Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:27]3[N:23]([C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:25][N:26]=3)[C:22]3[CH:34]=[CH:35][CH:36]=[CH:37][C:21]=3[N:20]([CH2:38][C:39](=[O:51])[N:40]([CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH:41]([CH3:43])[CH3:42])[C:19]2=[O:52])=[N:9]1)=O)(C)(C)C.Cl>CCOC(C)=O>[CH2:44]([N:40]([CH:41]([CH3:43])[CH3:42])[C:39](=[O:51])[CH2:38][N:20]1[C:19](=[O:52])[CH:18]([CH2:17][C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:8][N:9]=2)[C:27]2[N:23]([C:24]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[N:25][N:26]=2)[C:22]2[CH:34]=[CH:35][CH:36]=[CH:37][C:21]1=2)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)C(Cc2n[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21
Yield: 5.2 %

Procedure:
Following the procedure described in Example 3(B), Step B, 3-{6-[(benzyl-isopropyl-carbamoyl)-methyl]-5-oxo-1-phenyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulen-4-ylmethyl}-indazole-1-carboxylic acid tertbutyl ester (19.1 mg, 0.274 mmol) was deprotected with HCl (4.0M in dioxane, 0.8 mL) over 24 hours. The reaction was diluted with EtOAc, and the organic solution was washed with aqueous NaHCO3 (1×), dried (Na2SO4), filtered and concentrated. Purification by preparative chromatography eluting with 5% MeOH in CH2Cl2 provided 8.5 mg of N-benzyl-2-[4-(1H-indazol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-acetamide as a racemic mixture. 1H NMR (CD2Cl2) δ 7.97 (t, 1H), 7.12-7.64 (m, 15H), 7.05 (m, 1H), 6.92 (m, 1H), 5.08 (d) and 4.81 (d, total 1H), 4.60-4.74 (m, 2H), 4.49 (s, 1H), 4.45 (t, 1H), 4.29-4.39 (m, 1H), 3.96-4.13 (m, 2H), 1.16 (dd, 3H), 1.05 (dd, 3H); MS 596.2 (M+1), 594.2 (M−1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[N:8][CH:9]=1)(=[O:3])[CH3:2].[Cl:12][C:13]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:14]=1[CH:15]=O.[OH-].[K+]>>[Cl:12][C:13]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:14]=1/[CH:15]=[CH:2]/[C:1]([C:4]1[CH:9]=[N:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[O:3]
Reactant: O=Cc1cc(Cl)ccc1Cl
Reactant: COc1ccc(C(C)=O)cn1
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(C(=O)/C=C/c2cc(Cl)ccc2Cl)cn1

Procedure:
In analogy to example 170, step 1, 5-acetyl-2-methoxypyridine was reacted with 2,5-dichlorobenzaldehyde in the presence of potassium hydroxide to give the title compound as a colourless solid. MS (ESI+): m/z=308.1 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH:9]2[CH:4]([CH2:5][CH:6]([C:16]([OH:18])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1.Br[CH2:20][CH3:21]>C(#N)C>[O:1]=[C:2]1[CH2:11][CH2:10][CH:9]2[CH:4]([CH2:5][CH:6]([C:16]([O:18][CH2:20][CH3:21])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1
Reactant: CCBr
Reactant: COC(=O)N1CC2CCC(=O)CC2CC1C(=O)O
Solvent: CC#N
Product: CCOC(=O)C1CC2CC(=O)CCC2CN1C(=O)OC
Temperature: 50 °C

Procedure:
In Scheme II, Step A, 6-oxo-2-(Pg)-decahydroisoquinoline-3-carboxylic acid (Pg is as defined hereinabove) is esterified by reaction with a compound of formula R3—Br (where R3 is as herein defined above) to provide the 6-oxo-2-(Pg)-decahydroisoquinoline-3-carboxylate intermediate of compound (1). For example 6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylic acid is dissolved in acetonitrile and treated with tiethylamine and bromoethane. The reaction is heated at 50° C. for about 3 hours, cooled and partitioned between 50:50 ethyl acetate/heptane and 1N HCL. The organic phase is isolated and washed 3 times with water, saturated sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide Ethyl 6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylate, a compound of structure (1). This crude material may then be purified under standard conditions well known in the art. For example, the crude material is dissolved in 10% ethyl acetate/heptane and applied to a plug of silica gel (10 g in 10% ethyl acetate/heptane). The plug is eluted with, 10% ethyl acetate/heptane, 15% ethyl acetate/heptane, and 25% ethyl acetate/heptane. The eluents are combined and concentrated under vacuum to provide the purified compound of structure (1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:16][OH:17])[CH:7]([CH3:15])[C:8](=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]([CH3:15])=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[O:17][N:16]=1
Reactant: CCOC(=O)C(=O)C(C)C(=NO)c1ccco1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1onc(-c2ccco2)c1C
Temperature: 25 °C
Yield: 62.7 %

