Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][C@@H:16]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)=[N:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=1.[ClH:28]>O1CCOCC1.CCO>[ClH:1].[ClH:28].[Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[N:4][C:3]=1[NH:15][C@@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1
Reactant: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)c(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCNC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of tert-butyl (3R)-3-({3-chloro-5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate (0.98 g) and 4N hydrogen chloride in dioxane solution (5 ml) in EtOH (10 ml) was stirred at ambient temperature for 4 hours. The reaction mixture was evaporated in vacuo and the residue was triturated with hexane was collected by filtration to give ethyl (2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylate dihydrochloride (0.9 g).ethyl (2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylate dihydrochloride
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:20][SH:21].[Na]>CN(C)C=O>[CH3:20][S:21][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CS
Reactant: N#Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1F
Agent: [Na]
Solvent: CN(C)C=O
Product: CSc1cc(-c2ccc(C(F)(F)F)cc2)ccc1C#N
Temperature: 60 °C
Reaction time: 6 h
Yield: 75.4 %

Procedure:
To 3.0 g (11.3 mmol) of 2-fluoro-4-(4-trifluoromethylphenyl)benzonitrile in 50 ml of N,N-dimethylformamide, 7.0 g (15.0 mmol) of 15% aqueous sodium methyl mercaptan was added dropwise at room temperature. After 6 hours of stirring at 60° C., the reaction mixture was poured into 200 ml of ice-cold water and extracted with 100 ml of ethyl acetate twice. The ethyl acetate layer was washed with 100 ml of water twice and dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography afforded 2.5 g of 2-methylthio-4-(4-trifluoromethylphenyl)benzonitrile (yield 75%) as white crystals (m.p. 128-129° C.).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[F:25][C:26]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:9]=[C:4]([C:3]([OH:2])=[O:24])[C:5]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([F:25])[C:31]=4[F:32])=[CH:6][CH:7]=3)[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: OB(O)c1cccc(F)c1F
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1cccc(F)c1F
Yield: 69.2 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 2,3-difluorophenylboronic acid (available from Combi-Blocks Inc.; 63 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2′,3′-difluoro-biphenyl-2-carboxylic acid (64 mg, 69%). 1H NMR (400 MHz, DMSO-d6) δ 13.26 (br s, 1H), 8.52 (s, 1H), 8.50 (d, J=1.5 Hz, 1H), 8.34 (s, 1H), 8.31 (d, J=8.0 Hz, 1H), 8.10 (d, J=8.5 Hz, 1H), 7.74-7.81 (m, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.42-7.53 (m, 1H), 7.19-7.36 (m, 2H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[NH:10][CH:9]=1)=[O:7])[CH3:4].Cl[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][CH:17]=1.O>CN(C)C=O>[CH2:3]([O:5][C:6]([C:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[CH:9]=1)=[O:7])[CH3:4]
Reactant: Clc1ccnc2ccccc12
Reactant: CCOC(=O)c1c[nH]c(C)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(-c2ccnc3ccccc23)c(C)c1C
Temperature: 40 °C
Reaction time: 0.3 h

