Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[S:34](Cl)(=[O:36])=[O:35]>N.CO>[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[S:34]([N:11]1[C:12]2[C:8](=[C:7]3[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]3=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)(=[O:36])=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Reactant: O=S(=O)(Cl)c1cccs1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=S(=O)(c1cccs1)n1ccc2c3c(ccc21)OCCNC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. Thiophene-2-sulfonyl chloride (18 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (10.2 mg). MS m/z 335 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[OH:27][CH:28]([CH2:41][OH:42])[CH2:29][NH:30][C:31]([C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1)=[O:32]>>[OH:27][CH:28]([CH2:41][OH:42])[CH2:29][NH:30][C:31](=[O:32])[C:33]1[CH:40]=[CH:39][C:36]([C:37]2[NH:10][C:9]3[CH:8]=[CH:7][C:6]([NH:13][C:14](=[O:26])[C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH2:25][CH2:24][CH2:23][CH2:22]5)=[CH:17][CH:16]=4)=[CH:5][C:4]=3[N:1]=2)=[CH:35][CH:34]=1
Reactant: O=Cc1ccc(C(=O)NCC(O)CO)cc1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCCC2)cc1
Product: O=C(NCC(O)CO)c1ccc(-c2nc3cc(NC(=O)c4ccc(N5CCCC5)cc4)ccc3[nH]2)cc1

Procedure:
Compound 229 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-pyrrolidinylbenzamide and 4-(2,3-dihydroxypropyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C28H29N5O4: 500.23; found: 500.56.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[C:16]([F:23])[CH:15]=2)[CH2:10][CH:9]1[CH2:24][O:25][CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[OH-].[OH-].[Pd+2].CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:15]=[C:16]([F:23])[CH:17]=[C:18]([NH2:20])[CH:19]=2)[CH2:10][CH:9]1[CH2:24][O:25][CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: COCC1CC(Oc2cc(F)cc([N+](=O)[O-])c2)CN1C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COCC1CC(Oc2cc(N)cc(F)c2)CN1C(=O)OC(C)(C)C

Procedure:
A mixture of 23 g of 4-(3-fluoro-5-nitro-phenoxy)-2-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (7), 100 mL MeOH and 2 g of Pd(OH)2/C was stirred for 2 hours under a 50 psi hydrogen atmosphere. The mixture was filtered off through a pad of diatomaceous earth and concentrated to give a quantitative yield of 4-(3-amino-5-fluoro-phenoxy)-2-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (8).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[N:20]=[N:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:25][C:26]1([NH2:30])[CH2:29][O:28][CH2:27]1>>[CH3:25][C:26]1([NH:30][C:21]([C:18]2[N:19]=[N:20][C:15]([O:14][CH2:13][C:12]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:9]=[N:10][C:11]=3[CH3:24])=[CH:16][CH:17]=2)=[O:23])[CH2:29][O:28][CH2:27]1
Reactant: CC1(N)COC1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)nn1
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)NC2(C)COC2)nn1
Yield: 94 %

Procedure:
As described for example 75b, 6-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyridazine-3-carboxylic acid (85 mg, 0.26 mmol), was converted, using 3-methyl-3-oxetanamine instead of isopropylamine, to the title compound (96 mg, 94%) which was obtained as a light yellow solid. MS: m/e=399.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[S:15][C:14]([NH2:16])=[N:13][CH:12]=1.[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:16][C:14]1[S:15][C:11]([C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:12][N:13]=1)=[O:21]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Cn1c(-c2cnc(N)s2)cc2ccccc21
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1c(-c2cnc(NC(=O)c3ccccc3Cl)s2)cc2ccccc21
Reaction time: 8 h
Yield: 97 %

Procedure:
To a mixture of 5-(1-methylindol-2-yl)-1,3-thiazole-2-ylamine (53, 10 mg, 0.043 mmol) in 1 ml DCM were added 2-chlorobenzoyl chloride (11 μl, 2 eq), DIEA (37 μl, 3 eq) and DMAP (2 mg). After stirred at r.t for overnight, the reaction mixture was worked up with DCM/aq. NaCO3, the DCM phase was concentrated to dryness. The solid residue was dissolved in 2 ml THF/MeOH/H2O (5:4:1). 0.1 ml of 1N NaOH were added and mixture was stirred at r.t for 1 h before worked up DCM//aq. NaCO3. DCM phase was concentrated and subjected to silica gel flash column to give 15.3 mg of (2-chlorophenyl)-N-[5-(1-methylindol-2-yl)(1,3-thiazol-2-yl)]carboxamide (54) as yellow solid (yield: 97%; purity>95%). LC-MS: calcd. for C18H14ClN3OS: 368 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:21][N:22]([CH2:26][C:27]([O-:29])=[O:28])[C:23]([NH2:25])=[NH:24].[K+]>>[C:1]([O:28][C:27](=[O:29])[CH2:26][N:22]([CH3:21])[C:23]([NH2:25])=[NH:24])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CN(CC(=O)[O-])C(=N)N
Agent: [K+]
Product: CCCCCCCCCCCCCCCCCC(=O)OC(=O)CN(C)C(=N)N
Temperature: 0 °C

