Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([C:12]1[CH:21]=[CH:20][C:15]([C:16](=O)[CH2:17]Cl)=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].C(=O)(O)[O-].[Na+]>C(O)(C)C>[C:8]([C:12]1[CH:13]=[CH:14][C:15]([C:16]2[N:1]=[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]3[CH:17]=2)=[CH:20][CH:21]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1ccc(C(=O)CCl)cc1
Reactant: Nc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)(C)c1ccc(-c2cn3ccccc3n2)cc1
Temperature: 80 °C
Yield: 61.8 %

Procedure:
A solution of 2-aminopyridine (0.512 g, 5.44 mmol) and 4-tert-butylphenacyl chloride (1.26 g, 5.98 mmol) in isopropanol (16 mL) was treated with sodium bicarbonate (0.914 g, 10.9 mmol) and heated in a sealed tube at 80° C. overnight. The mixture was concentrated under reduced pressure, re-dissolved in ethyl acetate (200 mL) and washed with water (2×100 mL) and saturated sodium chloride (100 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash silica gel chromatography, eluting with 20% acetone/hexanes to yield 0.841 g (62%) of the purified product. MS (ESI) m/z 251.1528; HPLC (Method B): r.t.=8.4 min., purity 100% at 210-370 nm, 100% at 306 nm. HRMS: calcd for C17H18N2+H+, 251.15427; found (ESI, [M+H]+), 251.1528.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[N:21]1([CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][NH2:38])[CH2:32][CH2:31]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(#N)C>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([C:11]([NH:38][CH2:37][CH2:36][N:33]3[CH2:32][CH2:31][CH:30]([CH2:29][CH2:28][CH2:27][N:21]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]4)[CH2:35][CH2:34]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: NCCN1CCC(CCCN2CCCCC2)CC1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2cc(Cl)ccc21
Solvent: CC#N
Product: O=C1Nc2cccnc2N(C(=O)NCCN2CCC(CCCN3CCCCC3)CC2)c2cc(Cl)ccc21
Yield: 10 %

Procedure:
Prepared analogously to Example 1 from 9-chloro-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[4-[3-(piperidin-l-yl)propyl]-piperidin-l-yl]ethanamine in a yield of 10% of theory. Colourless crystals, m.p. 176°-177° C. (acetonitrile).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH2:7][C@@H:8]2[N:14]([CH:15]=1)[C:13](=[O:16])[C:12]1[CH:17]=[C:18]([O:60][CH3:61])[C:19]([O:21][CH2:22][CH2:23][CH2:24][O:25][C:26]3[C:57]([O:58][CH3:59])=[CH:56][C:29]4[C:30](=[O:55])[N:31]5[CH:46]=[C:45]([O:47][S:48]([C:51]([F:54])([F:53])[F:52])(=[O:50])=[O:49])[CH2:44][C@H:32]5[C:33](=[O:43])[N:34]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:28]=4[CH:27]=3)=[CH:20][C:11]=1[N:10]([CH2:62][O:63][CH2:64][CH2:65][Si:66]([CH3:69])([CH3:68])[CH3:67])[C:9]2=[O:70].C([O-])([O-])=O.[Na+].[Na+].[CH3:77][CH2:78]OC(C)=O>C1(C)C=CC=CC=1.CCO.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>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH2:7][C@@H:8]2[N:14]([CH:15]=1)[C:13](=[O:16])[C:12]1[CH:17]=[C:18]([O:60][CH3:61])[C:19]([O:21][CH2:22][CH2:23][CH:24]([O:25][C:26]3[C:57]([O:58][CH3:59])=[CH:56][C:29]4[C:30](=[O:55])[N:31]5[CH:46]=[C:45]([O:47][S:48]([C:51]([F:54])([F:53])[F:52])(=[O:49])=[O:50])[CH2:44][C@H:32]5[C:33](=[O:43])[N:34]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:40])[CH3:41])[C:28]=4[CH:27]=3)[CH2:77][CH3:78])=[CH:20][C:11]=1[N:10]([CH2:62][O:63][CH2:64][CH2:65][Si:66]([CH3:67])([CH3:68])[CH3:69])[C:9]2=[O:70]
Reactant: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4cccs4)C[C@H]1C(=O)N3COCC[Si](C)(C)C)N(COCC[Si](C)(C)C)C(=O)[C@@H]1CC(OS(=O)(=O)C(F)(F)F)=CN1C2=O
Reactant: CCOC(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(CCOc1cc2c(cc1OC)C(=O)N1C=C(c3cccs3)C[C@H]1C(=O)N2COCC[Si](C)(C)C)Oc1cc2c(cc1OC)C(=O)N1C=C(OS(=O)(=O)C(F)(F)F)C[C@H]1C(=O)N2COCC[Si](C)(C)C
Reaction time: 24 h
Yield: 75 %

