Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:13]/[C:14]1[NH:15][CH:16]=[CH:17][C:18]=1[O:19][CH3:20])/[C:5](=[O:12])[NH:6]2.Cl.[CH:22](N)=N.O>C(O)C>[CH3:20][O:19][C:18]1[CH:17]=[CH:16][NH:15][C:14]=1/[CH:13]=[C:4]1\[C:5](=[O:12])[NH:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:11][CH:22]=[N:1][C:2]=3[C:3]\1=2
Reactant: N=CN
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(N)c21
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc3[nH]cnc3c21
Temperature: 25 °C

Procedure:
A mixture of (Z)-4,5-diamino-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl) methylene]-2H-indol-2-one (60 mg, 0.22 mmol) (from Example 15 above) and formamidine hydrochloride (177 mg, 2.2 mmol) (Aldrich) in ethanol (3 mL) was heated at reflux for 45 min. The mixture was cooled to room temperature, and water was slowly added to induce precipitation. The precipitate was collected by suction filtration, washed with water and dried in a vacuum oven overnight to give (Z)-8-[(3-methoxy-1H-pyrrol-2-yl)methylene]-3,6,7,8-tetrahydro-pyrrolo-[3,2-e]benzimidazol-7-one. (Yield 48 mg, 99%).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:10][S:9][C@@H:8]([CH2:11][SH:12])[CH2:7]1)=[O:5])C.[OH-].[Li+].O>C1COCC1>[C:4]([C@@H:6]1[CH2:10][S:9][C@@H:8]([CH2:11][SH:12])[CH2:7]1)([OH:5])=[O:3]
Reactant: CCOC(=O)[C@@H]1CS[C@@H](CS)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CS[C@@H](CS)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70 %

Procedure:
To a stirred solution of trans-4-ethoxycarbonyl-2-mercaptomethyltetrahydrothiophene (compound No. 15-1, 420 mg) in THF (28 ml), 1N lithium hydroxide solution (4.1 ml) was added and the mixture was stirred for 1.5 hours at room temperature. Water was added to the mixture and washed with ethyl acetate. The aqueous layer was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 254 mg (70%) of the titled compound (compound No. 7-1). The physical data was identified with the product obtained in Example 7.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:16][C@@H:15]2[N:17]([CH2:18][C:19]3[NH:24][C:23]([C:25]4[S:26][CH:27]=[CH:28][N:29]=4)=[N:22][C@@H:21]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=4[Cl:37])[C:20]=3[C:38]([O:40][CH3:41])=[O:39])[C@@H:11]([CH2:12][O:13][CH2:14]2)[CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH:9]1[CH2:10][C@@H:11]2[N:17]([CH2:18][C:19]3[NH:24][C:23]([C:25]4[S:26][CH:27]=[CH:28][N:29]=4)=[N:22][C@@H:21]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=4[Cl:37])[C:20]=3[C:38]([O:40][CH3:41])=[O:39])[C@@H:15]([CH2:14][O:13][CH2:12]2)[CH2:16]1
Reactant: COC(=O)C1=C(CN2[C@@H]3COC[C@H]2CC(NC(=O)OC(C)(C)C)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1=C(CN2[C@@H]3COC[C@H]2CC(N)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.8 %

