Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][C:29]([O:31]C)=[O:30])=[CH:22][CH:21]=2)=[O:18])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C@@H:16]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:24][CH:25]=2)=[O:18])=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCCc1ccc(NC(=O)C(Cc2ccc(OCc3ccccc3)cn2)NC(=O)OC(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(OCc2ccccc2)cn1)C(=O)Nc1ccc(CCCC(=O)O)cc1
Temperature: 60 °C
Yield: 89.3 %

Procedure:
A mixture of methyl 4-(4-(3-(5-(benzyloxy)pyridin-2-yl)-2-(tert-butoxycarbonylamino)propanamido)phenyl)butanoate (0.59 g, 1.07 mmol) and lithium hydroxide (0.26 g, 10.7 mmol) in 10 mL THF/H2O (1:1) was heated at 60° C. for 2 h (monitored by TLC). The solution was acidified to PH=2 and extracted with dichloromethane. The dichloromethane was separated, dried over magnesium sulfate, and concentrated in vacao to give 0.51 g of the desired compound (90%): (400 MHz in CDCl3, Bruker AVANCE-400): δ 1.30 (s, 9H, Boc), 1.74 (m, 2H, CH2), 2.17 (t, 2H, CH2—CH2—COOMe, J=7.34 Hz), 2.52 (t, 2H, CH2, J=7.55 Hz), 2.92-3.07 (m, 2H, CH2), 4.44 (m, 1H CH), 5.13 (s, 2H OBn), 7.09 (d, 1H, J=8.47 Hz, Ar—H), 7.21 (d, 1H, Ar—H, J=8.52 Hz), 7.31˜7.48 (m, 9H Ar—H), 8.26 (br, 1H, NH), 9.91 (br, 1H, OH).
Reaction SMILES: [C:1]1([N:7]2[N:11]3[C:12](=[O:22])[CH:13]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:15]=[C:10]3[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[C:1]1([N:7]2[CH:8]=[C:9]3[C:10]([N:15]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:13]=[C:12]3[OH:22])=[N:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1cc(-c2ccccc2)nc2ccn(-c3ccccc3)n12
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Oc1cc(-c2ccccc2)nc2nn(-c3ccccc3)cc12
Reaction time: 8 h

Procedure:
6.5 g. of 1,5-diphenylpyrazolo[1,5-a]pyrimidin7(1H)-one (0.0226 mol.) and 18 g. of diphenyl ether are heated at 250°-260° for 90 minutes. After standing overnight, the crystallized 2,6-diphenyl-2H-pyrazolo[3,4-b]pyridin-4-ol is filtered off, washed with ethanol and dried at 80°, yield: 6.1 g. (94%); m.p. 280°-281°.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:18]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:29][O:30][CH2:31][CH2:32][NH:33][CH3:34]>>[CH3:29][O:30][CH2:31][CH2:32][N:33]([CH2:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:18]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)=[O:8])=[CH:5][CH:4]=1)[CH3:34]
Reactant: CNCCOC
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Product: COCCN(C)Cc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1
Yield: 55 %

Procedure:
Conversion of 4-cloromethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide (84 mg, 0.20 mmol) with N-(2-methoxyethyl)-methylamin (178 mg, 2.0 mmol) using the general procedure C affords the product as white solid in 55% yield. MS: m/e=471 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:8]([O:25][CH3:26])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:24])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3Br)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C]=O.[C:41]([O:44][CH2:45]C)(=[O:43])C>CO.CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:8]([O:25][CH3:26])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:24])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[C:41]([O:44][CH3:45])=[O:43])=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(NC(=O)c2cc3cccc(Br)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: CCOC(C)=O
Agent: [C]=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cccc2cc(C(=O)Nc3cc(C(C)(C)C)cc(NS(C)(=O)=O)c3OC)n(C)c12

