Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:24])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[CH:35][C:36]([OH:39])=[N:37][CH:38]=2)O1>>[OH:21][CH2:20][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:9]2[S:8][C:6]3[C:5]([N:10]=2)=[CH:4][CH:3]=[C:2]([C:33]2[CH:38]=[N:37][C:36]([OH:39])=[CH:35][CH:34]=2)[N:7]=3)=[O:24])=[CH:14][CH:15]=1)([CH3:23])[CH3:22]
Reactant: CC1(C)OB(c2ccc(O)nc2)OC1(C)C
Reactant: CC(C)(CO)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Product: CC(C)(CO)c1ccc(C(=O)Nc2nc3ccc(-c4ccc(O)nc4)nc3s2)cc1
Yield: 21 %

Procedure:
The titled compound (yield=21%, tan solid) was prepared using a procedure analogous to that described in connection with 10 (Example 10) except 2F (Example 2) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ol were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (s, 6H) 3.48 (s, 2H) 6.48 (d, J=9.60 Hz, 1H) 7.58 (d, J=8.84 Hz, 2H) 7.96 (d, J=8.59 Hz, 1H) 8.09 (d, J=8.59 Hz, 2H) 8.14 (d, J=8.59 Hz, 1H) 8.20 (d, J=2.27 Hz, 1H) 8.27 (dd, J=9.60, 2.78 Hz, 1H) 11.99 (br. s., 1H) 12.93 (br. s., 1H); ESI-MS: m/z 421.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=O)[C:9](=[O:11])[CH:10]=1.[C:25]([Si:29]([CH3:40])([CH3:39])[O:30][CH2:31][CH2:32][N:33]1[CH:37]=[CH:36][C:35]([NH2:38])=[N:34]1)([CH3:28])([CH3:27])[CH3:26]>>[C:25]([Si:29]([CH3:40])([CH3:39])[O:30][CH2:31][CH2:32][N:33]1[CH:37]=[CH:36][C:35]([NH:38][C:13](=[O:15])[CH:12]([N:8]2[C:9](=[O:11])[CH:10]=[C:5]([O:4][C:3]3[C:20]([F:24])=[CH:21][CH:22]=[CH:23][C:2]=3[F:1])[CH:6]=[N:7]2)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:34]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Reactant: CC(C)CC(C(=O)O)n1ncc(Oc2c(F)cccc2F)cc1=O
Product: CC(C)CC(C(=O)Nc1ccn(CCO[Si](C)(C)C(C)(C)C)n1)n1ncc(Oc2c(F)cccc2F)cc1=O
Yield: 68 %

Procedure:
Using the method described in Example 49, 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid (Intermediate 28) and 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (Intermediate 3) afforded 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid {1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-amide as an off-white solid (1.15 g, 68%); ES+-HRMS m/e calcd for C27H37N5O4SiF2 [M+H+] 562.2656 found 562.2658. 1H NMR (300 MHz, DMSO-d6) δ ppm −0.06 (s, 6H) 0.81 (s, 9H) 0.84-0.92 (m, 6H) 1.45 (m, 1H) 1.70-1.87 (m, 1H) 2.09-2.24 (m, 1H) 3.86 (t, J=5.1 Hz, 2H) 4.07 (t, J=5.1 Hz, 2H) 5.53 (dd, J=11.2, 4.2 Hz, 1H) 6.04 (d, J=2.7 Hz, 1H) 6.36 (d, J=2.0 Hz, 1H) 7.31-7.52 (m, 3H) 7.54 (d, J=2.0 Hz, 1H) 8.28 (d, J=2.7 Hz, 1H) 10.82 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:8][C:6]1[NH:5][C:4]2[C:3]([N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=2)=[C:2]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:7]=1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1nc(N2CCOCC2)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 120 °C
Yield: 33.1 %

