Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][CH:11]3[C:15]4([CH2:18][CH2:17][CH2:16]4)[CH2:14][N:13]([C:19]([C:21]4([C:24]#[N:25])[CH2:23][CH2:22]4)=[O:20])[CH2:12]3)=[C:8]([C:26]([NH2:28])=[O:27])[CH:7]=[N:6][N:5]2[CH:29]=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][N:33]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N#N.ClCCl>O1CCOCC1.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]>[C:24]([C:21]1([C:19]([N:13]2[CH2:12][CH:11]([NH:10][C:9]3[C:4]4[N:5]([CH:29]=[C:2]([C:35]5[CH:34]=[N:33][C:32]([O:31][CH3:30])=[CH:37][CH:36]=5)[CH:3]=4)[N:6]=[CH:7][C:8]=3[C:26]([NH2:28])=[O:27])[C:15]3([CH2:16][CH2:17][CH2:18]3)[CH2:14]2)=[O:20])[CH2:23][CH2:22]1)#[N:25]
Reactant: COc1ccc(B(O)O)cn1
Reactant: N#CC1(C(=O)N2CC(Nc3c(C(N)=O)cnn4cc(Br)cc34)C3(CCC3)C2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(-c2cc3c(NC4CN(C(=O)C5(C#N)CC5)CC45CCC5)c(C(N)=O)cnn3c2)cn1
Temperature: 105 °C
Reaction time: 0.25 h
Yield: 52.4 %

Procedure:
A solution of (+/−)-6-bromo-4-((6-(1-cyanocyclopropanecarbonyl)-6-azaspiro[3.4]octan-8-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide from Step 3 of Example 320 (15.0 mg, 0.033 mmol), 2-Methoxy-5-pyridineboronic acid (10.03 mg, 0.066 mmol) in 1,4-dioxane (437 μl) and potassium phosphate (2.0M) (49.2 μl, 0.098 mmol) was degassed for several minutes with N2 gas. 1,1′-Bis(diphenylphosphino)ferrocenepalladium(II) dichloride, dichloromethane (2.70 mg, 3.28 μmol) was added, degassing was continued for 1 more minute. The vial was sealed, and the contents were heated @ 105° C. for 50 minutes. HPLC and LC/MS indicated that the reaction had essentially proceeded to completion as no starting material was detected. (m/e 486.24, no Bromine pattern, M+H for desired product). After cooling to room temperature the reaction was diluted with methanol, filtered through a VWR 0.45 micron Nylon filter disc and the crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×150 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-100% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 8.4 mg of the title compound. LC/MS: m/e 486.0 (M+H). 1H NMR (500 MHz, METHANOL-d4/CDCl3) δ 8.44 (dd, J=7.9, 2.5 Hz, 1H), 8.17 (d, J=9.4 Hz, 1H), 7.96 (ddd, J=8.4, 4.5, 2.5 Hz, 1H), 7.91 (dd, J=12.1, 1.7 Hz, 1H), 7.21-6.99 (m, 1H), 6.86 (d, J=8.4 Hz, 1H), 4.88 (d, J=1.5 Hz, 1H), 4.36 (dd, J=10.9, 5.0 Hz, 0.5H), 4.25 (d, J=10.9 Hz, 1H), 4.11 (d, J=10.9 Hz, 1H), 4.08 (d, J=2.5 Hz, 0.5H), 3.96 (d, J=1.5 Hz, 3H), 3.90 (dd, J=12.9, 4.5 Hz, 0.5H), 3.84-3.71 (m, 0.5H), 2.54-1.96 (m, 6H), 1.84-1.40 (m, 4H)
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[CH:6][CH:7]=1.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([NH:23][NH2:24])=O)=[CH:16][CH:15]=1>C(O)CCC>[S:9]1[CH:10]=[CH:11][N:12]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]2[N:3]([C:21]([CH2:20][C:17]3[CH:18]=[CH:19][C:14]([OH:13])=[CH:15][CH:16]=3)=[N:23][N:24]=2)[N:4]=1
Reactant: NNC(=O)Cc1ccc(O)cc1
Reactant: Clc1ccc(-c2nccs2)nn1
Solvent: CCCCO
Product: Oc1ccc(Cc2nnc3ccc(-c4nccs4)nn23)cc1
Temperature: 120 °C
Yield: 37.2 %

