Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[C:9]([NH:24][C:25]2[S:26][CH:27]=[C:28]([CH:30]3[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]3)[N:29]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[CH:21]=[CH:22][S:23][C:16]=23)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.Cl>C(Cl)Cl.O1CCOCC1>[O:1]([C:8]1[C:9]([NH:24][C:25]2[S:26][CH:27]=[C:28]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[N:29]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[CH:21]=[CH:22][S:23][C:16]=23)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2csc(Nc3ncc(Sc4ccnc5ccsc45)cc3Oc3ccccc3)n2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: c1ccc(Oc2cc(Sc3ccnc4ccsc34)cnc2Nc2nc(C3CCNCC3)cs2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
tert-Butyl 4-(2-(3-phenoxy-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate was dissolved in 1:1 CH2Cl2:methanol and 4N HCl in dioxane added and stirred for 1 hour at room temperature. The reaction was concentrated and the residue was partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and concentrated to afford 3-phenoxy-N-(4-(piperidin-4-yl)thiazol-2-yl)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-amine (238 mg, 52.5% yield over 2 steps) as a white solid
Reaction SMILES: [N:1]12[C:7](=[O:8])[CH2:6][CH:5]1[CH2:4][C:3](=[O:9])[CH:2]2[C:10]([O-:12])=[O:11].[Na+].[C:14]([O:20][CH2:21]Br)(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]>CN(C)P(N(C)C)(N(C)C)=O.C1C=CC=CC=1>[N:1]12[C:7](=[O:8])[CH2:6][CH:5]1[CH2:4][C:3](=[O:9])[CH:2]2[C:10]([O:12][CH2:21][O:20][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[O:11]
Reactant: O=C([O-])C1C(=O)CC2CC(=O)N21
Reactant: CC(C)(C)C(=O)OCBr
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(C)C(=O)OCOC(=O)C1C(=O)CC2CC(=O)N21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring suspension of sodium 1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (20 mg) in anhydrous hexamethylphosphoramide (0.5 ml) is added bromomethyl pivalate (35 mg). The resulting mixture is stirred at room temperature for 2 hrs, then diluted with benzene (5 ml) and washed thoroughly with H2O (5×2 ml) and brine. The benzene solution is dried with MgSO4, filtered, and concentrated under reduced pressure. Preparative tlc of the residue on a silica gel GF plate provides pivaloyloxymethyl 1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH3:12]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:12])(=[O:10])=[O:9]
Reactant: N
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Product: NS(=O)(=O)c1ccccc1Cl
Temperature: 70 °C

Procedure:
2-Chlorobenzenesulphonyl chloride (58 g) in either (60 ml) was added dropwise with stirring to concentrated ammonia solution (575 ml). When addition was complete, the mixture was stirred and heated at 70° C. for 1 hour. The mixture was then cooled and the solid filtered off, washed with water, and dried to give the required 2-chlorobenzenesulphonamide (39 g) with a melting point of 186° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[CH:12]=O.[C:14]1([CH2:20][C:21](OC)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC(C)([O-])C.[K+].C1(C)C=CC=CC=1>CN(C=O)C>[CH3:11][C:9]1[CH:10]=[C:6]2[N:5]=[CH:4][C:3]3[CH:12]=[C:20]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:21](=[O:22])[NH:1][C:2]=3[N:7]2[N:8]=1
Reactant: COC(=O)Cc1ccccc1
Reactant: Cc1cc2ncc(C=O)c(N)n2n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1cc2ncc3cc(-c4ccccc4)c(=O)[nH]c3n2n1
Temperature: 105 °C
Reaction time: 0.5 h

