Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([CH3:18])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:20]4[N:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH:17]=3)=[C:11]([CH3:18])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2cccc(F)c2)c1-c1c[nH]cn1
Reactant: Clc1ncccn1
Product: Cc1onc(-c2cccc(F)c2)c1-c1cn(-c2ncccn2)cn1
Yield: 72 %

Procedure:
As described for Example 40, 3-(3-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-methyl-isoxazole (100 mg, 0.41 mmol) using 2-chloropyrimidine instead of 4-fluoroacetophenone was converted to the title compound (95 mg, 72%) which was obtained as an off-white solid. MS: m/e=322.4 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)(=[O:12])=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH2:36]O)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH2:36][O:1][C:2]2[CH:3]=[C:4]([O:9][S:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=3)(=[O:12])=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 70.8 %

Procedure:
A solution of 3-trifluoromethylbenzenesulfonic acid 3-hydroxy-5-methylphenyl ester (332 mg, 1.0 mmol), as prepared in the preceding step, N-(tert-butoxycarbonyl)-4-piperidinemethanol (215 mg, 1.0 mmol), as prepared in step f of Example 1, and triphenylphosphine (263 mg, 1.0 mmol) in tetrahydrofuran (10 mL at 0° C. was treated with diethyl azodicarboxylate (175 mg, 1.0 mmol). The reaction mixture was stirred at 0° C. for 2 h and at room temperature for 3 h. Water (50 mL) was added. The reaction mixture was extracted into ethyl acetate (3×50 mL), washed sequentially with saturated NaHCO3 (2×50 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (1:2 ethyl acetate:hexane) to give the title compound as a colorless liquid (375 mg, 70%). 1H-NMR (300 MHz, CDCl3) δ 1.26 (m, 2H), 1.47 (s, 9H), 1.77 (m, 2H), 1.89 (m, 1H), 2.24 (s, 3H), 2.73 (t, 2H), 3.67 (d, 2H), 4.13 (m, 2H), 6.34 (d, 1H), 6.36 (s, 1H), 6.62 (s, 1H), 7.72 (t, 1H), 7.94 (d, 1H), 8.09 (d, 2H).
Reaction SMILES: [C:1]([C@@H:3]([NH:12][C:13]([C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]1C(OC(C)(C)C)=O)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)#[N:2].[Si]([O:35][CH2:36][CH2:37][NH:38][S:39]([C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1)(=[O:41])=[O:40])(C(C)(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].O1CCOCC1>[C:1]([C@@H:3]([NH:12][C:13]([C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][NH:16]1)=[O:14])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:45]2[CH:44]=[CH:43][C:42]([S:39](=[O:40])(=[O:41])[NH:38][CH2:37][CH2:36][OH:35])=[CH:47][CH:46]=2)=[CH:9][CH:10]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@H](C#N)Cc1ccc(I)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCNS(=O)(=O)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: N#C[C@H](Cc1ccc(-c2ccc(S(=O)(=O)NCCO)cc2)cc1)NC(=O)[C@@H]1CCCCN1
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 17.6 %

