirred in an external ice-bath, a saturated solution of NH4Cl (60 mL) was added slowly and carefully (especially the first few drops). After addition, the mixture was stirred at room temperature for 4 h, filtered to remove the solid. The phases were separated. The aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, concentrated to give the residue which was purified by CombiFlash (40 g silica gel column, EtOAc/Hexane: 0-40%) to afford 619 mg (15%) of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:23]2[C:22]([CH3:25])([CH3:24])[CH:21]=[CH:20][C:19]=2[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[CH:20]=[CH:21][C:22]([CH3:25])([CH3:24])[C:23]=4[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCC2=C1C(C)(C)C=C2
Product: CC1C2=C(C=CC2(C)C)CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,7,7-trimethyl-2,3,4,7-tetrahydro-1H-[2]pyrindine to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([C:8]#[N:9])=[C:6](S(C)(=O)=O)[S:5][N:4]=1.[CH2:14]([OH:18])[CH2:15][C:16]#[CH:17].[OH-].[K+].[I:21]I.[I-].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3]1[C:7]([C:8]#[N:9])=[C:6]([O:18][CH2:14][CH2:15][C:16]#[C:17][I:21])[S:5][N:4]=1
Reactant: II
Reactant: COc1nsc(S(C)(=O)=O)c1C#N
Reactant: C#CCCO
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nsc(OCCC#CI)c1C#N

Procedure:
2.2 Grams of 3-methoxy-4-cyano-5-methylsulfonylisothiazole was dissolved in 20 ml of DMF, and 1.5 g of 3-butyn-1-ol and 4.3 g of 30% KOH were added at room temperature with stirring, after which the reaction solution was stirred for 2 hours. The reaction solution was ice-cooled to 5° to 10° C., 5.1 g of iodine and 3.2 g of potassium iodide were added thereto with stirring, and then 6.6 g of 10% KOH was added dropwise. The temperature of the reaction solution was returned to room temperature, and after stirring for 1 hour, water was added to the reaction solution, which was then extracted with ethyl acetate. The extract was washed with water, dried and concentrated under reduced pressure to obtain crude crystals. The crystals were recrystallized from ether to obtain 2.1 g of crystals having a melting point of 71° to 73° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[CH:10]=[C:9]([N:11]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[CH3:22])[C:12]2=[O:23])[CH:8]=[CH:7][N:6]=1.CO>O1CCOCC1.C(Cl)(Cl)Cl>[CH3:1][O:2][C:5]1[CH:10]=[C:9]([N:11]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[CH3:22])[C:12]2=[O:23])[CH:8]=[CH:7][N:6]=1
Reactant: Cc1ccncc1N1CCN(c2ccnc(Cl)c2)C1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: COc1cc(N2CCN(c3cnccc3C)C2=O)ccn1
Temperature: 110 °C
Yield: 28.2 %

