Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[N:20](C3CCCCO3)[N:19]=2)=O)[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.Cl.CO.Cl>C1COCC1>[CH2:1]([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([NH:15][CH2:16][C:18]2[CH:22]=[C:21]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[NH:20][N:19]=2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cccc(NCc2ccccc2)n1)c1cc(-c2ccc(F)cc2)n(C2CCCCO2)n1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Fc1ccc(-c2cc(CNc3cccc(NCc4ccccc4)n3)n[nH]2)cc1
Temperature: 25 °C

Procedure:
BMS (2.2 mmol, 165 μL) (400 μL) was added to a solution of 6-bromo-N-(6-bromopyridin-2-yl)nicotinamide 4 (300 mg, 0.73 mmol) in THF (20 ml). The reaction mixture was refluxed for 16 hrs. Then the reaction mixture was cooled to RT, MeOH (2 mL) was added, followed by cone. HCl. and the reaction mixture was refluxed for 8 hrs. The reaction mixture was concentrated and diluted with water (2 ml), the pH adjusted to 14 and the reaction mixture was extracted with chloroform (50 ml×2). The combined organic phases were washed with brine, dried over Na2SO4. Evaporation of the solvent gave a crude product that was purified on silica gel (1:1, EtOAc: pet-ether) to give a white solid which was treated with MeOH/HCl to give N2-((6-(benzylamino)pyridin-3-yl)methyl)pyridine-2,6-diamine 5, hydrochloride salt (50 mg, 49%) as a white solid. Mp. 261-262° C.
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:12]([NH2:14])=[O:13])[CH2:2]1.[CH3:22]N(C=O)C.C(OC(OCC)N(C)C)C.COC(N(C)C)N(C)C>O>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:11]2[C:12](=[O:13])[NH:14][CH:22]=[C:2]3[C:3]=2[NH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:1]3)=[CH:20][CH:19]=1
Reactant: NC(=O)C(=C1CSc2ccccc2N1)c1ccc(F)cc1
Reactant: CN(C)C=O
Agent: CCOC(OCC)N(C)C
Agent: COC(N(C)C)N(C)C
Solvent: O
Product: O=c1[nH]cc2c(c1-c1ccc(F)cc1)Nc1ccccc1S2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 4 parts of 2-(2H-1,4-benzothiazin-3(4H)-ylidene)-2-(4-fluorophenyl)acetamide in 80 parts of DMF is added 6 parts dimethylformamide diethyl acetal and the reaction mixture was stirred at room temperature for 2 to 6 hours then heated at 80°-140° C. for 1 to 6 hours. After cooling 6 parts of methoxy-bis-(dimethylamino)methane is added and the reaction mixture then heated at 50° to 80° C. for 2 to 24 hrs. The cooled reaction mixture is then diluted with 40 parts of water and refluxed for 2 to 18 hr. Upon cooling the precipitate present was collected and recrystallized from aqueous DMF to give 4-(4-fluorophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one which melts above 300°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].N1[C-]=NN=N1.C([NH2+]C(C)C)(C)C.[CH:23]([N:26]([P:30](N(C(C)C)C(C)C)[O:31][CH2:32][CH2:33][C:34]#[N:35])[CH:27]([CH3:29])[CH3:28])([CH3:25])[CH3:24]>ClCCl>[CH:23]([N:26]([P:30]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:10])[O:31][CH2:32][CH2:33][C:34]#[N:35])[CH:27]([CH3:28])[CH3:29])([CH3:24])[CH3:25]
Reactant: CC(C)N(C(C)C)P(OCCC#N)N(C(C)C)C(C)C
Reactant: COC(=O)CCCCCO
Agent: CC(C)[NH2+]C(C)C
Agent: [c-]1nnn[nH]1
Solvent: ClCCl