Procedure:
(S)-tert-Butyl 2-((S)-1-cyano-2-(4-iodophenyl)ethylcarbamoyl)piperidine-1-carboxylate (0.15 g) and bis[1,2-bis(diphenylphosphino)ethane]palladium (0) (2.80 mg, 3.10 μmol) were added to dioxane (3 mL) and 4-(N-(2-(tert-butyldimethylsilyloxy)ethyl)sulfamoyl)-phenylboronic acid (0.167 g) was added to the mixture which was then stirred, under nitrogen, for 10 min. Potassium carbonate (2M solution) (0.310 mL) was added and the reaction mixture was heated at 75° C. for 3 h. The reaction mixture was poured onto a Isolute HM-N cartridge and product was eluted with DCM. Solvent was removed in vacuo and the residue was dissolved in THF (5 mL). The resulting solution was cooled in an ice-bath and TBAF (1M solution in THF, 0.626 mL) was added and stirring was continued for 2 h. The reaction mixture was concentrated in vacuo and dissolved in formic acid (5 mL). The resulting solution was heated at 50° C. for 10 min. The reaction mixture was concentrated in vacuo, dissolved in methanol and loaded onto an SCX cartridge. Non-basic impurities were washed off with methanol then the desired compound was eluted with 10% ammonia in methanol. Solvent was removed in vacuo to give the title compound (0.025 g).
Reaction SMILES: [F:1][C@@H:2]1[C:22]2[C@:17]([CH3:24])([CH:18]=[CH:19][C:20](=[O:23])[CH:21]=2)[C@@H:16]2[C@H:4]([C@H:5]3[C@:13]([CH3:26])([CH2:14][C@@H:15]2[OH:25])[C@@H:8]([C:9](=[O:12])[CH:10]=[O:11])[C@H:7]([CH3:27])[CH2:6]3)[CH2:3]1.CN(C)C=[O:31].FCCO.[C-]#N.[K+]>[O-2].[Mn+4].[O-2].C(O)(=O)C>[F:1][C@@H:2]1[C:22]2[C@:17]([CH3:24])([CH:18]=[CH:19][C:20](=[O:23])[CH:21]=2)[C@@H:16]2[C@H:4]([C@H:5]3[C@:13]([CH3:26])([CH2:14][C@@H:15]2[OH:25])[C@@H:8]([C:9](=[O:12])[C:10]([OH:31])=[O:11])[C@H:7]([CH3:27])[CH2:6]3)[CH2:3]1
Reactant: CN(C)C=O
Reactant: C[C@@H]1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@H]1C(=O)C=O
Agent: [Mn+4]
Agent: OCCF
Agent: [C-]#N
Solvent: CC(=O)O
Product: C[C@@H]1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@H]1C(=O)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1.4 g. of 6α-fluoro-11β-hydroxy-3,20-dioxo-16α-methyl-1,4-pregnadien-21-al is dissolved in 14 ml. of dimethylformamide and combined with 5 ml. of 2-fluoroethanol, 1.4 ml. of concentrated acetic acid, 2.8 g. of active manganese (IV) oxide, and 225 mg. of potassium cyanide. The reaction mixture is agitated for 10 minutes at room temperature and then filtered off from the manganese (IV) oxide. The filtrate is poured into water and extracted with dichloromethane. The organic phase is washed with water, dried with sodium sulfate, and concentrated under vacuum. The residue is chromatographed on silica gel. With 31-33% acetone-hexane, after recrystallization from acetone/hexane, 630 mg. of the 2-fluoroethyl ester of 6α-fluoro-11β-hydroxy-3,20-dioxo-16α-methyl-1,4-pregnadien-21-oic acid is obtained; m.p. 188.0° C. [α]D25 = +141° (chloroform). UV: ε242 = 16,900 (methanol)
Reaction SMILES: C(OC1C(NC([C@H]2N3C(=O)[C@@H](NC(=O)C4C=CC=CC=4)CC=CC[C@H]3CCC2)=O)CC(=O)O1)C.C(OC(=O)NC1CC(=O)OC1OCC)C=C.[C:51]([NH:59][C@@H:60]1[C:67](=[O:68])[N:66]2[C@H:69]([C:73]([OH:75])=[O:74])[CH2:70][CH2:71][CH2:72][C@H:65]2[CH2:64][CH:63]=[CH:62][CH2:61]1)(=[O:58])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.CCOC(C)=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>[C:51]([NH:59][C@@H:60]1[C:67](=[O:68])[N:66]2[C@H:69]([C:73]([OH:75])=[O:74])[CH2:70][CH2:71][CH2:72][C@@H:65]2[CH2:64][CH:63]=[CH:62][CH2:61]1)(=[O:58])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: O=C(N[C@H]1CC=CC[C@@H]2CCC[C@@H](C(=O)O)N2C1=O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=CCOC(=O)NC1CC(=O)OC1OCC
Agent: CCOC1OC(=O)CC1NC(=O)[C@@H]1CCC[C@@H]2CC=CC[C@H](NC(=O)c3ccccc3)C(=O)N21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1CC=CC[C@H]2CCC[C@@H](C(=O)O)N2C1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Preparation of (4S,7S,11aR)-7-benzoylamino-6-oxo-1,3,4,6,7,8,11,11a-octahydro-2H-pyrido[1,2-a]azocine-4-carboxylic acid (2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-amide (45) A catalytic amount of Pd(Ph3P)4 (35 mg, 0.03 mmol) is added to a solution of (2-Ethoxy-5-oxo-tetrahydrofuran-3-yl)-carbamic acid allyl ester (69 mg, 0.3 mmol) and N,N-dimethylbarbituric acid (156 mg, 1.0 mmol) in 2 mL CH2Cl2 at room temperature. The solution is stirred at rt for 15 minutes and (4S,7S,11aS)-7-benzoylamino-6-oxo-1,3,4,6,7,8,11,11a-octahydro-2H-pyrido[1,2-a]azocine-4-carboxylic acid, 44, (40 mg, 0.12 mmol) is added as a solution in 1 mL CH2Cl2, followed by 1-hydroxybenzotriazole (41 mg, 0.3 mmol) and 1-(3-dimethyl-aminopropyl)-3-ethyl-carbodiimide hydrochloride (58 mg, 0.3 mmol). The solution is stirred for 4 hours, diluted with EtOAc, washed with saturated NaHCO3 and brine, dried (MgSO4), and concentrated in vacuo. Purification by flash chromatography over silica gel afforded 32 mg of the desired product. 1H NMR (CDCl3) δ 7.88 (m, 2H), 7.72 (m, 1H), 7.51 (m, 3H), 5.75–5.25 (series of m, 4H), 5.02 (d, J=5.8 Hz, 1H), 4.66 (m, 2H), 3.98 (dq, J=9.3, 7.0 Hz, 1H), 3.73 (dq, J=9.3, 7.0 Hz, 1H), 3.24 (m, 1H), 2.96–1.45 (series of m, 11H), 1.37 (t, J=7.0 Hz, 3H); MS 470 (M+H)+.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:38])[CH2:4][C@@:5]1([C:22]2[S:23][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]4[O:37][CH:36]=[N:35][CH:34]=4)=[CH:29][CH:28]=3)=[CH:25][CH:26]=2)[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][N:8]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[O:15])[CH2:7][CH2:6]1.[ClH:39].CO>CO>[ClH:39].[OH:1][NH:2][C:3](=[O:38])[CH2:4][C:5]1([C:22]2[S:23][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]4[O:37][CH:36]=[N:35][CH:34]=4)=[CH:29][CH:28]=3)=[CH:25][CH:26]=2)[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][N:8]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[O:15])[CH2:7][CH2:6]1
Reactant: O=C(C[C@]1(c2ccc(-c3ccc(-c4cnco4)cc3)s2)CCN(C(=O)c2ccccn2)CCS1(=O)=O)NO
Agent: Cl
Solvent: CO
Product: O=C(CC1(c2ccc(-c3ccc(-c4cnco4)cc3)s2)CCN(C(=O)c2ccccn2)CCS1(=O)=O)NO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-hydroxy-2-[(S)-7-(5-(4-(5-oxazolyl)phenyl)-2-thienyl)-4-(2-pyridinecarbonyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (118 mg) in methanol (3 ml) was added 10% hydrochloric acid-methanol solution (5 ml) and the mixture was stirred at ambient temperature for 0.5 hour. After evaporation of solvent, the residue was triturated with isopropyl ether to give N-hydroxy-2-[7-(5-(4-(5-oxazolyl)phenyl)-2-thienyl)-4-(2-pyridinecarbonyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide hydrochloride as a pale yellow amorphous powder (119 mg).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][C:6]([C@@H:9]([NH2:11])[CH3:10])=[N:7][CH:8]=1.Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[NH:22][N:21]=2)[C:16]([N+:28]([O-:30])=[O:29])=[CH:15][N:14]=1.CCN(C(C)C)C(C)C>CCCCO>[N+:28]([C:16]1[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[NH:22][N:21]=2)=[N:18][C:13]([NH:11][C@H:9]([C:6]2[N:7]=[CH:8][C:3]([F:2])=[CH:4][N:5]=2)[CH3:10])=[N:14][CH:15]=1)([O-:30])=[O:29]
Reactant: C[C@H](N)c1ncc(F)cn1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)n1)c1ncc(F)cn1
Temperature: 60 °C
Yield: 77.9 %