Procedure:
Ethyl 4-(furan-2-yl)-4-(hydroxyimino)-3-methyl-2-oxobutanoate (10 g, 41.8 mmol) and concentrated sulfuric acid (10 mL) were added to 150 mL of absolute ethanol and the mixture was refluxed for 20 hours. After the mixture cooled to room temperature, saturated sodium bicarbonate solution was added to neutralize the mixture. The product was extracted with EtOAc and the combined organic layer was dried over MgSO4 and concentrated to give 5.8 g of the title compound. MS: (+) m/z 222.40 (M+1).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[F:11][C:12]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:13]=1[CH2:14][N:15]1[C:20]([CH3:21])=[C:19]([CH:22]=C=O)[C:18](=[O:25])[C:17]([Br:26])=[C:16]1[CH3:27].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.O>[F:11][C:12]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:13]=1[CH2:14][N:15]1[C:20]([CH3:21])=[C:19]([CH2:22][N:2]([CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=2)[CH3:1])[C:18](=[O:25])[C:17]([Br:26])=[C:16]1[CH3:27]
Reactant: Cc1c(Br)c(=O)c(C=C=O)c(C)n1Cc1c(F)cccc1F
Reactant: CNCCc1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1c(Br)c(=O)c(CN(C)CCc2ccccn2)c(C)n1Cc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2-Methylaminoethyl)pyridine (680 mg, 5.00 mmol) was added to a stirred solution of 1-(2,6-difluorobenzyl)-2,6-dimethyl-3-bromo-5-(carbonylmethyl)4-pyridone (430 mg, 1.16 mmol) in CH2Cl2 (15 mL). After 30 min., NaBH(OAc)3 (1.23 g, 5.80 mmol) was added in small portions, and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with H2O (15 mL) and the organic layer was separated and washed with sat. NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated in vacuo. The crude was used in the next step without any further purification. Crude yield 426 mg (75%). LRMS m/z 490.0 (M+−1), 492.0 (M++1).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9]([C@@H:11]2[CH2:17][CH2:16][C@@H:15]3[CH2:18][N:12]2[C:13](=[O:24])[N:14]3[O:19][S:20]([O-:23])(=[O:22])=[O:21])=[O:10])[CH2:3][CH2:2]1.C([N+](CCCC)(CCCC)CCCC)CCC.FC(F)(F)C(O)=O>ClCCl>[NH:1]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9]([C@@H:11]2[CH2:17][CH2:16][C@@H:15]3[CH2:18][N:12]2[C:13](=[O:24])[N:14]3[O:19][S:20]([OH:23])(=[O:21])=[O:22])=[O:10])[CH2:3][CH2:2]1
Reactant: O=C(N[C@H]1CCCNCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@H]1CCCNCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Reaction time: 2 h

Procedure:
To a solution of N,N,N-tributylbutan-1-aminium {[((2S,5R)-2-{[(4S)-azepan-4-ylamino]carbonyl}-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl)oxy]sulfonyl}oxidanide (30.9 mg, 0.067 mmol) in anhydrous dichloromethane (7 mL) at 0° C. under nitrogen was added trifluoroacetic acid (0.5 mL, 6.5 mmol) dropwise. The reaction mixture was stirred for two hours then concentrated under vacuum. Ether was added to the residue and the resulting white precipitate was collected by centrifugation. The precipitate was purified by HPLC on a Phenomenex Synergy Polar-RP 80A column and lyophilized to afford the title compound as a white solid. LC-MS (negative ionization) m/e 361 (M−H); LC-MS (positive ionization) m/e 385 (M+Na); 1H NMR (600 MHz, D2O; unreferenced) (δ, ppm) 4.17 (1H, br d, J=3 Hz), 3.96-4.03 (2H, m), 3.27-3.38 (3H, m), 3.15-3.22 (2H, m), 3.02 (1H, d, J=12 Hz), 1.62-2.18 (m, 12H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:8][C:9]3[C:15]([C:16]([O:18]C)=O)=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:2]=1.O.[NH4+:21]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:8][C:9]3[C:15]([C:16]([NH2:21])=[O:18])=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:2]=1
Reactant: COC(=O)c1cccc2nc(-c3cccnc3)oc12
Reactant: [NH4+]
Solvent: O
Product: NC(=O)c1cccc2nc(-c3cccnc3)oc12

