Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH2:104][CH2:105][CH2:106][NH:107][C:108]([O:110][C:111]([CH3:114])([CH3:113])[CH3:112])=[O:109])([NH:96][C:97]([O:99][C:100]([CH3:103])([CH3:102])[CH3:101])=[O:98])[CH2:3][CH2:4][CH2:5][N:6]([C:89]([O:91][C:92]([CH3:95])([CH3:94])[CH3:93])=[O:90])[CH2:7][CH:8]([C:56]([CH2:78][CH2:79][CH2:80][NH:81][C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])([CH2:66][CH2:67][CH2:68][CH2:69][NH:70][C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])[N:57]([CH3:65])[C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:55])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=[CH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=[CH:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][N:52]=[N+]=[N-].[H][H]>C(O)(C)(C)C.[Pd]>[CH3:1][C:2]([CH2:104][CH2:105][CH2:106][NH:107][C:108]([O:110][C:111]([CH3:114])([CH3:113])[CH3:112])=[O:109])([NH:96][C:97]([O:99][C:100]([CH3:103])([CH3:102])[CH3:101])=[O:98])[CH2:3][CH2:4][CH2:5][N:6]([C:89]([O:91][C:92]([CH3:93])([CH3:94])[CH3:95])=[O:90])[CH2:7][CH:8]([C:56]([CH2:78][CH2:79][CH2:80][NH:81][C:82]([O:84][C:85]([CH3:86])([CH3:87])[CH3:88])=[O:83])([CH2:66][CH2:67][CH2:68][CH2:69][NH:70][C:71]([O:73][C:74]([CH3:75])([CH3:76])[CH3:77])=[O:72])[N:57]([CH3:65])[C:58]([O:60][C:61]([CH3:62])([CH3:63])[CH3:64])=[O:59])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:55])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][NH2:52]
Reactant: [H][H]
Reactant: CN(C(=O)OC(C)(C)C)C(CCCCNC(=O)OC(C)(C)C)(CCCNC(=O)OC(C)(C)C)C(CCCCCCNC(=O)CCCCCCCCCCC=CCCCCCCCCCCC=CCCCCCCCCCCCN=[N+]=[N-])CN(CCCC(C)(CCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CC(C)(C)O
Product: CN(C(=O)OC(C)(C)C)C(CCCCNC(=O)OC(C)(C)C)(CCCNC(=O)OC(C)(C)C)C(CCCCCCNC(=O)CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCN)CN(CCCC(C)(CCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 40 °C

Procedure:
To E7 (184 mg) dissolved in tert-butanol at 40° C. was added Pd/C (50 mg) and the atmosphere changed to hydrogen. The hydrogenation was heated at 40° C. for 3 days, the catalyst filtered off and the solvent removed. The residues were purified by silica chromatography eluting initially with 100:10:0 CH2Cl2:MeOH:NH4OH to remove faster running impurities then with 100:10:1 to remove the title compound as a colourless gum, 61 mg, 34%. C91H178N8O13 requires 1591.3. Found ES+: MH+, 1592.3. δH (CDCl3) 1.24 (72H, br, H2N(CH2)2(CH2)32, CONH(CH2)2(CH2)4), 1.44 (66H, br, (Me)3C, CH2CH2N), 1.72 (4H, p, NCH2CH2CH2N), 1.98 (1H, br, CH), 2.14 (2H, t, CH2CO), 2.67 (2H, t, CH2NH2), 2.83 (6H, s, NMe), 2.95-3.30 (22H, m, NCH2), 5.62 (1H, br, CONH(CH2)6CH).
Reaction SMILES: [CH:1]1[C:14]2[C:5]([O:6][C:7]3[C:12]([N:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:4][C:3](=[O:15])[CH:2]=1.[Cl:16]Cl.O>C(O)(=O)C>[Cl:16][C:4]1[C:3](=[O:15])[CH:2]=[CH:1][C:14]2[C:5]=1[O:6][C:7]1[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=1)[N:13]=2
Reactant: ClCl
Reactant: O=c1ccc2nc3ccccc3oc-2c1
Solvent: O
Solvent: CC(=O)O
Product: O=c1ccc2nc3ccccc3oc-2c1Cl