Product: COC(=O)CCCCCOP(OCCC#N)N(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 0.786 g (5.37 mmole) of methyl-6-hydroxyhexanoate and 0.48 g (2.8 mmole) of diisopropylammonium tetrazolide in 25 ml of dichloromethane were added dropwise 1.62 g (5.37 mmole) of bis(diisopropyl amino)-2-cyanoethyoxyphosphine (Aldrich). The resulting solution was stirred at 25° C. for 2 hours and extracted with phosphate buffer at pH 7. Drying over magnesium sulfate and fast chromatography on silica gel (40% ethylacetate-hexanes, trace triethylamine) yielded the diisopropylamino-5-(carbomethoxy)pentyloxy-2-cyanoethoxy phosphine linking group as a colorless oil (1.30 g: 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2(O)[CH:13]([CH2:14][N:15]([CH3:17])[CH3:16])[CH2:12][CH2:11][O:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)=[CH:4][CH:3]=1.CS(O)(=O)=O.N[C@H](C(O)=O)CCSC>>[ClH:1].[Cl:1][C:2]1[CH:24]=[CH:23][C:5](/[CH:6]=[C:7]2\[C:8]3[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=3[O:10][CH2:11][CH2:12][CH:13]\2[CH2:14][N:15]([CH3:17])[CH3:16])=[CH:4][CH:3]=1
Reactant: CN(C)CC1CCOc2ccccc2C1(O)Cc1ccc(Cl)cc1
Agent: CS(=O)(=O)O
Agent: CSCC[C@H](N)C(=O)O
Product: CN(C)CC1CCOc2ccccc2/C1=C\c1ccc(Cl)cc1
Product: Cl

Procedure:
7.27 g (4RS,5RS)-5-(4-chlorobenzyl)-4-dimethylaminomethyl-2,3,4,5-tetrahydrobenzo[b]oxepin-5-ol were reacted with 43 ml methanesulfonic acid and 4.81 g methionine analogously to the procedure described in example 6. After similarly analogous working up, separation of the product and salt formation, the title compounds were obtained in the form of white crystals.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[CH2:20][C:21]([NH:23][C@H:24]([C:28]([NH:30][C@H:31]([C:44]([O:46]CC1C=CC=CC=1)=[O:45])[CH2:32][CH2:33][C:34]([O:36]CC1C=CC=CC=1)=[O:35])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])(=[O:17])[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][CH3:16]>C(OCC)(=O)C.CO.O.[Pd]>[C:1]([O:18][CH:19]([CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[CH2:20][C:21]([NH:23][C@H:24]([C:28]([NH:30][C@H:31]([C:44]([OH:46])=[O:45])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])(=[O:17])[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][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@H](C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(C)C
Agent: [Pd]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)C(C)C
Yield: 100.1 %

Procedure:
Dibenzyl N-[N-(3-hexadecanoyloxyoctadecanoyl)-L-valyl]-L-glutamate (950 mg) prepared by the method of Example 2 was dissolved in a mixture of ethyl acetate (200 ml) and methanol (50 ml). A suspended mixture of palladium black (800 mg) in water (10 ml) was added thereto. The mixture was subjected to catalytic hydrogenation at 2.5 atmospheric pressure. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dried up by using high vacuum pump to afford amorphus N-[N-(3-hexadecanoyloxyoctadecanoyl)-L-valyl]-L-glutamic acid (770 mg).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][N:14]=[C:13]([N:18]3[CH:22]=[C:21]([CH:23]4[CH2:25][CH2:24]4)[N:20]=[CH:19]3)[CH:12]=[C:7]12.[F:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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>[CH:23]1([C:21]2[N:20]=[CH:19][N:18]([C:13]3[CH:12]=[C:7]4[C:8]5[C:3]([CH2:4][CH2:5][N:6]4[C:16](=[O:17])[CH2:15][N:14]=3)=[C:2]([C:30]3[CH:31]=[N:32][C:27]([F:26])=[CH:28][CH:29]=3)[CH:11]=[CH:10][CH:9]=5)[CH:22]=2)[CH2:24][CH2:25]1
