Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23](O)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:52][CH2:51][NH:50]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:50]3[CH2:51][CH2:52][C:53]5[C:58](=[CH:57][CH:56]=[CH:55][CH:54]=5)[CH2:49]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Reactant: c1ccc2c(c1)CCNC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc2[nH]c(C(=O)N3CCc4ccccc4C3)cc2c1)N1CCN(C2CCCC2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 3,4-dihydro-1H-isoquinoline (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[C:18]([NH:19][C:20]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=3)=[O:21])=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[C:4]([O:6]C)=O.[CH3:34][Mg]Br.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[C:4]([C:3]1[C:2]([F:1])=[CH:11][CH:10]=[CH:9][C:8]=1[O:12][C:13]1[C:18]([NH:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=2)=[O:21])=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:6])[CH3:34]
Reactant: COC(=O)c1c(F)cccc1Oc1ncccc1NC(=O)Nc1ccc(OC(F)(F)F)cc1
Reactant: C[Mg]Br
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1c(F)cccc1Oc1ncccc1NC(=O)Nc1ccc(OC(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 18 h
Yield: 8.2 %

Procedure:
Methyl 2-fluoro-6-(3-(3-(4-(trifluoromethoxy)phenyl)ureido)pyridin-2-yloxy)benzoate (250 mg, 0.54 mmol) was diluted in THF (10 mL) and cooled to −78° C. Methylmagnesiumbromide (3.0 M in Et2O, 1.07 mL, 3.22 mmol) was added and mixture was warmed to rt and stirred for 18 h. Sodium sulfate decahydrate was added and stirring was continued for 30 min. The solution was filtered over a pad of Celite® and washed using ethyl acetate. The organic phase was evaporated and crude material was purified using preparative HPLC to yield the desired material (20 mg) (M+H)+=450. 1H NMR (400 MHz, Acetone) δ ppm 2.33-2.40 (m, J=1.77 Hz, 3H), 7.07-7.18 (m, 3 H), 7.27 (d, J=8.84 Hz, 2 H), 7.56 (td, J=8.34, 6.57 Hz, 1 H), 7.63-7.70 (m, 3 H), 8.20 (s, 1 H), 8.67 (dd, J=7.96, 1.64 Hz, 1 H), 8.91 (s, 1 H).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][C:10](=[O:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:26]=[CH:25][C:24]([Mg]Br)=[CH:23][CH:22]=1.ClC1C=CC(C2(O)CN(C(C3C=CC=CC=3)C3C=CC=CC=3)C2)=CC=1>>[F:19][C:20]([F:30])([F:29])[C:21]1[CH:26]=[CH:25][C:24]([C:10]2([OH:12])[CH2:11][N:8]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[CH:23][CH:22]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: FC(F)(F)c1ccc([Mg]Br)cc1
Agent: OC1(c2ccc(Cl)cc2)CN(C(c2ccccc2)c2ccccc2)C1
Product: OC1(c2ccc(C(F)(F)F)cc2)CN(C(c2ccccc2)c2ccccc2)C1

Procedure:
This compound was prepared from compound (3) and 4-(trifluoromethyl)phenylmagnesium bromide using the procedure described for compound (4).
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.Br[CH2:10][C:11]1[C:16]2[CH:17]=[CH:18][O:19][C:15]=2[C:14]([F:20])=[CH:13][CH:12]=1>C(#N)C>[F:20][C:14]1[CH:13]=[CH:12][C:11]([CH:10]=[O:5])=[C:16]2[C:15]=1[O:19][CH:18]=[CH:17]2
Reactant: C[N+]1([O-])CCOCC1
Reactant: Fc1ccc(CBr)c2ccoc12
Solvent: CC#N
Product: O=Cc1ccc(F)c2occc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the N-methylmorpholine-N-oxide (22.24) in acetonitrile (250 ml) containing 3 Å molecular sieves (8.71 g) was stirred at room temperature overnight, then cooled in ice. A solution of 4-bromomethyl-7-fluoro-benzofuran (23.45 g) in acetonitrile (50 ml) was added and the mixture stirred for 4 h. The mixture was filtered and the filtrate evaporated to dryness. Water and ether were added to the residue and the organic phase separated, washed with brine (2×200 ml), dried (MgSO4) and evaporated. The residue was triturated under ether (50 ml) and filtered to give the title compound as a pale yellow solid (5.45 g)
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH:8]([CH3:14])[N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=1[O:31][CH3:32].C(O)C>Cl.O>[CH:15]1([N:7]2[CH:8]([CH3:14])[CH2:9][C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CC1CC(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)C(C)CC(=O)N2C
Yield: 72.9 %