Procedure:
0.285 g (8.9 mmol) of sodium hydride, at 75% by weight in liquid petroleum jelly, is added at a temperature in the region of 20° C. under an argon atmosphere to a solution of 1.35 g (8.1 mmol) of 3-ethoxycarbonyl-4,5-dimethyl-1H-pyrrole in 8 mL of dimethylformamide. After stirring at a temperature in the region of 40° C. for 0.3 hour, 1.45 g (8.9 mmol) of 4-chloroquinoline and 2 mL of dimethylformamide are added. After stirring at a temperature in the region of 140° C. for 6 hours, the reaction mixture is poured into 100 mL of salt water and then extracted with twice 50 mL of ethyl acetate. The combined organic phases are washed with 15 mL of water, carefully separated by settling and then concentrated to dryness under reduced pressure (2.7 kPa) to give a brown oil which is purified by silica gel chromatography [eluent: cyclohexane/ethyl acetate (75/25 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa), 1.32 g of 3-ethoxycarbonyl-4,5-dimethyl-1-(quinol-4-yl)-1H-pyrrole are obtained in the form of a yellowish oil. 1H NMR spectrum (300 MHz, d6-(CD3)2SO, δ in ppm): 1.27 (t, J=7 Hz, 3H), 1.87 (s, 3H), 2.27 (s, 3H), 4.21 (mt, 2H), 7.37 (dd, J=8 and 1 Hz, 1H), 7.55 (s, 1H), 7.62 (d, J=5 Hz, 1H), 7.70 (ddd, J=8, 7 and 1 Hz, 1H), 7.89 (ddd, J=8, 7 and 1 Hz, 1H), 8.19 (broad d, J=8 Hz, 1H), 9.07 (d, J=5 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[NH:10][C:9](=[O:18])[C:8]=2[CH:19]=1)([O-])=O>C(O)(=O)C.O=[Pt]=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[NH:10][C:9](=[O:18])[C:8]=2[CH:19]=1
Reactant: O=C1Nc2ccccc2Sc2ccc([N+](=O)[O-])cc21
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: Nc1ccc2c(c1)C(=O)Nc1ccccc1S2
Yield: 65.8 %

Procedure:
2-Nitro-10,11-dihydrodibenzo[b,f][1,4]thiazepin-11-one (0.82 g) was dissolved in warm acetic acid (100 ml) and the resulting solution hydrogenated over Adam's catalyst (80 g) for 3 hours at atmospheric pressure. The catalyst was filtered off and the solution evaporated to dryness. Recrystallisation of the residue from methanol gave the product as a greenish powder (0.48 g, m/s, M+ =242).
Reaction SMILES: [OH-].[K+].[CH3:3][C@H:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([CH3:13])=[CH:9][CH:10]=2)[C@@H:5]1[NH:14][C:15]1[N:20]=[C:19]([NH2:21])[C:18]([C:22]#[C:23][Si](C)(C)C)=[CH:17][N:16]=1>CO.O>[CH3:3][C@H:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([CH3:13])=[CH:9][CH:10]=2)[C@@H:5]1[NH:14][C:15]1[N:20]=[C:19]([NH2:21])[C:18]([C:22]#[CH:23])=[CH:17][N:16]=1
Reactant: Cc1ccc2c(c1)[C@H](Nc1ncc(C#C[Si](C)(C)C)c(N)n1)[C@@H](C)C2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C#Cc1cnc(N[C@H]2c3cc(C)ccc3C[C@@H]2C)nc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.3 %

Procedure:
0.427 g of potassium hydroxide is added to a mixture of 0.47 g (1.34 mmol) of N2-[(1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-yl]-5-[(trimethylsilyl)ethynyl]pyrimidine-2,4-diamine (Ex.: 1.98) in 3 ml of methanol and 1 ml of water, the mixture is stirred for one hour at 25° C., concentrated by evaporation and taken up in water. Then, extraction is carried out with ethyl acetate, and the organic phase is dried and concentrated by evaporation. Following purification of the crude mixture by column-chromatographic separation, 0.139 g of N2-[(1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-yl]-5-ethynylpyrimidine-2,4-diamine is obtained (yield 33% at 90% purity).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:44]=[CH:43][C:12]([CH2:13][N:14]([CH2:33][CH2:34][NH:35]C(=O)OC(C)(C)C)[C:15](=[O:32])[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]4[C@H:30]([CH3:31])[CH2:29][CH2:28][C:24]=4[N:25]=[CH:26][N:27]=3)=[CH:18][CH:17]=2)=[CH:11][CH:10]=1>C(Cl)Cl>[NH2:35][CH2:34][CH2:33][N:14]([CH2:13][C:12]1[CH:11]=[CH:10][C:9]([Cl:8])=[CH:44][CH:43]=1)[C:15](=[O:32])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]3[C@H:30]([CH3:31])[CH2:29][CH2:28][C:24]=3[N:25]=[CH:26][N:27]=2)=[CH:18][CH:17]=1
Reactant: C[C@@H]1CCc2ncnc(-c3ccc(C(=O)N(CCNC(=O)OC(C)(C)C)Cc4ccc(Cl)cc4)cc3)c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CCc2ncnc(-c3ccc(C(=O)N(CCN)Cc4ccc(Cl)cc4)cc3)c21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 22.7 %