Procedure:
Argon is piped for 10 minutes through a suspension of 18.8 g 7-bromo-1-methyl-1H-indole-2-carboxylic acid-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-amide in 250 ml of methanol and 50 ml N,N-dimethylformamide. Then 7.2 ml triethylamine and 2.3 g [1,1′-bis(diphenylphosphino)ferrocene]-palladium-II-dichloride-dichloromethane complex are added and 2 bar of carbon monoxide are compressed in for 15 hours at 80° C. Then the solvents are eliminated in vacuo, the residue is taken up in ethyl acetate and washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution. After drying with magnesium sulphate the solvent is eliminated in vacuo and the residue is extracted from methanol. The solid is suction filtered, washed with a little methanol and dried.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1Cl)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[O:19]1[C:23]2[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=2[O:21][CH2:20]1>CN(C)C=O.O>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[O:28][C:26]1[CH:25]=[CH:24][C:23]2[O:19][CH2:20][O:21][C:22]=2[CH:27]=1)[CH3:2]
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CCOC(=O)c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cccnc1Oc1ccc2c(c1)OCO2

Procedure:
A solution 2-Chloro-nicotinic acid ethyl ester (5.0 grams, 27.0 mmole), cesium carbonate (2.96 grams, 67.5 mmole) and Benzo[1,3]dioxol-5-ol (4.19 grams, 29.7 mmole) in dimethylformamide (80 ml) was heated to 65° C. for 10 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to a solid (7.0 g). MW 287.275.
Reaction SMILES: [CH3:1][C:2]([S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:5])[C:3]#[N:4].B.C1COCC1>>[CH3:5][C:2]([S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:1])[CH2:3][NH2:4]
Reactant: CC(C)(C#N)Sc1ccccc1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(CN)Sc1ccccc1
Reaction time: 18 h

Procedure:
A solution of Example 266A (0.5 g, 2.82 mmol) in TH at room temperature was treated with 1M BH3.THF (15 mL), stirred for 18 hours, quenched with methanol (5 mL), and concentrated. The concentrate was treated with 2M HCl (50 mL) and concentrated. The concentrate was partitioned between dichloromethane and saturated sodium bicarbonate, and the organic phase was dried (MgSO4), filtered, and concentrated to provide the desired product. MS (DCI(+)) m/e 182 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH2:9][CH:10]=1.[NH2:23][O:24][K].C(O)(=O)C>CO.CO.C(Cl)(Cl)Cl>[OH:24][NH:23][C:3](=[O:2])[CH2:4][CH2:5][C:6]1[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH2:9][CH:10]=1
Reactant: COC(=O)CCC1=CCN(CCCc2ccc(C)cc2)C1=O
Reactant: NO[K]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(CCCN2CC=C(CCC(=O)NO)C2=O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
100 mg of 3-[2-oxo-1-(3-p-tolyl-propyl)-2,5-dihydro-1H-pyrrol-3-yl]-propionic acid methyl ester (40ag) prepared by the above Step 7 was dissolved in methanol solution (0.33 mM) and then 1.7 M methanolic suspension solution containing NH2OK (0.82 ml, 5.0 mM) was added thereto at 0° C. and the resulting mixture was stirred for 8 hrs at room temperature. The resulting mixture was neutralized with 0.02 ml of acetic acid, diluted with 10% methanol/chloroform solution, filtered and concentrated in vacuo. The resulting compound was purified by Silica gel column chromatography with a solvent mixture mixed with methanol and chloroform (1:9) as an eluant to give 50 mg of N-hydroxy-3-[2-oxo-1-(3-p-tolyl-propyl)-2,5-dihydro-1H-pyrrol-3-yl]-propionamide (40ah) (yield: 50%).
Reaction SMILES: C(O[CH2:5][CH2:6][C:7]1[N:8]([CH2:24]C2C=CC=CC=2[N+]([O-])=O)[C:9]([S:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)=[C:10]([CH:12]([CH3:14])[CH3:13])[N:11]=1)(=O)N.ClC1C=C(SC2N(CC3C=CC=CC=3[N+]([O-])=O)C(CCO)=[N:45]C=2C(C)C)C=C(Cl)C=1.C(OCCC1N(CC2C=CC([N+]([O-])=O)=CC=2)C(SC2C=C(Cl)C=C(Cl)C=2)=C(C(C)C)N=1)(=O)N>>[Cl:23][C:18]1[CH:17]=[C:16]([S:15][C:9]2[N:8]([CH3:24])[C:7]([CH2:6][C:5]#[N:45])=[N:11][C:10]=2[CH:12]([CH3:14])[CH3:13])[CH:21]=[C:20]([Cl:22])[CH:19]=1
Reactant: CC(C)c1nc(CCOC(N)=O)n(Cc2ccccc2[N+](=O)[O-])c1Sc1cc(Cl)cc(Cl)c1
Reactant: CC(C)c1nc(CCO)n(Cc2ccccc2[N+](=O)[O-])c1Sc1cc(Cl)cc(Cl)c1
Agent: CC(C)c1nc(CCOC(N)=O)n(Cc2ccc([N+](=O)[O-])cc2)c1Sc1cc(Cl)cc(Cl)c1
Product: CC(C)c1nc(CC#N)n(C)c1Sc1cc(Cl)cc(Cl)c1
Yield: 87 %