Procedure:
A mixture of 0.059 g (0.0002 mole) of (rac)-2-chloro-9-cyclopentyl-5,8-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-3), 0.033 g (0.0002 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated to 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.062 g of (rac)-4-(9-cyclopentyl-5,8-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-3-methoxy-benzoic acid (I-3) as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=1[NH2:4].B(O)(O)O.[C:15]([C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:27]=1[OH:28])[C:22](O)=O)([CH3:18])([CH3:17])[CH3:16]>C1(C)C(C)=CC=CC=1>[C:29]([C:26]1[CH:25]=[C:21]([C:22]2[O:1][C:2]3[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=3[N:4]=2)[CH:20]=[C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:27]=1[OH:28])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: COc1ccc(O)c(N)c1
Agent: OB(O)O
Solvent: Cc1ccccc1C
Product: COc1ccc2oc(-c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)nc2c1
Yield: 122.4 %

Procedure:
A solution of 2-hydroxy-5-methoxyaniline (36.9 mmole, 5.13 g), boric acid (36.9 mmole, 2.23 g) and 3,5-di-tert-butyl-4-hydroxybenzoic acid (36.9 mmole, 9.23 g) in xylene (550 ml) was refueled using a Dien Stark trap for approximately two days. The reaction mixture was then concentrated in vacuc to an oil. The oil was treated with ethyl acetate (200 ml) and washed with saturated aqueous sodium bicarbonate (3×200 ml). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to afford 15.96 g of a black oil. The material was subjected to preparatory chromatography eluting with 15 to 30% ethyl acetate: hexane over a 30 minute period. Fractions containing title compound were combined and concentrated in vacuo to afford 5.18 g of a solid.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:25])[C@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:16]=[CH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([Si:29]([CH3:32])([CH3:31])[CH3:30])C=C.C(Cl)(Cl)Cl>C(Cl)Cl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:25])[C@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)/[CH:16]=[CH:17]/[CH2:26][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C[C@@H](Cc1ccccc1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: C=CC[Si](C)(C)C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: C[Si](C)(C)C/C=C/[C@@H](Cc1ccccc1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1