Procedure:
Sodium methoxide (225 mg, 4.165 mmol) was added dropwise to a stirred solution of 1-(2-chloro-pyridin-4-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (58A: 100 mg, 0.374 mmol) in 1,4-dioxane (20 mL) over a period of 10 minutes. The resulting mixture was heated to 110° C. and maintained at the same temperature for 4 days. The reaction was monitored by TLC (10% MeOH in CHCl3). The solvent was distilled from the reaction mixture and the concentrate was partitioned between water and ethylacetate. The organic layer was dried over Na2SO4 to afford the crude product. Purification by column preparative HPLC afforded 30 mg of the product (30.61% yield).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:39][CH2:40][CH3:41])[C:5]1[CH:6]=[C:7]([CH:11]2[CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])[CH:22]=3)[C:19](=O)[C:18]3[C:17]([C:35](OC)=[O:36])=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12]2)[CH:8]=[CH:9][CH:10]=1)[CH3:2].C(OC(OCC)C1C=C(C2C(C3C=CC=C(C(OCC)OCC)C=3)C(=O)C3C(C(OCC)=O)=CC=CC=3N2)C=CC=1)C.O.[NH2:85][NH2:86]>CO>[CH2:40]([O:39][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[CH:6]=[C:7]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:85][NH:86][C:35](=[O:36])[C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH:20]2[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([O:28][CH2:29][CH3:30])[O:31][CH2:32][CH3:33])[CH:22]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:41]
Reactant: NN
Reactant: CCOC(OCC)c1cccc(C2Nc3cccc(C(=O)OC)c3C(=O)C2c2cccc(C(OCC)OCC)c2)c1
Agent: CCOC(=O)c1cccc2c1C(=O)C(c1cccc(C(OCC)OCC)c1)C(c1cccc(C(OCC)OCC)c1)N2
Solvent: CO
Solvent: O
Product: CCOC(OCC)c1cccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2cccc(C(OCC)OCC)c2)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A mixture of methyl 2,3-bis(3-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate and ethyl 2,3-bis(3-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (370 mg, 0.59 mmol) in hydrazine monohydrate (5 mL) and methanol (5 mL) was stirred at 40° C. for 2 hr. The mixture was cooled to room temperature and filtered to give 8,9-bis(3-(diethoxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (250 mg, yield 77%) as a light yellow solid. LC-MS (ESI) m/z: 544 (M+1)+.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:29]([O:30]C(=O)C)[C@H:28]([O:34]C(=O)C)[C@@H:27]([CH2:38][O:39]C(=O)C)[O:26][C@H:6]1[O:7][C:8]1[CH:13]=[C:12]([C:14](=[O:16])[NH2:15])[CH:11]=[CH:10][C:9]=1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][CH:19]=1)(=O)C.C[O-].[Na+]>CO>[O:7]([C:8]1[CH:13]=[C:12]([C:14](=[O:16])[NH2:15])[CH:11]=[CH:10][C:9]=1[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH3:25])=[CH:22][CH:23]=1)[C@@H:6]1[O:26][C@H:27]([CH2:38][OH:39])[C@@H:28]([OH:34])[C@H:29]([OH:30])[C@H:5]1[OH:4]
Reactant: CCc1ccc(Cc2ccc(C(N)=O)cc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCc1ccc(Cc2ccc(C(N)=O)cc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
To a solution of 5-carbamoyl-2-(4-ethylbenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.13 g) in methanol (3 mL) was added sodium methoxide (28% methanol solution, 0.043 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was purified by column chromatography on benzenesulfonylpropyl silica gel (eluent: methanol). Diethyl ether was added to the obtained compound, and the resulting precipitated solid was collected by filtration and dried under reduced pressure to give 5-carbamoyl-2-(4-ethylbenzyl)phenyl β-D-glucopyranoside (0.079 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C(N[CH2:12][CH3:13])C.[CH2:14]([C:17]1[CH:22]=[CH:21][C:20]([C:23]#[CH:24])=[CH:19][CH:18]=1)[CH2:15][CH3:16]>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:21]([C:2]1[CH:7]=[CH:6][C:5]([C:24]#[C:23][C:20]2[CH:19]=[CH:18][C:17]([C:14]#[C:15][C:16]3[CH:19]=[CH:18][C:17]([CH2:22][CH2:12][CH3:13])=[CH:14][CH:15]=3)=[CH:22][CH:21]=2)=[CH:4][CH:3]=1)[CH2:20][CH3:23]
Reactant: C#Cc1ccc(CCC)cc1
Reactant: CCNCC
Reactant: Ic1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: O
Product: CCCc1ccc(C#Cc2ccc(C#Cc3ccc(CCC)cc3)cc2)cc1
Temperature: 25 °C

Procedure:
1,4-Diiodobenzene (2.5 g, 7.57 mmol) was added to diethylamine (80 ml) in nitrogen gas stream, followed by agitating the mixture at room temperature, successively adding copper iodide (60 mg) and dichlorobis(triphenylphosphine)palladium(II) (100 mg), adding 4-propylphenylacetylene (4.37 g, 30 mmol) in several steps, agitating the reaction mixture at room temperature overnight, adding water (200 ml), extracting the resulting deposited crystals with toluene (100 ml), washing the toluene solution with dilute hydrochloric acid, water, an aqueous solution of sodium hydrogen sulfate and water in this order, drying the solution on anhydrous sodium sulfate, passing it through a short column of activated alumina, distilling off toluene and recrystallizing the residue from ethyl acetate to obtain the objective 1,4-bis-(4-propylphenyl-ethynyl)benzene (1.92 g, 5.3 mmol). This product exhibited liquid crystal phases. C-N point: 179.1° C. N-I point: 245.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[OH:31]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:31][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[F:24])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: Oc1ccccc1F
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccccc4F)ncnc32)CC1