Procedure:
TFA (182 μL, 2.36 mmol) was added to a solution of (R)-tert-butyl 2-(N-(4-chlorobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamido)ethylcarbamate (49 mg, 0.094 mmol) in DCM (1 mL). The mixture was stirred at room temperature for 1.5 hours. The mixture was concentrated in vacuo. The crude product was purified by reverse phase HPLC to give (R)—N-(2-aminoethyl)-N-(4-chlorobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide as an oil (9 mg, 22%). MS (APCI+) [M+H]+421.2. 1H NMR (D2O, 500 MHz) δ 9.09 (s, 1H), 7.81 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.0 Hz, 2H), 7.35 (d, J=8.5 Hz, 2H), 7.15 (D, J=8.0 Hz, 2H), 4.63 (s, 2H), 3.87 (t, J=6.5 Hz, 2H), 3.82-3.79 (m, 1H), 3.26-3.11 (m, 4H), 2.63 (s, 2H), 2.50-2.42 (m, 1H), 1.86-1.81 (m, 1H), 0.86 (s, J=7.00 Hz, 3H).
Reaction SMILES: C([Li])CCC.[Br-].C1([C:13]([PH3+])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2C=CC=CC=2)C=CC=CC=1.[CH3:27][O:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[N:32]=[C:31]([NH:37][C:38]([NH:40][S:41](C2C=CC=CC=2C=O)(=[O:43])=[O:42])=[O:39])[N:30]=1>O1CCCC1>[CH3:27][O:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[N:32]=[C:31]([NH:37][C:38]([NH:40][S:41]([C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH:13]=[CH2:14])(=[O:42])=[O:43])=[O:39])[N:30]=1
Reactant: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2C=O)n1
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=Cc1ccccc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of 0.02 mol of n-butyllithium in 20 ml of anhydrous tetrahydrofuran is added 3.6 g of triphenylmethylphosphonium bromide. The above solution is stirred at room temperature for 4 hours. A slurry of 3.7 g of N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-2-formylbenzenesulfonamide in 30 ml of dry tetrahydrofuran is then added dropwise. The resulting mixture is refluxed overnight and allowed to cool to room temperature. The precipitate is removed by suction filtration and washed with methylene chloride. The combined filtrates are washed with dilute hydrochloric acid, water, dried and evaporated to dryness to yield the desired product.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1B(O)O>>[CH3:24][N:21]1[CH2:20][CH2:19][N:18]([C:15]2[CH:14]=[CH:13][C:12]([NH:11][C:8]3[N:7]=[CH:6][C:5]4=[CH:4][CH:3]=[C:2]([C:27]5[CH:28]=[N:29][CH:30]=[CH:31][C:26]=5[CH3:25])[N:10]4[N:9]=3)=[CH:17][CH:16]=2)[CH2:23][CH2:22]1
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Reactant: Cc1ccncc1B(O)O
Product: Cc1ccncc1-c1ccc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nn12