Procedure:
To a solution of (4R)-4-benzyl-3-[(2R)-2-benzylbut-3-enoyl]-1,3-oxazolidin-2-one (3.42 mmol, 1.10 g) and allyltrimethylsilane (10.26 mmol, 1.63 mL) in DCM (50 mL) at reflux was added 5 mol % of Grubbs' second generation catalyst (145 mg). After 68 hrs the solvent was removed in vacuo. The crude product was purified by column chromatography to yield a white solid. (1.37 g, 95%); 1H NMR (400 MHz, CDCl3): δ=7.0-7.32 (m, 10H), 5.62 (dt, J=8.1, 15.2, 1H), 5.29-5.36 (m, 1H), 4.82 (m, 1H), 4.61 (m, 1H), 4.01-4.15 (m, 2H), 3.22 (dd, J=8.3, 13.4, 1H), 3.02 (dd, J=3.3, 13.3, 1H), 2.85 (dd, J=6.1, 13.4, 1H), 2.57 (dd, J=9.1, 13.4, 1H) 1.42 (d, J=8.1, 1H) −0.08 (s, 9H); 13C NMR (100 MHz, CDCl3): δ=174.2, 138.9, 135.1, 131.6, 129.4, 128.9, 128.3, 127.2, 126.3, 124.9, 65.7, 55.2, 48.2, 38.9, 37.6, 23.1, −2.1; IR (CHCl3): v 3444, 2955, 1767, 1694, 1454, 1393, 1248, 1182 cm−1; MS (CI(NH3)): m/z 422 (M+H+); HMRS required for C25H32NO3Si ([M]+) 422.2158 found 422.2151; [α]D23=117.8° (c, 0.5 CHCl3); Mp 132-135° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[C:40]([NH:43][N:44]([C:46](=[O:73])[C@H:47]([N:55]([CH3:72])[C:56](=[O:71])[C@H:57]([NH:69][CH3:70])[CH2:58][C:59]1[CH:68]=[CH:67][C:66]2[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=2)[CH:60]=1)[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH3:45])(=[O:42])[CH3:41].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:69]([C@@H:57]([C:56](=[O:71])[N:55]([C@H:47]([CH2:48][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[C:46]([N:44]([CH3:45])[NH:43][C:40](=[O:42])[CH3:41])=[O:73])[CH3:72])[CH2:58][C:59]1[CH:68]=[CH:67][C:66]2[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=2)[CH:60]=1)[CH3:70])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)N(C)NC(C)=O
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NN(C)C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
To a solution of (2E)-5-(tert-butyloxycarbonylamino)-5-methylhex-2-enoic acid (0.066 g, 0.27 mmol) in methylene chloride (5 ml) was added 1-hydroxy-7-azabenzotriazole (0.037 g, 0.27 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.052 g, 0.27 mmol) and the mixture was cooled to 0° C. Then (2R)-N-[(1R)-2-(N'-acetyl-N-methylhydrazino)-1-benzyl-2-oxoethyl]-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide (0.10 g, 0.22 mmol) and diisopropylethylamine (0.049 ml, 0.29 mmol) were added and the mixture was stirred at room temperature overnight. Then methylene chloride (50 ml) was added and the mixture was washed with water (10 ml), saturated sodium bicarbonate (10 ml), brine (10 ml), dried (MgSO4), filtered and concentrated in vacuo. The product was chromatographed on silica gel (40 g) with heptane:ethyl acetate (1:1) to give 0.10 g (66%) of ((3E)-4-[N-((1R)-1-(N-[(1R)-2-(N'-acetyl-N-methylhydrazino)-1-benzyl-2-oxoethyl]-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl]-1,1-dimethylbut-3-enyl)carbamic acid tert-butyl ester as a colourless oil.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:24][CH2:23][C:11]2([C:15](=[O:16])[NH:14][CH2:13][CH:12]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7].[CH3:34][N:35]([CH3:40])[CH2:36][CH2:37][CH2:38]Cl>>[F:31][C:28]([F:29])([F:30])[C:26]1[CH:25]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:27]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:15](=[O:16])[N:14]([CH2:38][CH2:37][CH2:36][N:35]([CH3:40])[CH3:34])[CH2:13][CH:12]2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:23][CH2:24]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCC2c1ccccc1
Reactant: CN(C)CCCCl
Product: CN(C)CCCN1CC(c2ccccc2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O

Procedure:
The title compound, MS: m/e=556.2 (M+H+), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-4-phenyl-2,8-diaza-spiro[4.5]decan-1-one and 3-dimethylamino-1-propyl chloride.
Reaction SMILES: N1CCC[C@H]1C(O)=O.[N:9]1([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[N:10]1.[CH3:22][C:23]1([CH3:31])[O:28][C:27](=[O:29])[CH2:26][C:25](=[O:30])[O:24]1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O>C(O)C.C(O)(C)C>[N:9]1([C:14]2[CH:21]=[CH:20][C:17]([CH2:18][CH:26]3[C:27](=[O:29])[O:28][C:23]([CH3:31])([CH3:22])[O:24][C:25]3=[O:30])=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[N:10]1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CC(C)O
Solvent: CCO
Product: CC1(C)OC(=O)C(Cc2ccc(-n3cccn3)cc2)C(=O)O1
Reaction time: 0.67 h