Procedure:
Solid Pd(PPh3)4 (7.66 mg, 6.63 μmol) was added to a stirred, cloudy solution of 14 (174 mg, 0.17 mmol), Na2CO3 (28 mg, 0.22 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboralan-2-yl)aniline (47 mg, 0.22 mmol) in toluene (2-5 mL), EtOH (1.25 mL) and H2O (125 mL) at room temperature. The reaction mixture was allowed to stir under a N2 atmosphere for 24 hours at which point the reaction was deemed complete by LC/MS major peak (@ 3.97 min, FW=1016, M+Na) and TLC (EtOAc). The solvent was removed by evaporation in vacuo and the resulting residue partitioned between EtOAc (60 mL) and H2O (30 mL). The layers were separated and the organic phase was washed with H2O) (20 mL), brine (30 mL) dried (MgSO4) filtered and evaporated in vacuo to provide the crude product 123 mg, 75% yield.
Reaction SMILES: [F:1][CH:2]([F:29])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:28])[CH3:27])=[O:4].[C:30]([O:34][C:35](=[O:45])[NH:36][CH2:37][C:38]1[N:39]=[N:40][C:41](Cl)=[CH:42][CH:43]=1)([CH3:33])([CH3:32])[CH3:31].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)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:30]([O:34][C:35](=[O:45])[NH:36][CH2:37][C:38]1[N:39]=[N:40][C:41]([C:15]2[CH:16]=[CH:17][C:12]([C@H:8]3[O:7][C:6]([CH3:28])([CH3:27])[N:5]([C:3](=[O:4])[CH:2]([F:1])[F:29])[C@@H:9]3[CH2:10][F:11])=[CH:13][CH:14]=2)=[CH:42][CH:43]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC1(C)O[C@H](c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[C@@H](CF)N1C(=O)C(F)F
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCc1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)nn1
Temperature: 80 °C
Yield: 24.6 %

Procedure:
To a stirred solution of 2,2-difluoro-1-{(4S,5R)-4-fluoromethyl-2,2-dimethyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazolidin-3-yl}-ethanone (0.849 g, 2.058 mmol) and (6-Chloro-pyridazin-3-ylmethyl)-carbamic acid tert-butyl ester (0.5 g, 2.058 mmol) in toluene:ethanol:water (20:10:5 mL) is added Na2CO3 (0.436 g, 4.115 mmol) at room temperature. Resulting reaction mixture is degassed with nitrogen for 20 minutes followed by addition of Pd (PPh3)4 (0.237 g, 0.206 mmol). The resulting reaction mixture is heated to 80° C. for 16 h. Solvent is evaporated in vacuo and the crude material is diluted using water and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, concentrated and purified by using Combi-flash eluting with 20% MeOH in DCM to afford the title compound (0.250 g): 1H NMR (400 MHz, DMSO-d6) 1.40 (s, 9H), 1.53 (s, 3H), 1.61 (s, 3H), 3.94 (s, 1H), 4.47 (d, J=6.08 Hz, 2H), 4.58-4.59 (m, 0.5H), 4.70-4.71 (m, 1H), 4.83-4.84 (m, 0.5H), 4.94-4.97 (m, 1H), 5.30 (d, J=3.32 Hz, 1H), 6.65 (t, J=52.32 Hz, 1H), 7.61-7.67 (m, 4H), 8.18 (d, J=8.12 Hz, 2H), 8.24 (d, J=8.84 Hz, 1H). LC-MS (m/z): [M+H]=495.2.
Reaction SMILES: C1([NH:7][C:8]([C:10]2[C:11](=[O:31])[N:12]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:13]3[C:18]([C:19]=2O)=[CH:17][C:16]([Cl:21])=[CH:15][N:14]=3)=O)CCCCC1.C(N(CC)CC)C.O=P(Cl)(Cl)[Cl:41]>>[Cl:41][C:19]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([Cl:21])[CH:17]=2)[N:12]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:11](=[O:31])[C:10]=1[C:8]#[N:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(Cn2c(=O)c(C(=O)NC3CCCCC3)c(O)c3cc(Cl)cnc32)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2c(=O)c(C#N)c(Cl)c3cc(Cl)cnc32)cc1
Yield: 95 %