Procedure:
To a 5 mL Wheaton vial was added was added 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (100 mg, 0.41 mmol) and morpholine (Aldrich Chemical Company) (0.18 mL, 2.1 mmol). A solution of K2CO3 (0.37 g, 2.7 mmol) in H2O (2.5.mL) was added, the vial was securely capped, and the reaction mixture was heated at 120° C. for 2 h. The reaction mixture was allowed to cool to room temperature and the resulting light-pink precipitate was collected by filtration, recrystallized from EtOAc and dried overnight in a 60° C. vacuum oven to give 0.04 g (33%) of the title compound as a white solid. Mp: 276° C. (dec.) 1H NMR (CDCl3; 500 MHz): δ 2.62 (s, 3), 3.87 (s, 4), 3.90 (s, 4), 6.79 (s, 1), 7.41 (t, 1, J=6.8), 7.48 (t, 2, J=7.4), 7.67 (d, 2, J=6.8), 8.17 (br s, 1). MS m/z: 295 (M+1). Anal. Calcd for C17H18N4O.0.25H2O: C, 68.32, H, 6.24, N, 18.75. Found: C, 67.90, H, 6.02, N, 18.64.
Reaction SMILES: C([Li])CCC.[CH2:6]([C:8]([O:15][CH2:16][O:17][CH3:18])([CH2:13][CH3:14])[CH2:9][CH2:10][C:11]#[CH:12])[CH3:7].[C:19]([O:27][CH:28]1[CH2:36][CH2:35][CH2:34][C:33]2([CH3:37])[CH:29]1[CH2:30][CH2:31][CH:32]2[C:38](=[O:40])[CH3:39])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[C:19]([O:27][CH:28]1[CH2:36][CH2:35][CH2:34][C:33]2([CH3:37])[CH:29]1[CH2:30][CH2:31][CH:32]2[C:38]([OH:40])([C:12]#[C:11][CH2:10][CH2:9][C:8]([CH2:13][CH3:14])([O:15][CH2:16][O:17][CH3:18])[CH2:6][CH3:7])[CH3:39])(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C#CCCC(CC)(CC)OCOC
Reactant: CC(=O)C1CCC2C(OC(=O)c3ccccc3)CCCC12C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(CC)(CCC#CC(C)(O)C1CCC2C(OC(=O)c3ccccc3)CCCC21C)OCOC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
0.32 ml of 1.6M hexane solution of butyl lithium was dropwise added to a solution of 120 mg of 5-ethyl-5-methoxymethoxy-1-heptyne dissolved in 4 ml of tetrahydrofuran, at -78° C. in a nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 30 minutes. Thereto was dropwise added a solution of 112 mg of 4-benzoyloxy-7a-methyl-2,3,3a,4,5,6,7,7a-octahydroinden-1-yl-ethanone dissolved in 3 ml of tetrahydrofuran. The reaction mixture was warmed to 0° C. and mixed with an aqueous ammonium chloride solution. The mixture was subjected to extraction with diethyl ether. The extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 97 mg of 2-(4-benzoyloxy-7a-methyl-2,3,3a,4,5,6,7,7a-octahydroinden-1-yl)-7-ethyl-7-methoxymethoxy-3-nonyn-2-ol having the following properties.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]([S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])([CH:6]1[CH2:11][CH2:10][CH2:9][C:8](=O)[CH2:7]1)[CH3:5].Cl.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31]N)=[CH:27][CH:26]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:22])[C:4]([S:13]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=[O:15])=[O:14])([CH:6]1[CH2:11][CH2:10][C:9]2[C:29]3[C:28](=[CH:27][CH:26]=[C:25]([Cl:24])[CH:30]=3)[NH:31][C:8]=2[CH2:7]1)[CH3:5]
Reactant: COC(=O)C(C)(C1CCCC(=O)C1)S(=O)(=O)c1ccccc1
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)C(C)(C1CCc2c([nH]c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Temperature: 40 °C
Yield: 100.7 %