Procedure:
Into a round bottom flask was added 7-amino-2-methylpyrazolo[1,5-a]pyrimidine-6-carbaldehyde (1-2) (5.30 g, 30 mmol), methy phenylacetate (18.0 g, 120 mmol), potassium tert-butoxide (5.80 g, 60 mmol), and toluene (100 mL). The reaction mixture was heated to 105° C. while stirring under an atmosphere of nitrogen for 30 min. Then DMF (100 mL) was added and the mixture was stirred at 100° C. for 3 days. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was dissolved in DCM (600 mL) and then water (400 mL) was added to the solution. The precipitated solid was collected by filtration and the solid was washed with water (50 mL) and DCM (100 mL). The solid was dried over an oil pump for 2 days to give 2-methyl-7-phenylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-8(9H)-one (1-3) as a yellow solid.
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:11]=[C:12]([NH:24][C:25]([NH:27][CH3:28])=[NH:26])[CH:13]=[CH:14][C:15]=1[O:16]CC1C=CC=CC=1)C1C=CC=CC=1>[Pd].C(O)C>[ClH:1].[OH:9][C:10]1[CH:11]=[C:12]([NH:24][C:25]([NH:27][CH3:28])=[NH:26])[CH:13]=[CH:14][C:15]=1[OH:16]
Reactant: CNC(=N)Nc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CNC(=N)Nc1ccc(O)c(O)c1
Reaction time: 4 h

Procedure:
1-(3',4'-Dihydroxyphenyl)-3-methylguanidine hydrochloride is prepared from a mixture of 28 gm (0.07 mole) of the 1-(3',4'-dibenzyloxyphenyl)-3-methylguanidine hydrochloride (prepared in Example I), 1.0 gm of 5 percent palladium on charcoal, and 250 ml of ethyl alcohol. The mixture was shaken under an initial hydrogen pressure of 50 psi and, after 4 hours of agitation, the reaction mixture was filtered and the filtrate evaporated to a thick residue which solidified after standing 2 hours. This solid was purified by recrystallization from a mixture of ethyl alcohol and ether (3:2 ratio). The resulting white crystalline solid melted at 185°-8° C and the infrared spectrum was consistent with the assigned structure.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[CH:23]=2)[S:9]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[Br:35][CH2:36][CH2:37]Br.[OH-].[Na+]>O>[Br:35][CH2:36][CH2:37][O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[CH:23]=2)[S:9]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])(=[O:11])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(OC3CCCCO3)c2)c2ccc(O)cc2)c(C)c1
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(OC3CCCCO3)c2)c2ccc(OCCBr)cc2)c(C)c1
Temperature: 25 °C
Yield: 26 %

Procedure:
To a suspension of N-(4-hydroxy-phenyl)-2,4,6-trimethyl-N-[3-(tetrahydro-pyran-2-yloxy)-benzyl]-benzenesulfonamide (0.238 g, 0.49 mmol) and 1,2-dibromoethane (0.43 mL, 4.94 mmol) in 1 mL water was added sodium hydroxide (0.020 g, 0.49 mmol, dissolved in 0.1 mL of water). The reaction mixture was heated at reflux for 3 hr. and was cooled to room temperature. The reaction mixture was diluted with 10 mL water and the aqueous solution was washed with ethyl acetate (3×15 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried (magnesium sulfate), and concentrated. Medium pressure silica gel chromatography (25% ethyl acetate/hexanes) afforded 0.075 g of the title compound of Step E.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]=1[N+:8]([O-:10])=[O:9].[OH:17]O>C(O)(=O)C>[CH3:1][S:2]([C:3]1[NH:4][CH:5]=[C:6]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:7]=1[N+:8]([O-:10])=[O:9])=[O:17]
Reactant: CSc1[nH]cc(-c2ccccc2)c1[N+](=O)[O-]
Reactant: OO
Solvent: CC(=O)O
Product: CS(=O)c1[nH]cc(-c2ccccc2)c1[N+](=O)[O-]
Reaction time: 5 h
Yield: 77.5 %