Procedure:
4-[4-(2-Fluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure A by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19) with 2-fluorophenol (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA) in acetonitrile. 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.97-2.07 (m, 4H), 2.97-3.07 (m, 2H), 4.05-4.12 (m, 2H), 4.98-5.05 (m, 1H), 7.31-7.50 (m, 4H), 8.38 (s, 1H), 8.55 (s, 1H). Mass spectrum MH+=414.
Reaction SMILES: C([C:5]1[C:10](O[SiH](C)C)=[C:9]([N+:15]([O-:17])=[O:16])[CH:8]=[CH:7][C:6]=1[N:18]=[C:19]=[O:20])(C)(C)C.[NH:21]([C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH2:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1C[O:38]CC1>>[OH:38][C:5]1[CH:10]=[C:9]([N+:15]([O-:17])=[O:16])[CH:8]=[CH:7][C:6]=1[NH:18][C:19]([NH:30][C:29]1[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=1[NH:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:20]
Reactant: C1CCOC1
Reactant: C[SiH](C)Oc1c([N+](=O)[O-])ccc(N=C=O)c1C(C)(C)C
Reactant: Nc1ccccc1Nc1ccccc1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1ccccc1Nc1ccccc1

Procedure:
The urea was synthesized by the treatment of 2-tertbutyldimethylsilyloxy 4-nitro phenyl isocyanate (example 9a, 0.419 g, 1.5 equiv.) with 2-anilino aniline (0.184 g, 1 equiv.) in THF overnight at 40° C. The desired product precipitated out of the reaction mixture (30 mg, 8%). EI-MS m/z 365 (M+H)+
Reaction SMILES: [CH3:1][NH:2][S:3](Cl)(=[O:5])=[O:4].[NH2:7][C:8]1[C:9]([Cl:26])=[CH:10][C:11]([Cl:25])=[C:12]([C:14]2[C:18]([Cl:19])=[C:17]([O:20][CH:21]([F:23])[F:22])[N:16]([CH3:24])[N:15]=2)[CH:13]=1.C(N(CC)CC)C.N1C=CC=N1>O1CCCC1.C(OCC)(=O)C>[Cl:19][C:18]1[C:14]([C:12]2[CH:13]=[C:8]([NH:7][S:3]([NH:2][CH3:1])(=[O:5])=[O:4])[C:9]([Cl:26])=[CH:10][C:11]=2[Cl:25])=[N:15][N:16]([CH3:24])[C:17]=1[O:20][CH:21]([F:22])[F:23]
Reactant: CNS(=O)(=O)Cl
Reactant: Cn1nc(-c2cc(N)c(Cl)cc2Cl)c(Cl)c1OC(F)F
Agent: c1cn[nH]c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CNS(=O)(=O)Nc1cc(-c2nn(C)c(OC(F)F)c2Cl)c(Cl)cc1Cl
Reaction time: 2 h
Yield: 71.7 %

Procedure:
N-Methylaminosulfonyl chloride (0.22 g, 1.67 mmoles) was added dropwise to a solution of 3-(5-amino-2,4-dichlorophenyl)-4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazole (0.44 g, 1.28 mmoles) and triethylamine (0.17 g, 1.67 mmoles) in 20 ml anhydrous tetrahydrofuran under cooling with ice to react with the pyrazole derivative. After the addition was finished, the reaction was continued further for 2 hours. Then ethyl acetate was added to the reaction product solution, and the mixture was washed with water. The separated organic layer was dehydrated, concentrated, and purified by recrystallization from a n-hexane-ether mixture, giving the title compound (0.40 g), m.p. 133.0° C., yield 71.7%.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[CH3:11][C:12]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16](=[O:17])[CH:15]=[C:14]([CH3:18])[O:13]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[CH3:11][C:12]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16](=[O:17])[CH:15]=[C:14]([CH:18]=[CH:7][C:6]2[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[O:13]1
Reactant: CC1=CC(=O)C(C)(c2ccccc2)O1
Reactant: N#Cc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(c2ccccc2)OC(C=Cc2ccc(C#N)cc2)=CC1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 41.9 %