Procedure:
To 0.14 g (0.43 mmol) (RS,SR)-2-benzenesulfonyl-2-(3-oxo-cyclohexyl)-propionic acid methyl ester in glacial acetic acid (3 mL), 88 mg (0.47 mmol, 1.1 eq) of (4-chloro-phenyl)-hydrazine hydrochloride were added and the reaction mixture was stirred at 40° C. over night. An aqueous solution of NaHCO3 was added until pH=7 was reached, and the mixture was extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. A column chromatography on silica gel with heptane/EtOAc 2:1 followed by a trituration with Et2O yielded 187 mg (65%) of (RS,SR)-2-benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-propionic acid methyl ester as a white solid, MS: 432 (MH+).
Reaction SMILES: [C:1]([C:11]1[CH:31]=[CH:30][C:14]([CH2:15][NH:16][C:17]2[CH:29]=[CH:28][C:20]3[O:21][C:22]([CH3:27])([CH3:26])[O:23][C:24](=[O:25])[C:19]=3[CH:18]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:32]1(/[CH:38]=[CH:39]/[C:40](Cl)=[O:41])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:1]([C:11]1[CH:31]=[CH:30][C:14]([CH2:15][N:16]([C:17]2[CH:29]=[CH:28][C:20]3[O:21][C:22]([CH3:26])([CH3:27])[O:23][C:24](=[O:25])[C:19]=3[CH:18]=2)[C:40](=[O:41])/[CH:39]=[CH:38]/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C(Cl)/C=C/c1ccccc1
Reactant: CCCCCCCCC#Cc1ccc(CNc2ccc3c(c2)C(=O)OC(C)(C)O3)cc1
Product: CCCCCCCCC#Cc1ccc(CN(C(=O)/C=C/c2ccccc2)c2ccc3c(c2)C(=O)OC(C)(C)O3)cc1

Procedure:
The title compound was prepared following the procedure E using 6-[(4-dec-1-ynylbenzyl)amino]-2,2-dimethyl-4H-1,3-benzodioxin-4-one and (2E)-3-phenylacryloyl chloride. HPLC, Rt: 6.3 min (purity: 95.5%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[C:9]([C:11]1[CH:30]=[CH:29][C:14]2[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]3[S:21][C:22]([C:25](=[NH:27])[NH2:26])=[CH:23][N:24]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].[OH-].[Na+]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:9]([C:11]1[CH:30]=[CH:29][C:14]2[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]3[S:21][C:22]([C:25](=[NH:26])[NH2:27])=[CH:23][N:24]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ncc(C(=N)N)s1)n2C)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Cn1c(CNc2ncc(C(=N)N)s2)nc2cc(C(=O)N(CCC(=O)O)c3ccccn3)ccc21

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(5-amidino-thiazol-2-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. Yield: % of theory, C22H22N8O3S (478.5) Rf value: (silica gel; dichloromethane/methanol=4:1)
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:11][C:4]1[N:3]=[C:2]([N:22]2[CH2:23][CH2:24][CH:19]([CH3:18])[CH2:20][CH2:21]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC1CCN(c2nc(Cl)ccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 102.9 %