Reactant: O=C1CN=C(n2cnc(C3CC3)c2)C=C2c3cccc(Br)c3CCN12
Reactant: OB(O)c1ccc(F)nc1
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: O
Solvent: COCCOC
Product: O=C1CN=C(n2cnc(C3CC3)c2)C=C2c3cccc(-c4ccc(F)nc4)c3CCN12
Temperature: 85 °C
Reaction time: 0.05 h
Yield: 67.4 %

Procedure:
Example 95-1. 9-bromo-2-(4-cyclopropyl-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (1.48 g, 3.73 mmol), (6-fluoropyridin-3-yl)boronic acid (1.05 g, 7.45 mmol) and a solution of Na2CO3 (1.97 g, 18.63 mmol) in water (14.5 mL) was treated with DME (58 mL). The suspension was degassed, Pd(PPh3)4 (646 mg, 0.56 mmol) was added and the mixture was heated at 85° C. for 2 h. The mixture was allowed to warm to RT and the solvent was removed under reduced pressure. The residue was dissolved in DCM and extracted with water, saturated aqueous NaHCO3 solution and brine. The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash-column chromatography over silicagel (Biotage Isolera Four, eluent: 1% MeOH in DCM for 3 min, then from 1% MeOH in DCM to 4% MeOH in DCM in 25 min, 4% MeOH in DCM for 5 min) to yield a beige foam (1.04 g). The residue was crystallized from AcOEt to afford the title compound as white crystals (720 mg). UPLC-MS: MS 414.2 (M+H+); UPLC rt 0.95 min. 1H NMR (600 MHz, DMSO-d6) δ ppm 0.66 (d, J=3.4 Hz, 2 H), 0.72-0.84 (m, 2 H), 1.70-1.88 (m, 1 H), 2.84 (br. s., 2 H), 3.72 (br. s., 2 H), 4.24 (br. s., 2 H), 7.18 (s, 1 H), 7.31 (d, J=8.5 Hz, 1 H), 7.43 (s, 1 H), 7.47-7.57 (m, 2 H), 7.97-8.14 (m, 3 H), 8.27 (s, 1 H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:42])[CH2:14][N:15]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][CH:25]([C:28]([NH:30][CH:31]6[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]6)=[O:29])[CH2:24][CH2:23]5)=[C:18]([C:38]([F:41])([F:40])[F:39])[CH:17]=4)[C:5]=3[C:4]=2[CH:3]=1.[N:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=[C:45](B(O)O)[CH:44]=1.CC(C1C=C(C(C)C)C(C2C(P(C(C)(C)C)C(C)(C)C)=CC=CC=2)=C(C(C)C)C=1)C>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:37][N:34]1[CH2:33][CH2:32][CH:31]([NH:30][C:28]([CH:25]2[CH2:24][CH2:23][N:22]([C:19]3[CH:20]=[CH:21][C:16]([N:15]4[C:5]5[C:4]6[CH:3]=[C:2]([C:45]7[CH:44]=[N:43][C:52]8[C:47]([CH:46]=7)=[CH:48][CH:49]=[CH:50][CH:51]=8)[CH:11]=[CH:10][C:9]=6[N:8]=[CH:7][C:6]=5[NH:12][C:13](=[O:42])[CH2:14]4)=[CH:17][C:18]=3[C:38]([F:41])([F:40])[F:39])[CH2:27][CH2:26]2)=[O:29])[CH2:36][CH2:35]1
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: CN1CCC(NC(=O)C2CCN(c3ccc(N4CC(=O)Nc5cnc6ccc(Br)cc6c54)cc3C(F)(F)F)CC2)CC1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN1CCC(NC(=O)C2CCN(c3ccc(N4CC(=O)Nc5cnc6ccc(-c7cnc8ccccc8c7)cc6c54)cc3C(F)(F)F)CC2)CC1
Temperature: 25 °C
Yield: 3.1 %

Procedure:
To a solution of 8.5 1-(4-(9-bromo-3-oxo-3,4-dihydropyrazino[2,3-c]quinolin-1(2H)-yl)-2-(trifluoromethyl)phenyl)-N-(1-methylpiperidin-4-yl)piperidine-4-carboxamide (46 mg, 0.07 mmol, 1 equiv.) in dioxane (2 mL) and 1N sodium carbonate solution (0.6 mL) in a sealed tube at room temperature was added 7 quinolin-3-yl-boronic acid (24 mg, 0.14 mmol, 2 equiv.), t-butyl-Xphos (3 mg, 0.007 mmol, 0.1 equiv.), and PdCl2(Ph3P)2 (4.9 mg, 0.007 mmol, 0.1 equiv.). The resulting mixture was degassed, sealed and heated overnight to 100° C. Upon cooling to room temperature, the reaction mixture was filtered through celite and washed with EtOAc (2 mL). The collected solution was evaporated and the residue was purified via HPLC to afford the desired product 8.6 N-(1-methylpiperidin-4-yl)-1-(4-(3-oxo-9-(quinolin-3-yl)-3,4-dihydropyrazino[2,3-c]quinolin-1(2H)-yl)-2-(trifluoromethyl)phenyl)piperidine-4-carboxamide 1.5 mg. LC-MS: (M+H) 694.40
