Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[C:9]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:4]=2[CH:3]=1.Cl[CH2:19][C:20](=[O:22])[CH3:21].C(N(CC)CC)C>C(O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[C:9]3[CH2:14][CH2:13][N:12]([CH2:19][C:20](=[O:22])[CH3:21])[CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:4]=2[CH:3]=1
Reactant: CC(=O)CCl
Reactant: Cc1cc2oc(=O)c3c(c2cc1C)CCNC3
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)CN1CCc2c(c(=O)oc3cc(C)c(C)cc23)C1
Yield: 63.4 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-8,9-dimethyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one (30 g, 0.13 mole), 1-chloro-2-propanone (23.6 g, 0.25 moles), and triethylamine (27.3 g, 0.27 moles) in 550 ml of absolute ethanol is stirred at reflux for 21 hours. The reaction mixture is evaporated, and the residue is partitioned between dichloromethane (700 ml) and water (500 ml). The two-phase mixture is made basic with conc. ammonium hydroxide, the layers are separated, and the aqueous phase is extracted with fresh dichloromethane. The combined organic layers are backwashed with water, dried over sodium sulfate, and evaporated. Recrystallization of the residue from absolute ethanol yielded the product (23.5 g), mp 136°-138° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[NH:11][C:4]=2[CH:3]=1.Br[CH2:19][CH2:20][CH2:21][Cl:22].[OH-].[Na+].C(C(C)=O)C>C1C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]([CH2:19][CH2:20][CH2:21][Cl:22])[C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)Nc1ccccc1OCO2
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)=O
Solvent: c1ccccc1
Product: ClCCCN1c2ccccc2OCOc2ccc(Cl)cc21
Temperature: 20 °C
Reaction time: 10 h

Procedure:
A mixture of 14.9 g. (0.06 moles) of 2-chloro-12H-dibenzo[d,g][1,3,6]dioxazocine, 37.8 g. (0.24 moles) of 1-bromo-3-chloropropane, 19.6 g. (0.48 moles) of sodium hydroxide and 180 ml. of methyl ethyl ketone is stirred under reflux for 10 hours. Thereafter further 19.6 g. (0.48 moles) of sodium hydroxide are added and the stirring under reflux continued for 10 hours. The reaction mixture is cooled to 20° C. and poured to 300 g. of broken ice under stirring. 100 ml. of benzene are added, the organic phase is separated and the solvent is removed in vacuo. The residue is subjected to vacuum destillation. There are obtained 14.3 g. of a yellow viscous liquid, b.p./0.3 mmHg: 165° to 171° C. This liquid solidifies upon trituration with petrol ether. Recrystallization from isopropanol affords 12.5 g. (64.0%) of a white product, melting at 105° to 108° C.
Reaction SMILES: OC1CC2N([C:10]([C:12]3[CH:24]=[CH:23][C:15]4[N:16]([CH2:19][CH2:20][C:21]#[N:22])[CH:17]=[N:18][C:14]=4[CH:13]=3)=[O:11])C(CC2)C1.[N-:25]=[N+:26]=[N-:27].[Na+].[Cl-].[NH4+]>CN(C=O)C>[NH:22]1[C:21]([CH2:20][CH2:19][N:16]2[C:15]3[CH:23]=[CH:24][C:12]([CH:10]=[O:11])=[CH:13][C:14]=3[N:18]=[CH:17]2)=[N:27][N:26]=[N:25]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCCn1cnc2cc(C(=O)N3C4CCC3CC(O)C4)ccc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc2c(c1)ncn2CCc1nnn[nH]1
Temperature: 100 °C