Procedure:
A solution of 2,6-dichloro-3-nitro-pyridine (1.47 g, 7.61 mmol) in toluene (40 mL) was treated with, solid K2CO3 (1.26 g, 9.13 mmol) and 4-methyl-piperidine (0.90 mL, 7.6 mmol). The reaction was stirred at room temperature for 1.5 h, additional toluene (10 mL) was added, and the reaction was stirred an additional 5 h. The reaction was diluted with EtOAc and washed with water. The aqueous layer was further extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford the title compound (2.00 g, 100%) as a waxy, bright yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 8.06 (d, 1H, J=4.0 Hz), 7.61 (d, 1H, J=4.0 Hz), 3.83-3.75 (m, 2H), 3.08-2.97 (m, 2H), 1.77-1.68 (m, 2H), 1.57 (br s, 1H), 1.37-1.23 (m, 2H), 0.98 (d, 3H, J=6.4 Hz). LC-MS (ESI, m/z): Calcd. for C11H14ClN3O2, 256.1 (M+H), found 256.1.
Reaction SMILES: BrCCCCC[N:7]1[C:18](=[O:19])[C:17]2[N:15]([CH3:16])[CH:14]=[N:13][C:12]=2[N:10]([CH3:11])[C:8]1=[O:9].C(N(CC)CC)C.[ClH:27]>C1(C)C=CC=CC=1>[ClH:27].[NH:7]1[C:18](=[O:19])[C:17]2[N:15]([CH3:16])[CH:14]=[N:13][C:12]=2[N:10]([CH3:11])[C:8]1=[O:9]
Reactant: Cn1cnc2c1c(=O)n(CCCCCBr)c(=O)n2C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cn1cnc2c1c(=O)[nH]c(=O)n2C

Procedure:
In toluene, 7.9 g of 1-(5-bromo-n-pentyl)theobromine, 5.0 g of N-benzyhydrylpiperazine and 4 g of triethylamine are stirred under reflux for 30 hours. The subsequent treatments are carried out in the same manner as described in Example 96. The obtained crude crystal is converted to a hydrochloride according to customary procedures to obtain 4.7 g of intended 1-}5-[4-benzhydrylpiperazinyl-(1)]-n-pentyl}-theobromine hydrochloride (the yield being 40.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([Cl:12])=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Cc1ccc(N=C=O)cc1Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)Nc2ccc(Cl)c([N+](=O)[O-])c2)cc1Cl

Procedure:
A solution of 29.8 mmol (5 g) of 3-chloro-4-methylphenyl isocyanate in 90 ml of toluene is heated to 70° C., and 29.8 mmol (5.15 g) of 4-chloro-3-nitroaniline are poured in. The solution is heated at reflux for 24 hours. The reaction mixture is cooled using ice, and the precipitate formed is filtered off and then rinsed with diethyl ether to yield the expected product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[NH:32][C:31]4[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=4[N:29]=3)[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].Cl[CH2:45][CH:46]=[C:47]([CH3:49])[CH3:48]>>[CH3:43][O:42][C:38]1[CH:37]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:39]=1[O:40][CH3:41])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[N:29]([CH2:45][CH:46]=[C:47]([CH3:49])[CH3:48])[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[N:32]=3)[CH2:23][CH2:22]2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Reactant: CC(C)=CCCl
Product: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5n4CC=C(C)C)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 35.1 using 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine and 1-chloro-3-methylbut-2-ene to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]([CH3:20])[CH3:19])/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[NH2:21][C:22]1[S:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[S:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=[C:22]1[NH:21][C:13](=[O:15])/[C:12](/[C:4]1[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=1)=[N:16]/[O:17][CH:18]([CH3:20])[CH3:19]
Reactant: Nc1nc2ccccc2s1
Reactant: CC(C)O/N=C(/C(=O)O)c1ccc(S(C)(=O)=O)c(Cl)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)O/N=C(/C(=O)Nc1nc2ccccc2s1)c1ccc(S(C)(=O)=O)c(Cl)c1
Reaction time: 2 h
Yield: 54.2 %