Procedure:
A 20 mL round bottom flask was charged with (S)-1-(5-Fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 0.25 g, 1.77 mmol), 2-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-nitropyrimidin-4-amine (Method 37, 0.3 g, 1.0 mmol), and DIEA (0.30 g, 2.34 mmol). Anhydrous n-BuOH (5 mL) was added, and the flask was heated at 60° C. for 4 hours. The reaction mixture was washed with brine (5 mL×3), and the organic layer was dried and concentrated. The resulting residue was separated by silica gel column to afford desired product (0.3 g, 75%). LC-MS, 386 (M+1). 1H NMR (DMSO-d6) δ 12.3 (s, 1H), 10.5 (s, 1H), 9.1 (s, 1H), 9.0 (s, 1H), 8.80 (s, 2H), 6.1 (s, 1H), 5.2 (dd, 1H), 2.0 (m, 1H), 1.7 (d, 3H), 1.0 (m, 2H), 0.8 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][C:16]2[CH:18]=[C:19](Br)[CH:20]=[N:21][C:15]=2[NH:14][C:13](=[O:23])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[CH:25]=[CH2:26].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][C:16]2[CH:18]=[C:19](/[CH:26]=[CH:25]/[C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:20]=[N:21][C:15]=2[NH:14][C:13](=[O:23])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: O=C1CN(C(=O)OCc2ccccc2)Cc2cc(Br)cnc2N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCC#N
Product: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)CN(C(=O)OCc1ccccc1)CC(=O)N2
Reaction time: 0.33 h
Yield: 52.3 %

