Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH2:10])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(N(CC)CC)C.[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>ClCCl.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a stirred solution of 5-Indole amine (0.6 g, 4.54 mmol) in anhydrous dichloromethane (15 mL), triethylamine (1.3 mL, 9.0 mmol) and pivaloyl chloride (0.45 mL, 5.4 mmol) were added and stirred at room temperature for 2 h. The reaction mixture was diluted with water; the organic layer was separated and concentrated in vacuo. The resultant residue was purified by flash column chromatography to give N-(1H-indol-5-yl)pivalamide (0.88 g, 89%); MS: 217.0 (M+1).
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH2:4][CH2:3][CH2:2]1.[H][H]>C(O)(=O)C.O=[Pt]=O>[NH:1]1[CH:10]2[CH:5]([CH:6]([OH:11])[CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCC2=C1CCCN2
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: OC1CCCC2NCCCC12
Temperature: 0 °C
Yield: 36.2 %

Procedure:
The procedure of Grob et al. (Helv. Chim. Acta 1965, 48, 799-808) was followed. A solution of 66.70 g (0.441 mol) of 2,3,4,6,7,8-hexahydro-5(1H)-quinolinone in 250 ml of glacial acetic acid containing 2 g of PtO2 was hydrogenated at 450 psi and 50° C. for 75 hours. Hydrogen uptake was only 57.2% of the theoretical. The sample was filtered, concentrated (to remove most of the acetic acid), cooled to 0° C., basified with 6N sodium hydroxide to a pH of 12 and extracted three times with 500 ml of methylene chloride. The combined methylene chloride extract was dried over magnesium sulfate, filtered and concentrated to give 24.80 g (36.2%) of decahydro-5-quinolinol, which was a three component isomeric mixture by gas chromatography (GC) analysis, as a light brown oily-solid. This mixture was carried on to the next step without further purification.
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[CH:23]=[C:22]2[C:11]([C:12]([CH3:25])([CH3:24])[C:13]3[CH:17]=[CH:16][N:15]([CH2:18][C@H:19](O)[CH3:20])[C:14]=32)=[CH:10][CH:9]=1.C(N(CC)CC)C.[N-:33]=[N+:34]=[N-:35].[Na+]>ClCCl.CN(C)C=O.O>[N:33]([C@@H:19]([CH3:20])[CH2:18][N:15]1[CH:16]=[CH:17][C:13]2[C:12]([CH3:25])([CH3:24])[C:11]3[C:22]([C:14]1=2)=[CH:23][C:8]([O:7][CH3:6])=[CH:9][CH:10]=3)=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)C2(C)C
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)-c1c(ccn1C[C@H](C)N=[N+]=[N-])C2(C)C
Yield: 50.6 %

Procedure:
2.0 ml of methanesulfonyl chloride were added dropwise while stirring to a solution, cooled to 0°, of 3.42 g of (R)-1-(7-methoxy-4,4-dimethyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol and 7.3 ml of triethylamine in 70 ml of dichloromethane, and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 170 ml of dichloromethane, washed twice with 90 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 90 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The green oil obtained was dissolved in 70 ml of anhydrous dimethylformamide, treated with 1.35 g of sodium azide and the reaction mixture was heated to 60° for 20 hours while stirring. After cooling, the solution was poured into 100 ml of water and extracted three times with 100 ml of ethyl acetate each time. The combined organic phases were washed once with 100 ml of water and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (hexane/ethyl acetate 4:1). 1.89 g (50%) of (S)-1-(2-azido-propyl)-7-methoxy-4,4-dimethyl-1,4-dihydro-indeno[1,2-b]pyrrole were obtained as a yellow oil.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([C:20]([CH2:38][CH3:39])([C:23]3[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([CH2:35][CH3:36])([OH:34])[CH2:32][CH3:33])=[C:25]([CH3:37])[CH:24]=3)[CH2:21][CH3:22])=[CH:15][C:14]=2[CH3:40])[CH:12]=1.[Cl-].[NH4+]>CO.O1CCCC1>[CH2:21]([C:20]([C:16]1[CH:17]=[C:18]([CH3:19])[C:13]([C:11]2[CH:12]=[C:7]([CH2:6][C:5]([OH:41])=[O:4])[CH:8]=[N:9][CH:10]=2)=[C:14]([CH3:40])[CH:15]=1)([C:23]1[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([CH2:32][CH3:33])([OH:34])[CH2:35][CH3:36])=[C:25]([CH3:37])[CH:24]=1)[CH2:38][CH3:39])[CH3:22]
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2cc(C)c(-c3cncc(CC(=O)OC)c3)c(C)c2)cc1C)CC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2cc(C)c(-c3cncc(CC(=O)O)c3)c(C)c2)cc1C)CC
Temperature: 25 °C
Reaction time: 6 h
Yield: 45.9 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.150 mL, 0.150 mmol) was added to a solution of (E)-[5-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propyl}-2,6-dimethyl-phenyl)-3-pyridinyl]-acetic acid methyl ester (Example 120-(1); 26.2 mg, 0.050 mmol) in methanol-tetrahydrofuran (1:1, 2 mL), and the mixture was stirred at room temperature for six hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=10:1) to give the target compound as a colorless oil (11.8 mg, 46%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:38](Cl)=[O:39])[CH2:34][CH2:33]1>N1C=CC=CC=1>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH:24]3[CH2:29][CH2:28][N:27]([C:38]([N:35]4[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]4)=[O:39])[CH2:26][CH2:25]3)[N:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)[C:22]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCNCC1
Reactant: CN1CCN(C(=O)Cl)CC1
Agent: Cl
Solvent: c1ccncc1
Product: CN1CCN(C(=O)N2CCC(n3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 44.5 %