Procedure:
[4-(4-Methyl-piperazin-1-yl)-phenyl]-[7-(4-methyl-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine was prepared from (7-bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine and 4-methylpyridine-3-boronic acid in an analogous manner to Example 1031b. Product isolated as a yellow foam (28 mg, 25%). LCMS (m/e) 400 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.75-8.69 (m, 2H), 8.58-8.52 (m, 1H), 7.35 (d, 2H, J=7.5 Hz), 7.31-7.25 (m, 1H), 6.88-6.79 (m, 3H), 6.79-6.74 (m, 1H), 6.65 (s, 1H), 3.17-3.10 (m, 4H), 2.61-2.54 (m, 4H), 2.35 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:15]=[CH:16][C:17]4[O:21][CH2:20][CH2:19][C:18]=4[CH:22]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:23].[CH3:24][O:25][C:26]1[N:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:21]1[C:17]2[CH:16]=[CH:15][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:29]5[CH:30]=[N:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=5)[C:3]([CH3:23])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:22][C:18]=2[CH2:19][CH2:20]1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)CCO5)CC3)ccc2C)cn1
Yield: 59.8 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide (95 mg, 0.3 mmol) in 1,2-dimethoxyethane (3 mL) was added 6-methoxypyridin-3-ylboronic acid (66 mg, 0.4 mmol), tetrakis(triphenylphosphine)palladium (0) (33 mg, 0.03 mmol), and 2 M sodium carbonate (0.45 mL, 0.9 mmol). The reaction mixture was irradiated in the microwave at 120° C. for twenty minutes. The reaction mixture was diluted with ethyl acetate (5 mL) and washed with water (5 mL). The organics were dried over sodium sulfate and evaporated to dryness. The crude reaction mixture was purified by silica gel chromatography (eluting with 0-50% ethyl acetate in hexanes) to yield the product (72 mg, 62%). ESI-MS m/z calc. 401.17. found 402.5 (M+1)+. Retention time 1.86 minutes.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][N:7]([CH:9]2[CH2:12][CH:11]([OH:13])[CH2:10]2)[CH:8]=1)([O-:3])=[O:2].CCN(CC)CC.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(Cl)Cl>[N+:1]([C:4]1[N:5]=[CH:6][N:7]([C@H:9]2[CH2:10][C@H:11]([O:13][S:27]([C:24]3[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=3)(=[O:29])=[O:28])[CH2:12]2)[CH:8]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1cn(C2CC(O)C2)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)O[C@H]2C[C@H](n3cnc([N+](=O)[O-])c3)C2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-(4-nitro-imidazol-1-yl)-cyclobutanol (Preparation 4, Step 1; 4 g, 22 mmol) was treated with Et3N (7.7 mL, 55 mmol) in methylene chloride (150 mL) followed by p-toluenesulfonyl chloride (TsCl) (5 g, 26.4 mmol) and 4-N,N-dimethylaminopyridine (DMAP) (268 mg, 2.2 mmol). The resulting mixture was stirred at room temperature for 24 h. Analysis by thin layer chromatography showed two new spots. The reaction mixture was diluted with methylene chloride and was washed with water (1×) and brine (1×). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. Purification by silica gel chromatography (1:1 to 2:1 hexanes-ethyl acetate) allowed for separation of the trans and cis diastereomers. The first spot to elute (high Rf) was the trans-isomer, trans-toluene-4-sulfonic acid 3-(4-nitro-imidazol-1-yl)-cyclobutyl ester (2.7 g, 37% yield); 1H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.77 (m, 2H), 7.44 (d, J=1.7 Hz, 1H), 7.36 (dd, J=0.5, 8.0 Hz, 2H), 5.034 (m, 1H), 4.94 (m, 1H), 2.9 (m, 2H), 2.7 (m, 2H); MS (AP/CI): 338.1 (M+H)+. The second spot to elute was the cis-isomer, cis-toluene-4-sulfonic acid 3-(4-nitro-imidazol-1-yl)-cyclobutyl ester (2.9 g, 39% yield); 1H NMR (400 MHz, CDCl3) δ 7.8 (m, 3H), 7.43 (d, J=1.4 Hz, 1H), 7.36 (dd, J=0.6, 8.5 Hz, 2H), 4.74 (m, 1H), 4.30 (m, 1H), 3.05 (m, 2H), 2.6–2.5 (m, 2H), 2.45 (s, 3H); MS (AP/CI): 338.1 (M+H)+. Relative configurations were determined by the measurement of nuclear Overhauser effects.
Reaction SMILES: CO[C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:5][CH:4]=1.[F:31]C1C=CC(C=O)=CC=1>>[F:31][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Product: O=C(NCCNCc1ccc(F)cc1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]-amide using 4-fluorobenzaldehyde instead of 4-methoxy benzaldehyde. LCMS (ESI) 410 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (1H, br. s.) 10.25 (1H, s) 7.99-8.07 (2H, m) 7.77 (1H, d, J=5.42 Hz) 7.46 (1H, d, J=5.42 Hz) 7.31 (3H, dt, J=5.72, 2.82 Hz) 7.06 (2H, t, J=8.91 Hz) 6.79 (1H, d, J=5.42 Hz) 6.43 (1H, dd, J=3.47, 1.95 Hz) 3.65 (2H, s) 3.34 (2H, d, J=5.86 Hz) 2.62 (2H, t, J=6.49 Hz)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:22][O:23][CH2:24][CH2:25][NH:26][CH2:27][CH2:28][O:29][CH3:30]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][N:26]([CH2:27][CH2:28][O:29][CH3:30])[CH2:25][CH2:24][O:23][CH3:22])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: COCCNCCOC
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: COCCN(CCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1)CCOC