Procedure:
To a solution of 3-[5-(3-Hydroxy-8-aza-bicyclo[3.2.1]octane-8-carbonyl)-benzoimidazol-1-yl]-propionitrile (250 mg, 0.7 mmol) in DMF (5 mL) was added sodium azide (184 mg, 2.83 mmol) and ammonium chloride (152 mg, 2.83 mmol) and heated to 100° C. for 12 h. The solvent was evaporated completely; methanol (20 mL) was added and filtered. The filtrate was concentrated and the residue purified by preparative HPLC to give 36 mg (13%) of 3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-{1-[2-(1H-tetrazol-5-yl)-ethyl]-1H-benzoimidazol-5-yl}-methanone. MS-ESI m/z 368 (M+1); 1H NMR (300 MHz, DMSO-d6) δ 1.3-2.0 (m, 8H), 3.15 (s, 1H), 3.5 (t, 2H), 3.9-4.0 (m, 2H), 4.6 (br, 1H), 4.75 (t, 2H), 7.4 (dd, 1H), 7.6-7.7 (m, 2H), 8.25 (s, 1H).
Reaction SMILES: [Cl:1][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:25][CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]2)[CH2:24][CH2:23][CH2:22][CH2:21]1>ClCCl.CO>[ClH:1].[N:20]1([CH2:25][CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][N:29]([C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:28]2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C1CNCC(CCN2CCCC2)C1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Solvent: ClCCl
Solvent: CO
Product: Cl
Product: O=C1Nc2cccnc2N(C(=O)N2CCCC(CCN3CCCC3)C2)c2ccccc21
Yield: 58 %

Procedure:
Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 3-[2-(1-pyrrolidinyl)ethyl]piperidine in a yield of 58% of theory. Colourless crystals, Rf 0.25 (Merck DC ready made TLC plates, silica gel 60 F254 ; eluant: dichloromethane/methanol/conc. ammonia 90/10/1, v/v/v).
Reaction SMILES: O[CH2:2][C@H:3](C)[C:4](OC)=O.[C:9]([O-:12])(O)=O.[Na+].[BH4-].[Na+].C(O)(=O)[CH2:17][C:18]([CH2:23]C(O)=O)([C:20](O)=O)[OH:19]>C(OC(C)(C)C)(=O)C.CO>[C:18]([O:19][CH2:2][C@H:3]([CH3:4])[CH2:9][OH:12])([CH3:17])([CH3:20])[CH3:23]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: O=C([O-])O
Reactant: COC(=O)[C@@H](C)CO
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)OC(C)(C)C
Product: C[C@H](CO)COC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 68 %

Procedure:
A solution of (S)-(+)-methyl 3-hydroxy-2-methylpropionate (1.18 g, 10 mmol) in t-butyl acetate (30 mL) was treated with 70% HClO4 (0.1 mL) and the reaction mixture was left at room temperature in a tightly closed flask for 24 hours. The mixture was then poured into a saturated solution of NaHCO3 and extracted with ethyl ether. The ether was removed in vacuo and the residue was dissolved in THF (50 mL). To the resulting solution was added NaBH4 (925 mg, 25 mmol) and at 55° C. dropwise methanol (10 mL). The reaction was continued at 55° C. for 1 hours, then it was cooled to ambient temperature, acidified with 10% citric acid to pH 5 and extracted with ethyl acetate. The acetate extract was washed with water, brine, dried with MgSO4 and concentrated in vacuo. The residue was chromatographed (silica gel, 2:1 hexane-ethyl acetate) to provide (R)-3-t-butoxy-2-methyl-1-propanol (yield: 1 g, 68%). 1H NMR (300 MHz, CDCl3) δ 0.85 (d, J=7 Hz, 3H), 1.20 (s, 9H), 2.03 (m, 1H), 3.30 (t, J=12 Hz, 1H), 3.53 (dd, J=4.5 Hz, 12 Hz, 1H), 3.70 (m, 2 H); MS (DCI/NH3) m/z 164 (M+NH4)+.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7]1>CN(C)C=O>[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([S:1]([Cl:5])(=[O:3])=[O:2])=[CH:14][C:9]=2[CH2:8][CH2:7]1
Reactant: O=S(=O)(Cl)Cl
Reactant: c1ccc2c(c1)CCO2
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc2c(c1)CCO2
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 71.7 %

