Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28]>C1COCC1>[C:8]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=[C:6]([C:4]([C:23]2[CH:24]=[C:25]([O:29][CH3:30])[C:26]([O:27][CH3:28])=[C:21]([O:20][CH3:19])[CH:22]=2)=[O:5])[CH:7]=1
Reactant: COc1cc([Mg]Br)cc(OC)c1OC
Reactant: CON(C)C(=O)c1cccc(-c2ccccc2)c1
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2cccc(-c3ccccc3)c2)cc(OC)c1OC
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
To a solution of 38a (FIG. 2) (0.174 g, 0.72 mmoL) in 5 mL THF was added a THF solution of 3,4,5-trimethoxyphenylmagnesiumbromide (0.5 N, 1.08 mmol) at 0° C. The mixture was allowed to stir for 30 min and quenched with satd. NH4Cl, extracted with ethyl ether, dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 1a as a white solid (43.8%). NMR (CDCl3) δ 8.02 (t, 1H), 7.84-7.74 (m, 2H), 7.64-7.38 (m, 6H), 7.11 (s, 2H), 3.95 (s, 3H), 3.88 (s, 6H); MS (ESI) m/z 371.1 (M+Na)+.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13]1[N:17]([CH2:18][C@H:19]2[CH2:23][CH2:22][CH2:21][O:20]2)[C:16]([CH3:24])=[C:15]([C:25]([NH:27][CH:28]2[CH:33]3[C:34]([CH3:36])([CH3:35])[C:30]([CH3:37])([CH2:31][CH2:32]3)[CH:29]2[O:38]C(=O)C)=[O:26])[CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CO>[OH:38][CH:29]1[C:30]2([CH3:37])[C:34]([CH3:36])([CH3:35])[CH:33]([CH2:32][CH2:31]2)[CH:28]1[NH:27][C:25]([C:15]1[CH:14]=[C:13]([C:4]2[CH:5]=[C:6]([C:9]([F:10])([F:11])[F:12])[CH:7]=[CH:8][C:3]=2[C:2]([F:43])([F:1])[F:42])[N:17]([CH2:18][C@H:19]2[CH2:23][CH2:22][CH2:21][O:20]2)[C:16]=1[CH3:24])=[O:26]
Reactant: CC(=O)OC1C(NC(=O)c2cc(-c3cc(C(F)(F)F)ccc3C(F)(F)F)n(C[C@H]3CCCO3)c2C)C2CCC1(C)C2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1c(C(=O)NC2C3CCC(C)(C2O)C3(C)C)cc(-c2cc(C(F)(F)F)ccc2C(F)(F)F)n1C[C@H]1CCCO1
Yield: 96.6 %

Procedure:
To a solution of acetic acid 3-({5-(2,5-bis-trifluoromethyl-phenyl)-2-methyl-1-[(R)-1-(tetrahydro-furan-2-yl)methyl]-1H-pyrrole-3-carbonyl}-amino)-1,7,7-trimethyl-bicyclo[2.2.1]hept-2-yl ester (60 mg) in MeOH (2 mL) was added 15 μL of a 1N K2CO3 solution. After 18 hours the reaction mixture was extracted with ethyl acetate and the organic phases were washed with brine, dried over sodium sulfate and filtered. Removal of the volatiles in vacuo and chromatography of the crude residue afforded the title compound (54 mg), MS (ISP) 631.5 (M+H)+.
Reaction SMILES: [C@H:1]1([NH:11][C:12]([C@@H:14]2[CH2:23][C:22]3[C:17](=[CH:18][C:19](OS(C(F)(F)F)(=O)=O)=[CH:20][CH:21]=3)[CH2:16][N:15]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.CS(C)=O.CCN(CC)CC>CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>[C@H:1]1([NH:11][C:12]([C@@H:14]2[CH2:23][C:22]3[C:17](=[CH:18][C:19]([C:32]([O:34][CH3:35])=[O:33])=[CH:20][CH:21]=3)[CH2:16][N:15]2[C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(OS(=O)(=O)C(F)(F)F)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC(=O)c1ccc2c(c1)CN(C(=O)OC(C)(C)C)[C@H](C(=O)N[C@@H]1CCCc3ccccc31)C2
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 182.4 %