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH2:11])[N:7]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:21]=[C:22]([CH:31]([CH3:35])[C:32](O)=[O:33])[CH:23]=[CH:24][C:25]=1[CH2:26][O:27][CH2:28][CH2:29][OH:30].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1.CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH:11][C:32](=[O:33])[CH:31]([C:22]2[CH:23]=[CH:24][C:25]([CH2:26][O:27][CH2:28][CH2:29][OH:30])=[C:20]([F:19])[CH:21]=2)[CH3:35])[N:7]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(CN)n(-c2ccc(F)cc2)n1
Reactant: CC(C(=O)O)c1ccc(COCCO)c(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C(=O)NCc1cc(C(C)(C)C)nn1-c1ccc(F)cc1)c1ccc(COCCO)c(F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 78.9 %

Procedure:
To a stirred solution of (3-tert-butyl-1-(4-fluorophenyl)-1H-pyrazol-5-yl)methanamine (60 mg, 0.25 mmol, 1.0 eq) in THF/DMF (1/20, v/v, 2 mL) was added 2-(3-fluoro-4-((2-hydroxyethoxy)methyl)phenyl)propanoic acid (61 mg, 0.25 mmol, 1 equiv.), HOBt (35 mg. 0.25 mmol, 1 equiv.), TBTU (80 mg, 0.25 mmo, 1 equiv.) and DIPEA (0.168 mL, 127 mg, 1.01 mmol, 4 equiv.) and the mixture was stirred for 3 d at room temperature. The reaction mixture was evaporated and the residue was purified by column chromatography (EtOAc/cyclohexane (1:2) as eluent) to give N-((3-tert-butyl-1-(4-fluorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-((2-hydroxyethoxy)methyl)phenyl)propanamide (93 mg, 78%).
Reaction SMILES: [C:1]([O: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][CH2:18][CH2:19][CH2:20][CH2:21]O)(=[O:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:47]I>C(Cl)Cl.C1C=CC=CC=1>[C:1]([O: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][CH2:18][CH2:19][CH2:20][CH2:21][I:47])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCCCCCCCCCCCCCCO
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: ClCCl
Product: CC(=O)OCCCCCCCCCCCCCCCCCI
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
17-Acetoxy-heptadecanol (4.4 g, 13.99 mmol), Ph3P (4.4 g, 16.78 mmol) and imidazole (1.57 g, 23.08 mmol) were dissolved in the mixture of CH2Cl2 (40 ml) and benzene (20 ml). The mixture was cooled to 0° C. and solid I2 (4.26 g, 16.78 mmol) was added in one portion. The mixture was stirred at 0° C. for 15 min and at room temperature for 30 min. The reaction was quenched by the addition of EtOH (1.5 ml), stirred for 10 min at room temperature, diluted with hexane-EtOAc (1:1) mixture and washed with aqueous NaHCO3—Na2S2O3 solution. The organic extract was dried Na2SO4 and evaporated. Residue was stirred with hexane (300 ml) for 20 min and the suspension was filtered to remove Ph3PO. The filtrate was evaporated and the residue was chromatographed on silica gel in hexane-EtOAc (98:2) to give 17-acetoxy-heptadecyl iodide (5.89 g, 99%).