Procedure:
3-Chloro-6-thiazol-2-yl-pyridazine (20 mg, 0.10 mmol) and (4-Hydroxy-phenyl)-acetic acid hydrazide (20 mg, 0.12 mmol) were combined in butanol (5 mL), fitted with water filled condenser and heated to 120° C. overnight. The reaction was concentrated in vacuo followed by purification by HPLC (10-80% CH3CN over 25 min) resulting in the title compound (11.5 mg, 37%) as a white solid.
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.Cl.[NH:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH3:15].CCN(CC)CC.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([N:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH3:15])=[O:5]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CNCC(=O)OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CN(C)C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 80.1 %

Procedure:
A solution of Boc-Gly-OH (2.70 g, 15.4 mmol) and the HCl salt of H2N-Sar-OMe (2.15 g, 15.4 mmol) in CH2Cl2 (50 mL) was treated sequentially with Et3N (2.2 mL, 15.8 mmol), DCC (3.20 g, 15.5 mmol), and DMAP (306 mg, 2.5 mmol) and the reaction mixture was stirred at 25° C. for 20 h. A white precipitate formed in the first 10 min and was removed by filtration at the end of the reaction. The filtrate was concentrated in vacuo. Flash chromatography (SiO2, 5×16 cm, 40% EtOAc-hexane eluent) afforded 200 (3.21 g, 4.01 g, theoretical, 80%) as a colorless oil which solidified on standing: mp 72-73° C. (EtOAc-hexane, colorless cubes); Rf=0.32 (50% EtOAc-hexane); 1H NMR (CDCl3, 400 MHz) 4:1 mixture of two conformers, for the major conformer: 5.44 (s, 1H), 4.14 (s, 2H), 4.02 (d, 2H, J=4.3 Hz), 3.73 (s, 3H), 3.02 (s, 3H), 1.43 (s, 9H); 13C NMR (CDCl3, 100 MHz) for major conformer: 169.3, 168.7, 155.7, 79.6, 52.2, 49.4, 42.2, 35.2, 28.3; IR (KBr)max 3419, 2978, 2934, 1754, 1715, 1667, 1488, 1424, 1367, 1249, 1208, 1175, 1120, 1051, 952, 871, 764, 712 cm−1; FABHRMS (NBA-NaI) m/z 283.1259 (M+Na+, C11H20N2O5 requires 283.1270).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18](Br)[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:24][N:25]([CH3:43])[C:26](=[O:42])[C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([C:30]5[CH:31]=[CH:32][C:27]([C:26]([N:25]([CH3:43])[CH3:24])=[O:42])=[CH:28][CH:29]=5)[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Reactant: CN(C)C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(C(=O)N(C)C)cc1
Temperature: 150 °C

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-methylphenyl)cyclopropanecarboxamide (0.10 mmol), N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.11 mmol), K2CO3 (240 μL, 1M), Pd-FibreCat (7 mg), and DMF (1 mL) were combined. The mixture was heated at 150° C. for 5 min (5 min ramp time) in a microwave reactor. After cooling, the mixture was filtered and purified by prep-HPLC to provide 4-[5-(1-benzo[1,3]dioxol-5-ylcyclopropyl)carbonylamino-2-methyl-phenyl]-N,N-dimethyl-benzamide. ESI-MS m/z calc. 442.2, found 443.5 (M+1)+; Retention time 3.12 minutes. 1H NMR (400 MHz, DMSO-d6) δ 1.02-1.08 (m, 2H), 1.37-1.44 (m, 2H), 2.17 (s, 3H), 2.96 (s, 3H), 3.00 (s, 3H), 6.01 (s, 2H), 6.87-6.93 (m, 2H), 6.98 (d, J=1.3 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.34-7.37 (m, 2H), 7.40-7.52 (m, 4H), 8.75 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:9]2[CH2:11][O:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N-:20]=[N+:21]=[N-:22].[Na+].[Cl-].[NH4+]>CO>[C:15]([O:14][C:13]([NH:12][C@@H:8]([CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C@H:9]([OH:10])[CH2:11][N:20]=[N+:21]=[N-:22])=[O:19])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@H]1CO1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@H](O)CN=[N+]=[N-]
Temperature: 70 °C