Procedure:
To 3.35 g of dimethylformamide, at 0° C. under an atmosphere of nitrogen, added 6.18 g of sulfuryl chloride. The mixture was stirred 15 min and treated with 4.69 g of 2,3-dihydrobenzofuran. The mixture was then heated at 100° C. for 1.5 h, cooled to about 40° C., poured onto ice, extracted with CH2Cl2, dried over MgSO4, filtered, and concentrated in vacuo. The residue was taken up in ethyl acetate, cooled to 5° C. for 16 h, and the resultant pink crystals collected by vacuum filtration to provide 6.12 g of the title product. TLC: Rf=0.41, 10% ethyl acetate in hexane. (1H)-NMR (CDCl3) consistent with structure.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)=O)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[BH4-].[Na+].Cl>O1CCCC1>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(CCOCCc1ccc2sccc2c1)N1CC(O)C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC1CN(CCCOCCc2ccc3sccc3c2)C1
Temperature: 10 °C
Reaction time: 1 h
Yield: 48.4 %

Procedure:
5.00 g of 3-(2-(1-benzothiophene-5-yl)ethoxy)-1-(3-hydroxy-1-azetidinyl)-1-propanone was dissolved in 20 ml of tetrahydrofuran, and 1.09 g of sodium borohydride was then added thereto. Thereafter, 4.25 ml of a boron trifluoride-tetrahydrofuran complex was added dropwise thereto at 10° C., and the obtained mixture was then stirred at the same temperature for 1 hour and then at 40° C. for 3 hours. Thereafter, the reaction solution was cooled to 10° C. Thereafter, 30 ml of 6 mol/l hydrochloric acid was added dropwise to the reaction mixture, followed by reflux for 1 hour. After cooling, the solvent was concentrated under a reduced pressure, and ethyl acetate was added thereto. The pH of the mixture was adjusted to pH 9.4 by addition of a 20% aqueous sodium hydroxide solution, and an organic layer was then separated. The organic layer was successively washed with water and a saturated saline solution, and then dried over anhydrous magnesium sulfate. The solvent was then distilled away under a reduced pressure. The residue was purified by column chromatography (eluent; chloroform:methanol=20:1 to 10:1), and then crystallized from toluene-diisopropyl ether (1:3; 14 ml), so as to obtain 2.31 g of 1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-azetidinol.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@H:12]2[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:4](N)[N:3]=1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1[OH:28]>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].CS(C)=O>[CH2:14]([O:13][C@@H:12]1[C@H:19]([OH:20])[C@@H:21]([CH2:23][OH:24])[O:22][C@H:11]1[N:8]1[C:9]2[N:10]=[C:2]([NH2:1])[NH:3][C:4](=[O:28])[C:5]=2[N:6]=[CH:7]1)[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)nc(N)nc21
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N)nc21