Procedure:
A 20 mL scintillation vial with a septum top was charged sequentially with (S)-tert-butyl 3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-7-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.39 g, 2.50 mmol), Pd(OAc)2 (0.028 g, 0.12 mmol), and 1,3-bis(diphenylphosphino)propane (0.052 g, 0.12 mmol). DMSO (3.7 mL), MeOH (2.5 mL), and Et3N (0.77 mL, 5.50 mmol) were then added, and the reaction mixture was stirred for 5 min. A CO balloon was then used to purge the reaction vial, turning the solution black. The reaction was topped with the CO balloon and heated to 70° C. for 12 h. The reaction mixture was then filtered through an ACRODISC®, and the filtrate was poured into a separatory funnel containing EtOAc and sat. aq. NH4Cl solution. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with sat. NaCl (2×), dried over MgSO4, filtered and concentrated in vacuo. The crude oil was purified by flash column chromatography (gradient elution from 0 to 50% EtOAc/hexanes) to afford the title compound (1.06 g, 2.28 mmol, 91%) as a light yellow solid. MS (ESI+) m/z 465.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:41][CH2:42][CH:43]([C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([O:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:46]=1)[OH:44]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@H:13]([C:14]([NH:41][CH2:42][CH:43]([OH:44])[C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([O:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:46]=1)=[O:15])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NCC(O)c1cccc(Oc2ccccc2)c1
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NCC(O)c1cccc(Oc2ccccc2)c1
Yield: 21.1 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (96 mg, 0.16 mmol) and 2-amino-1-(3-phenoxyphenyl)-1-ethanol (45 mg, 0.20 mmol) according to Method C with HPLC purification to give the title compound (25 mg) as a diasteromeric mixture. 1H-NMR (400 MHz, CD3OD) d 7.59 (d, J=1.7 Hz, 1H), 6.87 (dd, J=1.2 Hz, J=8.3 Hz, 1H), 4.66 (m, 3H), 4.55 (t, J=7.0 Hz, 1H), 4.23 (m, 1H), 3.02 (m, 2H), 3.52 (m, 1H), 2.90 (m, 1H), 2.69 (m, 1H), 1.34 (s, 9H); HRMS m/z 741.2925 (calc. of monoisotopic mass for C40H43N3O11 gives 741.2898).
Reaction SMILES: [C:1](OC(=O)C)(=O)C.C(O)=O.[C:11]1([C:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][C:25]#[C:26][C:27]3[N:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=3)[CH2:21][CH:22]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:11]1([C:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]#[C:26][C:27]3[N:32]=[CH:31][C:30]([NH:33][CH3:1])=[CH:29][CH:28]=3)[CH2:19][CH:18]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C#CCCN2CC=C(c3ccccc3)CC2)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O=CO
Solvent: C1CCOC1
Product: CNc1ccc(C#CCCN2CC=C(c3ccccc3)CC2)nc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To 0.50 mL (6.8 mmol) of acetic anhydride is added 0.32 mL (8.4 mmol) of 88% formic acid dropwise under nitrogen. Anhydrous tetrahydrofuran (10 mL) is added, and the solution is heated at 50° C. for 2 hours. To the cooled solution is added a suspension of 6-[4-(3,6-dihydro-4-phenyl-1(2H)-pyridinyl)-1-butynyl]-3-pyridinamine (Example 20) (0.8 g, 2.6 mmol) in 10 mL of tetrahydrofuran, and the solution is stirred at room temperature for 18 hours. The mixture is concentrated in vacuo, and the residue is partitioned between dichloromethane and 5% ammonium hydroxide. The organic layer is dried and concentrated in vacuo. The residue, in 10 mL of tetrahydrofuran, is added dropwise under nitrogen to a suspension of 0.14 g (3.9 mmol) of lithium aluminum hydride in 20 mL of dry tetrahydrofuran at 0° C. The reaction mixture is stirred at 0° C. for 5 hours. The reaction is quenched by sequential addition of 0.52 mL of 10% hydrochloric acid solution, 0.52 mL of 30% sodium hydroxide solution, and 0.52 mL of water. The resulting mixture is filtered through diatomaceous earth (Celite), evaporated in vacuo, and chromatographed (silica gel, 1% methanol/99% dichloromethane) to give the title compound, containing 0.5 mol of water; mp 164.5°-165.5° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][C:9]#[N:10])[C@@H:4]([CH2:11][OH:12])[CH2:3]1.C(N(CC)[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH3:24])C>>[OH:1][C@@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][C:9]2[NH:10][C:16](=[O:25])[C:17]3[C:18]([CH:24]=2)=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)[C@@H:4]([CH2:11][OH:12])[CH2:3]1
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Reactant: N#CCCN1C[C@@H](O)C[C@@H]1CO
Product: Cc1cccc2c(=O)[nH]c(CCN3C[C@@H](O)C[C@@H]3CO)cc12
Yield: 16.8 %