Procedure:
2-(2-Carbamoyloxyethyl)-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(o-nitrobenzyl)-1H-imidazole (128c) was obtained from (126c) by the same synthetic process as that for (128a) in Example 140 (yield 87%). mp 163-165° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[CH2:23]([C:25]([NH:27][CH3:28])=[O:26])[CH3:24].CNCCNC.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[Cu]I>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:27]([CH3:28])[C:25](=[O:26])[CH2:23][CH3:24])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccc(I)cc2)nn1)c1ccc(Cl)s1
Reactant: CCC(=O)NC
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCC(=O)N(C)c1ccc(-n2cc(CNC(=O)c3ccc(Cl)s3)nn2)cc1
Temperature: 120 °C
Reaction time: 15 h

Procedure:
The mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (100 mg, 0.22 mmol), C2H5CONHCH3 (77 μL, 0.88 mmol), CuI (42 mg, 0.22 mmol), N,N′-dimethylethylenediamine (24 μL, 0.22 mmol), cesium carbonate (290 mg, 0.88 mmol) in 5 mL dioxane in a sealed tube was stirred for 15 hrs at 120° C. The title compound was isolated directly from the reaction mixture using reverse phase prep HPLC. MS found for C18H18ClN5O2S (M+H)+ 404.1, 406.1 (Cl pattern).
Reaction SMILES: C(OC(Cl)=O)C(C)C.[C:9]([NH:16][C@H:17]([C:25]([OH:27])=O)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].CN1CCOCC1.[NH2:35][C:36]12[CH2:45][CH:40]3[CH2:41][CH:42]([CH2:44][CH:38]([CH2:39]3)[CH2:37]1)[CH2:43]2>C(Cl)Cl>[C:9]([NH:16][C@H:17]([C:25]([CH:37]1[CH:38]2[CH2:39][CH:40]3[CH2:41][CH:42]([CH2:43][C:36]1([NH2:35])[CH2:45]3)[CH2:44]2)=[O:27])[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10]
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)C1C2CC3CC(C2)CC1(N)C3
Temperature: -10 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere 6.5 ml of isobutylchloroformate is added to 100 ml of a stirred methylene chloride solution containing 2 g of 5A sieves, 13.26 g Boc-phenylalanine, and 5.5 ml of N-methylmorpholine at -50° C. Over a 30 minute period the reaction mixture is warmed to -10° C. and then recooled to -40° C., and 7.94 g of 1-aminoadamantane is added. The cooling bath is removed, and the reaction mixture is stirred at room temperature overnight. The solution is filtered and washed with 50 ml of cold 1 M potassium bisulfate solution followed by washes with 20 ml portions of 2 M potassium carbonate solution and saturated sodium chloride solution. The solution is then dried over sodium sulfate, filtered and concentrated to dryness to give Boc-L-phenylalanyl-1-aminoadamantane which is represented by the following formula ##STR32##
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][C:10]([O:12]CC)=O)=[C:6]([CH3:15])[N:5]=[C:4]([CH2:16][O:17][CH3:18])[N:3]=1.Cl.[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1.C([O-])(O)=O.[Na+]>C(O)CCC>[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:26]2[C:2]3[N:3]=[C:4]([CH2:16][O:17][CH3:18])[N:5]=[C:6]([CH3:15])[C:7]=3[CH2:8][CH2:9][C:10]2=[O:12])=[CH:23][CH:22]=1
Reactant: NCc1ccc(Br)cc1
Reactant: CCOC(=O)CCc1c(C)nc(COC)nc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: COCc1nc(C)c2c(n1)N(Cc1ccc(Br)cc1)C(=O)CC2
Yield: 73.6 %