Procedure:
2,6-diamino-9-(2' -O-pentyl-β-D-ribofuranosyl)purine (1.9 g) in 0.1 M sodium phosphate buffer (50 ml, pH 6.0) and DMSO (25 ml) was treated with adenosine deaminase (added in two aliquots--first aliquot 50 mg, second aliquot 80 mg) at 35° C. as per the procedure of Example 3 to yield 1.4 g of product. 1H NMR (DMSO-d6) δ 0.8 (t, 3, CH3), 1.16 (m, 4, 2x CH2), 1.4 (m, 2, CH2), 3.38, 3.6 (m, 4, OCH2, H-5'), 3.93 (s, 1, H-4'), 4.28 (m, 2, H-2', H-3'), 5.17 (br, 2, 5', 3'-OH), 5.8 (d, 1, H-1'), 6.53 (br s, 2, NH2), 8.0 (s, 1, H-8) and 10.68 (br, 1, NH).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])#[N:24].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[C:25]([C:23]#[N:24])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(c2cccc(Cl)c2)CN(Cc2ccccc2)CCC1=O
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=C1CCN(Cc2ccccc2)CC1(C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 1-benzyl-3-(3-chlorophenyl)-3-methyl-4-piperidone (50 mmole), ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL) ammonium acetate (400 mg), and benzene (50 mL) is heated to reflux in a Dean-Stark apparatus. After approximately 10 hours, additional ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL), and ammonium acetate (400 mg) are added. After an additional 10 hours, the reaction is cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (240 mL), brine (40 mL), and dried (Na2SO4). After filtering, the extract is concentrated in vacuo and the desired product, as a mixture of E- and Z-isomers, is isolated by column chromatography on silica gel, eluting with 5% ethyl acetate/petroleum ether.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.O.ON1C2C=CC=CC=2N=N1.Cl.[F:40][C:41]1[C:46]([F:47])=[CH:45][CH:44]=[CH:43][C:42]=1[CH2:48][S:49][C:50]1[N:55]=[C:54]([NH:56][S:57]([N:60]2[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)(=[O:59])=[O:58])[CH:53]=[C:52]([O:66][CH3:67])[N:51]=1.CN1CCOCC1>CN(C=O)C>[F:40][C:41]1[C:46]([F:47])=[CH:45][CH:44]=[CH:43][C:42]=1[CH2:48][S:49][C:50]1[N:55]=[C:54]([NH:56][S:57]([N:60]2[CH2:61][CH2:62][N:63]([C:10](=[O:12])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:64][CH2:65]2)(=[O:58])=[O:59])[CH:53]=[C:52]([O:66][CH3:67])[N:51]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COc1cc(NS(=O)(=O)N2CCNCC2)nc(SCc2cccc(F)c2F)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(NS(=O)(=O)N2CCN(C(=O)CNC(=O)OC(C)(C)C)CC2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(tert-butoxycarbonyl)glycine (0.11 g) in DMF (10 mL) was added 1,3-Dicyclohexylcarbodiimide (0.14 g) and 1-hydroxybenzotriazole hydrate (94 mg). After stirring at room temperature for 1 h, a solution of N-[2-[[(2,3-Difluorophenyl)methyl]thio]-6-methoxypyrimidin-4-yl]piperazine-1-sulfonamide, hydrochloride salt (the product of step i, 0.27 g) and N-methylmorpholine (78 μL) in DMF (5 mL) was added dropwise and stirring continued at room temperature for 24 h. The mixture was filtered, rinsed with DCM and the filtrate evaporated. The crude material was purified by column chromatography on silica gel using EtOAc/isohexane (3:2) as eluent to give the subtitle compound as a foam Yield: 0.24 g
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[NH:16][N:15]=2)=[CH:11][C:10]=1[C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28].[O:35]=[C:36]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:37](O)=[O:38].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[NH:16][N:15]=2)=[CH:11][C:10]=1[C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:37](=[O:38])[C:36]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:35])[CH2:31][CH2:30]1)=[O:28]
Reactant: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCNCC1
Reactant: O=C(O)C(=O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(C(=O)N1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 33.9 %

Procedure:
4-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one TFA salt (311 mg, 0.65 mmol), 2-oxo-2-phenylacetic acid (900 mg, 6 mmol), DIPEA (2 ml, 11.6 mmol), and HATU (1010 mg, 2.65 mmol) were mixed in DMF (50 ml), the resulting reaction mixture was stirred at room temperature for 4 days until the reaction finished (monitored by TLC). The reaction mixture was then partitioned between DCM and water (100 ml each, the water phase was extracted with DCM (100 ml)). The combined organic phase was washed with water, sat. aqueous sodium bicarbonate, and brine, dried over sodium sulphate, filtered, and concentrated to yield the crude product. Then the crude product was firstly purified by column chromatography on silica gel (DCM:MeOH=100:1) and re-purified by preparative TLC (DCM:MeOH=40:1) to afford the desired product (110 mg, 32.9%) as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH2:23][CH3:24])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(=[O:28])=[O:27]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH2:23][CH3:24])[CH2:10][CH2:11][N:38]2[CH2:37][CH2:36][CH:35]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[S:26]([CH3:25])(=[O:28])=[O:27])[CH2:40][CH2:39]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCN1C(=O)c2ccccc2C1C(CC=O)c1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)c1ccccc1C1CCNCC1
Product: CCN1C(=O)c2ccccc2C1C(CCN1CCC(c2ccccc2S(C)(=O)=O)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 103 %