Procedure:
In the same manner as in Example 1b (e) and using 3-[(2R,4S)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]propionitrile (0.47 g) and N,N-diethyl-2,3-dimethylbenzamide (2.1 g), 3-{2-[(2R,4S)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]ethyl}-5-methyl-2H-isoquinolin-1-one (0.14 g) was obtained.
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.[C:28](O)(=[O:32])[CH:29]([CH3:31])[CH3:30]>>[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:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CC(C)C(=O)O
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1NC(=O)OC(C)(C)C
Product: CC(C)C(=O)Nc1ccc(F)c([C@@]2(C)N=C(N)N(C)C(=O)C2(C)C)c1

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 F) and isobutyric acid followed by deprotection of the intermediate yielded the title compound as a colorless oil. MS (ESI): m/z=349.3 [M+H]+.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH2:18]([OH:22])[CH:19]([OH:21])[CH3:20].[CH3:23][O:24][CH2:25][CH:26]=O.C1CCCCC1>O>[CH3:23][O:24][CH2:25][CH:26]1[O:21][CH:19]([CH3:20])[CH2:18][O:22]1
Reactant: COCC=O
Reactant: CC(O)CO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: C1CCCCC1
Product: COCC1OCC(C)O1
Yield: 93 %

Procedure:
1 g of pyridinium p-toluenesulfonate was added to a mixture consisting of 152 g (2 moles) of 1,2-propanediol, 148 g (2 moles) of 85% strength methoxyacetaldehyde and 400 ml of cyclohexane, and the resulting mixture was refluxed under a water separator until water no longer separated off. The solution obtained was washed with water, the solvent was stripped off under reduced pressure and the residue was subjected to fractional distillation under reduced pressure. 245 g (93% yield) of 2-methoxymethyl-4-methyl-1,3-dioxolane of boiling point 79°-82° C./70 mbar were obtained.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2[C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:2]=1.N[C:18](N)=[O:19]>>[C:1]1([CH3:16])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:8]3[N:9]=[CH:10][CH:11]=[CH:12][C:13]=3[CH2:14][NH:15][C:18]2=[O:19])[CH:2]=1
Reactant: NC(N)=O
Reactant: Cc1cccc(Nc2ncccc2CN)c1
Product: Cc1cccc(N2C(=O)NCc3cccnc32)c1
Temperature: 180 °C
Yield: 53.9 %

Procedure:
To a mixture of 4.3 g 2-(m-toluidino)-3-aminomethylpyridine and 12 g of urea was heated at 180° C for 2 hours and further heated at 200° C for 30 minutes. After cooling, crude reaction product precipitated was collected by filtration and washed with sufficient amounts of warm water. This product was purified by recrystallization from methanol to give 2.6 g of 1-(m-tolyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine as colorless prisms, melting at 212° - 214° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[C:18]([NH:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][CH:27]=[N:28]4)=[CH:23][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:28]1[C:29]2[C:24](=[CH:23][CH:22]=[C:21]([NH:20][C:18]3[CH:19]=[C:14]([C:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=4)[N:15]=[CH:16][N:17]=3)[CH:30]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(Nc3ccc4cccnc4c3)ncn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1=C(c2cc(Nc3ccc4cccnc4c3)ncn2)CCNC1