Procedure:
A solution of 6-chloro-4-hydroxy-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid cyclohexylamide (93) (10.6 g, 24 mmol) and triethylamine (8.33 mL, 60 mmol) was heated in neat POCl3 overnight at 90° C. The solution was cooled and the excess POCl3 was distilled under vacuum. The residue was suspended in saturated NaHCO3 solution, sonicated briefly and filtered. The solids were dissolved in dichloromethane, washed subsequently by saturated NaHCO3 solution, water and brine. The organic phase was dried over MgSO4 and evaporated to yield 8.2 g (95%) of 4,6-dichloro-1-(4-methoxybenzyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (95) as white solids. MP 208° C. 1H-NMR (DMSO-d6): δ 3.69 (s, 3H), 5.50 (s, 2H), 6.82 (m, 2H), 7.87 (m, 2H), 8.59 (d, J=2.8 Hz, 1H), 8.94 (d, J=2.8 Hz, 1H); EIMS m/z 362 (M+2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1ccc(F)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 70.5 %

Procedure:
A suspension of 4-fluorophenylacetic acid (10.0 g, 64.9 mmol) in concentrated sulfuric acid (100 ml) was cooled to 0° C. Concentrated nitric acid (4.5 ml, 65 mmol) was added drop-wise, keeping the temperature at 0-5° C. At the end of the addition the mixture was poured into ice-water (400 ml). The precipitate was filtered off, washed thoroughly with water and dried with suction to yield 1i (9.11 g, 70%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:15])=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]#[CH:13])[C:6]=2[CH:14]=1.[C:16](Cl)(Cl)=[O:17]>C(OCC)(=O)C>[F:15][C:3]1[C:2]([N:1]=[C:16]=[O:17])=[CH:14][C:6]2[N:7]([CH2:11][C:12]#[CH:13])[C:8](=[O:10])[S:9][C:5]=2[CH:4]=1
Reactant: O=C(Cl)Cl
Reactant: C#CCn1c(=O)sc2cc(F)c(N)cc21
Solvent: CCOC(C)=O
Product: C#CCn1c(=O)sc2cc(F)c(N=C=O)cc21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution of 22.5 g of 5-amino-6-fluoro-3-(2-propynyl)-2-benzothiazolinone in 350 ml of ethyl acetate is added dropwise at 30° C. during 2 hours while stirring to a solution of 60.0 g of phosgene in 300 ml of ethyl acetate. The resulting suspension is stirred at 50° C. for 2 hours and subsequently heated slowly to the boiling point. The clear solution is then evaporated to dryness and there is thus obtained as the residue 6-fluoro-5-isocyanato-3-(2-propynyl)-2-benzothiazolinone, yellow crystals. This product serves, inter alia, as the starting material in the manufacture of 3-[6-fluoro-2-oxo-3-(2-propynyl)-5-benzothiazolinyl]-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione (see Example 1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:3]=1[NH2:16].S1C=CC=C1.[O-2].[Ca+2].[H][H]>CO.[Pd]>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][C:4]1[C:3]([NH2:16])=[CH:2][N:7]=[CH:6][N:5]=1
Reactant: [H][H]
Reactant: Nc1c(Cl)ncnc1NCc1ccccn1
Agent: [Pd]
Agent: [Ca+2]
Agent: [O-2]
Solvent: c1ccsc1
Solvent: CO
Product: Nc1cncnc1NCc1ccccn1
Yield: 100 %