Procedure:
3-(3,4-Dichlorophenyl)-3-(2-ethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.724 g) was coupled to 4-(2-methylsulfonyl-phenyl)piperidine (0.706 g) by a method similar to that described in Example 8. The reaction product was not purified by chromatography but converted to the hydrochloride salt to afford the title compound (0.64 g); mp 168°-175° C. (d); MS: m/z=585(M+1); NMR (CDCl3): 1.19 (m,3), 2.0 (m,3), 2.35 (m,7), 2.95 (s,3), 4.87 (m,1), 6.56-8.01 (m,11). Analysis for C31H34Cl2N2O3S.1.5 HCl.1.5 H2O: Calculated: C, 55.79; H, 5.82, N, 4.20; Found: C, 55.90; H, 5.45; N, 4.20.
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH3:4].[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:16])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.[Na+].Cl>>[Cl:16][C:10]1[CH:9]=[CH:8][C:7]2[N:6]=[C:3]([CH3:4])[CH:2]=[CH:1][C:15]=2[C:11]=1[C:12]([OH:14])=[O:13]
Reactant: C/C=C/C=O
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Agent: Cl
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Product: Cc1ccc2c(C(=O)O)c(Cl)ccc2n1

Procedure:
Crotonaldehyde (1.5 mL) was added dropwise over a period of 1 hour to a mixture of 5-amino-2-chlorobenzoic acid (1.7 g), ferrous sulphate heptahydrate (0.77 g), sodium m-nitrobenzenesulphonate (1.2 g) and concentrated hydrochloric acid (11 mL) at 95° C. The reaction mixture was heated for a further 15 minutes then filtered whilst still hot. The collected solid was extracted with boiling 2M aqueous hydrochloric acid solution (20 mL) and the extract combined with the filtrate. Ammonium acetate was then added to give a solution of pH 4, which was cooled in ice and the resultant precipitate collected by filtration and washed with water. The product was converted to its hydrochloride salt by treatment with hydrochloric acid (4M in 1,4-dioxane) and the solid dried in vacuo to give the sub-title compound (0.5 g) as a solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](C#N)[CH:5]=[CH:4][CH:3]=1.[C:10]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)(=[O:12])[CH3:11].[C:19](#[N:21])C>>[C:10]([N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:3]=[CH:4][C:5]([C:19]#[N:21])=[CH:6][N:7]=2)[CH2:15][CH2:14]1)(=[O:12])[CH3:11]
Reactant: CC#N
Reactant: N#Cc1cccc(Cl)n1
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(c2ccc(C#N)cn2)CC1

Procedure:
6-Chloropyridine-2-carbonitrile (104 mg, 0.75 mmol) and 1-acetylpiperazine (384 mg, 0.75 mmol) in acetonitrile (2.5 mL) were stirred and irradiated using a microwave reactor (300 W, 150° C., 60 min). The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography, eluting with CH2Cl2 and increasing the polarity to 10% MeOH/CH2Cl2 to afford 6-(4-acetyl-piperazin-1-yl)-nicotinonitrile as an off-white solid (172 mg, quant.).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:9]([O:10][CH2:11][CH2:12][F:13])=[CH:8][C:7]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[C:6]([F:20])[CH:5]=1.[NH:21]1[CH:25]=[CH:24][N:23]=[C:22]1[C:26]1[C:34]2[C:29](=[N:30][CH:31]=[CH:32][CH:33]=2)[N:28]([CH2:35][C:36](O)=[O:37])[N:27]=1>>[Cl:3][C:4]1[C:9]([O:10][CH2:11][CH2:12][F:13])=[CH:8][C:7]([N:14]2[CH2:15][CH2:16][N:17]([C:36](=[O:37])[CH2:35][N:28]3[C:29]4=[N:30][CH:31]=[CH:32][CH:33]=[C:34]4[C:26]([C:22]4[NH:21][CH:25]=[CH:24][N:23]=4)=[N:27]3)[CH2:18][CH2:19]2)=[C:6]([F:20])[CH:5]=1.[CH:9](=[O:10])[CH3:8]
Reactant: FCCOc1cc(N2CCNCC2)c(F)cc1Cl
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Agent: Cl
Product: CC=O
Product: O=C(Cn1nc(-c2ncc[nH]2)c2cccnc21)N1CCN(c2cc(OCCF)c(Cl)cc2F)CC1