Procedure:
This compound could be prepared from 4-[6-(quinolin-7-ylamino)-pyrimidin-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester in the presence of TFA and CH2Cl2.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[NH:6][C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=2[CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=2)[C:27]([NH:29][CH3:30])=[O:28])[C:20]([Cl:34])=[CH:19][N:18]=1>>[Cl:34][C:20]1[C:21]([NH:23][C:24]2[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=2)[C:27]([NH:29][CH3:30])=[O:28])=[N:22][C:17]([NH:1][C:2]2[CH:15]=[CH:14][C:5]3[NH:6][C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=3[CH:3]=2)=[N:18][CH:19]=1
Reactant: CNC(=O)c1cccc(Nc2nc(Cl)ncc2Cl)c1
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Product: CNC(=O)c1cccc(Nc2nc(Nc3ccc4c(c3)C(C)(C)CCC(=O)N4)ncc2Cl)c1
Yield: 19 %

Procedure:
In an analogous procedure to Example 651, part c, 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 3-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide were combined to yield 3-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (19.47 mg, 19% yield) as a white amorphous solid. 1H-NMR (CDCl3) δ 8.10 (s, 1H), 8.01 (s, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.58 (d, J=8.60 Hz, 1H), 7.48 (m, 1H), 7.38 (m, 1H), 7.38 (m, 1H), 7.32 (s, 1H), 7.17 (d, J=14.9 Hz, 1H), 7.07 (s, 1H), 6.81 (d, J=7.8 Hz, 1H), 6.06 (br s, 1H), 2.97 (s, 3H), 2.37 (m, 2H), 2.07 (m, 2H), 1.33 (s, 6H). LC/MS (ESI+)=465 (M+H). MP=184.5° C.
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]1[C:16](=[O:17])[CH2:15][CH2:14][N:13]([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[C:12](=[O:26])[CH2:11][CH2:10]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:19]([CH2:18][N:13]1[C:12](=[O:26])[CH2:11][CH2:10][N:9]([CH2:8][C:6]([OH:7])=[O:5])[C:16](=[O:17])[CH2:15][CH2:14]1)([OH:21])=[O:20]
Reactant: CC(C)(C)OC(=O)CN1CCC(=O)N(CC(=O)OC(C)(C)C)CCC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1CCC(=O)N(CC(=O)O)CCC1=O
Reaction time: 8 h

Procedure:
1.4 g of tert-butyl (5-tert-butoxycarbonylmethyl-2,6-dioxoperhydro-1,5-diazocin-1-yl)acetate (starting material A3) are dissolved in 6 ml of dichloromethane, and 6 ml of trifluoroacetic acid are added. The mixture is stirred overnight and then concentrated using a rotary evaporator, and the residue is triturated with ethyl acetate/petroleum ether (1:1). The residue is filtered off with suction and dried under reduced pressure. This gives 0.89 g of the title compound which starts to melt at 250° C. (decomposition); the mass spectrum shows the molecular peaks MH+ and MNH4+ at 259 and 276 Da, respectively.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[C:24]#[N:25])=[CH:4][C:5](=[O:16])[N:6]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:7]=1.FC(F)(F)S(O[CH2:32][CH2:33][O:34][CH3:35])(=O)=O>>[Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[C:24]#[N:25])=[CH:4][C:5](=[O:16])[N:6]([CH:8]([CH2:32][CH2:33][O:34][CH3:35])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:7]=1
Reactant: CC(C)(C)OC(=O)Cn1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: COCCOS(=O)(=O)C(F)(F)F
Product: COCCC(C(=O)OC(C)(C)C)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
500 mg (1.32 mmol) of tert-butyl [5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]acetate in the presence of 1.58 ml (1.58 mmol, 1.2 eq.) of bis(trimethylsilyl)lithium amide (1M in THF) were reacted with 556 mg (purity 74%, 1.98 mmol, 1.5 eq.) of 2-methoxyethyl trifluoromethanesulphonate according to General Method 7B. Yield: 455 mg (purity 80%, 63% of theory)
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:40])([F:39])[C:12]([F:38])([F:37])[O:13][C:14]([F:36])([F:35])[C:15]([F:34])([F:33])[O:16][C:17]([F:32])([F:31])[C:18]([F:30])([F:29])[C:19]2[CH:24]=[CH:23][C:22]([O:25]C(=O)C)=[CH:21][CH:20]=2)=[CH:7][CH:6]=1)(=O)C.Cl>CO>[OH:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([F:29])([F:30])[C:17]([F:31])([F:32])[O:16][C:15]([F:33])([F:34])[C:14]([F:35])([F:36])[O:13][C:12]([F:37])([F:38])[C:11]([F:40])([F:39])[C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=2)=[CH:20][CH:21]=1
Reactant: CC(=O)Oc1ccc(C(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)c2ccc(OC(C)=O)cc2)cc1
Agent: Cl
Solvent: CO
Product: Oc1ccc(C(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)c2ccc(O)cc2)cc1
Yield: 46 %