Procedure:
To a solution of p-cyanobenzaldehyde (0.84 g, 6.4 mM) and 2,5-dimethyl-2-phenyl-3(2H)-furanone (1.0 g, 5.3 mM) in ethanol (50 mL), was added 1N aqueous sodium hydroxide (0.5 mL, 0.5 mm). The reaction solution was stirred at room temperature for two days. Then, saturated aqueous sodium chloride (200 mL) was added. The aqueous layer was extracted with diethyl ether (3×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a beige solid. The crude product was recrystallized from ethanol to afford a yellow solid (671 mg, 42% yield), m.p. 187°-188° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][CH2:6][N:7]([CH2:26][CH3:27])[C:8]([N:10]1[CH2:24][C@H:23]([OH:25])[CH2:22][C@H:11]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:9])[CH3:2].[CH3:29][O:30][CH:31]=[CH:32][C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[CH3:29][O:30][CH:31]=[CH:32][C:33]1[CH:38]=[CH:37][C:36]([O:25][C@@H:23]2[CH2:24][N:10]([C:8]([N:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:28])[CH2:26][CH3:27])=[O:9])[C@H:11]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])[CH2:22]2)=[CH:35][CH:34]=1
Reactant: CCOC(=O)CCN(CC)C(=O)N1C[C@H](O)C[C@H]1C(=O)OCc1ccccc1
Reactant: COC=Cc1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)CCN(CC)C(=O)N1C[C@@H](Oc2ccc(C=COC)cc2)C[C@H]1C(=O)OCc1ccccc1

Procedure:
Equimolar amounts of (trans)-1-[[(3-ethoxy-3-oxopropyl)ethylamino]carbonyl]-4-hydroxy-L-proline, phenylmethyl ester and 4-(2-methoxyethenyl)phenol are reacted in the presence of triphenylphosphine and diethylazodicarboxylate to give (cis)-4-[4-(2-methoxyethenyl)phenoxy]-1-[[(3-ethoxy-3-oxopropyl)ethylamino]carbonyl]-L-proline, phenylmethyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([OH:11])=[CH:4][C:3]=1[CH3:12].[H][H]>CO.[Pd]>[NH2:8][C:7]1[CH:6]=[C:5]([OH:11])[CH:4]=[C:3]([CH3:12])[C:2]=1[NH2:1]
Reactant: Cc1cc(O)cc([N+](=O)[O-])c1N
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(O)cc(N)c1N

Procedure:
2.00 g (11.06 mmol) 4-amino-3-methyl-5-nitrophenol were placed in 50 mL methanol and hydrogenated under a hydrogen atmosphere and with the addition of 1.00 g Pd/C (10%) at 50° C. and a hydrogen pressure of 5 bar until all the hydrogen had been taken up. The catalyst was filtered off and the filtrate was evaporated down i.vac.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C([Li])CCC.[S:20](Cl)([Cl:23])(=[O:22])=[O:21]>O1CCCC1.CCCCCC>[O:10]1[CH2:11][CH2:12][CH:7]([O:6][C:5]2[CH:13]=[CH:14][C:2]([S:20]([Cl:23])(=[O:22])=[O:21])=[CH:3][CH:4]=2)[CH2:8][CH2:9]1
Reactant: O=S(=O)(Cl)Cl
Reactant: Brc1ccc(OC2CCOCC2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=S(=O)(Cl)c1ccc(OC2CCOCC2)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 2.8 g of 4-(4-Bromo-phenoxy)-tetrahydropyran in 75 mL of dry tetrahydrofuran was added 7.5 mL of n-butyllithium (1.6 N in hexane) at −78° C. After stirring at −78° C. for 2 hours the reaction mixture was allowed to warm to −40° C. and a solution of 4.1 mL of sulfuryl chloride in 75 mL of dry hexane was added within 15 minutes. Stirring was continued for 1 hour at −30° C. and subsequently for another hour at 5° C., The mixture was poured on ice, extracted with diethyl ether and the ether extract washed with cold water and brine, dried (sodium sulfate), and concentrated. The residue was purified by silica chromatography (isohexane/ethyl acetate=4/1) yielding 0.62 g of 4-(tetrahydropyran-4-yloxy)-benzenesulfonyl chloride as a colorless oil. EI-MS: 276 (M+).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]([C:20]1[S:21][C:22]2[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:23]=2[N:24]=1)([OH:19])[CH2:17]Cl.C(OCC)(=O)C>CN(C)C=O.O>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]([C:20]1[S:21][C:22]2[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:23]=2[N:24]=1)([OH:19])[CH2:17][N:3]1[CH:7]=[N:6][CH:5]=[N:4]1
Reactant: N#Cc1ccc2nc(C(O)(CCl)c3ccc(F)cc3F)sc2c1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2nc(C(O)(Cn3cncn3)c3ccc(F)cc3F)sc2c1
Temperature: 60 °C
Yield: 71.8 %

