Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.Cl[C:30]1[N:35]=[CH:34][C:33]([C:36]2[O:40][N:39]=[C:38]([C:41]3[N:46]=[C:45]([N:47]([CH3:54])[C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[N:44]=[C:43]([NH2:55])[N:42]=3)[N:37]=2)=[CH:32][CH:31]=1.[F:56][C:57]([F:61])([F:60])[CH2:58][NH2:59].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:54][N:47]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:45]1[N:44]=[C:43]([NH2:55])[N:42]=[C:41]([C:38]2[N:37]=[C:36]([C:33]3[CH:34]=[N:35][C:30]([NH:59][CH2:58][C:57]([F:61])([F:60])[F:56])=[CH:31][CH:32]=3)[O:40][N:39]=2)[N:46]=1
Reactant: NCC(F)(F)F
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(Cl)nc3)n2)n1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(NCC(F)(F)F)nc3)n2)n1
Yield: 6 %

Procedure:
DavePhos (2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, 0.023 g, 0.058 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.024 g, 0.026 mmol) were added to a mixture of 6-[5-(6-chloropyridin-3-yl)-1,2,4-oxadiazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-triazine-2,4-diamine (Intermediate 135, 0.100 g, 0.263 mmol) and 2,2,2-trifluoroethan-1-amine (0.084 mL, 1.050 mmol) in THF (1 mL) under nitrogen at room temperature. The reaction mixture was degassed by nitrogen bubbling and a 1M solution of LiHMDS in THF (2.10 mL, 2.10 mmol) was added drop wise at room temperature. The reaction mixture was heated under microwave conditions (200 W, T=120 C) for 40 min (20 min ramp, 20 min at 120 C) while being stirred. At room temperature the reaction mixture was diluted with EtOAc and filtered. The collected solid was taken in MeOH, filtered and wash with a large amount of MeOH and further purified by preparative HPLC, to afford the title compound (7 mg, 6%).
Reaction SMILES: [OH:1][CH:2]1[CH:6]([NH:7][C:8]([CH2:10][N:11]2[CH2:17][C:16]([CH2:18][NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26](OC)=[CH:25][CH:24]=3)(=[O:22])=[O:21])=[CH:15][CH2:14][CH:13]([NH:31][C:32]([C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH:35]=3)=[O:33])[C:12]2=[O:44])=[O:9])[CH2:5][C:4](=[O:45])[O:3]1.OC1C(NC(CN2CC(CNS(C3C=C(C)C=CC=3)(=O)=O)=CCC(NC(C3C=CC4C(=CC=CC=4)C=3)=O)C2=O)=O)CC(=O)O1>>[C:23]1([S:20]([NH:19][CH2:18][C:16]2[CH2:17][N:11]([CH2:10][C:8](=[O:9])[NH:7][CH:6]3[CH2:5][C:4](=[O:45])[O:3][CH:2]3[OH:1])[C:12](=[O:44])[CH:13]([NH:31][C:32]([C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH:35]=3)=[O:33])[CH2:14][CH:15]=2)(=[O:22])=[O:21])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COc1ccc(S(=O)(=O)NCC2=CCC(NC(=O)c3ccc4ccccc4c3)C(=O)N(CC(=O)NC3CC(=O)OC3O)C2)cc1
Agent: Cc1cccc(S(=O)(=O)NCC2=CCC(NC(=O)c3ccc4ccccc4c3)C(=O)N(CC(=O)NC3CC(=O)OC3O)C2)c1
Product: O=C(CN1CC(CNS(=O)(=O)c2ccccc2)=CCC(NC(=O)c2ccc3ccccc3c2)C1=O)NC1CC(=O)OC1O