Procedure:
To a solution of methyl (4R)-6-[[(1S,5R)-7-(tert-butoxycarbonylamino)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate 60a (300 mg, 0.49 mmol) in DCM (5 mL) was added TFA (2 mL). The mixture was stirred at 25° C. for 5 h. The mixture was concentrated in vacuo to afford methyl (4R)-6-[[(1S,5R)-7-amino-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate 60b (240 mg, 96%) which was used for next step without further purification. MS: calc'd (MH+) 506, measured (MH+) 506.
Reaction SMILES: C([O:7][C:8]1[CH:13]=[C:12]([C:14]2[O:18][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]4[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=4)[CH:20]=3)=[N:16][N:15]=2)[C:11]([O:35]CCCCCC)=[CH:10][C:9]=1[C:42]1[O:46][C:45]([C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([O:53][C:54]3[CH:59]=[CH:58][C:57]([N+:60]([O-:62])=[O:61])=[CH:56][CH:55]=3)[CH:48]=2)=[N:44][N:43]=1)CCCCC.B(Br)(Br)Br>ClCCl>[N+:60]([C:57]1[CH:56]=[CH:55][C:54]([O:53][C:49]2[CH:48]=[C:47]([C:45]3[O:46][C:42]([C:9]4[CH:10]=[C:11]([OH:35])[C:12]([C:14]5[O:18][C:17]([C:19]6[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]7[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=7)[CH:20]=6)=[N:16][N:15]=5)=[CH:13][C:8]=4[OH:7])=[N:43][N:44]=3)[CH:52]=[CH:51][CH:50]=2)=[CH:59][CH:58]=1)([O-:62])=[O:61]
Reactant: CCCCCCOc1cc(-c2nnc(-c3cccc(Oc4ccc([N+](=O)[O-])cc4)c3)o2)c(OCCCCCC)cc1-c1nnc(-c2cccc(Oc3ccc([N+](=O)[O-])cc3)c2)o1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Oc2cccc(-c3nnc(-c4cc(O)c(-c5nnc(-c6cccc(Oc7ccc([N+](=O)[O-])cc7)c6)o5)cc4O)o3)c2)cc1
Yield: 16.5 %

Procedure:
3.04 g of 5,5′-(2,5-bis(hexyloxy)-1,4-phenylene)bis(2-(3-(4-nitrophenoxy)phenyl)-1,3,4-oxadiazole) (3.6 mmol) prepared in Synthesis Example 9 was dissolved in 120 ml of dichloromethane at −78□, and 3.5 ml of boron tribromide (35.6 mmol) was added thereto, followed by slowly raising the temperature to 0□. Thereafter, the reaction was quenched by addition of methanol, followed by adding excess water. The resultant solution was neutralized with dichloromethane, filtered, and performing silica gel column chromatography (developed with trichloromethane) to yield 0.4 g of a product having Formula 38. 1H NMR (300 MHz, CDCl3) analytical results of the product were as follows:
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[CH:5][C:4]=1[N+:12]([O-])=O>[OH-].[OH-].[Pd+2].CO>[ClH:1].[NH2:12][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:3]=1[NH2:2])[C:7]([NH2:9])=[NH:8]
Reactant: N=C(N)c1ccc(N)c([N+](=O)[O-])c1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: N=C(N)c1ccc(N)c(N)c1
Reaction time: 1.5 h

Procedure:
A suspension of 4-amino-3-nitrobenzamidine monohydrochloride (15 g, 69 mmol) and Pearlman's catalyst [Pd(OH)2, 1.0 g, 7.12 mmol) in methanol (200 mL) was shaken under hydrogen atmosphere 50 psi for 1.5 h. The suspension was filtered through Celite and the filtrate was added dropwise to anhydrous diethyl ether (400 mL) to precipitate 3,4-diaminobenzamidine monohydrochloride as a tan solid.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4[CH:21]=[CH:22][C:23]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:24][C:19]=4[O:18][CH2:17]3)[C:9]2=[O:30])C=CC=CC=1.[H][H]>CO.C(O)(=O)C.[Pd]>[F:29][C:26]([F:27])([F:28])[O:25][C:23]1[CH:22]=[CH:21][C:20]2[C:10]3([CH2:17][O:18][C:19]=2[CH:24]=1)[C:11]1[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:8][C:9]3=[O:30]
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc(OC(F)(F)F)ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: O=C1Nc2ccccc2C12COc1cc(OC(F)(F)F)ccc12
Yield: 74.7 %

Procedure:
To a suspension of 1′-(diphenylmethyl)-6-(trifluoromethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (6.00 g, 12.3 mmol) in methanol (100 mL) and acetic acid (1.00 mL) was added 10% palladium on carbon (0.65 g, 0.62 mmol), and the mixture was hydrogenated at ambient temperature under 130 psi of hydrogen for 5 days. The reaction mixture was filtered over celite and the filtrate was concentrated in vacuo to dryness. The residue was subjected to flash chromatography eluting with 30% ethyl acetate in hexane to give the title compound (2.95 g, 75%) as a white solid: mp 180-182° C.; 1H NMR (300 MHz, CDCl3) δ 9.19 (s, 1H), 7.29-6.92 (m., 4H), 6.86-6.64 (m, 3H), 5.03 (d, 1H), 4.75 (d, 1H); 13C NMR (75 MHz, CDCl3) δ 179.9, 161.9, 150.6, 132.3, 129.4, 127.4, 125.6, 124.3, 124.2, 123.8, 120.5, 114.1, 110.7, 104.3, 80.8, 58.2; MS (ES+) m/z 322 (M+1).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH2:29]([N:31]=[C:32]=[O:33])[CH3:30]>>[CH2:29]([NH:31][C:32]([N:20]1[CH2:21][CH2:22][C:16]2[C:15]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[N:14][C:13]([C:10]3[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=3)=[N:18][C:17]=2[CH2:19]1)=[O:33])[CH3:30]
Reactant: CCN=C=O
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)NCC)C3)cc1