Reaction SMILES: Cl.Cl.Cl.Cl.[Zr:5].[CH3:6][CH2:7][CH2:8][CH2:9][CH3:10]>C1(C)C=CC=CC=1>[CH-:8]1[CH:9]=[CH:10][CH:6]=[CH:7]1.[CH-:8]1[CH:9]=[CH:10][CH:6]=[CH:7]1.[Zr+2:5]
Reactant: CCCCC
Reactant: [Zr]
Agent: Cl
Solvent: Cc1ccccc1
Product: [Zr+2]
Product: c1cc[cH-]c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.58 g (6.79 mmol) of zirconium tetrahydrochloride are added in portions to a suspension, cooled to -78° C., of 2.60 g (6.79 mmol) of the bistrimethylsilyl-substituted dilithium salt in 100 ml of toluene. The mixture is allowed to warm to room temperature, giving, after stirring for 24 hours, an orange suspension. Insoluble constituents are separated off, and the solvent is evaporated to dryness, giving a red oil. Addition of 20 ml of pentane followed by work-up gives the two diastereomers of the ansa-zirconocene as an orange powder in a crude yield of 1.54 g (43%); m.p. 151° C. (decomp., DSC).
Reaction SMILES: [C:1]([CH2:4][C@@H:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:8][CH2:7][CH2:6]1)(O)=[O:2].S(Cl)(Cl)=O.CN1CCCC1=O.[CH:37]([NH2:40])([CH3:39])[CH3:38]>ClCCl>[CH:37]([NH:40][C:1]([CH2:4][C@@H:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([S:16]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)(=[O:17])=[O:18])[CH2:8][CH2:7][CH2:6]1)=[O:2])([CH3:39])[CH3:38]
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H](CC(=O)O)c3ccccc32)cc1
Reactant: CC(C)N
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H](CC(=O)NC(C)C)c3ccccc32)cc1
Reaction time: 3 h

Procedure:
To a solution of (5R)-5-carboxymethyl-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-benzazepine (115.6 g) in dry dichloromethane (700 ml) are added thionyl chloride (70 ml) and 1-methyl-2-pyrrolidone (1 ml), and the mixture is refluxed with stirring for three hours. The solution is added dropwise into a solution of isopropylamine (274 ml) in dichloromethane (300 ml) under ice-cooling, and the mixture is stirred for 12 hours. The mixture is evaporated under reduced pressure to remove the dichloromethane, and to the residue is added a 3N aqueous sodium hydroxide solution (1 liter), and the mixture is extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is recrystallized from a 75% aqueous methanol (700 ml) to give (5R)-5-isopropylaminocarbonylmethyl-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-benzazepine (63.2 g).
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].[C:10](O)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][CH:12]=1>>[C:10]([O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:6][CH2:7][CH2:8][CH3:9])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][CH:12]=1
Reactant: CCCCC(CC)CO
Reactant: O=C(O)c1cccnc1
Product: CCCCC(CC)COC(=O)c1cccnc1
Temperature: 200 °C
Reaction time: 6 h

Procedure:
2-Ethylhexyl alcohol (215.5 g, 1.65 mol) was charged to a 500 ml resin kettle and equipped with mechanical stir, a Dean-Stark trap and a thermocouple. The mixture was stirred at 300 rpm and nicotinic acid (61.5 g, 0.5 mol) was added in portions through a powder funnel. The mixture was heated to 200° C. with sub-surface nitrogen flow and held for 6 hours. The mixture was then cooled to 150° C. and vacuum was applied to −15 in Hg and held for 45 min. 22.9 g process oil was added and the mixture was then allowed to cool to room temperature under nitrogen atmosphere. The resulting mixture was then filtered twice through Celite Hyflow and Whatman #1 filter paper to yield desired product.