Procedure:
To a solution of 1.2 g of 3H-phenoxazin-3-one in acetic acid (25 ml) was added K2Cr2O7 (3.7 g). A solution of chlorine in acetic acid was added dropwise to the resulting suspension. After disappearance of the starting material, as monitored by TLC, the reaction mixture was poured into 200 ml of H2O and the resulting precipitate was filtered (1.2 g) and chromatographed on silica gel to yield the title compound.
Reaction SMILES: [ClH:1].[C:2]1([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH2:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]=1.Cl.C1([C@H]2CCC[C@H]2N)CCCCC1.COC1CCCCN=1>>[ClH:1].[CH:2]1([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[N:13]=[C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][NH:22]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: N[C@@H]1CCC[C@@H]1c1ccccc1
Reactant: COC1=NCCCCC1
Agent: COC1=NCCCC1
Agent: Cl
Agent: N[C@@H]1CCC[C@@H]1C1CCCCC1
Product: C1CCC([C@H]2CCC[C@H]2N=C2CCCCN2)CC1

Procedure:
Following the procedure of Example 1, only substituting for cis-2-phenylcyclopentylamine hydrochloride and O-methylcaprolactim, appropriate amounts of cis-2-(cyclohexyl)cyclopentylamine hydrochloride and O-methylvalerolactim respectively the desired product was obtained. M.P. 195.5°-197° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:36][C:37]1[CH:38]=[C:39]([C:59](=[O:66])[NH:60][C:61]2[NH:62][CH:63]=[CH:64][N:65]=2)[C:40]2[N:44]=[C:43]([NH:45][C:46]([C:48]3[N:49]=[CH:50][C:51]4[C:56]([CH:57]=3)=[CH:55][CH:54]=[CH:53][CH:52]=4)=[O:47])[NH:42][C:41]=2[CH:58]=1>CN(C=O)C.CCN(C(C)C)C(C)C.[Cl-].[Na+].O>[NH:62]1[CH:63]=[CH:64][N:65]=[C:61]1[NH:60][C:59]([C:39]1[C:40]2[NH:44][C:43]([NH:45][C:46]([C:48]3[N:49]=[CH:50][C:51]4[C:56]([CH:57]=3)=[CH:55][CH:54]=[CH:53][CH:52]=4)=[O:47])=[N:42][C:41]=2[CH:58]=[C:37]([NH:36][C:9](=[O:11])[CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:38]=1)=[O:66]
Reactant: Nc1cc(C(=O)Nc2ncc[nH]2)c2nc(NC(=O)c3cc4ccccc4cn3)[nH]c2c1
Reactant: O=C(O)CCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCc1ccccc1)Nc1cc(C(=O)Nc2ncc[nH]2)c2[nH]c(NC(=O)c3cc4ccccc4cn3)nc2c1
Yield: 61.8 %

Procedure:
60 mg (0.4 mmol) of 3-phenyl-propionic acid and 170 mg (0.45 mmol) of HBTU in a mixture of 1.0 mL of DMF and 0.5 mL of DIEA was reacted with 120 mg (0.3 mmol) of the isoquinoline-3-carboxylic acid [6-amino-4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide (See Example 130) as described in general procedure A. After the reaction was complete, it was diluted with brine (20 mL). The resulting solid was filtered, washed with water, ethyl acetate and dried under vacuum to give 101 mg (66%) of isoquinoline-3-carboxylic acid [7-(1H-imidazol-2-ylcarbamoyl)-5-(3-phenyl-propionylamino)-1H-benzoimidazol-2-yl]-amide as a solid. LCMS: 545 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[F:17][C:18]([F:30])([F:29])[O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[F:17][C:18]([F:29])([F:30])[O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=2)[C:5]([CH:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]2)=[O:6])=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccc(OC(F)(F)F)cc3)c2)CC1

