Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:13][C:14]3([CH2:17][OH:18])[CH2:16][CH2:15]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[C:19](N1C=CN=C1)(N1C=CN=C1)=[O:20]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:13]3[C:19](=[O:20])[O:18][CH2:17][C:14]43[CH2:15][CH2:16]4)[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: OCC1(Nc2nc(-c3ccc(Br)cc3)cs2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: O=C1OCC2(CC2)N1c1nc(-c2ccc(Br)cc2)cs1
Temperature: 165 °C
Reaction time: 0.03 h
Yield: 74 %

Procedure:
A mixture of (1-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}cyclopropyl)methanol (0.7598 g 2.34 mmol), prepared in previous step, and 15 mL of anhydrous acetonitrile were sonicated for 1 min and then stirred on a vortex stirrer for 2 min. To the resulting solution, carbonyldiimidazole (0.5683 g, 3.5 mmol) was added and the mixture again sonicated for 1 min and stirred on a vortex stirrer for 2 min. The resulting solution was then heated in an Emrys™ Optimizer microwave oven at 165° C. for 20 min. Upon cooling to room temperature crystals began to form. The crystals were collected by filtration and the filtrate was concentrated under reduced pressure. The residue was partitioned between methylene chloride and 2N HCl. The organic layer was separated, washed with water, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The material obtained was combined with the crystalline material previously isolated to give the title compound (607.9 mg 75%) as a white solid, mp 201-202° C.; MS (ESI) m/z 351. HRMS: calcd for C14H11BrN2O2S+H+, 350.97973; found (ESI, [M+H]+), 350.9806.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=O)[CH:15]=3)[N:10]([CH3:24])[C:9]=2[CH3:25])=[CH:4][CH:3]=1.[CH2:26]([NH:29][CH2:30][CH:31]=[CH2:32])[CH:27]=[CH2:28]>>[CH2:26]([N:29]([CH2:30][CH:31]=[CH2:32])[C:19](=[O:21])[C:18]([O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:24])[C:9]([CH3:25])=[C:8]2[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)([CH3:22])[CH3:23])[CH:27]=[CH2:28]
Reactant: Cc1c(-c2ccc(Cl)cc2)c2cc(OC(C)(C)C(=O)O)ccc2n1C
Reactant: C=CCNCC=C
Product: C=CCN(CC=C)C(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccc(Cl)cc1)c(C)n2C

Procedure:
The above compound was prepared from 2-[3-(4-chlorophenyl)-1,2-dimethyl-1H-indole-5-yloxy]-2-methyl-propanoic acid and diallylamine using a procedure analogous to that of Example 130.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[C:6]2[CH:12]=[N:11][NH:10][C:7]2=[N:8][CH:9]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[C:52]([O:56][C:57]([N:59]1[CH2:63][CH2:62][CH2:61][C@H:60]1[C@H:64]([C:68]1[CH:73]=[CH:72][C:71]([Cl:74])=[CH:70][CH:69]=1)[C:65](O)=[O:66])=[O:58])([CH3:55])([CH3:54])[CH3:53]>C(Cl)Cl>[Cl:3][C:4]1[C:5]([N:13]2[CH2:14][CH2:15][N:16]([C:65](=[O:66])[C@H:64]([C@@H:60]3[CH2:61][CH2:62][CH2:63][N:59]3[C:57]([O:56][C:52]([CH3:54])([CH3:53])[CH3:55])=[O:58])[C:68]3[CH:73]=[CH:72][C:71]([Cl:74])=[CH:70][CH:69]=3)[CH2:17][CH2:18]2)=[C:6]2[CH:12]=[N:11][NH:10][C:7]2=[N:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](C(=O)O)c1ccc(Cl)cc1
Reactant: Clc1cnc2[nH]ncc2c1N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](C(=O)N1CCN(c2c(Cl)cnc3[nH]ncc23)CC1)c1ccc(Cl)cc1
Yield: 82.9 %

Procedure:
A solution of 5-chloro-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (75 mg, 0.205 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (“HATU”; 78.0 mg, 0.205 mmol), N-ethyl-N-isopropylpropan-2-amine (143 μL, 0.821 mmol), and (S)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-(4-chlorophenyl)acetic acid (83.7 mg, 0.246 mmol, see Example C) in CH2Cl2 (5 mL) was stirred at room temperature for 1 hour. The solvent was removed, and the resulting residue was redissolved in EtOAc (20 mL) and washed with water. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The crude obtained was purified by C-18 reverse phase column chromatography (Biotage C-18 12M+) using 10-90% CHsCN/water gradient on Biotage SP4 unit. The fractions containing the product were pooled, and the solvents were removed and evaporated from CH3CN (3×10 mL). The residue was transferred to a 25 mL round bottom flask using EtOAc (about 5 to about 10 mL). The residue was concentrated in vacuo and dried under high vacuum for 2 hours to provide (S)-tert-butyl 2-((S)-2-(4-(5-chloro-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-1-(4-chlorophenyl)-2-oxoethyl)pyrrolidine-1-carboxylate (95 mg, 0.170 mmol, 82.7% yield) as a solid. LCMS (APCI+) m/z 459.1 [(M-Boc)+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3Br)[C:18]2=[O:27])=[CH:12][CH:11]=1.B(O)(O)[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[N:32][CH:31]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[C:30]3[CH:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(Br)cccc3C2=O)cc1
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2cccc3c2CN(Cc2ccc(C(=O)Nc4ccccc4N)cc2)C3=O)cn1
Yield: 68 %

Procedure:
The procedure of Example 2 was repeated except for using N-(2-aminophenyl)-4-((4-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 9 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 6-methoxypyridin-3-yl-3-boronic acid instead of phenyl boronic acid, to obtain the title compound (68%).
Reaction SMILES: [F:1][C:2]([F:24])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1)[C:3]1[N:12]=[C:11](O)[C:10]2[C:5](=[C:6]([N+:14]([O-:16])=[O:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.P(Br)(Br)(Br)=O.CCN(C(C)C)C(C)C.[CH3:39][C:40]1[NH:44][N:43]=[C:42]([NH2:45])[CH:41]=1>CN(C=O)C.O.C1(C)C=CC=CC=1>[F:1][C:2]([F:24])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1)[C:3]1[N:12]=[C:11]([NH:45][C:42]2[CH:41]=[C:40]([CH3:39])[NH:44][N:43]=2)[C:10]2[C:5](=[C:6]([N+:14]([O-:16])=[O:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: O=[N+]([O-])c1cccc2c(O)nc(C(F)(F)c3ccc(F)cn3)nc12
Agent: O=P(Br)(Br)Br
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3c([N+](=O)[O-])cccc23)n[nH]1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-nitroquinazolin-4-ol (312 mg, 0.92 mmol) were added phosphoryl tribromide (1.66 g), toluene (3 mL), and DIEA (0.325 mL, 1.85 mmol), and the mixture was heated at 90° C. for 0.75 h. The mixture was allowed to cool and was partitioned between EtOAc and a saturated aq sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated. To the residue was added a solution of 5-methyl-1H-pyrazol-3-amine (220 mg, 2.3 mmol) in DMF (4 mL) and the mixture was stirred at rt for 0.5 h. Water was added and the resulting precipitate was collected by filtration and dried on the funnel to give a crude solid (406 mg, quantitative). An analytical sample was prepared by purification with preparative HPLC (Varian diphenyl reverse phase column, eluting with a gradient of solvent B=0.05% HOAc/ACN and solvent A=0.05% HOAc/H2O) to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)-8-nitroquinazolin-4-amine. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.18 (s, 3H) 5.95 (s, 1H) 7.78 (t, J=8.01 Hz, 1H) 7.95-8.07 (m, 2H) 8.38 (d, J=7.54 Hz, 1H) 8.67 (s, 1H) 8.94 (d, J=8.10 Hz, 1H) 11.18 (br s, 1H) 12.25 (br s, 1H); LC-MS (ESI) m/z 416 (M+H)+.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.CCN(C(C)C)C(C)C.Cl.[Cl:36][C:37]1[CH:38]=[C:39]([CH:45]=[CH:46][C:47]=1[N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[C:40]([NH:42][CH2:43][CH3:44])=[O:41]>C(#N)CC.CS(C)=O>[Cl:36][C:37]1[CH:38]=[C:39]([CH:45]=[CH:46][C:47]=1[N:48]1[CH2:49][CH2:50][N:51]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]4[C:7](=[O:17])[NH:6][C:5]=3[CH:4]=2)[CH2:52][CH2:53]1)[C:40]([NH:42][CH2:43][CH3:44])=[O:41]