Procedure:
1H NMR (CD3OD) δ 8.45 (s, 1H), 8.01–7.89 (m, 6H), 7.67–7.55 (m, 5H), 5.67 (bs, 1H), 5.43–5.38 (d, d, J=12.3, 3.9 Hz, 1H), 4.69–4.59 (m, 2H), 4.40–4.32 (m, 1H), 4.19 (s, 2H), 3.51 (s, 2H), 3.46–3.45 (d, J=3.6 Hz, 1H), 2.77–2.64 (m, 2H), 2.60–2.41 (m, 2H); MS 607 (M+H). Naphthalene-2-carboxylic acid {1-[(2-hydroxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-6-[(4-methoxy-benzenesulfonylamino)-methyl}-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl}-amide: 1H NMR (CD3OD) δ 8.46 (s, 1H), 8.02–7.92 (m, 4H), 7.85–7.82 (d, J=8.7 Hz, 2H), 7.64–7.56 (m, 2H), 7.14–7.11 (d, J=9.3 Hz, 1H), 5.67 (bs, 1H), 5.41–5.35 (d, d, J=12.6, 4.2 Hz, 1H), 4.69–4.66 (d, d, J=4.8, 4.2 Hz, 1H), 4.62–4.58 (d, J=16.5 Hz, 1H), 4.40–4.31 (m, 1H), 4.25–4.13 (m, 2H), 3.96 (s, 3H), 3.53–3.33 (m, 3H), 2.77–2.64 (m, 2H), 2.57–2.49 (m, 2H); MS 637.4 (M+H). Naphthalene-2-carboxylic acid {1-[(2-hydroxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-2-oxo-6-[(toluene-3-sulfonylamino)-methyl]-2,3,4,7-tetrahydro-1H-azepin-3-yl}-amide: 1H NMR (CD3OD) δ 8.46 (s, 1H), 8.02–7.91 (m, 4H), 7.72–7.68 (m, 2H), 7.62–7.56 (m, 2H), 7.51–7.49 (m, 2H), 5.67 (bs, 1H), 5.43–5.37 (d, d, J=12.9, 4.5 Hz, 1H), 4.69–4.66 (d, d, J=4.5, 3.9 Hz, 1H), 4.65–4.59 (d, J=16.8 Hz, 1H), 4.40–4.31 (m, 1H), 4.26–4.19 (d, J=16.5 Hz, 1H), 4.18–4.12 (d, J=16.5 Hz, 1H), 3.53–3.46 (m, 3H), 2.77–2.67 (m, 2H), 2.57–2.49 (m, 2H), 2.47 (s, 3H); MS 621.2 (M+H).
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[NH2:17])\[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2.[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C:27]#N)[CH:22]=[CH:23][C:24]=1[Cl:25].C(O)C.Cl>C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C:27]2[O:1][N:2]=[C:3]([CH2:4][O:5][C:6]3[CH:7]=[C:8]4[C:13](=[CH:14][CH:15]=3)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]4)[N:17]=2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: N#CNc1ccc(Cl)c(Cl)c1
Reactant: N/C(COc1ccc2c(c1)CCC(=O)N2)=N/O
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1CCc2cc(OCc3noc(Nc4ccc(Cl)c(Cl)c4)n3)ccc2N1
Temperature: 25 °C
Reaction time: 12 h
Yield: 7 %

Procedure:
To a solution of (E)-N′-hydroxy-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetimidamide (0.1 g, 0.425 mmol) in ethyl acetate (10 mL) was added a 0.5M solution of zinc chloride (0.073 mL, 0.510 mmol) followed by N-(3,4-dichlorophenyl)cyanamide (0.080 g, 0.425 mmol) and stirred at room temperature for 12 h. Then reaction mixture was concentrated. Ethanol (10.00 mL) was added along with HCl (0.1 mL, 3.29 mmol) and the reaction mixture was heated at 80° C. for 6 h. The reaction mixture was concentrated and basified with sodium bicarbonate solution, then the resulting solid was filtered and was washed with acetonitrile to give 6-((5-((3,4-dichlorophenyl)amino)-1,2,4-oxadiazol-3-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one as a white solid (12 mg, 6.8% yield). 1H NMR 400 MHz, DMSO-d6: δ 2.41 (t, J=15.20 Hz, 2H), 2.84 (t, J=15.20 Hz, 2H), 4.94 (s, 2H), 6.77-6.79 (m, 1H), 6.84-6.87 (m, 1H), 6.93 (d, J=2.80 Hz, 1H), 7.30 (s, 1H), 7.37 (s, 1H), 7.80 (s, 1H), 9.91 (s, 1H). LCMS: RT 1.963 min; LCMS (ES-API), m/z 403.0 [M−H]−.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:31]=[C:30](Cl)[N:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:40]1([CH3:49])[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1B(O)O>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:31]=[C:30]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[CH3:49])[N:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(Cl)nc(-c3ccccc3)n2)CC1
Reactant: Cc1ccccc1B(O)O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(-c3ccccc3C)nc(-c3ccccc3)n2)CC1