Procedure:
According to the method in example 5, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and bis(2-methoxyethyl) amine were converted to yield [3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl]-bis-(2-methoxy-ethyl)-amine as orange oil, MS: 479 (MH+, 1Br).
Reaction SMILES: C1COCC1.[CH2:6]([N:10]=[C:11]=[O:12])[CH2:7][CH2:8][CH3:9].[N:13]1([C:19]2[N:20]=[CH:21][C:22]3[CH2:27][C:26](=[O:28])[N:25]([CH3:29])[C:23]=3[N:24]=2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C(N(CC)CC)C>[CH2:6]([NH:10][C:11]([CH:14]1[CH2:15][NH:16][CH2:17][CH2:18][N:13]1[C:19]1[N:20]=[CH:21][C:22]2[CH2:27][C:26](=[O:28])[N:25]([CH3:29])[C:23]=2[N:24]=1)=[O:12])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCN=C=O
Reactant: CN1C(=O)Cc2cnc(N3CCNCC3)nc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCNC(=O)C1CNCCN1c1ncc2c(n1)N(C)C(=O)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.1 %

Procedure:
THF (30 ml), 1 ml of triethylamine and 0.43 g (4.34 mmoles) of n-butyl isocyanate were added to 0.5 g (2.14 mmoles) of 2-piperazino-5,6-dihydro-7-methyl-6-oxo(7H)pyrrolo[2,3-d]pyrimidine, and the mixture was stirred at room temperature for 3 hours. It was concentrated under reduced pressure, and after addition of water, extracted with chloroform. The chloroform layer was concentrated under reduced pressure, and the residue purified by silica gel column chromatography to give 0.15 g (yield 21%) of the desired product.
Reaction SMILES: C([O:3][C:4]([C:6]1(C(OCC)=O)[CH2:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[NH2:18])=[CH:8][N:7]1C(=O)C)=[O:5])C.Br>>[Cl:17][C:14]1[CH:13]=[C:12]2[C:11](=[CH:16][CH:15]=1)[C:9]([CH2:10][C@@H:6]([C:4]([OH:3])=[O:5])[NH2:7])=[CH:8][NH:18]2
Reactant: CCOC(=O)C1(C(=O)OCC)CC(c2ccc(Cl)cc2N)=CN1C(C)=O
Agent: Br
Product: N[C@@H](Cc1c[nH]c2cc(Cl)ccc12)C(=O)O
Yield: 91.1 %