Procedure:
tert-Butyl (S)-2-cyclohexyl-1-((S)-oxiran-2-yl)ethylcarbamate (492 mg, 1.82 mmol), sodium azide (600 mg, 9.2 mmol), and ammonium chloride (540 mg, 10 mmol) were dissolved in MeOH (26 mL). The reaction was heated to 70° C. for 15 h. The solution was cooled to rt and quenched with water (80 mL). The solution was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4, and the solvent was removed. The crude (2R,3S)-3-amino-1-azido-4-cyclohexylbutan-2-ol (524 mg) was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:12])=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].P([O-])(O)(O)=[O:14].[Na+].Cl([O-])=O.[Na+]>CS(C)=O.O>[F:1][C:2]1[C:3]([OH:12])=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[C:5]([OH:14])=[O:6]
Reactant: COc1ccc(C=O)c(O)c1F
Reactant: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(C(=O)O)c(O)c1F
Temperature: 20 °C
Reaction time: 16 h
Yield: 67.8 %

Procedure:
To a mixture of 3-fluoro-2-hydroxy-4-methoxybenzaldehyde (10.0 g) and sodium dihydrogenphosphate (22.9 g) in DMSO (100 mL) and water (25.0 mL) was added dropwise an aqueous solution (30.0 mL) of sodium chlorite (14.5 g), and the mixture was stirred at 20° C. for 16 hr. The solvent was evaporated under reduced pressure, the residue was diluted with water, and the mixture was extracted with ethyl acetate (×6). The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (7.42 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]([N:21]=[N+]=[N-])=[O:20])[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(N[C@H](C(NN)=O)CC1N=CNC=1)=O)C1C=CC=CC=1.[CH:46]1([NH:52][C:53]([C@@H:55]2[CH2:59][CH2:58][CH2:57]N2)=[O:54])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]([N:21]1[CH2:57][CH2:58][CH2:59][C@H:55]1[C:53]([NH:52][CH:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1)=[O:54])=[O:20])[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Reactant: O=C(NC1CCCCC1)[C@@H]1CCCN1
Agent: NNC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)NC1CCCCC1)OCc1ccccc1

Procedure:
To 30 ml of an ethyl acetate solution of compound (4) prepared from 1.52 g of compound (3) by the method shown in Reference example 2 was added 785 mg of (S)-N-cyclohexyl-2-pyrrolidinecarboxamide (36) prepared by a known method and then the reaction was maintained overnight in a refrigerator. The reaction mixture was concentrated and the residue thus formed was subjected to silica gel column chromatography. By eluting the product with chloroform-methanol-aqueous ammonia (90:10:1), 1.30 g of Nα -benzyloxycarbonyl-L-histidyl-N-cyclohexyl-L-prolinamide (37) was obtained.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][CH:11]([CH2:13][CH2:14][OH:15])[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.[NH2:58][CH:59]1[CH2:64][CH2:63][N:62]([CH3:65])[CH2:61][CH2:60]1.C(N(CC)CC)C>ClCCl>[CH:1]1([N:6]2[CH2:12][CH:11]([CH2:13][CH2:14][OH:15])[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:58][CH:59]5[CH2:64][CH2:63][N:62]([CH3:65])[CH2:61][CH2:60]5)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(CCO)C(=O)N2C
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(CCO)C(=O)N2C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 143.4 %