Procedure:
To a solution of 4-iodophenyl acetate (26.8 g, 0.102 mole) and 1,8-dioodoperfluoro-3,6-dioxaoctane (20.0 g, 0.034 mole) in 125 ml of N,N-dimethylformamide was added copper bronze (17.3 g, 0.273 g atom). This slurry was stirred under nitrogen at 105°-110° C for 96 hours. The cooled reaction mixture was added to a stirred mixture of 200 ml of ether and 300 ml of water. The cuprous salts and excess copper were filtered off and washed with ether on the frit. The ether layer was then washed repeatedly with water until free from the reaction solvent. The ethereal solution was evaporated to dryness to give 23 g of brown oil which was refluxed in 20 ml of acetic anhydride for 40 minutes. The excess acetic anhydride was distilled off and the residue was distilled under reduced pressure to give 13.5 g of 1,8-bis(4-acetoxyphenyl)perfluoro-3,6-dioxaoctane, bp 158°-161° C/0.005 mm. This water-white oil was refluxed for 40 minutes in a solution of 22 ml of concentrated hydrochloric acid in 225 ml of methanol. The solvent was evaporated under reduced pressure and the resultant tan residue was taken up in a liter of hexane. This solution was treated with charcoal, filtered, and cooled to give 8.20 g (46% yield) of light pink crystals, mp 118°-120° C.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[CH3:12][C:13]1([CH3:21])[C:17](=[O:18])[CH:16]([CH3:19])[NH:15][C:14]1=[O:20].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([N:15]2[CH:16]([CH3:19])[C:17](=[O:18])[C:13]([CH3:21])([CH3:12])[C:14]2=[O:20])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: COc1cc(I)ccc1C#N
Reactant: CC1NC(=O)C(C)(C)C1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1cc(N2C(=O)C(C)(C)C(=O)C2C)ccc1C#N

Procedure:
Using 4-iodo-2-methoxybenzonitrile (835 mg), 3,3,5-trimethylpyrrolidine-2,4-dione (350 mg), cesium carbonate (1.21 g), tris(dibenzylideneacetone)dipalladium(0) (227 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (287 mg), and in the same manner as in Reference Example 3, the title compound was obtained as a colorless solid (yield: 330 mg, 49%).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O>C(OCC)(=O)C.CO.[Pd]>[NH:12]1[C:7]2[C:6](=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:5][CH2:4][C:3]1=[O:2]
Reactant: COC(=O)CNc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1CNc2ccccc2N1
Yield: 99.4 %

Procedure:
A solution of N-(2-nitrophenyl)glycine methyl ester (740 mg, 3.6 mmol) in ethyl acetate (50 ml) and methanol (25 ml) was hydrogenated at atmospheric pressure over a catalytic amount of 10% palladium on carbon. After 1 h the mixture was filtered and reduced to afford 1,2,3,4-tetrahydroquinoxalin-2-one as a yellow solid (530 mg, 99%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:14][C:9]2[N:10]=N[CH:12]=[CH:13][C:8]=2[C:7]=1[OH:15])=[O:5])[CH3:2].COC(=O)C1C=C[C:22]([Cl:25])=NC=1Cl>>[CH2:1]([O:3][C:4]([C:6]1[O:14][C:9]2=[N:10][C:22]([Cl:25])=[CH:12][CH:13]=[C:8]2[C:7]=1[OH:15])=[O:5])[CH3:2]
Reactant: COC(=O)c1ccc(Cl)nc1Cl
Reactant: CCOC(=O)c1oc2nnccc2c1O
Product: CCOC(=O)c1oc2nc(Cl)ccc2c1O