Procedure:
L-Proline (4.07 g, 35.0 mmol) was added to a semi-heterogeneous mixture of 4-(1H-pyrazol-1-yl)benzaldehyde (30.0 g, 174 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (25.6 g, 174 mmol) in ethanol (996 mL) at room temperature. After 40 minutes, diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (44.1 g, 174 mmol) was added in one portion followed by ethanol (125 mL). After overnight stirring, the mixture was concentrated under reduced pressure to afford a yellow solid. Isopropanol (300 mL) was added and the heterogeneous mixture was sonicated for 30 minutes. The mixture was filtered and the filter cake was washed with isopropanol. The solids were collected and dried under vacuum to provide the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[Br:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH:19]=[CH:20][C:21](O)=O>>[Br:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[CH:19]=[CH:20]/[C:21]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: COc1ccc(C=CC(=O)O)cc1Br
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(Br)c3)nc2n(CC)c1=O
Yield: 17.1 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.00 g (10.1 mmol) of 5,6-diamino-1,3-diethyluracil and 2.72 g (10.6 mmol) of 3-bromo-4methoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane to give 726 mg (yield 17%) of Compound 118 as pale brown needles.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=2[NH2:15])=[CH:5][CH:4]=1.C([C:20]1[C:21]([N:29]=[CH:30][N:31]([CH3:33])C)=[N:22][C:23]([CH:26]2[CH2:28][CH2:27]2)=[CH:24][CH:25]=1)#N.NC1C=C(C)C=CC=1SC1C=CC(O)=CC=1.C(C1C(N=CN(C)C)=NC(C)=CC=1)#N>>[CH:26]1([C:23]2[CH:24]=[CH:25][C:20]3[C:33]([NH:15][C:9]4[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:8]=4[O:7][C:6]4[CH:16]=[CH:17][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)=[N:31][CH:30]=[N:29][C:21]=3[N:22]=2)[CH2:27][CH2:28]1
Reactant: CN(C)C=Nc1nc(C2CC2)ccc1C#N
Reactant: COc1ccc(Oc2ccc(C)cc2N)cc1
Agent: Cc1ccc(C#N)c(N=CN(C)C)n1
Agent: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Product: COc1ccc(Oc2ccc(C)cc2Nc2ncnc3nc(C4CC4)ccc23)cc1

Procedure:
The product from Example 116B was reacted with the product from Example 119A using the procedure from Example 102 substituting the product from Example 116B for the product from Example 6c and substituting the product from Example 119A for the product from Example 10B to provide the crude residue which was purified by trituration with methanol to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.02-1.20 (m, J=6.25 Hz, 4H), 2.21-2.37 (m, 1H), 2.31 (s, 3H), 3.66 (s, 3H), 6.75-6.92 (m, 5H), 7.06 (dd, J=8.64, 0.92 Hz, 1H), 7.37 (s, 1H), 7.51 (d, J=8.46 Hz, 1H), 8.49 (s, 1H), 8.63 (d, J=8.82 Hz, 1H), 9.74 (s, 1H); MS (ESI)+ m/z 399 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[CH:9][CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:5]2[N:4]=1.O1CCCC1.CO.[Br:25]N1C(=O)CCC1=O>>[Br:25][C:9]1[CH:10]=[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:5]2[C:6]=1[CH:7]=[N:8][C:3]([S:2][CH3:1])=[N:4]2
Reactant: CSc1ncc2ccc(-c3ccccc3)n2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: C1CCOC1
Product: CSc1ncc2c(Br)cc(-c3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
Into a 30 mL vial, 2-Methylsulfanyl-7-phenyl-pyrrolo[2,1-f][1,2,4]triazine (0.295 g, 0.00122 mol), Tetrahydrofuran (10 mL, 0.1 mol) and Methanol (5 mL, 0.1 mol) were added. N-Bromosuccinimide (0.239 g, 0.00134 mol) was added over 10 minutes. The reaction was stirred at room temperature overnight. The solvent was removed under vacuum. The solid was partitioned with water, filtered and washed with water to give a yellow solid. The solid was dried under vacuum over night to give 5-Bromo-2-methylsulfanyl-7-phenyl-pyrrolo[2,1-f][1,2,4]triazine as a yellow solid (0.34 g, 87%). NMR 1H (DSMO-d6)-8.93 (s, 1H), 8.19 (d, 2H, J=7.61 Hz), 7.61 (s, 1H), 7.53 (t, 2H, J=8.60 Hz), 7.42 (t, 1H, J=7.37), 2.58 (s, 3H)
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)([CH:13]=[O:14])[CH2:12][CH:7]2[CH2:6]1)=[O:4].O.O.P([O-])(O)(O)=[O:26].[Na+].Cl([O-])=O.[Na+].CC(=CC)C>O1CCCC1.O>[CH:16]1([CH2:15][C:11]2([C:13]([OH:26])=[O:14])[CH2:12][CH:7]3[CH2:6][N:5]([C:3](=[O:4])[N:2]([CH3:1])[CH3:22])[CH2:9][CH:8]3[CH2:10]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN(C)C(=O)N1CC2CC(C=O)(CC3CCCCC3)CC2C1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)N1CC2CC(CC3CCCCC3)(C(=O)O)CC2C1
Temperature: 0 °C
Yield: 99.8 %