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 4-(trifluoromethoxy)benzoyl chloride (36 μL, 0.229 mmol) and mixing for 24 h, 50.1 mg (>100%) of the title compound were recovered.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.FC(F)(F)C(O)=O.[Cl:27][CH2:28][CH2:29][CH2:30][C:31](=[CH:35][C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH:46]=[C:45]([CH3:47])[N:44]=[CH:43]2)=[C:38]([O:48][CH3:49])[CH:37]=1)[C:32]([OH:34])=O.[F:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[C:57]([NH2:60])([CH3:59])[CH3:58]>CN(C=O)C.C(OCC)(=O)C.O.C(Cl)CCl>[F:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[C:57]([NH:60][C:32](=[O:34])[C:31](=[CH:35][C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH:46]=[C:45]([CH3:47])[N:44]=[CH:43]2)=[C:38]([O:48][CH3:49])[CH:37]=1)[CH2:30][CH2:29][CH2:28][Cl:27])([CH3:58])[CH3:59]
Reactant: CC(C)(N)c1ccccc1F
Reactant: COc1cc(C=C(CCCCl)C(=O)O)ccc1-n1cnc(C)c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cc(C=C(CCCCl)C(=O)NC(C)(C)c2ccccc2F)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
IPEA (0.5 mL), EDC (192 mg) and HOBT (135 mg) were added to a solution of 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (150 mg) and 1-(2-fluorophenyl)-1-methylethylamine (102 mg) in DMF (5 mL), and the reaction solution was stirred at room temperature for 3 hours. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (1-(2-fluorophenyl)-1-methylethyl)amide. Sodium hydride (containing mineral oil at 40%, 40 mg) was added to a solution of the resulting 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (1-(2-fluorophenyl)-1-methylethyl)amide in DMF (5 mL), and the reaction solution was stirred at room temperature for 20 minutes. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 70 mg of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:14][O:15][C:16]1[CH:17]=[C:18](O)[CH:19]=[CH:20][CH:21]=1>>[CH3:14][O:15][C:16]1[CH:21]=[C:20]([CH:19]=[CH:18][CH:17]=1)[O:13][C@H:10]1[CH2:11][CH2:12][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: COc1cccc(O)c1
Product: COc1cccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)c1
Yield: 81 %

Procedure:
The title compound was prepared from (R)-(−)-N-boc-3-pyrrolidinol and 3-methoxyphenol, using the same method as that described for preparation 3, as a gum in 81% yield.
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2]CC.I[CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16]>>[CH2:9]([O:8][P:1]([CH2:16][CH2:15][CH2:14][CH:13]=[CH2:12])(=[O:2])[O:5][CH2:6][CH3:7])[CH3:10]
Reactant: CCOP(OCC)OCC
Reactant: C=CCCCI
Product: C=CCCCP(=O)(OCC)OCC
Temperature: 130 °C

Procedure:
1H NMR (CDCl3) δ=5.8 (m, 1H), 5.0 (m, 2H), 3.2 (t, 2H), 2.2 (sq, 2H), 1.8 (sq, 2H). Triethyl phosphite (400 mL, 2.3 mol, 3.5 eq.) was added to the 1-iodo-4-pentene, and the mixture was heated to 130° C. for three hours. Diethyl ethyl phosphonate was removed by fractional vacuum distillation, revealing the desired 4-pentenyl phosphonic acid diethyl ester which was used without further purification. 1H NMR (CDCl3) δ=5.7 (m, 1H), 4.8 (m, 2H), 4.0 (m, 4H), 2.0 (sq, 2H), 1.7 (m, 4H), 1.2 (t, 6H). 31P NMR (CDCl3) δ=33.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]1[O:10][CH2:9][C:8]([C:17]([OH:19])=[O:18])=[CH:7][C:6]2=1>[Pd].CO.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]1[O:10][CH2:9][CH:8]([C:17]([OH:19])=[O:18])[CH2:7][C:6]2=1
Reactant: COc1ccc2ncc3c(c2c1)C=C(C(=O)O)CO3
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2ncc3c(c2c1)CC(C(=O)O)CO3
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.7 %