Procedure:
A mixture of 0.047 g (0.0001 mole) of (rac)-4-[9-cyclopentyl-7-(2-hydroxy-ethyl)-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-benzoic acid (I-49a), 0.043 g (0.00011 mole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.027 g (0.000023 mole) of 4-amino-1-methylpiperidine, 0.05 mL of triethylamine and 2 mL of dichloromethane was stirred at room temperature for 1.5 hours and then concentrated under reduced pressure. The residue purified by C18 reverse phase silica gel chromatography, eluting with an acetonitrile-water gradient (10:90-100:0) to give 0.0182 g of (rac)-4-[9-cyclopentyl-7-(2-hydroxy-ethyl)-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-49)
Reaction SMILES: [N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[C:8]([C:10]3[CH:19]=[C:18]4[C:13]([CH:14]([C:21]5[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=5)[CH2:15][N:16](C)[CH2:17]4)=[CH:12][C:11]=3[F:29])[CH:7]=[CH:6][C:5]=12.CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.ClC(OC(Cl)C)=O.[C:53]([OH:62])(=[O:61])[C@@H:54]([C@H:56]([C:58]([OH:60])=[O:59])[OH:57])[OH:55]>ClCCCl.C(Cl)Cl.C(#N)C.O>[C:58]([C@@H:56]([C@H:54]([C:53]([OH:62])=[O:61])[OH:55])[OH:57])([OH:60])=[O:59].[N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[C:8]([C:10]3[CH:19]=[C:18]4[C:13]([CH:14]([C:21]5[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=5)[CH2:15][NH:16][CH2:17]4)=[CH:12][C:11]=3[F:29])[CH:7]=[CH:6][C:5]=12
Reactant: CN1Cc2cc(-c3ccc4ncnn4c3)c(F)cc2C(c2ccc(Cl)c(Cl)c2)C1
Agent: CC(Cl)OC(=O)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: Fc1cc2c(cc1-c1ccc3ncnn3c1)CNCC2c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 140.5 %

Procedure:
To (+)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinoline (160 mg, 0.37 mmol) and N1,N1,N8,N8-tetramethylnaphthalene-1,8-diamine (160 mg, 0.37 mmol) in 1,2-dichloroethane (5 mL) was added 1-chlorethyl chloroformate (0.082 mL, 0.75 mmol) dropwise. The mixture was heated to reflux for 3 hours and then cooled to ambient temperature. The reaction mixture was diluted with methylene chloride and washed with 1N HCl, water, dried over sodium sulfate, filtered, and concentrated in vacuo. To the residue was added methanol (15 mL) and the mixture was heated to reflux. After 1 h, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was taken up in ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate (10 mL), water (10 mL), brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (methylene chloride to 90:9:1 methylene chloride/methanol/ammonium hydroxide) and preparative TLC (90:9:1 methylene chloride/methanol/ammonium hydroxide). To the obtained material (10 mg, 0.024 mmol) in acetonitrile (1.5 mL) was added L-tartaric acid (3.6 mg, 0.024 mmol) in water (2 mL). The resultant solution was lyophilized to give (+)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline, L-tartrate salt (19 mg, 9%, AUC HPLC>99%) as a white powder: 1H NMR (CD3OD, 500 MHz) 9.03 (s, 1H), 8.47 (s, 1H), 7.93 (d, J=9.0 Hz, 1H), 7.87 (d, J=9.5 Hz, 1H), 7.60-7.56 (m, 2H), 7.50 (d, J=2.0 Hz, 1H), 7.24 (dd, J=8.0, 1.5 Hz, 1H), 6.80 (d, J=11.5 Hz, 1H), 4.56-4.46 (m, 3H), 4.43 (s, 2.3H), 3.78-3.73 (m, 1H), 3.41-3.38 (m, 1H); ESI MS m/z 413 [M+H]+; [ ]24D+21.2° (c 0.11, methanol).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[N:14]1[CH2:19][CH2:18][CH:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH:15]1[NH2:27])[C:8]([OH:10])=O)(=[O:4])=[O:3].CS(C1C=C(C=CC=1F)C(OC)=O)(=O)=O.C(C1CCN(N)CC1)(OC(C)(C)C)=O.[Cl-].C[N+]1C=CC=CC=1Cl.[Cl-].[NH2:67][C:68]([NH2:70])=[NH2+:69].C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[NH2:69][C:68]([NH2:70])=[N:67][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][C:13]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:16][CH:15]2[NH2:27])=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=1
Reactant: NC(N)=[NH2+]
Reactant: CC(C)(C)OC(=O)C1CCN(c2ccc(C(=O)O)cc2S(C)(=O)=O)C(N)C1
Agent: CC(C)(C)OC(=O)C1CCN(N)CC1
Agent: COC(=O)c1ccc(F)c(S(C)(=O)=O)c1
Agent: C[n+]1ccccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)C1CCN(c2ccc(C(=O)N=C(N)N)cc2S(C)(=O)=O)C(N)C1
Reaction time: 0.25 h