Procedure:
A solution of 3-(4-phenoxyphenyl)-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.300 g, 0.780 mmol) in pyridine (5 mL) at 0° C. was treated with 4-methyl-1-piperazinecarbonyl chloride hydrochloride (0.127 g, 0.780 mmol). The reaction mixture was stirred for 5 min at 0° C., after which the ice bath was removed, and the reaction stirred at room temperature over night. An additional equivalent of 4-methyl-1-piperazinecarbonyl chloride hydrochloride (0.127 g, 0.780 mmol) was added and stirred for 2 h. Solvent was removed under reduced pressure. Dichloromethane (10 mL) and sodium bicarbonate (5 mL) saturated aqueous solution were added to the solid. The layers were separated using an Empore extraction cartridge. The organic layer was removed under reduced pressure to give 0.417 g of crude material. The crude product was purified by flash chromatography on silica gel eluting 8% methanol in dichloromethane, 15% methanol in dichloromethane, and then 20% methanol in dichloromethane as eluent to give 0.178 g (45%) of 4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino(4-methylpiperazino)methanone. A hot solution of 4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino(4-methylpiperazino)methanone (0.178 g, 0.347 mmol) in ethyl acetate was treated with a hot solution of maleic acid (0.081 g, 0.693 mmol) in ethyl acetate. Upon cooling of the solvent a precipitate formed, was filtered under nitrogen, and dried under high vacuum to give 0.124 g of 4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino(4-methylpiperazino)methanone bis-maleate.
Reaction SMILES: CN(C=O)C.[C:6]([O:10][C:11]([N:13]1[CH2:16][CH:15]([O:17][C:18]2[CH:23]=[C:22]([Br:24])[CH:21]=[CH:20][C:19]=2[OH:25])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O>[C:6]([O:10][C:11]([N:13]1[CH2:14][CH:15]([O:17][C:18]2[CH:23]=[C:22]([Br:24])[CH:21]=[CH:20][C:19]=2[O:25][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:16]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Br)ccc2O)C1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(Br)ccc2OCc2ccccc2)C1
Reaction time: 48 h
Yield: 99.8 %

Procedure:
To a DMF (10 mL) solution of the title compound of Step C (0.52 g, 1.5 mmol), Cs2CO3 (0.54 g, 1.7 mmol) and KI (0.20 g, 1.20 mmol) was added benzyl bromide (0.20 mL, 0.29 g, 1.7 mmol). After 48 h, H2O was added and the mixture extracted with EtOAc (2×). The combined organics were washed with brine (2×) and dried. Silica gel chromatography (5-20% EtOAc in hexanes) gave 0.65 g (99%) of the title compound as a clear oil. 1H NMR (CDCl3): 7.42-7.36 (m, 3H), 7.34-7.31 (m, 2H), 7.03 (dd, J=8.6, 2.3 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 6.70 (d, J=2.3 Hz, 1H), 5.09 (s, 2H), 4.88-4.83 (m, 1H), 4.26 (ddd, J=9.7, 6.5, 0.9 Hz, 2H), 4.05 (dd, J=9.8, 4.0 Hz, 2H), 1.45 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:11]1[N:12]=[C:13]([NH2:16])[S:14][CH:15]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[Cl:18][CH2:19][C:20](Cl)=[O:21]>CN(C)C=O.C(OCC)(=O)C.O>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:11]1[N:12]=[C:13]([NH:16][C:20](=[O:21])[CH2:19][Cl:18])[S:14][CH:15]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)C(C(=O)OCC)c1csc(N)n1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1csc(NC(=O)CCl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a solution of 2-(2-amino-4-thiazolyl)malonic acid diethyl ester in N,N-dimethylformamide (10 parts) is added monochloroacetyl chloride (1.3 equivalents) under ice cooling. After stirring under ice cooling for 30 minutes and at room temperature for 1 hour, the reaction mixture is diluted with ethyl acetate and water, washed with water, dried, and concentrated in vacuum to give 2-(2-monochloroacetamido-4-thiazolyl)malonic acid diethyl ester. Yield: 99.6%.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7](=[CH:10][NH:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:8]=O)=[CH:4][CH:3]=1.C(O)C[OH:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[C:12]([C:13]([O:15][CH2:16][CH2:17][OH:22])=[O:14])[NH:11][CH:10]=2)=[CH:18][CH:19]=1
Reactant: OCCO
Reactant: CCOC(=O)CNC=C(C=O)Oc1ccc(Cl)cc1
Product: O=C(OCCO)c1cc(Oc2ccc(Cl)cc2)c[nH]1
Temperature: 25 °C