Procedure:
Sodium hydride (440 mg) was suspended in dimethylformamide (10 ml), and 1,2,4-triazole (948 mg) was added to the suspension, to which a solution of 1-(2,4-difluorophenyl)-1-(6-cyanobenzothiazol-2-yl)-2-chloro-ethanol (1.49 g) in dimethylformamide (10 ml) was added. The mixture was heated at 60° C. for 4 hours. After the liquid reaction mixture was cooled to room temperature, ethyl acetate and water were added thereto. An organic layer separated was washed three times with water and then dried over magnesium sulfate, and the solvent was distilled out. The residue was recrystallized from dichloromethane-diisopropyl ether to obtain the intended compound (1.17 g). Melting point: 170°-172° C.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:10])[CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[N:6]1.[NH3:11]>CO>[NH2:11][CH2:2][CH:3]([OH:10])[CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[N:6]1
Reactant: OC(CCl)Cn1ccnn1
Reactant: N
Solvent: CO
Product: NCC(O)Cn1ccnn1
Temperature: 25 °C
Yield: 100 %

Procedure:
1-Chloro-3(1,2,3)triazol-1-ylpropan-2-ol (2.3 g, 13 mmol) was treated with the solution of NH3 in methanol (25% by weight, 20 mL) at 60° C. overnight in a sealed pressure vessel. After cooling to room temperature, nitrogen was bulbbed into the reaction mixture to remove the ammonia. Evaporation of solvent gave the hydrogen chloride salt of 1-amino-3-(1,2,3)triazol-1-ylpropan-2-ol (2.57 g, 100%). 1H NMR (DMSO-d6) δ 2.68 (dd, J=8.8, 12.8 Hz, 1H), 2.97 (dd, J=3.6, 12.8 Hz, 1H), 4.15 (m, 1H), 4.44 (dd, J=6.4, 14 Hz, 1H), 4.57 (dd, J=4.6, 14 Hz, 1H), 5.95 (d, J=5.2 Hz, 1H, OH), 7.77 (s, 1H), 8.01 (brs., 3H, NH3+), 8.12 (s, 1H). MS (m/z) 143.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[N:21]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[N:22]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26](Br)[CH:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[S:40]1[CH:44]=[CH:43][CH:42]=[C:41]1NC.[CH3:47][N:48](C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.C(O[Na])(C)(C)C>O1CCOCC1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6](=[O:39])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[N:21]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[N:22]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:48][CH2:47][C:41]5[S:40][CH:44]=[CH:43][CH:42]=5)[CH:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4cccc(Br)c4)nn(COCC[Si](C)(C)C)c3n2)CC1
Reactant: CNc1cccs1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4cccc(NCc5cccs5)c4)nn(COCC[Si](C)(C)C)c3n2)CC1

Procedure:
To a stirred solution of {4-[3-(3-bromo-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 39 supra) (300 mg, 0.48 mmol), thiophen-2-yl-methylamine (120 mg, 1.06 mmol), DavePhos (20 mg, 0.048 mmol) and t-BuONa (56 mg, 0.58 mmol) in 1,4-dioxane (10 mL), Pd2(dba)3 (28 mg, 0.48 mmol) was added in one portion under N2 atmosphere. The resultant mixture was stirred at 100° C. for 4 hours. The mixture was cooled and filtered; the filtrate was evaporated under reduced pressure to give the crude product. It was purified by chromatography (silica gel, 200-300 mesh, dichloromethane:MeOH, 100:1, v/v) to give {4-[3-{3-[(thiophen-2-ylmethyl)-amino]-phenyl}-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester. (Yield 290 mg, 92.9%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].Cl[CH2:14][C:15]1[CH:19]=[CH:18][S:17][CH:16]=1>CN(C)C=O>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:14][C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: ClCc1ccsc1
Reactant: O=Cc1ccc(O)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccsc2)cc1O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 14.8 %

Procedure:
A stirred solution of 2,4-dihydroxybenzaldehyde (31.8 g) in dry dimethylformamide (150 ml) at ambient temperature was treated with sodium hydride (11.96 g; 60% dispersion in mineral oil), portionwise, during 30 minutes. After a further period of 15 minutes, the mixture was treated, dropwise, with a solution of 3-chloromethylthiophene (35 g) in dimethylformamide (50 ml). The mixture was stirred at 70° C. for 2 hours, cooled and the solvent evaporated. The residue was partitioned between ethyl acetate (200 ml) and 0.5N hydrochloric acid (200 ml) and the aqueous layer was extracted twice with ethyl acetate (100 ml). The combined organic phases were washed with brine (100 ml), dried over magnesium sulphate, and evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (1:4, v/v), to give a colourless oil, which crystallised on standing. This solid was recrystallized from diisopropyl ether, to give the title compound (8 g) as a white solid.