Procedure:
This compound was prepared using a method analogous to that of 5-hydroxyfuro[2,3-c]pyridazine-6-carboxylic acid ethyl ester (A.2.3.1), 2,6-dichloronicotinic acid methyl ester replacing 3-chloropyridazine-4-carboxylic acid ethyl ester;
Reaction SMILES: [CH2:1]([O:8]C1(C(N)=O)CC1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15]1([C:18]2[N:22]([CH3:23])[C:21]([CH:24]=[O:25])=[CH:20][N:19]=2)[CH2:17][CH2:16]1>>[CH2:1]([O:8][C:15]1([C:18]2[N:22]([CH3:23])[C:21]([CH:24]=[O:25])=[CH:20][N:19]=2)[CH2:17][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(C=O)cnc1C1CC1
Reactant: NC(=O)C1(OCc2ccccc2)CC1
Product: Cn1c(C=O)cnc1C1(OCc2ccccc2)CC1

Procedure:
2-(1-Benzyloxy-cyclopropyl)-3-methyl-3H-imidazole-4-carbaldehyde was prepared from 1-benzyloxy-cyclopropanecarboxylic acid amide in the same manner as 2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH2:8][CH2:7][C:6](=[O:9])[CH:5]=1)[CH3:2].C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:17][C:5]1[C:6](=[O:9])[CH2:7][CH2:8][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC1=CC(=O)CC1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC1=C(Br)C(=O)CC1

Procedure:
3-Ethoxy-cyclopent-2-enone (Intermediate NINE1) (commercially available from Aldrich) (10.0 g, 77.6 mmol) in carbon tetrachloride (15 mL) at 0° C. was treated with NBS (15.3 g, ˜85 mmol) added portion-wise over 30 m. After 1 h at 0° C. the mixture was partitioned between CH2Cl2 and saturated NaHCO3. The aqueous layer was extracted with CH2Cl2. The pooled organic layers were washed with H2O (2×) and dried over MgSO4. The mixture was filtered and evaporated to dryness. The solid was recrystallized from pentane:ether to give 13.3 g of 2-bromo-3-ethoxy-cyclopent-2-enone (Intermediate NINE2).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]1[C:15]([C:17]1[C:29](=[O:30])[N:25]2[CH2:26][CH2:27][O:28][C:23]3[C:24]2=[C:19]([CH:20]=[C:21]([O:31][CH3:32])[CH:22]=3)[C:18]=1[OH:33])=[O:16])=[O:5])C.[OH-].[Na+].C(O)C>O1CCCC1>[C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]1[C:15]([C:17]1[C:29](=[O:30])[N:25]2[CH2:26][CH2:27][O:28][C:23]3[C:24]2=[C:19]([CH:20]=[C:21]([O:31][CH3:32])[CH:22]=3)[C:18]=1[OH:33])=[O:16])([OH:5])=[O:3]
Reactant: CCOC(=O)C1Cc2ccccc2N1C(=O)c1c(O)c2cc(OC)cc3c2n(c1=O)CCO3
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc2c3c(c1)c(O)c(C(=O)N1c4ccccc4CC1C(=O)O)c(=O)n3CCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.9 %

Procedure:
A mixture of 2,3-dihydro-6-(2-ethoxycarbonyl-1-indolinylcarbonyl)-7-hydroxy-9-methoxy-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (2.8 g), 1N-sodium hydroxide (20 ml), ethanol (20 ml) and tetrahydrofuran (20 ml) was stirred for 2 hours at room temperature. The solvent was evaporated. The residue was dissolved in water and washed with ethyl acetate. The aqueous layer was acidified with hydrochloric acid to give precipitates, which were collected and washed with ethanol to afford crystals of 2,3-dihydro-6-(2-carboxy-1-indolinylcarbonyl)-7-hydroxy-9-methoxy-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (1.6 g).