Procedure:
2-Methylthio-3-nitro-4-phenylpyrrole (3.00 g, 0.013 mol) was suspended in glacial acetic acid (200 ml), and 30% hydrogen peroxide (1.45 g, 0.013 mol) was added. The mixture was stirred at 80° for five hours, after which the mixture was evaporated to dryness and the solid residue was recrystallised from isopropanol to give 2-methylsulphinyl-3-nitro-4-phenyl pyrrole (2.52 g), m.p. 197° dec.
Reaction SMILES: C(=NN[C:16]1[CH:17]=[C:18]([CH2:37][N:38]([CH3:40])[CH3:39])[S:19][C:20]=1[CH:21]=[N:22][N:23]=C(C1C=CC=CC=1)C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:40][N:38]([CH3:39])[CH2:37][C:18]1[S:19][C:20]2[CH:21]=[N:22][NH:23][C:16]=2[CH:17]=1
Reactant: CN(C)Cc1cc(NN=C(c2ccccc2)c2ccccc2)c(C=NN=C(c2ccccc2)c2ccccc2)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN(C)Cc1cc2[nH]ncc2s1
Temperature: 85 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
To [4-(N′-Benzhydrylidene-hydrazino)-5-(benzhydrylidene-hydrazonomethyl)-thiophen-2-ylmethyl]-dimethyl-amine [Intermediate (4)] in ethanol (100 mL) was added 50 mL of concentrated hydrochloric acid. The dark red mixture is stirred at 85° C. for 2 hours. Water is added followed by solid sodium carbonate until pH is slightly basic. The reaction mixture is then extracted twice with ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated. The residue is chromatographed (ethyl acetate—1.0M ammonia in methanol, 90:10 as eluant) to produce dimethyl-(1H-thieno[3,2-c]pyrazol-5-ylmethyl)-amine [1.06 g, 45% Intermediate (5)] as a brown solid. LC/MS: RT=0.4 minutes, 182.09 m/e (M+H).
Reaction SMILES: [C:1]([O:5][O:6][C:7]([CH2:10][CH3:11])([NH2:9])[CH3:8])(=[O:4])[CH:2]=[CH2:3].[C:12]1([N:18]=[C:19]=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(#N)C>[C:1]([O:5][O:6][C:7]([CH2:10][CH3:11])([NH:9][C:19]([NH:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:20])[CH3:8])(=[O:4])[CH:2]=[CH2:3]
Reactant: O=C=Nc1ccccc1
Reactant: C=CC(=O)OOC(C)(N)CC
Solvent: CC#N
Product: C=CC(=O)OOC(C)(CC)NC(=O)Nc1ccccc1
Reaction time: 5 h
Yield: 43.2 %

Procedure:
Into a solution of 15.9 g of ethyl-β-amino-β-ethoxy acrylate in 30 ml of acetonitrile there was dropped 11.9 g of phenyl isocyanate while cooling, and the resulting mixture was allowed to stand at room temperature for 5 hours. The acetonitrile was then distilled away. To the residue was added 100 ml of ether, which was then dried over anhydrous sodium sulfate. The ether was distilled away and the residue obtained was distilled under reduced pressure. Thus, 12 g of ethyl-β-phenylureido-β-ethoxy acrylate of a boiling point of 83° to 84° C./0.5 mmHg was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH3:33])=[CH:8][C:9]=2[CH2:11][O:12][CH2:13][C:14]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[CH2:4][NH:3]1>FC(F)(F)C(O)=O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH3:33])=[CH:8][C:9]=2[CH2:11][O:12][CH2:13][C:14]2([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)[CH:4]=[N:3]1
Reactant: Cc1cc2c(c(COCC3(c4ccccc4)CCN(C(=O)OC(C)(C)C)CC3)c1)N(C)NC2
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COCC2(c3ccccc3)CCNCC2)c2c(cnn2C)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
tert-Butyl 4-(((1,5-dimethyl-2H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (24 mg, 0.053 mmol) was dissolved in trifluoroacetic acid (25% in dichloromethane, 1.5 mL) and stirred at room temperature for 45 min. The reaction was concentrated, and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol to give 18.8 mg (quant.) as a colorless film. 1H-NMR (CDCl3, 500 MHz) δ 7.81 (s, 1H), 7.39 (s, 1H), 7.26 (m, 4H), 7.18 (m, 1H), 6.94 (s, 1H), 4.63 (s, 2H), 3.89 (s, 3H), 3.42 (s, 2H), 2.80 (m, 2H), 2.69 (m, 2H), 2.39 (s, 3H), 2.08 (m, 2H), 1.81 (m, 2H), 1.50-2.00 (bs, 1H); 13C-NMR (CDCl3, 126 MHz) δ 144.3, 137.4, 132.0, 130.8, 129.3, 128.3, 127.2, 126.1, 126.0, 120.5, 119.9, 79.0, 71.2, 42.7, 41.7, 38.0, 33.7, 21.1. Mass spec.: 350.05 (MH)+. Accurate mass spec.: m/z 350.2222 [MH]+, Δ=3.0 ppm.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.[CH:19]1([CH2:22][NH2:23])[CH2:21][CH2:20]1.Cl([O-])(=O)(=O)=O.[Li+]>>[CH:19]1([CH2:22][NH:23][CH2:2][C:3]2([OH:1])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:5][CH2:4]2)[CH2:21][CH2:20]1
Reactant: NCC1CC1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)CO2
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: O=C(OCc1ccccc1)N1CCC(O)(CNCC2CC2)CC1