Procedure:
Methyl 2-(pyridin-3-yl)benzo[d]oxazole-7-carboxylate (135 mg, 0.53 mmol) in ammonium water (15 mL) was stirred at 25° C. overnight. The solvent was removed under reduced pressure. The crude product was purified by pre-HPLC to obtain 2-(pyridin-3-yl)benzo[d]oxazole-7-carboxamide a solid (39 mg, yield 31%). 1H-NMR (400 MHz, DMSO-d6) δ 7.50-7.54 (t, J=8 Hz, 1H), 7.65-7.69 (q, 1H), 7.65-7.69 (q, 1H), 7.85-7.87 (d, J=8 Hz, 1H), 7.91-7.93 (d, J=8 Hz, 2H), 7.99-8.01 (d, J=8 Hz, 1H), 8.64-8.66 (d, J=8 Hz, 1H), 8.81-8.82 (d, J=4 Hz, 1H), 9.46-9.47 (s, J=4 Hz, 1H); LC-MS (ESI) m/z 240 [M+1]+.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([N:34]2[CH2:39][CH2:38][N:37]([CH3:40])[C:36](=[O:41])[CH2:35]2)[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:30]4[CH2:31][CH:32]([N:34]5[CH2:39][CH2:38][N:37]([CH3:40])[C:36](=[O:41])[CH2:35]5)[CH2:33]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: CN1CCN(C2CNC2)CC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCN(C)C(=O)C4)C3)n(C)c2n1
Reaction time: 16 h
Yield: 81.5 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (162 mg, 0.41 mmol), 4-azetidin-3-yl-1-methylpiperazin-2-one (77 mg, 0.46 mmol) and 4 Å powdered molecular sieves (250 mg) in DCE (10 mL) was stirred at room temperature for 2 h before the addition of sodium triacetoxyborohydride (175 mg, 0.83 mmol). The reaction mixture was stirred for 16 h then filtered through celite, washing with DCM. The organic phase was washed with brine (×1) and concentrated in vacuo. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-30%) affording 556 as a yellow foam (182 mg, 82%). LCMS (Method I): RT 2.34 min [M+H]+ 545.3. 1H NMR (CDCl3, 400 MHz): δ 8.02-7.97 (m, 1 H); 7.77-7.72 (m, 1 H); 7.29-7.22 (m, 2 H); 4.35 (m, 4 H); 3.89-3.84 (m, 6 H); 3.83 (s, 3 H); 3.59 (t, J=5.3 Hz, 2 H); 3.39-3.31 (m, 4 H); 3.18-3.10 (m, 3 H); 3.05 (m, 2 H); 2.96 (s, 3 H); 2.59 (t, J=5.3 Hz, 2 H) and 1.43 (t, J=7.5 Hz, 3 H)
Reaction SMILES: C[O:2][C:3](=[O:30])[C@H:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)[NH:5][C:6]([C:8]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[Cl:31][C:32]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:33]=1[C:34](Cl)=[O:35].N1C(C)=CC=CC=1C>ClCCl.CCOCC>[Cl:31][C:32]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:33]=1[C:34]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][C@@H:4]([C:3]([OH:2])=[O:30])[NH:5][C:6]([C:8]2([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:24][CH:25]=1)=[O:35]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)C1(Cc2ccc(OC)cc2)CCCC1
Solvent: ClCCl
Solvent: CCOCC
Solvent: Cc1cccc(C)n1
Product: COc1ccc(CC2(C(=O)N[C@@H](Cc3ccc(NC(=O)c4c(Cl)cccc4Cl)cc3)C(=O)O)CCCC2)cc1
Reaction time: 4 h
Yield: 29.1 %