Procedure:
A mixture of 62.2 parts of 6-chloro-N4 -(2-pyridinylmethyl)-4,5-pyrimidinediamine, 3 parts of a solution of thiophene in methanol 4%, 20 parts of calcium oxide and 400 parts of methanol was hydrogenated at normal pressure and at 50° C. with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 63.5 parts (100%) of N4 -(2-pyridinylmethyl)-4,5-pyrimidinediamine as a residue (interim. 15).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=1)=O.[CH:18]1([C:23](=O)[CH2:24][C:25]#[N:26])[CH2:22][CH2:21][CH2:20][CH2:19]1>>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:23]([CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:24]([C:25]#[N:26])=[C:9]2[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=1
Reactant: Cc1cc(C(=O)c2cc(Cl)ccc2N)ccn1
Reactant: N#CCC(=O)C1CCCC1
Product: Cc1cc(-c2c(C#N)c(C3CCCC3)nc3ccc(Cl)cc23)ccn1

Procedure:
The title compound was prepared in analogy to example 101 step B from (2-amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone (prepared in analogy to example 126 step B) and 3-cyclopentyl-3-oxo-propionitrile (prepared as described in example 105 step A). White solid. MS (ESI): 348.4 (M+H)+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[O:10][C:11]1[CH:12]=[C:13]([C:19]2[CH:24]=[CH:23][NH:22][C:21](=[O:25])[N:20]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]>CO.[Ni]>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[O:10][C:11]1[CH:12]=[C:13]([CH:19]2[CH2:24][CH2:23][NH:22][C:21](=[O:25])[NH:20]2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(-c2cc[nH]c(=O)n2)cc1OC1Cc2ccccc2C1
Agent: [Ni]
Solvent: CO
Product: COc1ccc(C2CCNC(=O)N2)cc1OC1Cc2ccccc2C1
Yield: 6.2 %

Procedure:
The pyrimidinone of Example 67 (0.32 g, 0.96 mmol) is dissolved in 15 ml of methanol, treated with Raney Nickel and hydrogenated under 40 psi for 8 hours at room temperature. The mixture is filtered through Celite and the catalyst washed several times with methanol. The organics are concentrated in vacuo and the crude residue triturated from ether to provide 20 mg (58%) of the product as a crystalline solid.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:15][C:14]=3[O:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[N:8][CH2:7]1)C.[BH4-].[Li+].O>O1CCCC1.CO.CCCCCC.C(OCC)(=O)C>[CH3:30][S:27]([C:24]1[N:23]=[CH:22][C:21]([O:20][C:16]2[CH:17]=[C:18]3[C:13](=[C:14]([O:31][CH:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[CH:15]=2)[NH:12][C:11]([C:9]2[S:10][CH:6]([CH2:5][CH2:4][OH:3])[CH2:7][N:8]=2)=[CH:19]3)=[CH:26][CH:25]=1)(=[O:28])=[O:29]
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC4CCOCC4)c3[nH]2)S1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CCO)S4)cc3c2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.2 %

Procedure:
To a solution of ethyl{2-[5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (500 mg) in tetrahydrofuran (10 mL) and methanol (15 mL) was added at room temperature lithium tetrahydroborate (80 mg) 3 times at 30 min intervals, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (ethyl acetate:hexane=0:100 to 100:0, volume ratio) and further to silica gel column chromatography (methanol:ethyl acetate:hexane=0:0:100 to 10:90:0, volume ratio). The obtained crude product was purified by preparative HPLC to give the title compound (112 mg, yield 24%) as a colorless amorphous solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[CH2:31]([N:33]([CH2:44][CH3:45])[C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][C:35]=1[CH3:43])[CH3:32]>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>[Si:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=2)=[CH:3][C:2]=1[C:37]1[CH:38]=[CH:39][C:34]([N:33]([CH2:44][CH3:45])[CH2:31][CH3:32])=[C:35]([CH3:43])[CH:36]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CCN(CC)c1ccc(B(O)O)cc1C
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCO[Si](C)(C)C(C)(C)C)c(Br)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)c1ccc(-c2ccc(OCCCO[Si](C)(C)C(C)(C)C)c(-c3ccc(N(CC)CC)c(C)c3)c2)cc1
Yield: 95.5 %