Procedure:
The object product (2.53 g, 99%) was obtained in the same manner as in Example 24(1) and using benzyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (1.98 g), 1-cyclopropylmethanamine (570 mg) and lithium perchlorate (960 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:15])[C:11]([NH:13][CH3:14])=[O:12].[BH4-].[Na+]>CO>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([OH:15])[C:11]([NH:13][CH3:14])=[O:12]
Reactant: CNC(=O)C(=O)c1ccccc1COC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNC(=O)C(O)c1ccccc1COC

Procedure:
Racemic 2-(2-methoxymethyl-phenyl)-N-methyl-2-hydroxyacetamide was synthesized by reducing 2-(2-methoxymethyl-phenyl)-N-methyl-2-oxo-acetamide with NaBH4 in methanol.
Reaction SMILES: [C:1]([O:4][CH:5]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:9]2[CH:19]=[C:20]([CH2:22][CH3:23])[S:21][C:8]=2[N:7]2[N:24]=[C:25]([C:27]([NH2:29])=[O:28])[N:26]=[C:6]12)(=O)C>S(=O)(=O)(O)O.CO>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[C:9]2[CH:19]=[C:20]([CH2:22][CH3:23])[S:21][C:8]=2[N:7]2[N:24]=[C:25]([C:27]([NH2:29])=[O:28])[N:26]=[C:6]2[CH:5]([O:4][CH3:1])[N:11]=1
Reactant: CCc1cc2c(s1)-n1nc(C(N)=O)nc1C(OC(C)=O)N=C2c1ccccc1Cl
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCc1cc2c(s1)-n1nc(C(N)=O)nc1C(OC)N=C2c1ccccc1Cl

Procedure:
To a solution of 0.086 g. of 4-acetoxy-6-(2-chlorophenyl)-8-ethyl-4H-thieno[3,2-f]-s-triazolo[1,5-a][1,4]diazepine-2-carboxamide in 3 ml. of methanol is added one drop of concentrated sulfuric acid and the resulting mixture is refluxed for 5 minutes. After evaporation of the solvent a saturated aqueous sodium hydrogen carbonate solution is added to the residue. The resulting precipitate is collected by filtration to give 6-(2-chlorophenyl)-8-ethyl-4-methoxy-4H-thieno[3,2-f]-s-triazolo[1,5-a][1,4]diazepine-2-carboxamide as crystals. Recrystallization from ethyl acetate gives powdery crystals melting at 200° to 201° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[N:10][N:9]=1.[C:13]1([C:19](Cl)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([C:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:11]=[N:10][N:9]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Brc1ccccc1-c1nnn[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Brc1ccccc1-c1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 0.50 g of 5-(2-bromophenyl)-1H-tetrazole in 20 ml of CH2Cl2 is added 0.65 g of triphenylmethyl chloride followed by 0.37 ml of triethylamine. The solution is refluxed for 2.5 hours, cooled to room temperature and then washed with water, dried over MgSO4 and concentrated in vacuo. The residue is purified by flash chromatography eluting with ethyl acetate/hexanes (1:5) to provide the desired product.
Reaction SMILES: [C:1]1([C:7]([CH3:9])=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:10]N1C(=O)CCC1=O.BrC1C=CC=CC=1>>[Br:10][CH2:8][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH2:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(C)c1ccccc1
Solvent: Brc1ccccc1
Product: C=C(CBr)c1ccccc1
Temperature: 25 °C
Yield: 46.2 %