Procedure:
4-Amino-N-[[1-[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-L-phenylalanine methyl ester (66 mg, 0.17 mmol) and 2,6-dichlorobenzoyl chloride (50 mg, 0.23 mmol) were dissolved in 5 mL of dichloromethane and 2,6-lutidine (50 μL, 0.43 mmol) were added. After 4 hours, the mixture was diluted with ether and dichloromethane and washed with 1 N HCl, water, and saturated NaHCO3 and was dried (MgSO4). The crude product was dissolved in methanol (4 mL) and treated with 4 N NaOH (0.1 mL). After 2 hours, the excess base was quenched with acetic acid (0.1 mL), the solution was filtered through a 0.2μ nylon filter and the filtrate was purified by RP-HPLC on a 4×30 cm Rainin C-18 column using a gradient of 5 to 95% acetonitrile:water containing 0.75% trifluoroacetic acid at a flow of 49 mL/min over 35 min. The peak eluting at 79% acetonitrile was concentrated and lyophilized to give 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-L-phenylalanine (28.2 mg), HR-FABMS: obs. mass 591.1445. Calcd. mass 591.1430 (M+Na).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.[ClH:16].CO>C(Cl)Cl.CO>[ClH:16].[OH:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCN)c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: NCCc1cccc(O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2-(3-methoxyphenyl)ethylamine (10.0 g, 66.2 mmol) in dry CH2Cl2 (100 mL) at −78° C. was added a 1M solution of BBr3 in CH2Cl2 (200 mL, 3 eq.) and the solution was allowed to slowly warm to RT. After stirring for 3 h at RT the resulting precipitate was filtered off, washed with CH2Cl2 (200 mL) and dried. The off-white solid was dissolved in cold H2O (50 mL) and the insoluble material was filtered off. The acidic filtrate (pH 1.2) was made basic (pH 13.0) with 10 N NaOH and the resulting yellow solution was extracted with ether (100 mL) and the organic layer was discarded. The aqueous layer was re-acidified with conc. HCl to pH 1.5 and then made alkaline (pH 9-10) with conc. NH4OH. The aqueous layer was then extracted with n-butanol (2×150 mL), dried (K2CO3) and concentrated to dryness to afford a viscous oil. The oily residue was then dissolved in MeOH (10 mL) and a solution of saturated HCl/MeOH was added. The solution was concentrated to small volume and ether was added to give a precipitate. The ether was decanted off to afford the desired compound as an off white solid (6.5 g, 57%). 1H NMR (D2O) 2.79 (t, 2H, J=7.2 Hz), 3.08 (t, 2H, J=7.2 Hz), 6.60-6.78 (m, 3H), 7.11 (t, 1H, J=7.7 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:18][C@@H:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][OH:21])=[N:4][C:5]([C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[N:13]3)=[CH:6][N:7]=1.NC1C(N[C@@H](C2C=CC=CC=2)[CH2:38][OH:39])=NC(Br)=CN=1.N1C2C=CC=C(B(O)O)C=2C=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[OH:21][CH2:20][C@@H:19]([N:18]1[C:3]2=[N:4][C:5]([C:8]3[CH:17]=[CH:16][CH:15]=[C:14]4[C:9]=3[CH:10]=[CH:11][CH:12]=[N:13]4)=[CH:6][N:7]=[C:2]2[NH:1][C:38]1=[O:39])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ncc(Br)nc1N[C@H](CO)c1ccccc1
Reactant: Nc1ncc(-c2cccc3ncccc23)nc1N[C@H](CO)c1ccccc1
Agent: O=C([O-])[O-]
Agent: OB(O)c1cccc2ncccc12
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c2ncc(-c3cccc4ncccc34)nc2n1[C@H](CO)c1ccccc1
Yield: 51 %