Procedure:
10% Palladium on activated carbon (140 mg, 0.14 mmol, 0.05 eq) is added at room temperature to a stirred solution of 6-methoxy-2H-1-oxa-9-aza-phenanthrene-3-carboxylic acid (700 mg, 2.72 mmol, 1.0 eq) in methanol (20 mL) and tetrahydrofuran (20 mL). The resulting mixture is stirred under hydrogen flow (3 bars) at room temperature for 48 hours. The catalyst is then removed by filtration and the solution is concentrated to afford 6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthrene-3-carboxylic acid as a light yellow semisolid (520 mg, 74% yield) which is directly engaged in the next step.
Reaction SMILES: ClC1C=CC(C([N:8]2[CH2:13][CH2:12][C:11]3[S:14][C:15]4[C:20]([C:10]=3[CH2:9]2)=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[C:18]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:17]([CH2:36][N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])[N:16]=4)=O)=CC=1.[OH-].[K+]>O.C(O)C>[CH2:40]([N:37]([CH2:36][C:17]1[N:16]=[C:15]2[S:14][C:11]3[CH2:12][CH2:13][NH:8][CH2:9][C:10]=3[C:20]2=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[C:18]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:38][CH3:39])[CH3:41]
Reactant: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CN(C(=O)c1ccc(Cl)cc1)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CNCC3

Procedure:
A mixture of the compound (1.8 g) obtained in Example 53A, a solution of potassium hydroxide (0.6 g) in water (10 ml) and ethanol (20 ml) was heated under refluxing conditions for 5 hours, poured over water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated under reduced pressure to yield ethyl 2-diethylaminomethyl-4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydrothieno[2,3-b:4,5-c']dipyridine-3-carboxylate as an oil.
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)=[O:3].N1C2C(=CC=CC=2)C=CC=1.[S]>[Pd].O1CCCC1>[CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)=[O:3]
Reactant: O=C(Cl)c1ccc2c(c1)COC2=O
Agent: [Pd]
Agent: [S]
Solvent: c1ccc2ncccc2c1
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)COC2=O
Reaction time: 3 h
Yield: 68.5 %

Procedure:
A mixture of 7 g (0.036 mole) of 5-chlorocarbonylphthalide, 50 ml of tetrahydrofuran, 0.1 ml of the quinoline/sulfur mixture and 1 g of 10% Pd/C is hydrogenated at 3.5 bar and 35÷40° C. for 3 hours. After 3 hours a stoppage of the hydrogen absorption is observed. Thus, the mixture is cooled, diluted with dichloromethane, filtered, and by a HPLC control the presence of equivalent amounts of alcohol and aldehyde is observed. The mixture is concentrated under vacuum and the residue is taken up with ethyl acetate. The crystalline product is filtered and dried to obtain 4 g of 5-formylphthalide with a purity (HPLC)=44% (yield 30%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10])[NH2:5].C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:5][CH:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1cc(N)cc(F)c1OC
Solvent: CCO
Product: CCOC(=O)C(=CNc1cc(F)c(OC)c(OC)c1)C(=O)OCC
Temperature: 80 °C
Yield: 97.7 %

Procedure:
To the suspension of 3-fluoro-4,5-dimethoxyaniline (73 g, 426 mmol) in Ethanol (100 mL) was added diethyl 2-(ethoxymethylene)malonate (85 mL, 426 mmol), and the resulting mixture was heated at 80° C. for 1 h. LCMS indicated completion of the reaction. The mixture was concentrated in vacuo to remove ethanol, and the residue was washed with hexane to afford diethyl 2-(((3-fluoro-4,5-dimethoxyphenyl)amino)methylene)malonate (142 g, 416 mmol, 98% yield) as a yellow solid. LCMS: (M+H)+: 342.1.
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[CH:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>>[OH:16][C@@H:9]([P:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: CCOP([O-])OCC
Agent: Cl
Product: CCOP(=O)(OCC)[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
The solution of ALB in tetrahydrofuran (0.1 M, 0.40 ml) obtained in Example 1 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added diethyl phosphite (0.40 mmol) at room temperature. After stirring at room temperature for 30 minutes, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes. Then, benzaldehyde (0.40 mmol) was added thereto. After reacting for 90 hours, 1N hydrochloric acid was added thereto to stop the reaction. The mixture was extracted with ethyl acetate (10 ml×three times), and the combined extracts were washed with brine and dried over Na2SO4. The solvent was distilled, and the residue was purified by flash column chromatography (acetone/hexane=1/5, on SiO2) to obtain diethyl (S)-hydroxy-phenylmethylphosphonate as a final product in a yield of 39%. The chemical reaction in this Example is shown in chemical formula 33. ##STR27##
Reaction SMILES: [CH2:1]([C:3]1([C:33]([O:35]CC)=[O:34])[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]3[CH:16]=[C:17]([CH2:30][O:31][CH3:32])[C:18]4[S:22][C:21]([NH:23][C:24](=[O:28])[NH:25][CH2:26][CH3:27])=[N:20][C:19]=4[CH:29]=3)=[CH:11][N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[OH-].[Na+]>CCO.O>[CH2:1]([C:3]1([C:33]([OH:35])=[O:34])[CH2:8][CH2:7][N:6]([C:9]2[N:10]=[CH:11][C:12]([C:15]3[CH:16]=[C:17]([CH2:30][O:31][CH3:32])[C:18]4[S:22][C:21]([NH:23][C:24](=[O:28])[NH:25][CH2:26][CH3:27])=[N:20][C:19]=4[CH:29]=3)=[CH:13][N:14]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)OCC)CC4)nc3)cc(COC)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)O)CC4)nc3)cc(COC)c2s1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 64.5 %