Reactant: O=C1Nc2cc(CO)cnc2N2CCCC[C@@H]12
Reactant: CCNC(=O)c1ccc(N2CCNCC2)c(Cl)c1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CS(C)=O
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)c(Cl)c1
Temperature: 90 °C
Yield: 41.8 %

Procedure:
To a suspension of (S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (81 mg, 0.347 mmol) in propiononitrile (1.2 mL) was added (cyanomethyl)trimethylphosphonium iodide (101 mg, 0.417 mmol) and DIEA (182 μl, 1.042 mmol) and finally 3-chloro-N-ethyl-4-(piperazin-1-yl)benzamide hydrochloride (106 mg, 0.347 mmol). The vial was heated to 90° C. for 16 hours. The crude rxn was cooled to RT, DMSO (1 ml) was added, and purified via HPLC (55-90, basic). The fractions were collected, concentrated until a precipitate was visible and filtered. The solids were washed with water and collected to retrieve the product as a white solid (70 mg, 20% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.48 (s, 1H), 8.43 (t, J=5.4 Hz, 1H), 7.87 (d, J=2.3 Hz, 1H), 7.76 (dd, J=8.3, 2.0 Hz, 1H), 7.66 (d, J=1.8 Hz, 1H), 7.17 (d, J=8.6 Hz, 1H), 6.97 (d, J=2.0 Hz, 1H), 4.50 (d, J=12.9 Hz, 1H), 3.84 (dd, J=11.4, 2.8 Hz, 1H), 3.38 (s, 2H), 3.18-3.31 (m, 2H), 3.03 (br. s., 4H), 2.60 (td, J=12.7, 2.7 Hz, 1H), 2.51 (br. s., 4H), 2.04 (d, J=12.9 Hz, 1H), 1.85 (d, J=12.1 Hz, 1H), 1.64 (d, J=12.6 Hz, 1H), 1.32-1.58 (m, 3H), 1.10 (t, J=7.1 Hz, 3H). [M+H] calc'd for C25H31ClN6O2, 483; found, 483.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1.O[CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[NH2:10][C:9]1[N:1]=[CH:2][N:3]=[C:4]2[C:8]=1[N:7]=[CH:6][N:5]2[CH:16]1[CH2:17][CH2:12][CH2:13][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]1
Reactant: Nc1ncnc2[nH]cnc12
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(n2cnc3c(N)ncnc32)C1
Reaction time: 0.25 h
Yield: 11 %

Procedure:
To a solution of 9H-purin-6-amine (945 mg, 7 mmol, 1.0 eq) in THF (1 mL) was added tert-butyl 3-hydroxypiperidine-1-carboxylate (2.996 g, 14 mmol, 2.0 eq) and PPh3 (3.67 g, 14 mmol, 2.0 eq). After stirring for the solution for 15 min, DIAD (2.83 g, 14 mmol, 2.0 eq) was added the reaction was continued to be stirred rt for 1 h. The solvent was removed in vacuo and the residue was purified on a silica gel column (PE/EA=5:1) to afford the title compound as a yellow solid (245 mg, yield 11%). 1H NMR (400 MHz, CD3OD) δ: 8.44 (s, 1H), 8.42 (s, 1H), 5.04-4.98 (m, 1H), 3.77-3.73 (m, 1H), 3.68-3.62 (m, 1H), 3.52-3.48 (m, 1H), 3.18-3.11 (m, 1H), 2.45-2.32 (m, 2H), 2.22-2.17 (m, 1H), 2.05-1.97 (m, 1H), 1.49 (s, 9H). ESI-MS: 319.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]23[O:15][C@@:12]([CH2:16][OH:17])([CH2:13][O:14]2)[C@@H:11]([OH:18])[C@H:10]([OH:19])[C@H:9]3[OH:20])=[CH:4][C:3]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][O:38][C:39](=[O:41])[CH3:40].O>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]23[O:15][C@@:12]([CH2:16][OH:17])([CH2:13][O:14]2)[C@@H:11]([OH:18])[C@H:10]([OH:19])[C@H:9]3[OH:20])=[CH:4][C:3]=1[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:36][CH2:37][O:38][C:39](=[O:41])[CH3:40])=[CH:26][CH:27]=1
Reactant: OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(O)cc4)c3)(O1)[C@H](O)[C@@H](O)[C@@H]2O
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CC(=O)OCCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Yield: 22 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-5-[4-chloro-3-(4-hydroxy-benzyl)-phenyl]-1-hydroxymethyl-6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol (38 mg, 0.093 mmol) in acetonitrile (0.9 mL) was added potassium carbonate (40 mg, 0.28 mmol) followed by the addition of acetic acid 2-bromo-ethyl ester (0.012 mL, 0.112 mmol) and the resulting mixture was heated to 50 degrees Celsius for 72 hours. The reaction showed some product formation but the majority of starting material remained. An additional 2 equivalents of acetic acid 2-bromo-ethyl ester was added and the mixture was heated at 50 degrees Celsius for an additional 24 hours. Water (20 mL) and ethyl acetate were added, the two phases separated and the aqueous phase was extracted 3 times with ethyl acetate (20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography over silica gel using the ISCO automated chromatography unit (4 g silica gel column) and eluting with a gradient of 0 to 30% methanol in dichloromethane. 