Procedure:
A suspension of 7-bromo-2-oxo-1,2,3,5-tetrahydro-pyrido[2,3-e][1,4]diazepine-4-carboxylic acid benzyl ester (0.52 g, 1.4 mmol) in propionitrile (10 mL) and DMF (3 mL) was de-oxygenated with Ar for 20 min. The mixture was treated with tert-butyl acrylate (0.83 mL, 10 mmol) and (i-Pr)2EtN (0.50 mL, 2.9 mmol) and was de-oxygenated with Ar for 10 min. Pd(OAc)2 (34 mg, 0.15 mmol) and P(o-tol)3 (84 mg, 0.27 mmol) were added simultaneously, and the mixture was de-oxygenated a third time for 5 min. The mixture was heated to reflux overnight, then allowed to cool. The resulting precipitate was isolated by filtration, washed with EtOAc and dissolved in CH2Cl2. The solution was filtered through Celite and the solvent was removed in vacuo to give the title compound (0.31 g, 53%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ 8.49-8.57 (m, 1H), 8.30 (s, 1H), 7.43-7.73 (m, 2H), 7.33 (s, 4H), 7.17-7.18 (m, 1H), 6.21-6.40 (m, 1H), 5.05-5.11 (m, 2H), 4.46-4.68 (m, 4H), 1.54-1.57 (m, 9H); MS (ESI) m/e 424 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH2:18][OH:19])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([CH3:13])[CH:6]=1.[H-].[Na+].Cl[C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[CH2:31][CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>CN(C=O)C>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][O:19][C:23]2[CH:24]=[C:25]3[N:32]([CH3:33])[CH2:31][CH2:30][N:26]3[C:27](=[O:29])[N:28]=2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([CH3:13])[CH:6]=1
Reactant: Cc1cc(Oc2ccc(CO)cc2F)ccc1C#N
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(COc3cc4n(c(=O)n3)CCN4C)cc2F)ccc1C#N