Procedure:
Method as example 33 using 1-Ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (example 82) and ethyl isocyanate as starting materials.
Reaction SMILES: C(N(C(C)C)C(Cl)=O)(C)C.[CH:11]([N:14]([C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH:15]([CH3:17])[CH3:16])([CH3:13])[CH3:12].[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][CH:29]=[C:28]2[O:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1.C1(C)C=CC=CC=1>C(O)C>[CH:11]([N:14]([C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH:15]([CH3:17])[CH3:16])([CH3:12])[CH3:13].[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][CH:29]=[C:28]2[O:37][C:38]1[CH:39]=[CH:40][C:41]([NH:42][C:21]([NH:20][C:18]([N:14]([CH:15]([CH3:17])[CH3:16])[CH:11]([CH3:12])[CH3:13])=[O:19])=[S:22])=[CH:43][CH:44]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: CC(C)N(C(=O)Cl)C(C)C
Agent: CC(C)N(C(=O)N=C=S)C(C)C
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)N(C(C)C)C(C)C)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
(Diisopropylamino)methanoyl isothiocyanate was prepared using commercially available N,N-diisopropylcarbamic chloride (80 mg) as a starting compound according to the description of the literature. (Diisopropylamino)methanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (50 mg, yield 62%).
Reaction SMILES: [CH2:1]([N:8]([CH2:14][C:15](O)([CH2:21][CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(S(F)(F)[F:30])CC>ClCCl>[CH2:1]([N:8]([CH2:14][C:15]([F:30])([CH2:21][CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(O)(CC)CN(Cc1ccccc1)C1CCCC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(F)(CC)CN(Cc1ccccc1)C1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To ethyl 2-((benzyl(cyclopentyl)amino)methyl)-2-hydroxybutanoate (2.9 g, 9.1 mmol) in 30 ml of dichlormethane at −78° C., was added DAST (2.4 ml, 18 mmol) dropwise. The reaction mixture was gradually warmed up to room temperature and stirred for 1 h. It was then diluted to dichloromethane, washed by NaHCO3, brine and water. Organic extract dried and concentrated to a residue, which was purified on silica gel column chromatographically (Hex/EtOAc=40:1 to 20:1) to give 2.2 g product (75%) as light yellow liquid. [M+H] calc'd for C19H28FNO2, 322. found 322.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].O(C(C)(C)C)[K].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1(C)C=CC=CC=1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Brc1ccnc2ccccc12
Agent: [Pd]
Agent: CC(C)(C)O[K]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccnc3ccccc23)CC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
To a degassed solution of 4-bromo-quinoline (4.00 g, 19.23 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (4.62 g, 23.08 mmol, 1.2 equiv; commercially available) in toluene (40 mL) was added KOtert-Bu (5.40 g, 48.07 mmol, 2.5 equiv), dicyclohexyl-(2′,4′,6′-triisopropyl-biphenyl-2-yl)-phosphane (0.18 g, 0.39 mmol, 0.02 equiv; X-Phos ligand [CAS RN 564483-18-7]; commercially available from Strem Chemicals, USA) and tris(dibenzylideneacetone) dipalladium(0) (1.59 g, 1.54 mmol, 0.08 equiv). The reaction mixture was stirred under nitrogen at 100° C. for 16 h, cooled to rt, filtered and the filtrate concentrated by evaporation under reduced pressure. The crude material was purified with silica column chromatography eluting with a gradient of ethyl acetate/triethylamine (10:0→20:1) to provide 3.40 g (54%) of the title compound in 90% purity according to 1H NMR. 1H NMR (400 MHz, DMSO): δ 1.39 (s, 9H), 1.55-1.70 (m, 2H), 1.93 (d, J=10.4 Hz, 2H), 2.93 (br s, 2H), 3.96-4.06 (m, 2H), 4.06-4.15 (m, 1H), 7.00 (d, J=7.0 Hz, 1H), 7.62-7.71 (m, 1H), 7.86-7.95 (m, 2H), 8.54 (d, J=6.9 Hz, 2H), 8.60 (d, J=8.6 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([N:14]([C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])=[N:9][CH:8]=[CH:7]2)([O-])=O.[H][H]>CO.C1COCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([N:14]([C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[C:15]([C:17]([CH3:19])([CH3:20])[CH3:18])=[O:16])=[N:9][CH:8]=[CH:7]2
Reactant: [H][H]
Reactant: CC(C)(C)C(=O)N(C(=O)C(C)(C)C)c1nccc2cc([N+](=O)[O-])ccc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C(=O)N(C(=O)C(C)(C)C)c1nccc2cc(N)ccc12
Yield: 104 %