Procedure:
This compound was prepared using a method analogous to that of Example 86, step 86.1, 4-{(S)-4-tert-butoxycarbonyl-2-[(6-chloro-2-phenyl-pyrimidine-4-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester replacing 2-chloro-6-methyl-pyrimidine-4-carboxylic acid methyl ester and 2-tolylboronic acid replacing phenylboronic acid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:28][C:29]([F:39])([F:38])[CH:30]([C:34]([F:37])([F:36])[F:35])[C:31](O)=[O:32]>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:23])([CH3:24])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:31](=[O:32])[CH:30]([C:29]([F:38])([F:28])[F:39])[C:34]([F:37])([F:36])[F:35])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1NC(=O)OC(C)(C)C
Reactant: O=C(O)C(C(F)(F)F)C(F)(F)F
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC(=O)C(C(F)(F)F)C(F)(F)F)ccc2F)N=C1N

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate F2) and 3,3,3-trifluoro-2-trifluoromethyl-propionic acid followed by deprotection of the intermediate yielded the title compound as a white solid. MS (ESI): m/z=457.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][OH:11])=[N:6][C:7]=1[NH:8][CH3:9]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:10]=[O:11])=[N:6][C:7]=1[NH:8][CH3:9]
Reactant: CNc1nc(CO)ccc1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CNc1nc(C=O)ccc1C

Procedure:
A suspension of 0.33 g of (5-methyl-6-methylaminopyridin-2-yl)methanol (2.17 mmol) and 1.6 g of manganese dioxide (18.4 mmol) in 12 ml of chloroform is heated under reflux for 1 hour. The insoluble matter is removed by filtration on celite and then the solvent evaporated under vacuum. The title product is purified by chromatography on a silica column (eluent: chloroform). 0.25 g of a yellow solid is recovered.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([S:15]([NH2:18])(=[O:17])=[O:16])[CH:6]=[N:7][C:8]=1[O:9][C@@H:10]1[CH2:14][CH2:13][NH:12][CH2:11]1.[F:19][CH:20]([F:23])[CH2:21]I.C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Cl:2][C:3]1[CH:4]=[C:5]([S:15]([NH2:18])(=[O:16])=[O:17])[CH:6]=[N:7][C:8]=1[O:9][C@@H:10]1[CH2:14][CH2:13][N:12]([CH2:21][CH:20]([F:23])[F:19])[CH2:11]1
Reactant: FC(F)CI
Reactant: NS(=O)(=O)c1cnc(O[C@@H]2CCNC2)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cnc(O[C@@H]2CCN(CC(F)F)C2)c(Cl)c1
Temperature: 25 °C

Procedure:
A reaction mixture of EXAMPLE 422B (353 mg), 1,1-difluoro-2-iodoethane (268 mg) and Na2CO3 (283 mg) in N,N-dimethylformamide (10 mL) was heated at 80° C. overnight. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified with 2.5-3% methanol/dichloromethane to afford the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:8]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:10]=1)=[O:4].[OH-].[Na+].Cl>C1COCC1>[CH3:14][S:11]([C:9]1[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:8]=1)(=[O:12])=[O:13]
Reactant: COC(=O)c1cc(S(C)(=O)=O)ccc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)O)c1
Temperature: 60 °C
Yield: 95 %