Procedure:
Prepared in a manner similar to that described for E1 using 4-(2-fluoro-4-(hydroxymethyl)phenoxy)-2-methylbenzonitrile (1.00 g, 3.89 mmol) in DMF (10 mL), sodium hydride (0.280 g, 11.7 mmol) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]p-yrimidin-5(1H)-one (0.721 g, 3.89 mmol).
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]2[CH:13]=[C:12]([CH2:14][O:15][Si](C(C)(C)C)(C)C)[CH:11]=[CH:10][N:9]=2)=[N:4][CH:3]=1.[SH:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30]([O:32]C)=[O:31])[CH:25]=1.C[O-].[Na+].[OH-].[Na+].Cl>CO.CN(C)C=O>[OH:15][CH2:14][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:5]2[S:6][C:2]([S:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([C:30]([OH:32])=[O:31])[CH:25]=3)=[CH:3][N:4]=2)[CH:13]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccnc(Nc2ncc(Br)s2)c1
Reactant: COC(=O)c1cc(S)ccn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(O)c1cc(Sc2cnc(Nc3cc(CO)ccn3)s2)ccn1
Temperature: 65 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
A solution of 5-bromo-N-(4-((tert-butyldimethylsilyloxy)methyl)pyridine-2-yl)thiazol-2-amine (0.907 g, 2.27 mmol, described in the synthesis of bromides or thioisocyanates, Example A) in methanol (15 mL) was treated with the previously prepared solution of methyl 4-mercaptopicolinate in N,N-dimethylformamide and sodium methoxide (1.47 mL, 25% in MeOH, 6.3 mmol). The reaction was stirred at 65° C. for 1 hour. The solvent was then evaporated and the residue was dissolved in ethyl acetate/tetrahydrofuran. The reaction was acidified with 1N hydrochloric acid and the solvents were evaporated. The crude residue was then diluted in methanol (10 mL) and treated with sodium hydroxide (5N, 4.5 mL, 22.7 mmol) at 23° C. and the reaction was stirred overnight. The reaction was then acidified with 1N hydrochloric acid and the solvent was evaporated. The residue was dissolved in N,N-dimethylformamide (8 mL) and precipitated by addition of water. This was allowed to stand at 0° C. The solid was then filtered and dried under high vacuum to give the title material (0.411 g, 50%) as a solid. LC/MS (M+H)+: 361. HPLC ret. time (Condition B): 1.067 min.
Reaction SMILES: N.[OH:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[Na]>C(O)C>[CH3:14][O:13][C:10]1[CH2:11][CH:12]=[C:7]([CH2:6][CH2:5][CH2:4][CH2:3][OH:2])[CH2:8][CH:9]=1
Reactant: COc1ccc(CCCCO)cc1
Agent: N
Agent: [Na]
Solvent: CCO
Product: COC1=CCC(CCCCO)=CC1
Reaction time: 0.17 h

Procedure:
Ammonia (75 mL) is liquified in a flask at -40° and a solution of 5 g (28 mmol) of p-(4-hydroxybutyl)anisole in 25 mL ethanol is added. 2.76 g (0.12 mmol) of sodium is added in small pieces over 1 hour. The blue solution is then stirred at -40° for 10 minutes during which time the solution decolorizes with the formation of a white precipitate. The reaction is quenched using 5.88 g solid ammonium chloride followed by 25 mL water. The solvent is evaporated under a stream of nitrogen and then poured into brine and extracted with ether (4×100 mL). The organic extracts are combined, dried, filtered and subjected to evaporation to give 1-methoxy-4-(4-hydroxybutyl)cyclohexa1,4-diene as an oil.
Reaction SMILES: [CH2:1]([CH2:8][Si:9]([C:12]([Si](CCC1C=CC=CC=1)(C)C)=O)([CH3:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH3-])#[N:26].[Na+].C([O-])(=O)C.[NH4+].[OH-].[Na+]>CO>[CH3:10][Si:9]([CH3:12])([CH3:11])[CH:8]([NH2:26])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: C[Si](C)(CCc1ccccc1)C(=O)[Si](C)(C)CCc1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: C[Si](C)(C)C(N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of benzyltrimethylsilylketone (1.40 g, 7.3 mmol) of sodium cyanoborohydride (0.321 g, 5.1 mmol) and ammonium acetate (5.93 g, 73 mmol) in anhydrous methanol (25 ml) was stirred at room temperature for 48 hours. The mixture was poured into 2N sodium hydroxide (20 ml) and extracted with diethyl ether (3×100 ml). The organic phase was dried over anhydrous magnesium sulphate. Trituration, removal of the solvent, inuacuo, and chromatography from silica gel (ethyl acetate/cyclohexane 1:1) yielded the crude α-(trimethylsilyl)benzeneethanamine which was directly converted to the product of this step using 1 equivalent of (BOC)2O in THF. Rf: 0.74 (ethyl acetate/cyclohexane 1:1)
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([Cl:22])=[C:7]([N+:19]([O-])=O)[CH:8]=[CH:9][C:10]=1[S:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:3])[CH3:2].O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.[Zn]>[C:1]([NH:4][C:5]1[C:6]([Cl:22])=[C:7]([CH:8]=[CH:9][C:10]=1[S:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[NH2:19])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(Sc2ccc(F)cc2)ccc([N+](=O)[O-])c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(Sc2ccc(F)cc2)ccc(N)c1Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
A mixture of 3-acetamido-2-chloro-4-(4-fluorophenylsulphanyl)nitrobenzene (Method 15) (0.1 g), ferric chloride hexahydrate (0.238 g) and zinc dust (0.192 g in DMF (1 ml) and water (1 ml) was stirred and heated (oil bath 100° C.) for 1 hour then cooled. Water (15 ml) was added and the mixture was basified to pH 11 with saturated aqueous sodium carbonate solution (3 ml) then extracted with DCM (3×15 ml). The extracts were washed with brine then dried. Volatile material was removed by evaporation and the residue was left under high vacuum (2 mm Hg) overnight to give the title compound (0.087 g) as a solid. NMR: 1.95 (s, 3H), 5.72 (brs, 2H), 6.73 (d, 1H), 7.05-7.20 (m, 5H), 9.54 (brs, 1H); m/z: 309.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)#[N:2].[NH4+].[OH-:13]>S(=O)(=O)(O)O>[NH:5]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:11]2[C:3]([C:1]([NH2:2])=[O:13])=[CH:4]1
Reactant: N#Cc1c[nH]c2ncccc12
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: NC(=O)c1c[nH]c2ncccc12
Yield: 91 %