10 mg (22% yield) of a ˜2:1 mixture of the desired product contaminated with some unidentified compound was obtained. LCMS 539 M+HCOO−, negative mode).
Reaction SMILES: [CH3:1][Si:2]([CH3:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:3]1[C@@H:7]([CH2:8][OH:9])[C:6]([CH2:10][O:11]C(OC)(C)C)=[CH:5][CH2:4]1.[H-].[Na+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.N12CCNC=C1CCCC=C2>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[CH3:23][Si:2]([CH3:1])([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C@@H:3]1[C@@H:7]([CH2:8][O:9][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:6]([CH2:10][OH:11])=[CH:5][CH2:4]1
Reactant: COC(C)(C)OCC1=CC[C@H]([Si](C)(C)c2ccccc2)[C@H]1CO
Reactant: BrCc1ccccc1
Agent: C1=CN2CCNC=C2CCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: C1CCOC1
Product: C[Si](C)(c1ccccc1)[C@H]1CC=C(CO)[C@@H]1COCc1ccccc1
Temperature: 60 °C
Yield: 119.1 %

Procedure:
To a 250-mL 3-necked round bottomed flask equipped with a mechanical stirrer and a thermometer was charged 75 (35 g, 0.1 moles) and THF (60 mL) under an atmosphere of argon. NaH (6 g, 60%, mineral oil suspension, 0.15 moles) was added to the solution. The mixture was heated at 60° C. for 1 hour and then cooled to room temperature. Benzyl bromide (23.8 mL, 0.2 moles) and tetrabutylammonium bromide (10 g, 0.03 moles) were added to the suspension. The reaction mixture was heated at 70° C. for 6 hours and then the reaction mixture was cooled to room temperature. 1,9-diazabicyclo[5.4.0]undecen-7-ene (45 mL, 0.2 moles) was added and heated at 50° C. for 45 min. The reaction mixture was cooled to room temperature, quenched with 1N HCl to pH ˜1 and extracted with a mixture of EtOAc-hexane (250 mL). The organic layer was washed with water (500 mL), brine (100 mL) and concentrated in vacuo to afford the title compound (42 g) as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C:4]([CH3:9])([CH3:8])[CH:5]([OH:7])[CH3:6].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.Cl>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:10])[C:4]([CH3:9])([CH3:8])[CH:5]([O:7][S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18])[CH3:6]
Reactant: COC(=O)C(C)(C)C(C)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)C(C)(C)C(C)OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 75.1 %

Procedure:
To a cooled (0°) solution of 3-hydroxy-2,2-dimethyl-butyric acid methyl ester (52.0 g, 0.36 mol) in pyridine (100 ml) was added gradually, p-toluene sulfonyl chloride (69.0 g, 0.36 mol). The mixture was allowed to warm to room temperature and was stirred for 60 h. The reaction was again cooled in ice and was acidified by addition of HCl (2 M). The resultant solution was extracted with ethyl acetate, the extracts were washed with HCl, then brine, dried and evaporated to give an oil which formed a white precipitate upon standing. This mixture was dissolved in the minimum amount of ethyl acetate and then light petroleum was added to afford a white precipitate which was collected and washed with more light petroleum. The filtrate was partially evaporated and a second crop of crystals was collected and added to the first to afford 2,2-dimethyl-3-(toluene-4-sulfonyloxy)-butyric acid methyl ester (81.2 g, 76%).