Procedure:
(S)-2-(3-Amino-6-(quinolin-5-yl)pyrazin-2-ylamino)-2-phenylethanol. (S)-2-(3-Amino-6-bromopyrazin-2-ylamino)-2-phenylethanol (0.882 g, 2.26 mmol), quinoline-5-boronic acid (0.544 g, 2.48 mmol) tetrakis(triphenylphosphine)-palladium (0.331 g, 0.287 mmol), potassium carbonate (1.25 g, 9.08 mmol), water (8 mL) and dimethylformamide (30 mL) were reacted according to General Procedure B. The crude material was purified via Biotage silica gel chromatography (0-10% methanol/dichloromethane, 40S column) to afford the title compound (0.524 g, 51% yield). MS (ESI) m/z 358.3 [M+1]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11](F)[CH:10]=[CH:9][C:8]=1[S:14]([CH2:17][C:18]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([O:28][CH3:29])[C:21]([C:30]2[CH:34]=[CH:33][O:32][CH:31]=2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:2].Br[C:38]1C(OC)=C(C(CS(C2C=CC=CC=2/C=C\CN2CCCCC2)(=O)=O)=CC=1)C(OC)=O>>[O:32]1[CH:33]=[CH:34][C:30]([C:21]2[C:22]([O:28][CH3:29])=[C:23]([C:18]([CH2:17][S:14]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3/[CH:6]=[CH:5]\[CH2:4][N:3]3[CH2:35][CH2:36][CH2:38][CH2:2][CH2:1]3)(=[O:16])=[O:15])=[CH:19][CH:20]=2)[C:24]([O:26][CH3:27])=[O:25])=[CH:31]1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2/C=C\CN2CCCCC2)ccc(Br)c1OC
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Cc1ccc(-c2ccoc2)c(OC)c1C(=O)OC
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2/C=C\CN2CCCCC2)ccc(-c2ccoc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 160, starting from (Z)-methyl 3-bromo-2-methoxy-6-((2-(3-(piperidin-1-yl)prop-1-enyl)benzenesulfonyl)methyl)benzoate (Intermediate 199).
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][O:26][C:27]4[CH:31]=[CH:30][O:29][N:28]=4)[O:22][C:21]3=[O:32])=[CH:16][C:15]=2[F:33])[CH2:10]1)(C(C)(C)C)(C)C.O>C(O)(=O)C>[OH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][O:26][C:27]4[CH:31]=[CH:30][O:29][N:28]=4)[O:22][C:21]3=[O:32])=[CH:16][C:15]=2[F:33])[CH2:10]1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)C1
Solvent: O
Solvent: CC(=O)O
Product: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CC[C@@H](O)C2)c(F)c1

Procedure:
3-(4-((3R)-3-t-Butyldimethylsilyloxy-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one (1.8 g, 3.77 mmol) was stirred in a mixture of acetic acid, water, and tetrahydroftiran (3:1:1, 40 ml) at 90° for four hours. Solvent was evaporated, and the residue purified by chromatography on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 10% MeOH in dichloromethane. Relevant fractions were combined and evaporated to givc the desired product (420 mg) as a foam. MS (ESP): 364 (MH+) for C17H18FN3O5.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[F:10][C:11]1[N:26]=[CH:25][CH:24]=[CH:23][C:12]=1[C:13](NC1C=CC=CC=1C)=[O:14]>>[F:10][C:11]1[N:26]=[CH:25][CH:24]=[CH:23][C:12]=1[C:13]([NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)=[O:14]
Reactant: NCc1ccc(F)cc1
Reactant: Cc1ccccc1NC(=O)c1cccnc1F
Product: O=C(NCc1ccc(F)cc1)c1cccnc1F
Yield: 100 %

Procedure:
4-Fluorobenzylamine (Aldrich, 0.18 mL, 1.6 mmol) was converted to the desired compound (0.099 g, 100%) in a manner similar to the preparation of 2-fluoro-N-o-tolylnicotinamide (Step A of Example 8). MS(ESI+) m/z 249 (M+H)+.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[C:4]([O-:12])(=[O:11])[C@H:5]([CH2:7][C:8]([O-:10])=[O:9])[OH:6].[Na+].[Na+]>>[C:4]([OH:12])(=[O:11])[C@H:5]([CH2:7][C:8]([OH:10])=[O:9])[OH:6]
Reactant: O=C([O-])C[C@H](O)C(=O)[O-]
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Na+]
Product: O=C(O)C[C@H](O)C(=O)O