Procedure:
A mixture of ethyl 3-(4-chloro-6-methyl-2-methoxymethylpyrimidin-5-yl)propionate (3.6 g, 0.013 mol), 4-bromobenzylamine hydrochloride (3.0 g, 0.013 mol), NaHCO3 (2.4 g, 0.028 mol), and nBuOH (25 mL) was heated under reflux for 24 h. The mixture was concentrated, taken up in water, and extracted with CH2Cl2. The combined extracts were dried (MgSO4) and concentrated to give a brown oil. Purification by flash chromatography (5% MeOH/CH2Cl2) gave 3.6 g (72%) of product as an off-white solid, mp 64°-66° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:13](=[O:14])[N:12]([CH2:15][CH2:16][CH2:17][F:18])[N:11]=[N:10]2)=[C:4]([N+:19]([O-])=O)[C:3]=1[OH:22]>C(O)(=O)C.[Fe]>[NH2:19][C:4]1[C:3]([OH:22])=[C:2]([Cl:1])[CH:7]=[C:6]([F:8])[C:5]=1[N:9]1[C:13](=[O:14])[N:12]([CH2:15][CH2:16][CH2:17][F:18])[N:11]=[N:10]1
Reactant: O=c1n(CCCF)nnn1-c1c(F)cc(Cl)c(O)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1c(O)c(Cl)cc(F)c1-n1nnn(CCCF)c1=O
Temperature: 25 °C
Yield: 88.8 %

Procedure:
Iron powder (2.3 g) was added to a solution of 1-(4-chloro-6-fluoro-3-hydroxy-2-nitrophenyl)-4-(3-fluoropropyl)-1,4dihydro-5-oxo-5H-tetrazole (3.4 g) in acetic acid (50 ml) and stirred at room temperature over night. The reaction mixture was filtered through a celite bed. The filtrate was concentrated under reduced pressure and purified by a silica gel column, eluted with hexane-ethyl acetate (2:1) to give yellow crystals (2.75 g).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])(=[O:3])[CH3:2].S(Cl)(Cl)(=O)=O.CC1C=C(C)C=C(C)N=1>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCCC1CCCC1=O
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O=S(=O)(Cl)Cl
Product: CC(=O)OCCCCCC1=CCCC1=O