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([C:12]2([CH2:18][CH2:19][N:20]3[CH:25]4[CH2:26][CH2:27][CH:21]3[CH2:22][CH:23]([N:28]3[C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=5[N:30]=[C:29]3[CH3:37])[CH2:24]4)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1)[CH3:4].C(N(CC)CC)C.[Cl:45][C:46]1[CH:54]=[CH:53][C:49]([C:50](O)=[O:51])=[CH:48][C:47]=1[S:55](=[O:58])(=[O:57])[NH2:56].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[Cl:45][C:46]1[CH:54]=[CH:53][C:49]([C:50]([N:15]2[CH2:16][CH2:17][C:12]([C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:3][CH3:4])[CH:7]=3)([CH2:18][CH2:19][N:20]3[C@H:21]4[CH2:27][CH2:26][C@@H:25]3[CH2:24][CH:23]([N:28]3[C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=5[N:30]=[C:29]3[CH3:37])[CH2:22]4)[CH2:13][CH2:14]2)=[O:51])=[CH:48][C:47]=1[S:55]([NH2:56])(=[O:58])=[O:57]
Reactant: NS(=O)(=O)c1cc(C(=O)O)ccc1Cl
Reactant: CCOc1cccc(C2(CCN3C4CCC3CC(n3c(C)nc5ccccc53)C4)CCNCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cccc(C2(CCN3[C@@H]4CC[C@H]3CC(n3c(C)nc5ccccc53)C4)CCN(C(=O)c3ccc(Cl)c(S(N)(=O)=O)c3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
A mixture of 1-(8-{2-[4-(3-ethoxyphenyl) piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole dihydrochloride (0.40 g, 0.78 mmol), triethylamine (0.35 mL, 2.5 mmol) and 4-chloro-3-sulfamoylbenzoic acid (184 mg, 0.78 mmol) in dimethylformamide (2.5 mL) was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (327 mg, 0.86 mmol) and the resulting mixture was stirred for 1 h at rt. The mixture was diluted with water and the resulting precipitate was collected, washed with saturated sodium bicarbonate solution and water, dried and purified by chromatography on silica gel eluting with a chloroform:methanol:ammonium hydroxide 400:15:1 to 200:15:1 gradient to give 2-chloro-5-[(4-(3-ethoxy phenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)carbonyl]benzenesulfonamide as a solid (0.34 g, 62%). 1H NMR (400 MHz, CD3OD) δ 8.08 (s, 1H), 7.67 (m, 1H), 7.59 (m, 1H), 7.51 (m, 1H), 7.41 (m, 1H), 7.29 (m, 1H), 7.17 (m, 2H), 6.93-6.98 (m, 2H), 6.81 (m, 1H), 4.74 (m, 1H), 4.17 (m, 1H), 4.04 (m, 2H), 3.54 (m, 1H), 3.30 (m, 4H), 2.52 (s, 3H), 2.40-2.48 (m, 4H), 2.27 (m, 1H), 2.14 (m, 1H), 1.83-2.04 (m, 10H), 1.70 (m, 2H), 1.40 (t, 3H). HRMS C37H44ClN5O4S m/z 690.2881 (M+H)Cal., 690.2901 (M+H)Obs..