Procedure:
1.0 g of 3-methylsulphonyl-4-(4-BOC-aminopiperidino)benzoic acid [obtainable by reacting methyl 3-methylsulphonyl-4-fluorobenzoate with 4-BOC-aminopiperidine and subsequently hydrolyzing the product to give the free acid] is dissolved in 15 ml of 1-methylpyrrolidone, and 0.67 g of 1-methyl-2-chloropyridinium chloride is added to this solution, which is stirred for 15 min. 0.9 g of guanidinium chloride and 2.6 ml of diisopropylethylamine are then added and the mixture is stirred at room temperature for 1 hr. After customary working-up, and after chromatography on silica gel (flash process, ethylacetate/10% methanol), N-diaminomethylene-3-methylsulphonyl-4-(4-BOC-aminopiperidino)benzamide is obtained.
Reaction SMILES: C[O:2][C:3](=[O:26])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:25])[N:15]([CH3:24])[C:16]([CH3:23])=[CH:17][C:18]=2[C:19]([F:22])([F:21])[F:20])=[CH:9][CH:8]=1)[NH2:5].[CH3:27][CH:28]([C:30]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[C:31]=1[C:32](Cl)=[O:33])[CH3:29]>>[CH3:29][CH:28]([C:30]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[C:31]=1[C:32]([NH:5][C@H:4]([C:3]([OH:2])=[O:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:25])[N:15]([CH3:24])[C:16]([CH3:23])=[CH:17][C:18]=2[C:19]([F:22])([F:20])[F:21])=[CH:9][CH:8]=1)=[O:33])[CH3:27]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1
Reactant: Cc1cccc(C(C)C)c1C(=O)Cl
Product: Cc1cccc(C(C)C)c1C(=O)N[C@@H](Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1)C(=O)O

Procedure:
N-[[2-(1-methylethyl)-6-methylphenyl]carbonyl]-4-[ 1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine was prepared from 4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester and 2-(1-methylethyl)-6-methylbenzoyl chloride using the general procedures described in example 33. ES-HRMS m/e calcd for C28H29F3N2O4 (M+Na) 537.1972, found 537.1977.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([N:15]1[CH2:20][CH2:19][C:18]([CH2:22][CH3:23])([CH3:21])[CH2:17][CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>>[CH2:22]([C:18]1([CH3:21])[CH2:19][CH2:20][N:15]([C:13](=[O:14])[CH2:12][N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3](=[O:4])[CH2:2][NH:1][C:32]([NH:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([CH3:24])[CH:26]=2)=[O:33])[CH2:16][CH2:17]1)[CH3:23]
Reactant: CCC1(C)CCN(C(=O)CN(C(=O)CN)c2ccccc2)CC1
Reactant: Cc1cccc(N=C=O)c1
Product: CCC1(C)CCN(C(=O)CN(C(=O)CNC(=O)Nc2cccc(C)c2)c2ccccc2)CC1
Yield: 21.1 %

Procedure:
The procedure is analogous to that described in Example 1, but 1.7 g of 2-amino-N-[2-(4-ethyl-4-methylpiperidino)-2-oxoethyl]-N-phenylacetamide and 0.7 g of 3-methylphenyl isocyanate are used as the starting material. After recrystallization from ethyl acetate, 0.5 g of N-[2-(4-ethyl-4-methylpiperidino)-2-oxoethyl]-2-[3-(3-methylphenyl)ureido]-N-phenylacetamide melting at 204° C is obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>>[F:31][C:32]1[CH:37]=[C:36]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]2)[NH:20][C:19]3=[O:29])[CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Reactant: OB(O)c1cccc(F)c1
Product: O=C(O)c1cnn(-c2nc3ccc(-c4cccc(F)c4)cc3c(=O)[nH]2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E, using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 69 product from step B) and 3-fluorophenylboronic acid in step C. MS (ESI): mass calcd. for C18H11FN4O3, 350.1; m/z found, 351.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.01 (br s, 2H), 8.98 (s, 1H), 8.38 (d, J=2.0 Hz, 1H), 8.29 (s, 1H), 8.22-8.20 (m, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.68-7.64 (m, 2H), 7.58-7.54 (m, 1H), 7.28-7.24 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:29])([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[CH2:11]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:49]C(Br)(Br)Br>ClCCl>[F:1][C:2]([O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[CH2:11][Br:49])([F:29])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1
Reactant: OCc1cc(F)ccc1OC(F)(F)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ccc(OC(F)(F)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)c(CBr)c1
Yield: 81 %