Reaction SMILES: [C:1]([N:4]1[CH2:11][CH2:10][CH2:9][CH:5]1[C:6]([OH:8])=O)(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[NH:35][C:36](=[O:43])[C:37](=[CH:41][CH:42]=2)[C:38]([OH:40])=[O:39])=[CH:30][CH:29]=1>ClCCl.CN(C)C(=O)C>[C:1]([N:4]1[CH2:11][CH2:10][CH2:9][CH:5]1[C:6]([NH:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]2[NH:35][C:36](=[O:43])[C:37](=[CH:41][CH:42]=2)[C:38]([OH:40])=[O:39])=[CH:32][CH:33]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Reactant: CC(=O)N1CCCC1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCCC1C(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
To a solution of 11.8 g (75 m mol) of N-Acetyl-DL-proline and 10.5 ml (75 m mol) of triethylamine in 150 ml dichloromethane at -15° C., is added 9.75 ml (75 m mol) of isobutyl chloroformate. The reaction mixture is stirred at about -10° C. for 30 min. To this reaction mixture is added a cold solution of 11.5 g (50 m mol) of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid and 7.7 ml (55 m mol) triethylamine in 200 ml of N,N-dimethylacetamide, which is stirred while cooling in an ice bath for 3 hrs, then overnight at room temperature. The reaction mixture is evaporated to dryness, the residue is triturated with water, and the solid collected by filtration. The solid is washed with water and acetonitrile and dried to yield 13.2 g of 6-[4-(N-Acetyl-DL-prolylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid, m.p. 279°-281° dec.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=1.[C:16](Cl)(Cl)(Cl)Cl>>[CH3:5][O:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: COc1ncccc1C(=O)O
Reactant: ClC(Cl)(Cl)Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccnc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Thionyl chloride (50 ml.) was added to 2-methoxypyridine-3-carboxylic acid (5 g.) in 50 ml. of carbon tetrachloride and the mixture refluxed for 2 hours. The reaction mixture was cooled, evaporated to solids and chased with multiple portions of fresh carbon tetrachloride. The resulting acid chloride hydrochloride was dissolved in excess methanol (50 ml.), stirred for 16 hours at room temperature, then evaporated an oil and taken up in chloroform. The chloroform solution was washed with two portions of saturated sodium bicarbonate and then one portion of brine, dried over anhydrous magnesium sulfate, filtered and evaporated to yield title product as an oil [4.63 g.; pnmr/CDCl3 /delta (ppm): 3.9 and 4.1 (2s, 6H), 6.9 (m, 1H), 8.2 (m, 2H)].
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[C:4]([NH2:6])=[O:5].[C:10]1([C@@H:16]([NH2:18])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=[N:18][C@H:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:17])[C:4]([NH2:6])=[O:5]
Reactant: C[C@H](N)c1ccccc1
Reactant: CC(C)(C)C(=O)C(N)=O
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@H](N=C(C(N)=O)C(C)(C)C)c1ccccc1
Yield: 67.8 %

Procedure:
A solution of 35.0 g (271 mmol) of 3,3-dimethyl-2-oxobutyramide and 75.0 g (619 mmol) of (S)-1-phenylethylamine in 250 ml of toluene was boiled under reflux on a water separator for 92 hours. Subsequently, the solvent and excess amine were removed in a vacuum. The residual oil was crystallized from 300 ml of hexane. 51 g of crude material of melting point 96°-97° C. were obtained. After recrystallization from 400 ml of hexane there were obtained 42.7 g (68%) of analytically-pure (S)-3,3-dimethyl-2-(1-phenylethylimino)-butyramide of melting point 100°-101° C. [α]=-58.5 (c=1.0, CHCl3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:39]=[CH:38][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[CH:25]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36]C)=[O:35])=[O:30])[S:27][CH:28]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].[OH-].[Na+].O.Cl>C1COCC1.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[CH:25]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])[S:27][CH:28]=3)[CH:19]=2)=[CH:38][CH:39]=1)=[O:11]
Reactant: COC(=O)CCNC(=O)c1cc(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4csc(C(=O)NCCC(=O)O)c4)c3)cc2)c1
Temperature: 50 °C

Procedure:
To a stirred solution of methyl 3-{[(4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-2-thienyl)carbonyl]amino}propanoate (85 mg, 0.16 mmol) in a mixture of THF/MeOH (5 ml/5 ml) was added 1M NaOH solution (2 ml, 2 mmol). The mixture was heated at 50° C. for one hour and poured into 100 ml of water. 1M HCl was added dropwise with vigorous stirring until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give 3-{[(4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-2-thienyl)carbonyl]amino}propanoic acid as white solid. Yield: 80 mg, 96%.