Procedure:
6-Nitro-1-bis(tert-butyl carbonyl)aminoisoquinoline (75.00 g, 0.193 mol) in methanol/THF (500 ml/500 ml) was hydrogenated with a hydrogen balloon in the presence of Pd/C (5%, 5 g) for 2.0 h. Filtration of the Pd/C and concentration gave a solid, which was recrystallized from methanol to give 65.72 g (94.97%) of 1B as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.33 (m, 18H) 4.18 (s, 2H) 6.89 (d, J=2.20 Hz, 1H) 6.99 (dd, J=9.01, 2.42 Hz, 1H) 7.35 (d, J=6.59 Hz, 1H) 7.75 (d, J=8.79 Hz, 1H) 8.22 (d, J=5.71 Hz, 1H). LC-MS: 741 (2M+Na)+.
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4].[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>C(#N)C>[CH2:7]([NH:14][CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)CCl
Reactant: NCc1ccccc1
Solvent: O
Solvent: CC#N
Product: C[Si](C)(C)CNCc1ccccc1
Temperature: 25 °C
Yield: 63.4 %

Procedure:
To a stirred solution of chloromethyl-trimethyl-silane (25 g, 203.79 mmol, 1 eq.) in acetonitrile (250 mL) was added distilled benzyl amine (44.56 mL, 407.59 mmol, 2 eq) at room temperature. Resulting reaction mixture was refluxed for 16 hours. After consumption of starting material, reaction mixture was cooled to room temperature; benzyl amine hydrochloride salt was precipitate out. Solid was removed by filtration and filtrate was concentrated under reduced pressure to get yellow semi solid. Water was added to residue and extracted with ethyl acetate (3×100 mL). Combined organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford product as yellow liquid (25 g, crude). Crude used as such for next reaction. 1H-NMR (400 MHz, CDCl3) δ: 0.03 (s, 9H), 2.04 (s, 2H), 3.79 (s, 2H), 3.86 (s, 1H), 7.29-7.33 (m, 5H). (m/z): 193.8 (M+H)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:11][C:10]=1[C:22]([O:24]CC)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O>C1COCC1.O>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:11][C:10]=1[C:22]([OH:24])=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(C2CCCC2)n(C)c(=O)c1OCc1ccccc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(C2CCCC2)nc(C(=O)O)c(OCc2ccccc2)c1=O
Yield: 97 %

Procedure:
A mixture of ethyl 5-(benzyloxy)-2-cyclopentyl-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (prepared according to the procedure in Naidu, B. N. Synlett, 2008;) (1.1 g, 3.1 mmol) and LiOH.H2O (0.25 g, 6 mmol) in 2:1 THF/H2O (15 mL) was heated at 80° C. for 1 h then cooled. The reaction mixture concentrated and the residue acidified with 1 N aq. HCl and the resulting solid isolated by filtration to yield the title compound (0.98 g, 97% yield) as a white solid. 1HNMR (500 MHz, CDCl3) δ: 7.56-7.52 (2H, m), 7.36-7.28 (3H, m), 5.42 (2H, s), 3.59 (3H, s), 3.20-3.14 (1H, m), 2.08-2.01 (2H, m), 1.93-1.78 (4H, m), 1.74-1.67 (2H, m). HRMS (M+H) calcd for C18H21N2O4: 329.1501. found: 329.1489.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH2:6])=[O:5].[Br:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20](OC2C=CC=CC=2)=[O:21])=[N:17][CH:18]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:6][C:20]([NH:19][C:16]1[CH:15]=[CH:14][C:13]([Br:12])=[CH:18][N:17]=1)=[O:21])=[O:5]
Reactant: NC(=O)c1c(F)cccc1Cl
Reactant: O=C(Nc1ccc(Br)cn1)Oc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1Cl)Nc1ccc(Br)cn1