Procedure:
A reaction solution containing maleic acid (116 g) and 5N sodium hydroxide (200 ml) (having a total volume of 1,000 ml by adding water), which had been previously subjected to N2 substitution by carrying out agitation while blowing N2 gas in it for 30 minutes, was transferred into a jar fermenter having a volume of 3 L. The microbial cells of the both species (IFO 12669 strain: 20 g, AB-41 strain: 50 g), which had been recovered in Example 1 and in the item (1) described above, were added thereto, followed by agitation while supplying N2 at a velocity of 0.02 vvm to carry out a reaction at 30° C. for 36 hours with sealing. L-Malic acid was obtained in an amount of 104 g/L. Calcium chloride was added to the obtained solution of sodium L-malate to precipitate calcium malate, followed by washing with water. After that, L-malic acid was separated by using an ion exchange resin, and dried. Thus crystals of L-malic acid were obtained. The obtained crystals had an amount of 90 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]=[C:6]2[CH2:13][CH2:14][CH:15]1[CH2:19]OC2(CCC(O)CC2)[O:16]1>CC(O)=O.C1COCC1.O>[OH:16][C:15]1([CH2:14][CH2:13][C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)[CH2:19][CH2:4][C:3](=[O:2])[CH2:12][CH2:11]1
Reactant: COc1ccc2ncnc(CCC3COC4(CCC(O)CC4)O3)c2c1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2ncnc(CCC3(O)CCC(=O)CC3)c2c1

Procedure:
A solution of 8-([2-(6-methoxy-quinazolin-4-yl)-ethyl]-1,4-dioxa-spiro[4.5]decan-8-ol (0.623 g, 1.81 mmol) in AcOH/THF/H2O (3/2/2, 10 ml) was stirred at 60° C. for 30 hours. The reaction mixture was concentrated to dryness by rotary evaporation. The residue was diluted with sodium bicarbonate (100 ml) and ethyl acetate (100 ml), the phases were separated and the aqueous phase was extracted twice using 50 ml of ethyl acetate each time. The combined organic phases were dried over MgSO4, filtered and concentrated to dryness by rotary evaporation.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C:3]([C@@H:5]1[CH2:7][C@H:6]1[C@@H:8]1[CH2:12][C@H:11]([S:13]C(=O)C)[CH2:10][N:9]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:18])=[O:4].[OH-].[Na+].Cl.O>CO>[CH3:1][N:2]([CH3:30])[C:3]([C@@H:5]1[CH2:7][C@H:6]1[C@@H:8]1[CH2:12][C@H:11]([SH:13])[CH2:10][N:9]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:18])=[O:4]
Reactant: CC(=O)S[C@H]1C[C@@H]([C@@H]2C[C@H]2C(=O)N(C)C)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)C(=O)[C@@H]1C[C@H]1[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
To a solution of trans-N,N-dimethyl-2-[(2S,4S)-4-acetylthio -N-(4-nitrobenzyloxycarbonyl)pyrrolidin-2-yl]cyclopropanecarboxamide (220 mg, 0.5 mmol) in methanol (11 ml) was added 2N sodium hydroxide solution(0.50 ml, 1.0 mmol) under ice-cooling, and the solution stirred for 1 hour. To the reaction mixture was added 6N hydrochloric acid (0.17 ml, 1.0 mmol), and the mixture poured into water (10 ml) and extracted with methylene chloride (20 ml×2). The organic layer was dried (MgSO4) and evaporated in reduced pressure to give a residue of trans-N,N-dimethyl-2-[(2S,4S)-4-mercapto-N-(4-nitrobenzyloxycarbonyl) pyrrolidin-2-yl]cyclopropanecarboxamide. ##STR170##
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=3)[N:12]([CH:22]([CH3:24])[CH3:23])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:26][C:27]1[CH:28]=[CH:29][C:30]([O:36][CH3:37])=[C:31](B(O)O)[CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:16]=[C:17]([C:29]4[CH:28]=[C:27]([F:26])[CH:32]=[CH:31][C:30]=4[O:36][CH3:37])[CH:18]=[CH:19][CH:20]=3)[N:12]([CH:22]([CH3:24])[CH3:23])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)N1C(=O)N(S(=O)(=O)c2ccccc2)CC1c1cccc(Br)c1
Reactant: COc1ccc(F)cc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(F)cc1-c1cccc(C2CN(S(=O)(=O)c3ccccc3)C(=O)N2C(C)C)c1

Procedure:
In analogy to example 1, step 3,1-benzenesulfonyl-4-(3-bromo-phenyl)-3-isopropyl-imidazolidin-2-one (example 12, step 1) was reacted with 5-fluoro-2-methoxyphenylboronic acid in the presence of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct and sodium carbonate in dioxane/water to give 1-benzenesulfonyl-4-(5′-fluoro-2′-methoxy-biphenyl-3-yl)-3-isopropyl-imidazolidin-2-one as an off-white solid. MS: 469.2 ([M+H]+)