Procedure:
A mixture of 60 g (0.16 mol) of the compound of Example 11, and 450 ml. of 2 N aqueous HBr was heated under N2 at 95° for 30 hours. The solution was concentrated in vacuo and the residual salt was taken up in 300 ml of water. The solution was brought to pH 5.5 with 4N NaOH and the mixture was chilled in an icebath for 1 hour. The precipitate was collected, washed with cold water and dried to give 34.8 g of product. Crystallization from glacial acetic acid (360 ml.) afforded, after drying at 100°/ 0.2 mmHg, 30.8 g (82%) of white crystals, m.p. 280° (dec.) (lit. m.p. 285-286°), which was identical with an authentic sample.
Reaction SMILES: [C:1]1([C:7]2([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:17]1[C:18]2[C:25]([CH3:26])=[CH:24][NH:23][C:19]=2[N:20]=[CH:21][N:22]=1.C(N(CC)CC)C>C(O)(C)C>[CH3:26][C:25]1[C:18]2[CH:17]([N:10]3[CH2:9][CH2:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)([C:13]([OH:15])=[O:14])[CH2:12][CH2:11]3)[NH:22][CH:21]=[N:20][C:19]=2[NH:23][CH:24]=1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cc1c[nH]c2c1C(N1CCC(C(=O)O)(c3ccccc3)CC1)NC=N2
Temperature: 180 °C
Yield: 62 %

Procedure:
To a solution of 4-phenylpiperidine-4-carboxylic acid from step A (0.74 g, 3.1 mmol) in isopropanol (10 mL), was added 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (0.52 g, 3.1 mmol) and triethylamine (1.0 mL, 9.8 mmol). The reaction mixture was heated at 180° C. for 180 minutes under microwave condition, and then concentrated under vacuum. The residue was dissolved in ice water and neutralized to pH 4 by addition of 1 N aq. HCl. The product was isolated by filtration and dried under vacuum for 3 hours at 65° C. to give the title compound (62%) as a brown solid. MS (ES+) [M+H]+=336.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].CO.Cl[C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[N:10]=[C:11]([CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:28][CH2:27]1)[N:12]2[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1>O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:12]2[C:11]([CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:28][CH2:27]3)=[N:10][C:9]3[C:13]2=[N:14][CH:15]=[N:16][C:8]=3[O:2][CH3:1])=[CH:19][CH:20]=1
Reactant: Fc1ccc(Cn2c(CC3CCN(Cc4ccccc4)CC3)nc3c(Cl)ncnc32)cc1
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CO
Product: COc1ncnc2c1nc(CC1CCN(Cc3ccccc3)CC1)n2Cc1ccc(F)cc1
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To a previously prepared sodium methoxide solution, starting from 25 parts of sodium in 400 parts of methanol, were added 49.4 parts of 6-chloro-9-[(4-fluorophenyl)methyl]-8-[[1-(phenylmethyl)-4-piperidinyl]methyl]-9H-purine. After stirring for 8 hours at reflux temperature, the reaction mixture was cooled and 1000 parts of water were added. The precipitated product was filtered off and dried, yielding 34.5 parts (70.4%) of 9-[(4-fluorophenyl)methyl]-6-methoxy-8-[[1-(phenylmethyl)-4-piperidinyl]methyl]-9H-purine (compound 184).
Reaction SMILES: [CH3:1][C:2]([CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[OH:21][CH2:22][CH:23](CO)[OH:24].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:1][C:2]([CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH:22]([CH2:23][OH:24])[OH:21])=[O:7]
Reactant: OCC(O)CO
Reactant: COC(=O)CCC=C(C)CCCC(C)CCCC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=CCCC(=O)OCC(O)CO)CCCC(C)CCCC(C)C
Temperature: 100 °C
Reaction time: 18 h

Procedure:
1.0 g (3.5 mmol) of methyl 5,9,13-trimethyltetradec-4-enoate was slowly added dropwise to a solution of 0.65 g (7.1 mmol) of glycerol and 0.59 g (4.3 mmol) of potassium carbonate in dry N,N-dimethylformamide (3.5 mL) at 80° C. After the reaction mixture was stirred at 100° C. for 18 hours, 1M hydrochloric acid was added. The resulting solution was extracted with ether, and the extract was washed with saturated sodium bicarbonate aqueous solution and saturated brine, successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane mixture) to obtain the title compound.