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]([NH2:8])=[O:7])=[O:4].[Na].[CH:10](OCC)=O.Cl>O.C1C=CC=CC=1.C(O)C>[CH3:1][N:2]1[CH:10]=[N:8][C:6](=[O:7])[NH:5][C:3]1=[O:4]
Reactant: CCOC=O
Reactant: CNC(=O)NC(N)=O
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Solvent: c1ccccc1
Product: Cn1cnc(=O)[nH]c1=O
Temperature: 60 °C
Yield: 90 %

Procedure:
A reaction mixture consisting of 70.2 gm (0.6 mole) of the 1-methylbiuret prepared in Part A above, 3.5 liter absolute ethanol, and 200 ml. benzene is heated to the reflux temperature with stirring in a 5-liter, three-necked flask fitted with a reflux condenser, a stirrer, and thermometer. The top of the condenser is fitted with a nitrogen outlet, but no water is run through the condenser. After removing the nitrogen outlet, 200 ml. of the medium is allowed to distill through the condenser. The reaction mixture is then cooled to 60° C., before 28 gm. (1.2 mole) of sodium metal is added slowly over an interval of five (5) minutes. A white solid precipitates, but stirring is continued until all the sodium is dissolved. At this point, 104 gm. (1.4 mole) of ethyl formate is added in one portion and the reaction mixture is again heated to the reflux temperature (about 75° C.) and refluxed for three (3) hours. The reaction mixture is cooled to about 30° C. and hydrogen chloride gas is blown over the surface until an acid pH is attained. The reaction mixture is again heated at the reflux temperature for 15 minutes. The hot mixture is filtered through a diatomaceous earth filter and the filter is washed with hot ethanol. The filtrate and washings are concentrated to a volume of 200 to 300 ml. by removing medium by evaporation under reduced pressure. The concentrate is cooled to 5° C. and set aside at that temperature for several hours for crystallization. The crystals are collected on a filter and washed with cold ethanol. After drying the crystals under reduced pressure there is obtained 69 gm. (90% yield) of 1-methyl-5-azauracil having a melting range from 200° C. to 205° C. A sample recrystallized three times from ethanol has a melting point of 213° C. to 214° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=O)[NH:9][N:8]=2)[S:5][CH:6]=1.P(Cl)(Cl)([Cl:20])=O>ClC(Cl)C>[Cl:20][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([C:4]2[S:5][CH:6]=[C:2]([CH3:1])[CH:3]=2)=[N:8][N:9]=1
Reactant: Cc1csc(-c2n[nH]c(=O)c3ccccc23)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: Cc1csc(-c2nnc(Cl)c3ccccc23)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
200 mg of 4-(4-methyl-2-thienyl)phthalazinone and 2 ml of phosphorus oxychloride were dissolved in 4 ml of dichloroethane, and the solution was stirred at 100° C. for 4 hours. The reaction solution was distilled off, and a 1-N aqueous NaOH solution was added thereto under cooling with ice. The solution was extracted with chloroform, dried and concentrated to obtain 206 mg of 1-chloro-4-(4-methyl-2-thienyl)phthalazine.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>O>[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[CH:7]=2)[CH2:20][CH2:19]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1N1CCCCC1
Solvent: O
Product: CN1CCN(c2ccc([N+](=O)[O-])c(N3CCCCC3)c2)CC1
Temperature: 138 °C
Yield: 98.8 %

Procedure:
A mixture of 350 mg (1.45 mmol) of 1-(5-chloro-2-nitro-phenyl)-piperidine (as prepared in Example 4, step (a)) and 482 μL (4.35 mmol) of 1-methylpiperazine was heated in a sealed vial at 138° C. for 30 h. The mixture was cooled and poured into 60 mL of water and extracted with EtOAc (2×20 mL). The combined extracts were washed with brine (30 mL), dried (Na2SO4) and concentrated in vacuo to afford 436 mg (99%) of the title compound as a yellow resin: Mass spectrum (ESI, m/z): Calcd. for C16H24N4O2, 305.2 (M+H), found 305.2.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25]([O:27]CC)=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]3[CH2:39][CH2:38][CH2:37][NH:36][C:35]3=[O:40])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C(O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25]([OH:27])=[O:26])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]3[CH2:39][CH2:38][CH2:37][NH:36][C:35]3=[O:40])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N3CCCNC3=O)cc2n1Cc1ccc(OC(C(=O)OCC)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc2ccc(N3CCCNC3=O)cc2n1Cc1ccc(OC(C(=O)O)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 1b from 2-n-butyl-1-[4-[(α-ethoxycarbonyl)benzyloxy]benzyl]-6-(3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-benzimidazole and 1N sodium hydroxide solution in ethanol.