Procedure:
2-(4-Chlorophenoxy)-3-carbethoxymethylaminoacrylaldehyde (2 g.) was boiled in 5 ml. of ethylene glycol for 15 minutes. The reaction was cooled to room temperature, diluted with 10 ml. of water and product extracted into 10 ml. of ethyl acetate. The ethyl acetate was back-washed with water and concentrated to an oil (1.5 g.). The oil chromatographed on approximately 100 ml. of silica gel with ethyl acetate-1/hexane-1 as eluant, monitored by thin layer chromatography. Evaporation of middle fractions are ethyl 4-(4-chlorophenoxy)pyrrole-2-carboxylate (100 mg., oil, m/e 281, Rf 0.65 on silica gel thin layer chromatography with ethyl acetate-1/hexane-1/5% acetic acid as eluant; Rf 0.3 with ethyl acetate-1/hexane-1 as eluant). Repeat on a 5.5 g. scale gave an additional 400 mg. of product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:32]=[CH:31][C:15]([O:16][CH2:17][C:18]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:19]=3[O:20][CH:21]([CH3:25])[C:22]([OH:24])=[O:23])=[CH:14][CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].[CH2:33](I)[CH3:34]>C(#N)C>[Cl:1][C:2]1[C:3]([C:12]2[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:19]=3[O:20][CH:21]([CH3:25])[C:22]([O:24][CH2:33][CH3:34])=[O:23])=[CH:31][CH:32]=2)=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:9])[F:10]
Reactant: CCI
Reactant: Cc1ccc(COc2ccc(-c3nn(C)c(OC(F)F)c3Cl)cc2)c(OC(C)C(=O)O)c1
Solvent: CC#N
Product: CCOC(=O)C(C)Oc1cc(C)ccc1COc1ccc(-c2nn(C)c(OC(F)F)c2Cl)cc1
Yield: 60.6 %

Procedure:
A stirred solution of 1.6 grams (0.003 mole) of 2-[2-[4-(4-chloro-5-difluoromethoxy-1-methylpyrazol-3-yl)phenoxymethyl]-5-methylphenoxy]-propanoic acid, 0.32 mL (0.004 mole) of ethyl iodide, and 0.49 mL (0.3 mole) of 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU) in 40 mL of acetonitrile was heated at reflux for two hours. The reaction mixture was then cooled and concentrated under reduced pressure to a residue. The residue was taken up in water and extracted with three 60 mL portions of ethyl acetate. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, using 3:7 diethyl ether in heptane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.9 gram of title compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Na].[I-:2].C([O-])(=O)C.[NH4+].C(OO)(=O)C.C([Sn](CCCC)(CCCC)[C:18]1[N:19]=[N:20][N:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:22]=1)CCC.C(#N)C>[OH-].[Na+].C(O)C>[I:2][C:18]1[N:19]=[N:20][N:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:22]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(CCCCCCCCCC(=O)O)nn1
Reactant: [I-]
Agent: CC(=O)OO
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC#N
Solvent: CCO
Product: O=C(O)CCCCCCCCCn1cc(I)nn1
Reaction time: 0.25 h