Procedure:
In a manner similar to that of Example 1d, by reacting 1 g (2 mmol) of ethyl 3′-bromo-4′-[3-(tert-butyldimethylsilanyloxy)propoxy]biphenyl-4-carboxylate (obtained in Example 6b) with 630 mg of 4-diethylamino-3-methylphenylboronic acid (3 mmol) in the presence of tetrakis(triphenylphosphine)palladium, 1.1 g of ethyl 4′-[3-(tert-butyldimethylsilanyloxy)propoxy]-4″-diethylamino-3″-methyl[1,1′;3′,1″]terphenyl-4-carboxylate (yield=95%) are obtained in the form of a pale yellow oil.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:13]([OH:15])=O)[CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:17][O:18][C:19](=[O:26])[C@H:20]([C@H:22]([CH2:24][CH3:25])[CH3:23])[NH2:21]>>[CH3:17][O:18][C:19](=[O:26])[C@H:20]([C@H:22]([CH2:24][CH3:25])[CH3:23])[NH:21][C:13](=[O:15])[C@H:11]([CH3:12])[NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)O
Reactant: CC[C@H](C)[C@H](N)C(=O)OC
Agent: Cl
Product: CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)Cc1ccccc1)C(=O)OC

Procedure:
Following General Procedure A and using N-(phenylacetyl)-L-alanine (from Example B1 above) and L-isoleucine methyl ester hydrochloride (Sigma), the title compound was prepared. The reaction was monitored by tlc (Rf=0.24 in 50% EtOAc/hexanes).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[CH:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O>[CH:6](=[N:1][C@H:2]([C:3]([OH:5])=[O:4])[CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1ccccc1
Reactant: NCC(=O)O
Solvent: O
Product: O=C(O)[C@@H](N=Cc1ccccc1)C(O)c1ccccc1
Reaction time: 16.5 h

Procedure:
In the process of this invention, there is no particular limitation on the sequence of charging the starting materials, the solvent, and the other materials. For example, an organic solvent having dissolved therein glycine, water and the aldehyde and optionally the phase transfer catalyst are charged, and with stirring, the alkali as a solid or an aqueous solution is charged or added dropwise to perform the reaction. Alternatively, it is possible to dissolve glycine in water and the alkali, and then add dropwise a solution of the benzaldehyde and the surface-active agent in an organic solvent to perform the reaction. Another method comprises charging or dropwise adding the alkali as a solid or aqueous solution into or to a mixture of glycine, water, the benzaldehyde, the organic solvent and the surface active agent, thereby performing the reaction. The reaction may be carried out at a temperature of 0° to 80° C. for 1 to 50 hours, preferably 10° to 60° C. for 3 to 30 hours. In this manner, the alkali metal or alkaline earth metal salt of the N-benzylidene-β-phenylserine is formed.
Reaction SMILES: [C@H:1]1([N:10]([C:39](=[O:45])[C:40]([CH3:44])([CH3:43])[CH2:41][F:42])[CH2:11]/[CH:12]=[CH:13]/[C:14]2[CH:15]=[C:16]3[CH2:38][C@@:21]4([C:29]5[C:24](=[N:25][CH:26]=[CH:27][CH:28]=5)[N:23](C(OC(C)(C)C)=O)[C:22]4=[O:37])[CH2:20][C:17]3=[N:18][CH:19]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl.[OH-].[Na+]>CN(C=O)C>[C@H:1]1([N:10]([CH2:11]/[CH:12]=[CH:13]/[C:14]2[CH:15]=[C:16]3[CH2:38][C@@:21]4([C:29]5[C:24](=[N:25][CH:26]=[CH:27][CH:28]=5)[NH:23][C:22]4=[O:37])[CH2:20][C:17]3=[N:18][CH:19]=2)[C:39](=[O:45])[C:40]([CH3:44])([CH3:43])[CH2:41][F:42])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@]2(Cc3cc(/C=C/CN(C(=O)C(C)(C)CF)[C@@H]4CCc5ccccc54)cnc3C2)c2cccnc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(CF)C(=O)N(C/C=C/c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21)[C@@H]1CCc2ccccc21