Procedure:
Ethyl 4-ethyl-1-[5-[2-(ethylcarbamoylamino)-7-(methoxymethyl)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]piperidine-4-carboxylate (23 mg, 0.042 mmol) was dissolved in EtOH (1 mL) and 2M aqueous NaOH (330 μL, 0.66 mmol) added. The reaction mixture was stirred at 70° C. for 15 mins before additional 2M NaOH (670 μL, 1.34 mmol) was added and the reaction continued for 1.5 h then temperature increased to 100° C. and reaction continued for 4 h after which time the reaction was allowed to cool to rt overnight. After this time LCMS indicated small amount of starting material still present and the reaction was completed by heating to 100° C. for a further 2 h after which time the reaction was cooled to rt, diluted with water and extracted with DCM (3×). The aqueous layer was acidified with 10% HCl (aq) before extracting with EtOAc (3×) and the combined EtOAc extracts dried and the solvent evaporated to yield the Compound 203 (13.5 mg, 64%). 1H NMR (MeOD) δ 8.54 (s, 2H), 7.66 (bd, J=1.4 Hz, 1H), 7.28 (s, 1H), 4.68 (s, 2H), 4.48 (dt, J=13.7, 3.6 Hz, 2H), 3.35-3.28 (m, 2H), 3.22-3.11 (m, 2H), 2.20-2.13 (m, 2H), 1.60 (q, J=7.5 Hz, 2H), 1.44-1.34 (m, 2H), 1.21 (t, J=7.2 Hz, 3H), 0.89 (t, J=7.5 Hz, 3H). MS: 499.12 [M+H]+
Reaction SMILES: COC[C@H](C)O[C:6]1[CH:7]=[C:8]([CH:12]=[C:13](O[C@@H](C)CC2C=CC=CC=2)[CH:14]=1)[C:9]([OH:11])=O.[N:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[CH:37]=[CH:36][C:35]([NH2:38])=[N:34]2)=[CH:28][CH:27]=1>S(Cl)(Cl)=O>[N:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[CH:37]=[CH:36][C:35]([NH:38][C:9](=[O:11])[C:8]3[CH:7]=[CH:6][CH:14]=[CH:13][CH:12]=3)=[N:34]2)=[CH:28][CH:27]=1
Reactant: COC[C@H](C)Oc1cc(O[C@@H](C)Cc2ccccc2)cc(C(=O)O)c1
Reactant: Nc1ccn(Cc2ccncc2)n1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccn(Cc2ccncc2)n1)c1ccccc1
Temperature: 70 °C
Reaction time: 96 h
Yield: 17 %