Procedure:
To 3.44 mmol 4-Methanesulfonyl-biphenyl-2-carboxylic acid methyl ester in 5 ml THF was added 37.9 mmol 5 M aq. NaOH solution and the mixture was heated at 60° C. for 16 h. The mixture was then cooled to RT, acidified to pH 1 with conc. hydrochloric acid, and extracted 3 times with ethyl acetate. The combined organic phases were dried with Na2SO4. Evaporation in vacuo afforded the title compound (95%) as an off-white crystalline solid. MS (m/e): 275.1 (M−H, 100%)
Reaction SMILES: [N:1]1([C:5]([C:7]2[S:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3Cl)[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:17][NH:18][C:19]([C:21]1[C:22]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:23]=2[S:24][C:25]=1[CH2:26][CH3:27])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:17][NH:18][C:19]([C:21]1[C:22]2[CH:31]=[CH:30][C:29]([O:32][C:13]3[CH:12]=[CH:11][N:10]=[C:9]4[CH:8]=[C:7]([C:5]([N:1]5[CH2:4][CH2:3][CH2:2]5)=[O:6])[S:15][C:14]=34)=[CH:28][C:23]=2[S:24][C:25]=1[CH2:26][CH3:27])=[O:20]
Reactant: CCc1sc2cc(O)ccc2c1C(=O)NC
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCc1sc2cc(Oc3ccnc4cc(C(=O)N5CCC5)sc34)ccc2c1C(=O)NC
Yield: 66.4 %

Procedure:
This material was prepared by reacting 2-(azetidin-1-ylcarbonyl)-7-chlorothieno[3,2-b]pyridine 25a (97 mg, 0.40 mmole) with 2-ethyl-6-hydroxybenzo[b]thiophene-3-carboxylic acid methylamide 134d (113 mg, 0.48 mmole) and Cs2CO3 (391 mg, 1.2 mmole)in a manner similar to that previously described for example 1 to give a yellow solid (120 mg, 52%). 1H NMR (DMSO-d6, 300 MHz) δ8.59 (1H, d, J=5.67 Hz), 8.31 (1H, m), 7.98 (1H, d, J=2.27 Hz), 7.89 (1H, s), 7.81 (1H, d, J=8.69 Hz), 7.33 (1H, dd, J=1.51, 8.69 Hz), 6.76 (1H, d, J=5.29 Hz), 4.62 (2H, t, J=7.37 Hz), 4.11 (2H, t, J=7.37 Hz), 3.00 (2H, q, J=7.55 Hz), 2.83 (3H, d, J=4.53 Hz), 2.35 (2H, m), 1.28 (3H, t, J=7.55 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:19][CH3:20])[CH:13]=[C:12]([O:21][CH3:22])[C:11]=2[C@@H:23]1[CH2:28][CH2:27][N:26](C#N)[CH2:25][C@H:24]1[O:31]C(=O)C.C([O-])([O-])=O.[Na+].[Na+]>OP(O)(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:19][CH3:20])[CH:13]=[C:12]([O:21][CH3:22])[C:11]=2[C@@H:23]1[CH2:28][CH2:27][NH:26][CH2:25][C@H:24]1[OH:31]
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccccc3Cl)oc2c1[C@@H]1CCN(C#N)C[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Product: COc1cc(OC)c2c(=O)cc(-c3ccccc3Cl)oc2c1[C@@H]1CCNC[C@H]1O
Temperature: 25 °C

Procedure:
Compound of example 127 (2 g, 4.14 mmol) was stirred with H3PO4 (6N, 50 mL) at 100° C. for 1.5 h. The solution was cooled to 25° C. and poured onto ice (100 g). It was made basic using a saturated aqueous Na2CO3 solution and extracted with EtOAc (3×150 mL). The organic extract was washed with water, dried (anhydrous Na2SO4), and concentrated. The crude obtained was purified using a silica gel column and 10% methanol+1% liquor NH3 in CHCl3 as eluant to furnish the title compound.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27]([OH:29])=O)[CH:22]=3)[CH:17]=1)[CH2:12]2.[NH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[N:30]1([C:27]([C:23]2[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[CH2:12][C:4]3([C:5]5[C:6](=[N:7][CH:8]=[CH:9][CH:10]=5)[NH:11][C:3]3=[O:2])[CH2:19]4)[CH:22]=2)=[O:29])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32][CH2:31]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1)N1CCCc2ccccc21

Procedure:
150 mg (0.37 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 50 μL (0.40 mmol) 1,2,3,4-tetrahydroquinoline, 0.15 mL (0.87 mmol) DI PEA and 130 mg (0.41 mmol) TBTU in 1.8 mL DMF were stirred overnight at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and lyophilised.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[C:9]([NH:17][NH2:18])(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:4]([C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:17][N:18]=2)[N:3]=1
Reactant: NNC(=O)c1ccccc1
Reactant: Clc1ccc(Cl)nn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: Clc1ccc2nnc(-c3ccccc3)n2n1
Yield: 55.3 %