Procedure:
161 g [0.76 mol ] of 2-(5-acetoxypentyl)-cyclopentanone were dissolved in 440 ml of carbon tetrachloride, and a solution of 76 ml [0.935 mol] of sulfuryl chloride in 75 ml of carbon tetrachloride was added dropwise, while stirring at 10°-15° C., and the whole was stirred for 4 hours at room temperature. The solvent was distilled off under reduced pressure, the residue dissolved in toluene, washed with water and bicarbonate solution and dried over magnesium sulfate. 150 ml [1.25 mols] of 2,4,6-trimethylpyridine were added to the filtered solution, which was then refluxed, while stirring, for 15 hours. After cooling, the solution was washed twice with 2 n HCl, once with water and once with sodium bicarbonate solution, dried over sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was distilled under a reduced pressure of 0.5 mm in a column having a length of 10 cm, and 106 g having a boiling point of 120°-125° C. at 0.5 mm Hg were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[CH:6]=[C:5]([C:14]2[C:15]([CH3:27])([CH3:26])[C:16](=[O:25])[N:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:18]=2)[CH:4]=1.[CH3:28][C:29]1[CH:30]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>>[CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[CH:6]=[C:5]([C:14]2[C:15]([CH3:27])([CH3:26])[C:16](=[O:25])[N:17]([CH:19]3[CH2:24][CH2:23][N:22]([S:35]([C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([CH3:28])[CH:30]=4)(=[O:37])=[O:36])[CH2:21][CH2:20]3)[N:18]=2)[CH:4]=1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: COc1cc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc2c1OC(C)(C)C2
Product: COc1cc(C2=NN(C3CCN(S(=O)(=O)c4cccc(C)c4)CC3)C(=O)C2(C)C)cc2c1OC(C)(C)C2

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(7-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B12) and 3-methylbenzenesulfonyl chloride as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and crystallization of the product containing fractions from DCM and diethyl ether to yield the title compound.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[I:12][C:13]1[CH:14]=[CH:15][C:16]2[NH:17][C:18]3[C:23]([C:24]=2[CH:25]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3.[OH-].[K+].O>CC(C)=O.C(Cl)Cl.CCO>[I:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([S:1]([C:4]3[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=3)(=[O:3])=[O:2])[C:18]3[C:23]([C:24]=2[CH:25]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Ic1ccc2[nH]c3ccccc3c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2c3ccccc3c3cc(I)ccc32)cc1
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
Tosyl chloride (8.4 g, 44 mmol) was added to a solution of 3-iodocarbazole (11.7 g, 40 mmol) and grounded KOH (2.7 g, 48 mmol) in 200 mL of acetone. The mixture was refluxed for 3 hours, and then cooled down. It was poured into 1 L of cold water while stirring. After sitting for 30 minutes, the liquid was decanted. The crude product was thus obtained as sticky solid on the beaker wall. About 11 g of pure 3-iodo-9-tosylcarbazole was obtained after recystallization from CH2Cl2/EtOH.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH2:21][S:22]([N:25]3[CH2:30][CH2:29][CH:28]([NH:31]C(=O)OC(C)(C)C)[CH2:27][CH2:26]3)(=[O:24])=[O:23])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[ClH:39]>>[ClH:39].[NH2:31][CH:28]1[CH2:27][CH2:26][N:25]([S:22]([CH2:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:11]2[CH:10]=[CH:9][C:8]([C:5]3[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=3)=[C:13]([F:14])[CH:12]=2)(=[O:23])=[O:24])[CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)Cc2ccccc2-c2ccc(-c3cnc(N)cn3)c(F)c2)CC1
Agent: Cl
Product: Nc1cnc(-c2ccc(-c3ccccc3CS(=O)(=O)N3CCC(N)CC3)cc2F)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61 %