Procedure:
220 mg (0.53 mmol) of (2-{difluoro-[4′-(trifluoromethyl)biphenyl-4-yl]methoxy}-5-fluorophenyl)-methanol from Example 40A, 154 mg (0.59 mmol) of triphenylphosphine and 194.6 mg (0.59 mmol) tetrabromomethane are stirred in 5 ml dichloromethane at RT for 12 hours. 2 g of silica gel are added to the reaction mixture, and the mixture is then dried in vacuo and purified by silica gel chromatography (mobile phase: cyclohexane/ethyl acetate 10:1). 217 mg (0.46 mmol, 95% purity, 81% yield) of a solid are isolated.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[N:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][C:26]2=[O:31])=[CH:21][CH:20]=1)=[C:17]=[O:18].[Br-].[Li+]>O1CCCC1>[O:18]=[C:17]1[N:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][C:26]3=[O:31])=[CH:21][CH:20]=2)[CH2:3][C@H:2]([CH2:4][N:5]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:15])[O:1]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Reactant: O=C=Nc1ccc(N2CCOCC2=O)cc1
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Yield: 88.4 %

Procedure:
(S)-2-(oxiran-2-ylmethyl)isoindoline-1,3-dione (3.87 g, 19.06 mmol, 1.1 eq.) and 4-(4-isocyanatophenyl)morpholin-3-one (3.77 g, 17.29 mmol) were dissolved in tetrahydrofuran (70 mL) respectively and then heated to reflux. Then lithium bromide (0.15 g, 1.74 mmol) was added, the mixture was reacted for 4 h, white solid was obtained by filtration (6.45 g, yield: 88.4%).
Reaction SMILES: C[O-].[Na+].[NH:4]([CH2:11][CH2:12][C:13]#[N:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O[CH:16]([C:22]1[CH:31]=[C:30]([O:32][CH3:33])[C:25]([NH:26][C:27](=[O:29])[CH3:28])=[C:24]([O:34][CH3:35])[CH:23]=1)CS(C)(=O)=O>CS(C)=O>[NH:4]([CH:11]=[C:12]([C:13]#[N:14])[CH2:16][C:22]1[CH:31]=[C:30]([O:32][CH3:33])[C:25]([NH:26][C:27](=[O:29])[CH3:28])=[C:24]([O:34][CH3:35])[CH:23]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COc1cc(C(O)CS(C)(=O)=O)cc(OC)c1NC(C)=O
Reactant: N#CCCNc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(CC(C#N)=CNc2ccccc2)cc(OC)c1NC(C)=O

Procedure:
A mixture of 3.78 g. of sodium methylate, 5.1 g. of β-anilino-propionitrile and 9.8 g. of 4'-[(1-hydroxy-2-(methylsulfonyl)-ethyl)]-2',6'-dimethoxy-acetanilide in 40 ml. of dimethylsulfoxide was stirred at 50° C. for 4 hours with the exclusion of moisture. The mixture was poured into 400 ml. of water and the resulting emulsion was extracted with three 500 ml. portions of ethyl acetate. The ethyl acetate extracts were washed with two 200 ml. portions of water, combined, dried over magnesium sulfate and evaporated under vacuum. Recrystallization of the residue from ethyl acetate gave 4'-(3-anilino-2-cyano-allyl)-2',6'-dimethoxyacetanilide having a melting point of 165°-167° C.