Procedure:
Finally, in a dry 2-necked, round bottomed flask, fixed with a separatory funnel, containing 21.27 g (70 mmol) of the prepared stearoyl chloride, and side arm water condenser fixed with a dry receiving flask, is placed 23.40 g (77 mmol) of potassium 2-(1-methylguanidino)acetate. The round bottomed flask is placed in an ice bath and the stearoyl chloride is added drop wise. After addition is completed the mixture is shaken and the ice bath is replaced by a heating mantle. The flask is then heated until no more solution is dropping into the receiving flask. This crude distillate is then further fractionally distilled to yield 2-(1-methylguanidino)acetic stearic anhydride.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[NH:8][C:9](=[O:17])[C:10]([C:15]#[N:16])=[C:11](SC)[N:12]=2)=[CH:4][CH:3]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[NH:8][C:9](=[O:17])[C:10]([C:15]#[N:16])=[C:11]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: CSc1nc(Cc2ccc(Cl)cc2)[nH]c(=O)c1C#N
Reactant: C1CCNC1
Product: N#Cc1c(N2CCCC2)nc(Cc2ccc(Cl)cc2)[nH]c1=O

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.34 mmol) of 2-(4-chlorobenzyl)-4-(methylsulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are reacted with 244 mg (3.43 mmol) of pyrrolidine to give 45 mg (42% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]2=1.CCCCC.[H-].[Na+].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:28][C:27]1[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=1)[C:10]1[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]2=1
Reactant: O=C1CCCc2[nH]c3ccc(Cl)cc3c21
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: O=C1CCCc2c1c1cc(Cl)ccc1n2Cc1ccc(F)cc1
Reaction time: 0.33 h
Yield: 93.5 %

Procedure:
6-Chloro-1,2,3,9-tetrahydro-4H-carbazol-4-one (0.4042 g, 0.0018 mol) is added to a slurry of pentane-washed NaH (0.091 g, 0.0023 mol) in DMF (2 mL) and after stirring for 20 min, p-fluorobenzyl bromide (0.28 mL, 0.0023 mol) is added. Additional DMF (1 mL) is added and the mixture is stirred for 4 h, at which time the mixture is partitioned between aq. sodium bicarbonate and ethyl acetate. The combined organic layers are washed with water, dried over sodium sulfate and concentrated to dryness. The resulting solids are chromatographed on silica gel (200 mL) using dichloromethane/heptane (60/40 and 80/20) to give 0.5519 g (92%) of the title compound; mp 207-207.75° C.; MS (ESI+) for C19H15ClFNO m/z 328.1 (M+H)+; IR (drift) 1628, 1511, 1467, 1448, 1360, 1226, 1218, 1145, 1096, 878, 849, 840, 804, 764, 649 cm−1; 1H NMR (CDCl3) δ2.23, 2.58, 2.86, 5.27, 6.99, 7.16, 8.27. Anal. Calcd for C19H15ClFNO: C, 69.62; H, 4.61; N, 4.27. Found (av): C, 69.08; H, 4.50; N, 4.26.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]([C:9]1[C:14]([CH2:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:17])[CH2:6][CH:7]=O)=[O:4].Cl.[NH2:19][OH:20].C(=O)(O)[O-].[Na+]>C(O)C>[Cl:1][CH2:2][C:3]([N:5]([C:9]1[C:14]([CH2:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:17])[CH2:6][CH:7]=[N:19][OH:20])=[O:4]
Reactant: CCc1cccc(C)c1N(CC=O)C(=O)CCl
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCc1cccc(C)c1N(CC=NO)C(=O)CCl
Yield: 51.2 %