Procedure:
The title compound was prepared following Protocol A. 1-[4-Chloro-2-fluoro-5-(2-fluoroethoxy)phenyl]-piperazine dihydrochloride and [3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]acetic acid were used as the coupling components. The crude product was purified by silica gel chromatography (2% to 3.5% MeOH in CH2Cl2) to provide 1-{4-[4-chloro-2-fluoro-5-(2-fluoroethoxy)phenyl]piperazin-1-yl}-2,3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]ethanone as a tan solid: 1H NMR (CDCl3, 400 MHz) □δ 8.79 (dd, 0.6; H, J=8.0, 1.8 Hz), 8.67 (d, 0.4; H, J=6.4 Hz), 8.57-8.55 (m, 1H), 7.30-7.25 (m, 1H), 7.11-7.06 (m, 2H), 6.63 (d, 0.6H, J=7.6 Hz), 6.57 (d, 0.4H, J=7.6 Hz), 6.54 (d, 1H, J=7.6 Hz), 5.45 (s, 0.7H), 5.43 (s, 1.3H), 4.83-4.80 (m, 1H), 4.71-4.68 (m, 1H), 4.31-4.18 (m, 2H), 3.82-3.76 (m, 3H), 3.50 (t, 1H, J=5.2 Hz), 3.23-3.04 (m, 4H); LC/MS m/z (M+H)+ 502.4.
Reaction SMILES: [I:1][C:2]1[C:3]([CH3:8])=[N:4][NH:5][C:6]=1[CH3:7].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.N1C=CC=CC=1>C(Cl)Cl>[I:1][C:2]1[C:3]([CH3:8])=[N:4][N:5]([S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:9])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[C:6]=1[CH3:7]
Reactant: Cc1n[nH]c(C)c1I
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)n2nc(C)c(I)c2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
In a 50 ml reaction vessel under argon, a solution of crude 4-iodo-3,5-dimethyl-1H-pyrazole x52 (1.15 g, 5.2 mmol) in 25 ml of dry CH2Cl2 is added to 4-methylbenzenesulfonyl chloride (1.18 g, 6.2 mmol). Pyridine (0.42 ml, 5.2 mmol) is added and the mixture is stirred for 16 h at room temperature. The organic phase is washed with water, dried over MgSO4, filtered and concentrated. The residue is purified by column chromatography on silicagel (CH2Cl2/hexane: 70/30 (v/v)) to afford 4-iodo-3,5-dimethyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrazole x53 (1.44 g).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].C[O-:7].[Na+].[N:9]1[C:18]2[C:13](=[C:14]([N:19]3[C:23]([CH:24]4[CH2:26][CH2:25]4)=[C:22]([C:27]([O:29]CC)=[O:28])[CH:21]=[N:20]3)[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1>C(O)C>[OH2:28].[OH2:7].[N:9]1[C:18]2[C:13](=[C:14]([N:19]3[C:23]([CH:24]4[CH2:25][CH2:26]4)=[C:22]([C:27]([NH:4][C:3]([NH2:5])=[NH:2])=[O:29])[CH:21]=[N:20]3)[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: N=C(N)N
Reactant: C[O-]
Reactant: CCOC(=O)c1cnn(-c2cccc3ncccc23)c1C1CC1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N=C(N)NC(=O)c1cnn(-c2cccc3ncccc23)c1C1CC1
Product: O
Yield: 75.7 %

Procedure:
A solution of guanidine hydrochloride (3.11 g, 32.6 mmol) in warm anhydrous ethanol (8 mL) under a nitrogen atmosphere was treated in one portion with sodium methoxide (1.76 g, 32.6 mmol). The resulting slurry was concentrated in vacuo. The residue was treated with anhydrous toluene (10 mL) and concentrated to dryness in vacuo (twice). Each time the vacuum was released to a nitrogen atmosphere. The residue was treated in one portion with ethyl 1-(quinolin-5-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylate (1.00 g, 3.26 mmol) in anhydrous ethanol (8 mL). The resulting mixture was concentrated in vacuo (rotatory evaporator, 80° C. water bath). The residue was treated with anhydrous toluene (10 mL) and the resulting mixture was concentrated in vacuo (three times). The resulting solid was triturated with water (85 mL) and filtered. The solid was air-dried to provide 0.880 g (76% yield) of [1-(quinolin-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine dihydrate.