Procedure:
A portion of 2-chloro-6-fluorobenzamide is dissolved in an organic solvent, and 5-bromo-2-pyridinylaminocarboxylic acid, phenyl ester is added. The reaction mixture is stirred with heating for a period of time, and is then evaporated under vacuum. The product, identical to the product of Example 2 above, is isolated from the residue by recrystallization:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[CH2:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C12BC(CCC1)CCC2.Br[C:26]1[C:27]2[N:34]([CH2:35][CH3:36])[C:33]([C:37]3[C:38]([NH2:42])=[N:39][O:40][N:41]=3)=[N:32][C:28]=2[CH:29]=[N:30][CH:31]=1.[OH-].[Na+]>O1CCCC1.ClCCl>[CH2:35]([N:34]1[C:27]2[C:26]([CH2:15][CH2:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:31][N:30]=[CH:29][C:28]=2[N:32]=[C:33]1[C:37]1[C:38]([NH2:42])=[N:39][O:40][N:41]=1)[CH3:36]
Reactant: C=CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCn1c(-c2nonc2N)nc2cncc(Br)c21
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCn1c(-c2nonc2N)nc2cncc(CCC3CCNCC3)c21
Temperature: 25 °C
Reaction time: 6 h
Yield: 6.7 %

Procedure:
A solution of 4-vinyl-piperidine-1-carboxylic acid tert-butyl ester (WO 9620192) (1.2 mM: 252 mg) in dry tetrahydrofuran (4 ml) was treated with a 0.5M solution of 9-borabicyclo[3.3.1]-nonane in tetrahydrofuran (1.2 mM; 2.4 ml) and stirred at room temperature for 6 hours under argon. The mixture was treated with the product of Example 100 (1.0 mM; 309 mg), 1,1′-bis(diphenylphosphino)ferrocene dichloro palladium(II) complex with dichloromethane (25 mg) and a 3M aqueous solution of sodium hydroxide (1 ml). The resulting mixture was heated at reflux under argon for 18 hours and purified on a 5 g SCX ion exchange cartridge. After removal of the solvent in vacuo the resulting yellow gum was treated with trifluoroacetic acid at room temperature for 2 hours and the solution passed through a 5 g SCX ion exchange cartridge. The solvent was removed in vacuo and the residue purified on a 5 g silica solid phase extraction cartridge eluting with 1-5-94 ammonia-methanol-dichloromethane to give the title compound as a white solid (23 mg). MS (ES+) m/e 342 [M+H]+.
Reaction SMILES: C1(C2CCC3C(=CC=C(OC4C(N)=CC(C(F)(F)F)=CC=4N)C=3)O2)C=CC=CC=1.[N+:30]([C:33]1[CH:54]=[C:53]([C:55]([F:58])([F:57])[F:56])[CH:52]=[C:51]([N+:59]([O-])=O)[C:34]=1[O:35][C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][CH:44]=1)[CH2:41][CH:40]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:39]2)([O-])=O>>[C:45]1([CH:40]2[CH2:39][C:38]3[C:42](=[CH:43][CH:44]=[C:36]([O:35][C:34]4[C:51]([NH2:59])=[CH:52][C:53]([C:55]([F:57])([F:58])[F:56])=[CH:54][C:33]=4[NH2:30])[CH:37]=3)[CH2:41]2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Oc1ccc2c(c1)CC(c1ccccc1)C2
Agent: Nc1cc(C(F)(F)F)cc(N)c1Oc1ccc2c(c1)CCC(c1ccccc1)O2
Product: Nc1cc(C(F)(F)F)cc(N)c1Oc1ccc2c(c1)CC(c1ccccc1)C2