Procedure:
3-((S)-2-Methoxy-1-methyl-ethoxy)-5-((S)-1-methyl-2-phenyl-ethoxy)-benzoic acid (0.58 mmol) is dissolved in thionylchloride (1.1 ml) and heated to 70° C. for 1 hour. After cooling to RT, the solvent is removed in vacuo. The residue is dissolved in dichloromethane (1.2 ml) and ethyldiisopropylamine (150 μl) is added and 1-pyridine-4-ylmethyl-1H-pyrazole-3-ylamine (1.2 eq.) is added. The suspension is stirred 4 days at room temperature. The reaction solution is extracted with water. The organic layer is washed with water and brine and dried over MgSO4 and the solvent is removed in vacuo. 3-(S)-2-Methoxy-1-methyl-ethoxy)-5-(S)-1-methyl-2-phenyl-ethoxy)-N-(1-pyridine-4-ylmethyl-1H-pyrazole-3-yl)-benzamide (“A8”) is isolated after column chromatography as colorless oil in a yield of 17%; HPLC (method B): 3.17 min; LC-MS (method B): 1.98 min, 501.3 (M+H+);
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2([C:24]3[CH:29]=[C:28]([CH3:30])[C:27]([O:31][Si](C(C)(C)C)(C)C)=[C:26]([CH3:39])[CH:25]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:9][C:8]=1[CH3:40])(C)(C)C.[N:43]1[CH:48]=[CH:47][CH:46]=[C:45](B(O)O)[CH:44]=1.C(N(CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C.O.ClCCl>[OH:6][C:7]1[C:8]([CH3:40])=[CH:9][C:10]([C:14]2([C:24]3[CH:29]=[C:28]([CH3:30])[C:27]([OH:31])=[C:26]([CH3:39])[CH:25]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:45]3[CH:44]=[N:43][CH:48]=[CH:47][CH:46]=3)[C:15]2=[O:23])=[CH:11][C:12]=1[CH3:13]
Reactant: Cc1cc(C2(c3cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c3)C(=O)Nc3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Reactant: OB(O)c1cccnc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C2(c3cc(C)c(O)c(C)c3)C(=O)N(c3cccnc3)c3ccccc32)cc(C)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.8 %

Procedure:
Combine 3,3-Bis-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-1,3-dihydro-indol-2-one (0.622 g, 1.03 mmol), pyridine-3-boronic acid (0.254 g, 2.07 mmol), copper (II) acetate (0.187 g, 1.03 mmol), triethylamine (0.29 mL, 2.07 mmol), 4 angstrom molecular sieves, and dichloromethane (15 mL). Stir at room temperature overnight under ambient atmosphere. Filter the reaction through Celite. Elute through a column of silica gel with 50% dichloromethane in hexanes. Dissolve the resulting compound (0.103 g, 0.152 mmol), in THF (4 mL). Add a solution of tetrabutylammonium fluoride (1.0M) in THF (0.40 mL). Stir for 1 h. Add 1N aqueous HCl(10 mL), water (40 mL), and ethyl acetate (50 mL). Separate the layers and concentrate the organic layer in vacuo. Chromatograph on silica gel eluting with ethyl acetate to give 0.036 g (8%) of the title compound: mass spectrum (ion spray): m/z=451 (M+1); 1H NMR(DMSO-d6): δ8.70 (d, 1H), 8.65 (dd, 1H), 8.25 (s, 2H), 7.98-7.94 (m, 1H), 7.62-7.59 (m, 1H), 7.34 (d, 1H), 7.25 (td, 1H), 7.14 (td, 1H), 6.84 (d, 1H), 6.75 (s, 4H), 2.07 (s, 12H).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].C(#N)C.Br[CH2:24][CH2:25][O:26][CH3:27]>C(OCC)(=O)C>[CH3:13][O:12][C:3]1[C:2]([O:1][CH2:24][CH2:25][O:26][CH3:27])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(O)c1OC
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COCCOc1cccc(C(=O)OC)c1OC
Temperature: 25 °C
Yield: 88.5 %

Procedure:
To a mixture of methyl 3-hydroxy-2-(methyloxy)benzoate (0.48 g, 2.6 mmol), potassium carbonate (0.73 g, 5.3 mmol) and acetonitrile (30 mL) was added 1-bromo-2-(methyloxy)ethane (0.37 mL, 4.0 mmol). The resulting mixture was heated at reflux 18 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL), filtered and concentrated. The residue was then diluted with ethyl acetate (100 mL) and washed with 5% sodium hydroxide solution, water and brine (100 mL each), dried over sodium sulfate, filtered and concentrated to give an oily residue which was purified by flash chromatography (silica gel, 30% ethyl acetate-hexane) to provide methyl 2-(methyloxy)-3-{[2-(methyloxy)ethyl]oxy}benzoate, (0.54 g, 2.3 mmol, 85% yield). 1H NMR (400 MHz, CDCl3): 7.35-7.33 (m, 1H), 7.11-7.04 (m, 2H), 4.18-4.17 (m, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.80-3.77 (m, 2H), 3.46 (s, 3H).