Procedure:
3,6-Dichloropyridazine (20 g, 134 mmol) was suspended in xylene (200 ml) with benzoylhydrazine (20.1 g, 1.1 mol eq) and triethylamine hydrochloride (20.3 g, 1.1 mol eq) and the reaction mixture was heated under reflux for 2 hours. The solvent was removed under high vacuum and the residue was purified by chromatography on silica gel using 1% methanol in dichloromethane as eluent to give the required product (17.1 g mp=199° C.). 1H NMR (250 MHz, CDCl3) δ7.16 (1 H, d, J=9.7 Hz), 7.53-7.61 (3 H, m), 8.16 (1 H, d, J=9.7 Hz), 8.44-8.50 (2 H, m); MS (ES+) m/e 231 [MH]+.
Reaction SMILES: Cl[C:2](=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH2:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:10]>ClCCl>[CH2:9]([N:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2](=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5])[CH3:10]
Reactant: CCNc1ccccc1
Reactant: COC(=O)CC(=O)Cl
Solvent: ClCCl
Product: CCN(C(=O)CC(=O)OC)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
Dichloromethane was added to a dry round bottom flask at 20-25° C. under nitrogen atmosphere. Methyl 3-chloro-3-oxo-propanoate (2.59 ml, 24.15 mmol) was added, followed by N-ethylaniline (2.97 ml 24.13 mmol), and the solution was stirred at r.t. for 14 h, then the solvent was removed under reduced pressure to obtain a yellowish oil. Yield: 100%. Te purity of the isolated product: 98% (HPLC, area %).
Reaction SMILES: C(N)C1C=CC=CC=1.C(OC([NH:19][C@H:20]([C:24]([NH:26][C@H:27]([C:31]([NH:33][C@H:34]([P:36](=[O:39])([OH:38])[OH:37])[CH3:35])=[O:32])[CH2:28][CH2:29][CH3:30])=[O:25])[CH2:21][CH2:22][CH3:23])=O)C1C=CC=CC=1>>[NH2:19][C@H:20]([C:24]([NH:26][C@H:27]([C:31]([NH:33][C@H:34]([P:36](=[O:37])([OH:39])[OH:38])[CH3:35])=[O:32])[CH2:28][CH2:29][CH3:30])=[O:25])[CH2:21][CH2:22][CH3:23]
Reactant: CCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC)C(=O)N[C@@H](C)P(=O)(O)O
Solvent: NCc1ccccc1
Product: CCC[C@H](NC(=O)[C@@H](N)CCC)C(=O)N[C@@H](C)P(=O)(O)O

Procedure:
In a manner analogous to that described in Example 5(A)(iii), from the monobenzylamine salt of (1R)-1-[(N-benzyloxycarbonyl-L-norvalyl-L-norvalyl)amino]-ethylphosphonic acid there was obtained (1R)-1-(L-norvalyl-L-norvalylamino)-ethylphosphonic acid of melting point 273°-275° C. (decomposition); [α]D20 =-36.0°; [α]36520 =-153°, (c=0.5% freshly prepared in 0.1-N sodium hydroxide).
Reaction SMILES: [F:1][CH:2]1[C:7](=[O:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.B(F)(F)F.[N+](=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N-].O=C1CCCCN1>O.CCOCC.C(Cl)Cl>[F:1][CH:2]1[CH2:3][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6][CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:7]1=[O:8]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: FB(F)F
Agent: O=C1CCCCN1
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC(F)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
A solution of tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (20.0 g, 92.1 mmol) in 1:1 (CH2Cl2:Et2O, 250 mL) was cooled to −60° C. using an IPA/dry ice bath. In a separate flask was added BF3-Etherate (12.8 mL, 101 mmol) and Et2O (40 mL) which was cooled to 0° C., then ethyl 2-diazoacetate (12.6 mL, 120 mmol) was added. This mixture was added to the oxopiperidine solution and the reaction mixture was slowly warmed to ambient temperature over 2 hours. Water was added (100 mL) and the mixture was stirred at ambient temperature for 30 minutes. The phases were separated and the aqueous phase was extracted with EtOAc (100 mL) and the combined organic phases were washed with 1N KHSO4, followed by brine and then dried over Na2SO4, filtered and concentrated. This provided the product as a thick, yellow oil (26 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[C:13](=[O:24])[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[C:17]([CH:22]=O)[CH:16]=4)[N:11]=2)=[CH:3][CH:2]=1.[CH:25]([NH:28][CH3:29])([CH3:27])[CH3:26]>>[CH:25]([N:28]([CH2:22][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[C:12]([C:10]3[N:11]=[C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[S:8][CH:9]=3)[C:13](=[O:24])[NH:14]2)=[CH:19][CH:18]=1)[CH3:29])([CH3:27])[CH3:26]
Reactant: O=Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1
Reactant: CNC(C)C
Product: CC(C)N(C)Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1