Procedure:
2-(2-Phenylindan-5-yloxy)-5-trifluoromethylbenzene-1,3-diamine was prepared as described for 2-(2-phenylchroman-6-yloxy)-5-trifluoromethylbenzene-1,3-diamine in Example 35(b) using 230 mg of 5-(2,6-dinitro-4-trifluoromethylphenoxy)-2-phenylindan. 1H-NMR (300 MHz, d6-DMSO): 7.33-7.27 (m, 4H), 7.22-7.18 (m, 1H), 7.14 (d, 1H, J 8.1 Hz), 6.73-6.69 (m, 2H), 6.31 (s, 2H), 4.98 (s, 4H), 3.64 (k, 1H, J 8.5 Hz), 3.26-3.18 (m, 2H), 2.96-2.86 (m, 2H).
Reaction SMILES: [CH2:1]([CH:3]1[O:7][C:6]([C:9]2[CH:10]=[C:11]([S:15][C:16]3[CH:21]=[CH:20][C:19]([C:22](=O)[CH3:23])=[CH:18][CH:17]=3)[CH:12]=[CH:13][CH:14]=2)([CH3:8])[CH2:5][O:4]1)[CH3:2].Cl.[NH2:26][OH:27]>>[CH2:1]([CH:3]1[O:7][C:6]([C:9]2[CH:10]=[C:11]([S:15][C:16]3[CH:21]=[CH:20][C:19]([C:22](=[N:26][OH:27])[CH3:23])=[CH:18][CH:17]=3)[CH:12]=[CH:13][CH:14]=2)([CH3:8])[CH2:5][O:4]1)[CH3:2]
Reactant: NO
Reactant: CCC1OCC(C)(c2cccc(Sc3ccc(C(C)=O)cc3)c2)O1
Agent: Cl
Product: CCC1OCC(C)(c2cccc(Sc3ccc(C(C)=NO)cc3)c2)O1
Yield: 31 %

Procedure:
Using an analogous procedure to that described in Example 68, 4'-[3-(2-ethyl-4-methyl-1,3-dioxolan-4-yl)phenylthio]acetophenone was reacted with hydroxylamine hydrochloride to give 4'-[3-(2-ethyl-4-methyl-1,3-dioxolan-4-yl)phenylthio]acetophenone oxime in 31% yield as a gum.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([O:18][C@@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=1)[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].F[C:25]1[CH:37]=[CH:36][C:28]2[S:29](=[O:35])(=[O:34])[CH2:30][CH2:31][CH2:32][O:33][C:27]=2[CH:26]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C.O>[O:35]=[S:29]1(=[O:34])[C:28]2[CH:36]=[CH:37][C:25]([O:1][C:2]3[CH:3]=[C:4]([CH:15]=[C:16]([O:18][C@@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=3)[C:5]([NH:7][C:8]3[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=3)=[O:6])=[CH:26][C:27]=2[O:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=S1(=O)CCCOc2cc(F)ccc21
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2cnc(C)cn2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCCCS3(=O)=O)cc(C(=O)Nc2cnc(C)cn2)c1
Temperature: 160 °C
Reaction time: 5 h
Yield: 34.8 %

Procedure:
A mixture of 3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide (0.15 g, 0.47 mmol), 8-fluoro-3,4-dihydro-2H-1,5-benzoxathiepine 5,5-dioxide (103 mg, 0.47 mmol) and potassium carbonate (131 mg, 0.95 mmol) in acetonitrile (5 mL) was stirred in a microwave reactor at 160° C. for 5 hours. The mixture was reduced in vacuo and ethyl acetate (50 mL) and water (50 mL) were added. The aqueous layer was re-extracted into ethyl acetate (50 mL) and the combined organics washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and reduced in vacuo to give a golden oil. The oil was chromatographed on silica, eluting with 40-100% ethyl acetate in isohexane, to give the desired compound as a white foam (84 mg). 1H NMR δ (CDCl3): 1.34 (d, 3H), 2.39-2.47 (m, 2H), 2.56 (s, 3H), 3.34-3.37 (m, 2H), 3.41 (s, 3H), 3.49-3.61 (m, 2H), 4.24-4.27 (m, 2H), 4.58-4.65 (m, 1H), 6.76 (d, 1H), 6.85-6.88 (m, 2H), 7.16 (t, 1H), 7.35 (t, 1H), 7.94 (d, 1H), 8.14 (s, 1H), 8.30 (s, 1H), 9.53 (s, 1H); m/z 514 (M+H)+