Procedure:
To a solution of tert-butyl (6S)-3-{(1E)-3-[(1R)-2,3-dihydro-1H-inden-1-yl(3-fluoro-2,2-dimethylpropanoyl)amino]prop-1-en-1-yl}-2′-oxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-1′(2′H)-carboxylate (130 mg, 0.213 mmol, described in step F) in DMF (2 mL) was added 1 N aqueous HCl (6.4 mL, 6.39 mmol). The reaction was stirred at ambient temperature and upon completion 1 N aqueous NaOH (4 mL) was added to bring to an approximately neutral pH. The mixture was then partitioned between 5% sodium bicarbonate and DCM. The organics were then washed once with half-saturated brine. The organics were dried over sodium sulfate, filtered, and concentrated in vacuo to provide a residue which still contained a considerable quantity of DMF. This residue was purified by reverse phase HPLC eluting with MeCN/Water (0.1% TFA). The product containing fractions were pooled, and neutralized with 10% NH4OH in MeOH. The bulk of the organics were then removed in vacuo, and the remaining mostly aqueous layer was extracted twice with DCM. The DCM solution was dried over sodium sulfate, filtered, and concentrated in vacuo to provide the title compound. MS: m/z=511 (M+1). Human CGRP receptor binding Ki=0.060 nM. HRMS: m/z=551.2517; calculated m/z=551.2504 for C31H31FN4O2.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:17])[C@@H:6]([CH3:16])[NH:7][C:8](=[O:15])[C@H:9]([CH2:11][C:12](=[O:14])[OH:13])[NH2:10])[CH2:2][CH3:3].Cl.C[O:20][C:21](=O)[C@H:22]([CH2:38]C1C=CC=CC=1)[NH:23]C(=O)[C@](N)(CC(=O)O)NC(=O)C(C)C>>[CH2:1]([O:4][C:5](=[O:17])[C@@H:6]([CH3:16])[NH:7][C:8](=[O:15])[C@H:9]([CH2:11][C:12](=[O:13])[OH:14])[NH:10][C:21](=[O:20])[C@@H:22]([CH3:38])[NH2:23])[CH2:2][CH3:3]
Reactant: CCCOC(=O)[C@@H](C)NC(=O)[C@@H](N)CC(=O)O
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@](N)(CC(=O)O)NC(=O)C(C)C
Agent: Cl
Product: CCCOC(=O)[C@@H](C)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](C)N

Procedure:
This compound was prepared from 1.9 g α-L-aspartyl-D-alanine n-propyl ester and 2.2 g N-benzyloxycarbonyl-D-alanine N-hydroxysuccinimide ester in a manner similar to Example 16 (C) and (D). Yield: 1.7 g, m.p.: 223°-225° C.
Reaction SMILES: C([S:4][C:5]1[S:11][CH:10]2[N:7]([C:8](=[O:15])[C@@H:9]2[C@H:12]([OH:14])[CH3:13])[C:6]=1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17])(=O)C.N1C=CN=C1>O1CCOCC1.O.Cl>[OH:14][C@@H:12]([C@H:9]1[C:8](=[O:15])[N:7]2[CH:10]1[S:11][C:5](=[S:4])[CH:6]2[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17])[CH3:13]
Reactant: CC(=O)SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)C2S1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=S)SC12

Procedure:
To a stirred solution of 0.039 g of 4-nitrobenzyl 3-acetylthio-6(S)-(1(R)-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-en-2-carboxylate in a mixture of 1.5 ml of dioxan and 0.15 ml of water was added 0.0069 g of imidazole at room temperature. After 5 minutes the mixture was diluted with 3 ml of 1M hydrochloric acid and 5 ml of water, and then extracted into ethyl acetate. The combined organic extracts were washed with water and dried over magnesium sulphate. The resulting solution was evaporated to give a mixture of the 5R and 5S isomers of the title compound as a foam.