Procedure:
A solution of 5 g (0.2 mol) alpha-(N-chloroacetyl-2-methyl-6-ethylphenylamino)acetaldehyde, 3.3 g (0.04 mol) hydroxylamine hydrochloride and 3.4 g (0.04 mol) sodium bicarbonate in 50 ml ethanol was heated at 40° C. for 40 minutes. The reaction mixture was filtered, evaporated under reduced pressure, diluted with ethyl ether, filtered again and evaporated under reduced pressure to give 5.5 g of a yellow oil which crystallized to a solid on standing. The crude solid was recrystallized from ethyl ether/hexane to give 3.2 g of the product as a white solid, m.p. 113°-115° C. The product is tabulated in Table I as Compound No. 12.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][CH:22]=[N:23][C:24]=2[NH2:28])(=[O:3])[CH3:2].P([O-])([O-])([O-])=O.C(=O)(O)[O-].[Na+]>>[C:1]([O:4][C@H:5]1[C@H:9]([OH:10])[C@@H:8]([CH2:14][OH:15])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][CH:22]=[N:23][C:24]=2[NH2:28])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: CC(=O)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)ncnc21

Procedure:
To a stirred suspension of 500 mg. of 9-(2,3,5-tri-O-acetyl-β-D-arabinofuranosyl)adenine (U.S. Pat. No. 3,651,045, supra) in 50 ml. of a 0.1 M pH 7 phosphate buffer is added 500 mg. of Bacillus subtilis ATCC 6633 cell paste or lyophilizate (U.S. Pat. No. 3,304,236, Example 9) and the mixture is stirred for 22 hours at 35°-40° C., with periodic addition of saturated aqueous sodium bicarbonate to maintain the pH at 7.0 to 7.5. The incubated mixture is then poured into 150 ml. of methanol and the resulting mixture is filtered through diatomaceous earth and the filtrate evaporated at reduced pressure. The residue is passed through a 1×30 cm. column of dry silica gel, and the column is eluted sequentially with 5:95, 10:90 and 20:90 (v/w) methanol-chloroform. The eluate is collected in 10-ml. fractions and those that contain the desired product, as established by thin layer chromatography, are combined and evaporated at reduced pressure to give the desired product 9-(2-O-acetyl-β-D-arabinofuranosyl)adenine; λmaxCH3OH =259 nm. The structure is confirmed by nmr spectra.
Reaction SMILES: [CH3:1][CH:2]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=1)=[O:4].Cl.ClC1C=C(C(=O)C(NC(C)(C)C)C)C=CC=1.C(N(CC)CC)C.[NH2:41][S:42]([C:45]1[C:46]([Cl:74])=[CH:47][C:48]([NH:67][CH2:68][C:69]2[O:70][CH:71]=[CH:72][CH:73]=2)=[C:49]([CH:66]=1)[C:50]([O:52][CH2:53][CH2:54][CH2:55][O:56][C:57](=[O:65])[CH2:58][CH2:59][C:60]([O:62][CH2:63]Cl)=[O:61])=[O:51])(=[O:44])=[O:43]>C(#N)C>[NH2:41][S:42]([C:45]1[C:46]([Cl:74])=[CH:47][C:48]([NH:67][CH2:68][C:69]2[O:70][CH:71]=[CH:72][CH:73]=2)=[C:49]([CH:66]=1)[C:50]([O:52][CH2:53][CH2:54][CH2:55][O:56][C:57](=[O:65])[CH2:58][CH2:59][C:60]([O:62][CH2:63][N:12]([C:13]([CH3:15])([CH3:14])[CH3:16])[CH:2]([CH3:1])[C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=1)=[O:4])=[O:61])=[O:51])(=[O:43])=[O:44]
Reactant: NS(=O)(=O)c1cc(C(=O)OCCCOC(=O)CCC(=O)OCCl)c(NCc2ccco2)cc1Cl
Reactant: CC(NC(C)(C)C)C(=O)c1cccc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C(=O)c1cccc(Cl)c1)N(COC(=O)CCC(=O)OCCCOC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1NCc1ccco1)C(C)(C)C