Procedure:
5-Cyclohexylmethyl-5-formyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 15b (0.713 g, 2.33 mmol) was dissolved in the solvent mixture of 60 mL of tetrahydrofuran and 30 mL of water. Upon cooling to 0° C., sodium dihydrogenphosphate dihydrate (1.09 g, 6.99 mmol), sodium chlorite (0.79 g, 6.99 mmol) and 2-methyl-2-butene (0.62 mL, 7.0 mmol) were added. The reaction mixture was reacted at 0° C. for 2 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated to remove tetrahydrofuran and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 5-cyclohexylmethyl-2-dimethylcarbamoyl-octahydro-cyclopenta[c]pyrrole-5-carboxylic acid 15c (0.75 g, yield 100%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH:21]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1)[C:22]([OH:24])=[O:23])[C:18]([OH:20])=[O:19]>CS(C)=O>[C:12]([C:11]1[C:2]([NH:16][CH:17]([CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[C:22]([OH:24])=[O:23])[C:18]([OH:20])=[O:19])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([Cl:15])=[CH:6][CH:5]=2)([OH:14])=[O:13]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: NC(C(=O)O)C(C(=O)O)c1cccc(F)c1
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(C(=O)O)C(C(=O)O)c1cccc(F)c1

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-(3-fluoro-phenyl)-succinic acid [prepared by analogy to J. Med. Chem. 1973, 16, 1277-1280.; using alkylation of diethyl acetamidomalonate by methyl bromo-(3-fluoro-phenyl)-acetate] in DMSO to provide the title compound in good yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C@H:23]3[CH2:28][CH2:27][C@H:26]([CH2:29][C:30](O)=[O:31])[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)=[O:15])=[N:11][N:10]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:66]1[CH2:75][CH2:74][CH:69]([C:70]([O:72][CH3:73])=[O:71])[CH2:68][CH2:67]1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C@H:23]3[CH2:28][CH2:27][C@H:26]([CH2:29][C:30]([N:66]4[CH2:75][CH2:74][CH:69]([C:70]([O:72][CH3:73])=[O:71])[CH2:68][CH2:67]4)=[O:31])[CH2:25][CH2:24]3)=[CH:21][CH:22]=2)=[O:15])=[N:11][N:10]=1
Reactant: COC(=O)C1CCNCC1
Reactant: O=C(O)C[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4ccccc4F)o3)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1CCN(C(=O)C[C@H]2CC[C@H](c3ccc(NC(=O)c4nnc(Nc5ccccc5F)o4)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (trans-4-{4-[({5-[(2-fluorophenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]phenyl}cyclohexyl)acetic acid (Example 112, 300 mg, 0.68 mmol) in DMF (3 mL) was added HATU (286 mg, 0.75 mmol), diisopropylethylamine (0.14 mL, 0.75 mmol) followed by methyl isonipecotate (0.15 mL, 0.75 mmol). The reaction mixture was allowed to stir at ambient temperature overnight. The DMF was evaporated and the residue re-dissolved in DMSO/MeCN/H2O (7:2:1); a suspension formed which was filtered, washed with ether (2×10 mL) and dried to leave the title compound (137 mg). The filtrate was purified on an acidic reverse phase HPLC system eluting 5-95% MeCN 0.2% TFA, isolated 112 mg of the title compound (249 mg, 65%) as a solid; 1H NMR δ 1.07-1.16 (m, 2H), 1.36-1.53 (m, 4H), 1.75-1.88 (m, 7H), 2.24 (d, 2H), 2.41-2.47 (m, 1H), 2.59-2.65 (m, 2H), 3.11 (t, 1H), 3.62 (s, 3H), 3.85 (d, 1H), 4.26 (d, 1H), 7.14-7.34 (m, 5H), 7.68 (d, 2H), 8.04 (t, 1H), 10.75 (s, 1H), 10.93 (s, 1H); MS m/e MH+ 564.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[C:21]1([NH:27]N)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:14]1([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NNc1ccccc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Product: O=c1ccn(-c2ccccc2)nc1-c1ccnn1-c1ccccc1
Yield: 81 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and phenylhydrazine according to the method described for Example 1 in 81% yield. MS: M=315.1 (M+H)+