Procedure:
This compound was prepared according to the method described in example 8758 step (b) employing 3-(2-pyridin-4-yl-thiazol-4-yl)-1H-quinolin-2-one-7-carbaldehyde and N-isopropyl-N-methylamine to provide the desired compound as a yellow solid. MS m/z; 391.0 (M+1).
Reaction SMILES: [Mg].II.CON(C)[C:7](=[O:19])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].[Cl-].[NH4+]>C1COCC1.BrCCC=C>[O:19]=[C:7]([CH2:10][CH2:9][CH:8]=[CH2:7])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17]
Reactant: CON(C)C(=O)CCCNC(=O)OC(C)(C)C
Agent: C=CCCBr
Agent: II
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=CCCC(=O)CCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 122.1 %

Procedure:
While under an atmosphere of nitrogen, a flame-dried round-bottomed flask was charged with magnesium (3.95 g, 0.162 mol) a small crystal of I2 and just enough dry THF to cover the magnesium. The mixture was heated to reflux until the color dissipated (about 10 min.). Next, a solution of 4-bromo-1-butene (16.4 mL, 0.162 mmol) in dry THF (70 mL) was added and heating was continued for 10 min. After cooling to room temperature, the newly formed Grignard reagent was then added to a ice-cooled solution of tert-butyl 4-(methoxy(methyl)amino)-4-oxobutylcarbamate (10 g, 0.041 mol) in dry THF (100 mL). After stirring overnight at room temperature, the solution was poured into saturated aqueous ammonium chloride (70 mL) and extracted with ether (2×). The organic extracts were combined and washed successively with 1.0 M aq HCl and sat'd aq sodium chloride, dried over MgSO4, filtered and concentrated. Purification by flash column chromatography (15-30% ethyl acetate in hexanes) gave tert-butyl 4-oxooct-7-enylcarbamate as a colorless oil (6.04 g, 62%). ESI MS found for C13H23NO3 m/z [264.3 (M+Na+)].
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[NH2:44][C:45]1[CH:46]=[CH:47][C:48]([Cl:51])=[N:49][CH:50]=1>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:33])([CH3:34])[C@:27]([C:36]2[CH:41]=[C:40]([NH:44][C:45]3[CH:50]=[N:49][C:48]([Cl:51])=[CH:47][CH:46]=3)[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: Nc1ccc(Cl)nc1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3ccc(Cl)nc3)ccc2F)N=C1N

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 5-amino-2-chloropyridine according to procedure B followed by deprotection yielded the title compound as an off-white foam. MS (ESI): m/z=390.2/392.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:22]Br)[CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N.O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH3:22])[CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CC[C@@H](CBr)NC(=O)OCc1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 97.3 %

Procedure:
To a solution of tert-butyl(4S)-4-{[(benzyloxy)carbonyl]amino}-5-bromopentanoate (4.5 g, 11.7 mmol) and tributyltin hydride (6.3 ml, 23.4 mmol) in toluene (45 ml) was added 2,2′-azobisisobutyronitrile (0.19 g, 1.2 mmol) and the mixture was stirred at 80° C. for 20 minutes. To the reaction mixture was added water, and the solution was extracted three times with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and the organic solvent was removed under reduced pressure. The residue was purified with silica gel chromatography to give tert-butyl (4R)-4-{[(benzyloxy)carbonyl]amino}pentanoate (3.5 g, 98%).