Procedure:
To sodium [123I] iodide, received in 5-20 μL 0.05M sodium hydroxide is added ammonium acetate buffer (100 μL pH 4.0, 0.2M), sodium [127I] iodide (10 μL, 1 mM solution in 0.01M sodium hydroxide, 1×10−8 moles), peracetic acid (PAA) solution (10 μL 1 mM solution, 1×10−8 moles) and finally 10-(4-tributylstannyl-[1,2,3]triazol-1-yl)-decanoic acid solution in ethanol or acetonitrile (53 μg, 1×10−7 moles). The reaction mixture is allowed to stand at room temperature for 15 minutes prior to HPLC purification of the iodinated product 10-(4-iodo-[1,2,3]triazol-1-yl)-decanoic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Si:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.II.[Mg].[O:15]=[C:16]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]1>C1COCC1>[OH:15][C:16]1([C:2]2[CH:7]=[CH:6][C:5]([Si:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=2)[CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19]1
Reactant: C[Si](C)(C)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)(c2ccc([Si](C)(C)C)cc2)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A 2 L-3neck flask equipped with mechanical stirrer, thermocouple, addition funnel and nitrogen inlet was charged with (4-bromophenyl)trimethylsilane (80.4 g, 0.35 mol), THF (600 mL), Mg (8.5 g), and I2 (catalytic amount). The suspension was refluxed at 68° C. for 1.5 hours until all magnesium disappeared. The solution was cooled to 0° C. in ice-bath. Then, a solution of tert-butyl 3-oxoazetidine-1-carboxylate (Preparation 2, 30 g, 0.17 mol) in THF (200 mL) was added slowly via addition funnel. The solution was stirred at 0° C. for 3 hours. LC/MS indicated the formation of desired product. The reaction was quenched with brine at 0° C. The aqueous layer was extracted with EtOAc (2×800 mL). The combined organics were dried over sodium sulfate, filtered and concentrated to give the desired product (47.4 g, 84% yield). 1H NMR (CDCl3) δ 7.3 (d, 2H), 7.2 (d, 2H), 4.0 (d, 2H), 3.9 (d, 2H), 2.9 (s, 1H), 1.2 (s, 9H), 0.0 (s, 9H).
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][C:17]([C:23](O)([CH3:25])[CH3:24])=[CH:18][C:19]2=4)[NH:14][C:13]=3[CH3:27])[N:9]([CH3:28])[CH2:8]1)=[O:5])[CH3:2].[BH4-].[Na+].N>C(O)(=O)C>[CH2:29]([N:3]([CH2:1][CH3:2])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][C:17]([CH:23]([CH3:24])[CH3:25])=[CH:18][C:19]2=4)[NH:14][C:13]=3[CH3:27])[N:9]([CH3:28])[CH2:8]1)=[O:5])[CH3:30]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(C(C)(C)O)cc4[nH]c(C)c(c34)C[C@H]2N(C)C1
Agent: N
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(C(C)C)cc4[nH]c(C)c(c34)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1,1-Diethyl-3-[13-(1-hydroxy-1-methyl-1-ethyl)-2,6-dimethyl- 8alpha-ergolinyl]-urea (0.5 mmol) is dissolved in 5 ml of glacial acetic acid and 0.25 g of sodium borohydride is added. After 15 minutes of stirring at room temperature, ice is added, it is made alkaline with conc. ammonia and extracted with ethyl acetate. The organic phases are dried with sodium sulfate and concentrated by evaporation, the residue is chromatographed on silica gel with dichloromethane/methanol, yield 76 mg (38% of theory).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([Cl:13])[CH:10]=[C:9](Cl)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:15]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16]1>C(O)(C)C>[CH:1]1([NH:6][C:7]2[N:8]=[C:9]([NH:20][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:10]=[C:11]([Cl:13])[N:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NC1CCCC1
Reactant: Clc1cc(Cl)nc(NC2CCCC2)n1
Solvent: CC(C)O
Product: Clc1cc(NC2CCCC2)nc(NC2CCCC2)n1
Reaction time: 6 h