Procedure:
A solution of 3-cyano-7-azaindole (3 g, 20.98 mmol) in concentrated sulfuric acid (50 mL) was stirred at room temperature for 1 h. The solution was slowly poured into ice and basified with concentrated NH4OH. The solution was concentrated under reduced pressure to produce brown residue which was extracted with acetone (4×100 mL). The organic extracts were dried and concentrated under reduced pressure to give title compound as a brown solid (3 g, 91%); Mass Spec.; MS 162 (M+1); 1H NMR (DMSO-d6; 500 MHz) 8.44(dd,1H),8.25(dd,1H), 8.14(s,1H), 7.45(brs,1H), 7.15(dd, 1H), 6.89(brs,1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](Cl)=[O:25])=[CH:19][CH:18]=1>ClCCl>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:25])=[CH:19][CH:18]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: Oc1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(Cl)cc1)Oc1ccc(Br)cc1
Temperature: 10 °C
Reaction time: 8 h

Procedure:
A cooled (10° C.) stirred solution of 4-bromophenol (3 g) and triethylamine (2.5 ml) in dichloromethane (100 ml) was treated with 4-chlorophenylacetyl chloride (3.3 g) in dichloromethane (50 ml). The mixture was stirred at room temperature overnight. The solution was washed with water, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography to give 4-bromophenyl 4-chlorophenylacetate.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:14])[NH:4][C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10](OC)=[O:11].CN(C)C=O.C(O)(=O)C>[OH-].[K+]>[CH3:1][N:2]1[C:10](=[O:11])[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[NH:4][C:3]1=[O:14]
Reactant: CNC(=O)Nc1ccsc1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cn1c(=O)[nH]c2ccsc2c1=O
Reaction time: 0.5 h

Procedure:
Methyl 3-(N'-methylureido)thiophene-2-carboxylate (4,2 g, 20 mmol) was suspended with stirring in 5% aqueous potassium hydroxide (50 ml). Dimethylformamide was added until a clear solution was obtained. Stirring was continued for 30 min, whereafter the solution was neutralized with acetic acid. This afforded a crystalline precipitate of the title compound, which was separated by filtration and washed with water. M.p.>300° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:10]([C:19]#[N:20])[CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:6]=[CH:7][C:8]=1[Cl:9].[C:21](Cl)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[C:5]([CH:10]([C:19]#[N:20])[CH2:11][CH2:12][CH:13]2[CH2:14][CH2:15][N:16]([C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:17][CH2:18]2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: N#CC(CCC1CCNCC1)c1ccc(Cl)c(Cl)c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CC(CCC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Reaction time: 2 h
Yield: 96.5 %

Procedure:
25 g of 1-(3,4-dichlorophenyl)-3-(4-piperidinyl)-1-cyanopropane hydrochloride (Example 1B) are dissolved in 400 ml of CH2Cl2. 22 g of trityl chloride and 21 ml of triethylamine are added dropwise to the solution. The reaction mixture is left for 2 hours without stirring, and washed successively with H2O, an aqueous solution buffered to pH=2, and a solution saturated with NaCl. It is dried over MgSO4 and evaporated. The residue is chromatographed on silica gel, eluent: heptane/ethyl acetate 9:1 (v/v). 39 g of oil are obtained.