Procedure:
A solution of bupropion[1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride (700), (U.S. Pat. No. 3,819,706 and U.S. Pat. No. 3,885,046) (0.025 mole), triethylamine (0.055 mole) and acetonitrile (30 mL) is stirred with cooling on an ice bath. A solution of chloromethyl 4-(3-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxy)propoxy)(4-oxo)butanoate (0.025 mole) in acetonitrile (30 mL) is added dropwise. After the addition is complete, the reaction is heated to reflux for 2 hours. The reaction is cooled, the volatiles removed by spin evaporation, and the residue partitioned between dichloromethane and 5% aqueous sodium bicarbonate. The organic layer is washed with water, and then with a saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which may be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give a solid that may be recrystallized to give 2-[(4-(3-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxy)propoxy)(4-oxo)butanoyloxymethyl)(1,1-dimethylethyl)amino]-1-(3-chlorophenyl)-1-propanone (920). See eg., U.S. Pat. No. 5,104,870 and Sandler, et al., Organic Functional Group Preparations, p. 324 (1968).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:36]1[N:37]=[CH:38][S:39][CH:40]=1)CCC>CN(C=O)C.C(OCC)(=O)C.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.[Cu]I>[OH:29][C@@H:24]1[C@@H:23]([N:13]2[C:12](=[O:30])[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]4=[C:9]([CH2:8][C:5]4[CH:6]=[N:7][C:2]([C:36]5[N:37]=[CH:38][S:39][CH:40]=5)=[CH:3][CH:4]=4)[CH:10]=3)[N:15]=[CH:14]2)[CH2:28][CH2:27][O:26][CH2:25]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1c2cc(Cc3ccc(-c4cscn4)nc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Temperature: 50 °C
Reaction time: 6 h

Procedure:
To a solution of 6-[(6-chloropyridin-3-yl)methyl]-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one (Example 1, 0.100 g, 0.237 mmol) in 1 mL of DMF under an atmosphere of nitrogen was added 4-(tributylstannyl)-1,3-thiazole (0.111 g, 0.296 mmol), tetrakis(triphenylphosphine)palladium(0) (0.055 g, 0.047 mmol), and copper(I) iodide (0.018 g, 0.095 mmol). The reaction was heated at 50° C. for 15 h, and then at 140° C. for an additional 6 h. The mixture was cooled to rt, diluted with ethyl acetate, and washed with brine and water. The solution was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 471.1478 for [M+H]+ [Calc'd for C26H23N4O3S, [M+H]+=471.1485]: 1H NMR (400 MHz, CD3OD) δ 9.18 (s, 1H), 9.01 (d, J=8.1 Hz, 1H), 8.62 (s, 1H), 8.58 (s, 1H), 8.54 (s, 1H), 8.39 (d, J=8.4 Hz, 1H), 8.32-8.30 (m, 1H), 8.08 (d, J=8.1 Hz, 1H), 7.98 (s, 1H), 7.76-7.68 (m, 2H), 4.72 (s, 2H), 4.72-4.66 (m, 1H), 4.36-4.24 (m, 1H), 4.09-3.99 (m, 2H), 3.53 (t, J=10.1 Hz, 1H), 3.23 (t, J=10.2 Hz, 1H), 2.36-2.34 (m, 1H), 2.00-1.95 (m, 1H).
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:6]=[C:7]([C:11](=[O:13])[CH3:12])[CH:8]=[N:9][CH:10]=1>O1CCCC1>[Br:4][C:5]1[CH:6]=[C:7]([C:11]([OH:13])([CH3:1])[CH3:12])[CH:8]=[N:9][CH:10]=1
Reactant: CC(=O)c1cncc(Br)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(O)c1cncc(Br)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Methyl magnesium bromide (5.3 mL, 0.075 mol) was added to a stirred solution of 1-(5-bromopyridin-3-yl)ethanone (1.0 g, 0.05 mol) in tetrahydrofuran (20.0 mL), cooled to 0° C. and the resulting mixture was allowed to warm to room temperature and stirred for 1.5 h. The reaction mixture was quenched with 1N hydrochloric acid (20 mL) and extracted with ethyl acetate (2×75 mL). The combined organic layers were dried over sodium sulphate and concentrated under vacuum to afford the crude compound which was purified by column chromatography to obtain 2-(5-bromopyridin-3-yl)propan-2-ol. MS (M+1): 217.1.
Reaction SMILES: [C:1]([O:11][CH2:12][C:13]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[C:15]([N+:22]([O-])=O)[CH:14]=1)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[H][H]>>[C:1]([O:11][CH2:12][C:13]1[CH:14]=[C:15]([NH2:22])[CH:16]=[C:17]([NH2:19])[CH:18]=1)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: [H][H]
Reactant: CCCCCCCCC(=O)OCc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Product: CCCCCCCCC(=O)OCc1cc(N)cc(N)c1
Yield: 100.1 %