Procedure:
A mixture of tert-butyl 1-((4′-(5-aminopyrazin-2-yl)-5′-fluorobiphenyl-2-yl)methylsulfonyl)piperidin-4-ylcarbamate (190 mg, 0.35 mmol) in HCl (20 mL, 6 N in methanol) was stirred at rt for 24 hours. The solvent was removed under reduced pressure and the residue purified by HPLC to give the title compound (80 mg HCl salt, 61%). MS (ESI): mass calcd. for C22H24FN5O2S, 441.16; m/z found, 442.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.10 (br, 4H), 7.95 (m, 1H), 7.64-7.55 (m, 1H), 7.52-7.32 (m, 4H), 4.80 (br, 4H), 4.37 (s, 2H), 3.50 (d, J=13.0, 2H), 3.10 (s, 1H), 2.76 (t, J=12.6, 2H), 1.91 (d, J=11.0, 3H), 1.58-1.41 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][CH2:24][CH3:25])=[C:6]([C:8]2[NH:9][C:10](=[O:21])[C:11]3[C:16]([CH3:17])=[N:15][N:14]([CH2:18][CH2:19][CH3:20])[C:12]=3[N:13]=2)[CH:7]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:55]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])(=[O:58])[CH:56]=[CH2:57]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:60]([O:59][C:55](=[O:58])/[CH:56]=[CH:57]/[C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][CH2:24][CH3:25])=[C:6]([C:8]2[NH:9][C:10](=[O:21])[C:11]3[C:16]([CH3:17])=[N:15][N:14]([CH2:18][CH2:19][CH3:20])[C:12]=3[N:13]=2)[CH:7]=1)([CH3:63])([CH3:62])[CH3:61]
Reactant: CCCOc1ccc(Br)cc1-c1nc2c(c(C)nn2CCC)c(=O)[nH]1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCOc1ccc(/C=C/C(=O)OC(C)(C)C)cc1-c1nc2c(c(C)nn2CCC)c(=O)[nH]1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
To a solution of 6-(5-bromo-2-n-propoxyphenyl)-3-methyl-1-n-propyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 11; 2.14 g, 0.0053 mol) and triethylamine (0.81 g, 0.008 mol) in acetonitrile (4 ml), was added palladium(II) acetate (0.06 g, 0.00027 mol), tri-o-tolylphosphine (0.16 g, 0.00053 mol) and t-butyl acrylate (1.03 g, 0.008 mol). The mixture was heated under reflux for 4 hours, cooled to room temperature and then partitioned between water (30 ml) and dichloromethane (30 ml). The organic phase was removed and the aqueous phase extracted with dichloromethane (2×30 ml). The combined organic solutions were dried (Na2SO4) and the solvent removed by evaporation under vacuum to give a greenish brown solid. Purification by column chromatography (SiO2, CH2Cl2 then 2% MeOH in CH2Cl2) and crystallisation from ethyl acetate-hexane afforded the title compound as white crystals (1.48 g, 58%), m.p. 181-182° C. Found: C, 66.50; H, 6.75; N, 12.27. C25H32N4O4 requires C, 66.35; H, 7.12; N, 12.38%.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=[N:21][C:22]([CH3:25])([CH3:24])[CH3:23].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1.C(Cl)Cl.O>[C:34]1([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH:20]=[N:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Cc1ccccc1C=NC(C)(C)C
Reactant: BrCCCCCCCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)N=Cc1ccccc1CCCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of diisopropylamine (29.14 g,0.289 mol) in tetrahydrofuran (450 mL) cooled to -5° C. was added n-butyllithium (2.5M, 114.3 mL, 0.286 mol) at a rate which maintained the solution temperature below 10° C. After the addition was complete, the solution was stirred 15 min with cooling. To this solution was added N-[(2-methylphenyl)-methylene]-1,1-dimethylethanamine (50.0 g, 0.286 mol) in tetrahydrofuran (65.0 mL) at such a rate as to keep the reaction temperature below 5° C. The reaction was stirred for 15 min with cooling then 1-bromo-7-phenylheptane (72.9 g, 0.286 mol) in tetrahydrofuran (75 mL) was quickly added. The reaction mixture was stirred for 1 h with cooling then allowed to warm to room temperature and stirred for an additional 14 h. The reaction mixture was assayed by gas chromatography for product imine (RT 19.8 min., DB-1, 30 m×0.53 mm, program, 100° C. for 5 min, 100°-260° C. at 15° C./min, hold at 260° C. for 12 min.). The product was isolated by dilution of the reaction mixture with water and methylene chloride, quickly washing the organic mixture with water, and concentrating the solution to an oil. The oil was purified by distillation.