Procedure:
This estimated 80% pure (E)-(3-chloro-4-methanesulfonyl-phenyl)-isopropoxyimino-acetic acid (prepared as in Example 6, 99 mg, 0.31 mmol), 2-aminobenzothiazole (512 mg, 0.34 mmol) and N,N-diisopropylethylamine (162 μL, 0.93 mmol) were combined in acetonitrile (1.25 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (118 mg, 0.31 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/hexanes) to afford (E)-N-benzothiazol-2-yl-2-(3-chloro-4-methanesulfonyl-phenyl)-2-isopropoxyimino-acetamide (76 mg, 54%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C19H18ClN3O4S2 [M+] 451.04, found 452 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.39 (d, J=6.3 Hz, 6 H, 2×CH3), 3.32 (s, 3 H, SO2CH3), 4.65 (m, J=6.3 Hz, 1 H, OCH), 7.36 (brt, J=7.8 Hz, 1H, Ar), 7.49 (brt, J=7.8 Hz, 1H, Ar), 7.64 (dd, Jo=8.2, Jm=1.6 Hz, 1 H, Ar), 7.74 (d, Jm=1.6 Hz, 1 H, Ar), 7.84 (m, 2H, Ar), 8.24 (d, Jo=8.2 Hz, 1 H, Ar), 10.20 (s, 1 H, NH).
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[OH:8][C:9]1[C:16]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][OH:12].[OH-].[K+]>O>[CH3:5][O:8][C:9]1[C:16]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][OH:12]
Reactant: COS(=O)(=O)OC
Reactant: OCc1cccc(Sc2ccccc2Cl)c1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1c(CO)cccc1Sc1ccccc1Cl
Yield: 96.6 %

Procedure:
Dimethyl sulfate (5.7 g) was added to a mixture of 2-hydroxy-3-(2-chlorophenylthio)benzyl alcohol (6 g) and potassium hydroxide (3.8 g) in water (20 ml) in 10 minutes with stirring. The mixture was stirred at 50° C. for 1.5 hours, and the reaction mixture was treated in a similar manner to that of Example 21-(4) to give oily 2-methoxy-3-(2-chlorophenylthio)benzyl alcohol (6.1 g). This product was purified by column chromatography (silica gel 100 g, benzene-ethyl acetate 10:1) to give purified oily substance (5.6 g). This product was identified with the compound obtained in Example 21-(5) by IR and NMR spectrum.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:9](Br)[CH:10]=1)=[O:4].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=1B(O)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:9]([C:20]2[CH:21]=[C:22]([C:25]([F:27])([F:28])[F:26])[CH:23]=[CH:24][C:19]=2[Cl:18])[CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc(OC2CCCC2)c(Br)c1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(OC2CCCC2)c(-c2cc(C(F)(F)F)ccc2Cl)c1
Temperature: 100 °C
Reaction time: 20 h
Yield: 61.4 %

Procedure:
5-Bromo-6-cyclopentyloxy-3-pyridinecarboxylic acid methyl ester (0.33 g, 1.1 mmol) was dissolved in DMF (3.5 mL). To this solution was added [2-chloro-5-(trifluoromethyl)phenyl]-boronic acid (370 mg, 1.6 mmol), palladium(II)acetate (7 mg), triphenylphosphine (18 mg) and triethylamine (0.46 mL). The whole mixture was heated with stirring at 100° C. for 20 h, cooled to room temperature and partitioned between dichloromethane and a mixture of water and concentrated ammonium hydroxide solution (water/ammonia 4:1 v/v). Organic phases were pooled, dried with MgSO4 and the solvent was evaporated. The residue was purified by column chromatography on silica (n-heptane/ethyl acetate 6:1) to yield 0.27 g of the title compound as a light yellow oil, MS (ISP) 400.4 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O.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>[Br:8][C:5]1[CH:4]=[N:3][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:6]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccc(Br)nc1
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: O
Solvent: C1CCOC1
Product: Brc1ccc(-c2ccccc2)nc1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
2,5-Dibromopyridine (0.948 g, 4 mmol), phenylboronic acid (0.488 g, 4 mmol) and tetrakis(triphenylphosphine)palladium (0.116 g, 0.1 mmol) were dissolved in anhydrous tetrahydrofuran (6 mL) and a solution of sodium carbonate (0.848 g, 8 mmol) in water (6 mL) was added. The mixture was put under nitrogen and stirred at 75° C. for 16 h. The mixture was concentrated in vacuo. The residue was dissolved in water (10 mL) and extracted with dichloromethane (3×5 mL). The combined organic extracts were dried with anhydrous sodium sulphate. Column chromatography of the residue (silica gel Fluka 60, hexanes/dichloromethane 1:1) afforded 3-bromo-6-phenylpyridine as a white crystalline product.
Reaction SMILES: [CH2:1]([N:8]1[C:13]2=[N:14][C:15]3[N:16]([CH3:24])[C:17](=[O:23])[N:18]([CH3:22])[C:19](=[O:21])[C:20]=3[N:12]2[C:11]([OH:25])=[C:10]([CH2:26][CH2:27][CH3:28])[C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:32])=[N-]>C(Cl)(Cl)Cl>[CH3:24][N:16]1[C:15]2[N:14]=[C:13]3[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:9](=[O:29])[C:10]([CH2:26][CH2:27][CH3:28])=[C:11]([O:25][CH3:32])[N:12]3[C:20]=2[C:19](=[O:21])[N:18]([CH3:22])[C:17]1=[O:23]
Reactant: C=[N+]=[N-]
Reactant: CCCc1c(O)n2c3c(=O)n(C)c(=O)n(C)c3nc2n(Cc2ccccc2)c1=O
Solvent: ClC(Cl)Cl
Product: CCCc1c(OC)n2c3c(=O)n(C)c(=O)n(C)c3nc2n(Cc2ccccc2)c1=O
Reaction time: 1.5 h