Procedure:
39.6 g (0.2mol) of 3,5-dinitrobenzyl alcohol, 23.7 g (0.3 mol) of pyridine and 200 ml of methyl ethyl ketone were introduced into a reactor and dissolved by stirring under a nitrogen gas stream at about 70° C. 35.3 g (0.2 mol) of pelargonic acid chloride was dissolved in 100 ml of methyl ethyl ketone and the resultant solution was added dropwise into the reactor as described above. After the completion of the addition, the mixture was refluxed and stirred under nitrogen for about 2 hours. Then the reactor was cooled by allowing to stand and pyridine hydrochloride was removed by filtration. The filtrate was concentrated and purified by using a column to give 50.8 g of 3,5-dinitrobenzyl pelargonate. 33.8 g of 3,5-dinitrobenzyl pelargonate and 4 g of a catalyst (5% palladium carried on active carbon) were introduced into a hydrogenation apparatus and reduced with hydrogen. After filtration and concentration, 27.8 g (0.1 mol) of 3,5-diaminobenzyl pelargonate was obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:17]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:23](Br)[O:22][C:18]=2[N:19]=[CH:20][N:21]=1.B(O)(O)[C:36]1[C:41]([C:42]([F:45])([F:44])[F:43])=[CH:40][CH:39]=[CH:38][CH:37]=1>COCCOC.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>[CH3:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:17]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:23]([C:40]3[CH:39]=[CH:38][CH:37]=[CH:36][C:41]=3[C:42]([F:45])([F:44])[F:43])[O:22][C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: COC(=O)CCCCCNc1ncnc2oc(Br)c(-c3ccc(OC)cc3)c12
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: [K+]
Solvent: COCCOC
Product: COC(=O)CCCCCNc1ncnc2oc(-c3ccccc3C(F)(F)F)c(-c3ccc(OC)cc3)c12
Reaction time: 15 h

Procedure:
Add 0.5 ml of 2 M aqueous potassium carbonate solution to a mixture of 224 mg (0.50 mmol) 6-{[6-bromo-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]amino}hexanoic acid methyl ester and 29 mg (0.03 mmol) tetrakis(triphenylphosphine)palladium(0) in 2.5 ml 1,2-dimethoxyethane. Next, add 119 mg (0.63 mmol) (2-trifluoromethyl)phenylboronic acid and stir the mixture for 15 h under reflux. Filter the reaction mixture and purify directly by preparative RP-HPLC (gradient: water/acetonitrile). 118 mg (46% of theor.) of the desired product is obtained.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([CH2:26][Cl:27])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][S:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:6]=1[NH2:25].[N:28]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.Cl.O>[Cl:27][CH2:26][CH:3]([CH2:2][Cl:1])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:6]=1[NH:25][N:28]=[C:11]2[S:12]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: Nc1c(CS(=O)(=O)c2cccc3ccccc23)cccc1OC(CCl)CCl
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2c(OC(CCl)CCl)cccc12
Temperature: 3 °C

Procedure:
A mixture of 2-(2-chloro-1-chloromethyl-ethoxy)-6-(naphthalene-1-sulfonylmethyl)-phenylamine (4) (2 g, 4.77 mmoles) in THF and 4M HCl (15 ml) was stirred, under nitrogen, at 3° C., treated dropwise with a solution of sodium nitrite (0.34 g, 5 mmoles) in H2O (2 ml). The reaction mixture was poured into a cold solution of saturated sodium bicarbonate and extracted with EtOAc. The extracts were combined, dried over Na2SO4 and concentrated under vacuum to afford the title compound as an off white solid (1.76 g, 4.05 mmoles), identified by HNMR analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].[CH2:34]([O:36][CH2:37][CH2:38][N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[NH:48][CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)[CH3:35]>>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:52]2[CH2:51][CH2:50][CH:49]([NH:48][C:40]3[N:39]([CH2:38][CH2:37][O:36][CH2:34][CH3:35])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)[CH2:54][CH2:53]2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:8]1)=[O:6]
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(-n5cnnn5)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine to give the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]([CH3:19])[CH2:10][C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH2:24][CH3:25])C>>[CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]([CH3:19])[CH:10]([CH2:7]/[CH:6]=[CH:5]/[C:25]2[CH:24]=[CH:4][CH:3]=[CH:2][CH:1]=2)[C:9]1=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCC
Reactant: CC1=Nc2ccccc2N(Cc2ccccc2)C(=O)C1
Product: CC1=Nc2ccccc2N(Cc2ccccc2)C(=O)C1C/C=C/c1ccccc1
Yield: 69 %

Procedure:
Using 1-benzyl-4-methyl-1,3-dihydro-1,5-benzodiazepin-2(2H)-one, the title compound was synthesized in substantially the same manner as in Working Example 21 in a yield of 69%, m.p. 152°-154° C. (diethyl ether).