Procedure:
5.0 g of 2-(cyclopentylamino)-4,6-dichloropyrimidine are dissolved in 25 ml of isopropanol, then 7.5 ml of cyclopentylamine are added and the mixture is boiled for 6 hours. Then the reaction mixture is evaporated, the residue is separated between 80 ml of chloroform and 15 ml of 10% sodium hydroxide solution. After separation the organic phase is washed 4 times with 20 ml of water each, dried and evaporated. The title compound is obtained by recrystallizing from hexane in a yield of 5.24 g (86.7%), m.p.: 94°-98° C.
Reaction SMILES: C(O)CCCC.[CH3:7][O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[OH:17].Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25](=[O:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C>[CH3:7][O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH2:26][C:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:19]=1)=[O:27]
Reactant: CC(=O)c1ccccc1Br
Reactant: COc1cccc(O)c1OC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCCCO
Solvent: CCOC(C)=O
Product: COc1cccc(OCC(=O)c2ccccc2)c1OC
Temperature: 150 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
Amyl alcohol (44 ml) was added to 2,3-dimethoxyphenol (5 g), 2'-bromoacetophenone (7 g), potassium carbonate (6.7 g) and copper acetate (1.1 g), followed by heating and stirring at 150° C. for 8 hours for reacting them together. To the reaction solution was added ethyl acetate (300 ml), and the resulting solution was washed in dilute hydrochloric acid, in water, and in a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvents therein were distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=8:1), to recover 2-(2,3-dimethoxyphenoxy)acetophenone (7.6 g; yield of 87%). By 1H-NMR (90 MHz, CDCl3), the compound has the peaks shown below.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:6][N:5]=[C:4]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[N+:18]([O-:20])=[O:19])[C:3]1=2.S(OCC)(O[CH2:25][CH3:26])(=O)=O>[OH-].[Na+]>[O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[N:6]([CH2:25][CH3:26])[N:5]=[C:4]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[N+:18]([O-:20])=[O:19])[C:3]1=2
Reactant: O=C1CCCc2[nH]nc(-c3ccc(Cl)cc3[N+](=O)[O-])c21
Reactant: CCOS(=O)(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCn1nc(-c2ccc(Cl)cc2[N+](=O)[O-])c2c1CCCC2=O
Reaction time: 1 h

Procedure:
2.08 g (7.13 mmol) of 4,5,6,7-tetrahydro-4-oxo-3-(4-chloro-2-nitrophenyl)-1H-indazole are dissolved in 80 ml of 10% aqueous sodium hydroxide solution, insolubles are filtered off, and 1.2 g (7.8 mmol) of diethyl sulfate are then added to the solution. Stirring is subsequently continued for 1.5 hours at room temperature and for 1 hour at 0° C., during which process a precipitate starts to separate out after as early as approx. 10 minutes. When the reaction is complete, the precipitate is filtered off with suction and chromatographed on silica gel using ethyl acetate/dichloromethane (1:2). The fraction of Rf =0.72 contains 0.34 g (15.3% of theory) of the desired product of the formula ##STR7## and of melting point 184° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:19])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:5]=[CH:6][C:7]=1Cl.[CH3:20][NH:21][NH2:22].O>CO>[Cl:1][C:2]1[C:3](=[O:19])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:5]=[CH:6][C:7]=1[N:21]([CH3:20])[NH2:22]
Reactant: CNN
Reactant: O=c1c(Cl)c(Cl)cnn1-c1cccc(C(F)(F)F)c1
Solvent: CO
Solvent: O
Product: CN(N)c1cnn(-c2cccc(C(F)(F)F)c2)c(=O)c1Cl
Temperature: 45 °C

Procedure:
To a solution consisting of 15.5 grams of 4,5-dichloro-2-(3-trifluoromethylphenyl)-pyridazine-3(2H)-one in 120 grams of methanol is added 9.2 grams methylhydrazine. The reaction mixture is heated to 45° C for three hours, cooled and poured onto 250 grams of water. The resulting precipitate is separated by filtration, washed with water and dried. The solid is crystallized from benzene to yield 4-chloro-2-(3-trifluoromethylphenyl)-5-(1-methylhydrazino)-pyridazin-3(2H)-one (m.p. 140° to 141° C, with decomposition).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][N:39]([CH2:20][C:17]2[CH:16]=[N:15][C:14]([NH:13][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:1])[CH3:28])[N:22]([CH:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)[C:8]=4[N:9]=3)=[CH:19][CH:18]=2)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C=O)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(CN4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n1C1CCCC1
Yield: 65.5 %

Procedure:
Following General Procedure B, 7-cyclopentyl-2-(5-formyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (0.35 g, 0.926 mmol) and piperazine-1-carboxylic acid tert-butyl ester (0.19 g, 1.02 mmol) gave 4-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-ylmethyl]-piperazine-1-carboxylic acid tert-butyl ester as a white solid (0.333 g, 60%). The material is used directly in the next step. MS (ESI) m/z 549.3 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[C:14]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)Cc1cccc(OC)c1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)Cc1cc(OC)ccc1C(=O)c1ccccc1

Procedure:
Methyl 3-methoxy-phenylacetate was treated with benzoyl chloride and aluminum chloride as described in J. Chem. Soc., Perkin Trans 1, 1991, 171 to give the title compound.