Procedure:
A mixture of 2-phenylpropene (22.4 g, 190 mmoles), N-bromosuccinimide (23.7 g, 133 mmoles) and bromobenzene (76 ml) was superheated on an oil bath at 160° C. until the N-bromosuccinimide was dissolved. The reaction mixture was cooled to room temperature, and the precipitate was subsequently removed by filtration and washed with chloroform. The filtrate was purified by distillation under reduced pressure to obtain 12.1 g of 3-bromo-2-phenylpropene (b.p. 80° C. to 85° C./3 mmHg). 1H-NMR (CDCl3)δ=4.39 (s, 2H), 5.49 (s, 1H), 5.56 (s, 1H), 7.33-7.51 (m, 5H); 13C NMR (CDCl3)δ=34.2, 117.2, 126.1, 128.3, 128.5, 137.6, 144.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[C:6]=1[CH3:20])=[O:4].[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH2:40])=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>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]>[CH3:1][O:2][C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10]([NH:40][C:37]3[CH:38]=[CH:39][C:34]([N:31]4[CH2:32][CH2:33][N:28]([C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[CH2:29][CH2:30]4)=[CH:35][N:36]=3)[N:11]=[CH:12][C:7]=2[C:6]=1[CH3:20])=[O:4]
Reactant: COC(=O)c1c(C)c2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1c(C)c2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n1C1CCCC1
Temperature: 100 °C
Yield: 17.5 %

Procedure:
A mixture of 2-chloro-7-cyclopentyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methyl ester (110 mg, 0.374 mmol), 4-(6-Amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (114.66 mg, 0.412 mmol), Pd2(dba)3 (17.144 mg, 0.02 mmol), Xantphos (21.67 mg, 0.037 mmol) and cesium carbonate (183 mg, 0.562 mmol) in dioxane (5 mL) is degassed and back-filled with nitrogen three times. The reaction mixture is heated to 100° C. for 4 h. Water is added and the solution is extracted with ethyl acetate three times. The organic layers are combined, washed with brine and dried over anhydrous sodium sulfate. The solvent is evaporated and the crude product is dissolved in a small amount of ethyl acetate. White solid precipitates out and filters to give 2-[5-(4-tert-Butoxycarbonyl-piperazin-1-yl)-pyridin-2-ylamino]-7-cyclopentyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methyl ester as a white solid (35 mg, 17%) which was carried onto the next step without further purification. [M+H]+=536.35.
Reaction SMILES: [Cl:1][C:2]([Cl:13])([Cl:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:16])=O>>[Cl:1][C:2]([Cl:13])([Cl:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([Cl:16])=[O:6]
Reactant: O=C(O)c1ccccc1C(Cl)(Cl)Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccccc1C(Cl)(Cl)Cl

Procedure:
Similarly, reaction of 2-trichloromethylbenzoic-acid with thionyl chloride affords 2-trichloromethylbenzoyl-chloride, which, on reaction with diethylamine, affords 2-trichloromethyl-N,N-diethylbenzamide. Following a procedure similar to that described in Preparation 5, reaction of the latter with s-butyl lithium and reaction of the resulting lithium salt with sulfur dioxide followed by sodium hydroxyl-amine-O-sulfonate affords 2-trichloromethyl-6-aminosulfonyl-N,N-diethylbenzamide, which, on heating in glacial acetic acid, affords 4-trichloromethylsaccharin.
Reaction SMILES: [C:1]1([NH:7][N:8]=[C:9]([C:12]#[N:13])[C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C=CC=CC=1.C(#N)CC#N.[NH:26]([C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1)[NH2:27]>>[NH2:11][C:10]1[C:9]([N:8]=[N:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:12]([NH2:13])[N:26]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:35][CH:36]=2)[N:27]=1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: N#CC(C#N)=NNc1ccccc1
Solvent: N#CCC#N
Solvent: Nc1ccccc1
Product: Nc1nn(-c2ccc(C(=O)O)cc2)c(N)c1N=Nc1ccccc1
Reaction time: 4 h