Procedure:
Dissolve 9-benzyl-1,3-dimethyl-6-hydroxy-7-(n-propyl)-pyrimido[2,1-f]purine-2,4,8(1H,3H,9H)-trione (3 g) in 200 ml chloroform at 0° C. and treate with an ethereal solution of diazomethane. Stir the solution at 0° for 1.5 hours and destroy the excess diazomethane by the addition of acetic acid. Wash the chloroform solution with a solution of sodium bicarbonate and remove the chloroform under reduced pressure. Chromatograph the solid obtained on silica gel using 1% methanol in chloroform to give the title compound, mp 199°-201° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:5]=2[CH:4]=1.Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(N(CC)CC)C>CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3[CH2:14][CH2:13][N:12]([CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:5]=2[CH:4]=1
Reactant: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Reactant: ClCCN1CCOCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc2c3c(c(=O)oc2c1)CN(CCN1CCOCC1)CC3
Reaction time: 4 h

Procedure:
A mixture of 10 g (0.043 m) of 1,2,3,4-tetrahydro-8-methoxy-5H-[1]benzopyrano [3,4-c]pyridin-5-one, 11.2 g (0.06 m) of N-(2-chloroethyl)morpholine HCl and 14.2 g of triethylamine (0.14 m) in 170 ml of abs. EtOH was refluxed with stirring and protection from moisture for 4 hours. The reaction was filtered hot, cooled slightly and treated with dry HCl. The resulting precipitate was filtered and washed with EtOH, then ether; yield 14.6 g (81%). Crystallization from methanol afforded analytical material, mp 237°-40° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C@H:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:13]([N+:26]([O-])=O)[CH:12]=2)=[CH:7][CH:6]=1)=[O:4]>[Pd].CO>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C@H:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:13]([NH2:26])[CH:12]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: CCCCCC[C@@H](C)Oc1ccc(-c2ccc(C(=O)OC)cc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CCCCCC[C@@H](C)Oc1ccc(-c2ccc(C(=O)OC)cc2)cc1N
Reaction time: 3 h
Yield: 100 %

Procedure:
A small scoop of 10% Pd/C catalyst was added to a solution of 41c in 15 ml methanol. The flask was evacuated and filled with hydrogen three time. The reaction mixture was stirred three hours under H2 balloon atmosphere and filtered through a pad of celite. Evaporation of solvent yielded 169 mg (100%) of a gray solid. The crude product was used without purification.