Procedure:
4-(3,5-diamino-4-phenylazopyrazol-1-yl)benzoic acid was prepared using 85 mg (0.5 mmol) of 2-(phenylhydrazono)malononitrile, which was derived from aniline (10 mL, 107 mmol) and malononitrile (161 mmol), and 4-hydrazinobenzoic acid (76 mg, 0.5° mmol). After reacting for 4 hrs, the reaction remained as a slurry; however, analysis of the reaction solution by TLC indicated that no starting material remained. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 22 mg (14%) of the compound as a brown solid.
Reaction SMILES: C([O:8][C:9]1[CH:43]=[CH:42][C:12]([CH2:13][N:14]2[CH:18]=[C:17](/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:26]CC3C=CC(OCC4C=CC=CC=4)=CC=3)=[N:15]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(O)C>[C].[Pd].O1CCCC1>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([OH:26])=[N:15]2)=[CH:42][CH:43]=1
Reactant: CCOC(=O)/C=C/c1cn(Cc2ccc(OCc3ccccc3)cc2)nc1OCc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
A mixture of ethyl(E)-3-[1-(4-benzyloxybenzyl)-3-(4-benzyloxybenzyloxy)-1H-pyrazol-4-yl]propenoate (6.61 g), 5% palladium-carbon (13.00 g), ethanol (150 ml), and tetrahydrofuran (150 ml) was stirred for one hour at room temperature under a hydrogen atmosphere. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The crystals obtained were collected by filtration to yield ethyl 3-[1-(4-hydroxybenzyl)-3-hydroxy-1H-pyrazol-4-yl]propionate (2.98 g, yield: 89%). This was recrystallized from ethyl acetate-hexane. Melting point: 143–144° C.
Reaction SMILES: [Mg].C(Br)C.[CH:5]([N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1)=[CH2:6].[Cl:12][C:13]1[CH:27]=[CH:26][C:16]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[O:18])=[CH:15][CH:14]=1.[Cl-].[NH4+]>O.O1CCCC1>[Cl:12][C:13]1[CH:27]=[CH:26][C:16]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)([C:8]2[N:7]([CH:5]=[CH2:6])[CH:11]=[CH:10][N:9]=2)[OH:18])=[CH:15][CH:14]=1
Reactant: C=Cn1ccnc1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCBr
Product: C=Cn1ccnc1C(O)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reaction time: 24 h

Procedure:
2.19 g (0.09 gr.at.) of magnesium and 10.9 g (0.1 mol) of ethyl bromide were converted into a Grignard compound in 50 ml. of refluxing anhydrous tetrahydrofuran. In the course of 5 minutes a solution of 8.46 g (0.09 mol) of 1-vinylimidazole in 20 ml. of anhydrous tetrahydrofuran was added with stirring to the refluxing mixture, after which the reaction mixture was refluxed for another two hours. A suspension of 22.6 g (0.09 mol) of 4,4'-dichlorobenzophenone in 50 ml. of anhydrous tetrahydrofuran was then added and refluxing was continued for 24 hours. The whole procedure was carried out under a nitrogen atmosphere. After cooling, the reaction mixture was poured into a mixture of ice, water and ammonium chloride. The mixture was then extracted with diethyl ether and the extract was washed with water, dried over sodium sulphate and concentrated. The solid residue was twice crystallized from a mixture of isopropyl alcohol and dimethyl formamide. α,α-Bis(p-chlorophenyl)-1-vinylimidazole-2-methanol was obtained. Melting point 173.5°- 174° C.