Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:14][C:15](=[O:44])/[C:16](/[C:19]1[N:20]=[C:21]([NH:24][C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:22][CH:23]=1)=[N:17]\[OH:18])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:52][C:53]#[N:54].C(OCC)C>CS(C)=O>[CH:1]([O:14][C:15](=[O:44])/[C:16](=[N:17]\[O:18][CH2:52][C:53]#[N:54])/[C:19]1[N:20]=[C:21]([NH:24][C:25]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[S:22][CH:23]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N#CCCl
Reactant: O=C(OC(c1ccccc1)c1ccccc1)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: N#CCO/N=C(\C(=O)OC(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Yield: 90.7 %

Procedure:
In 70 ml of dimethylsulfoxide was dissolved 11.9 g (0.02 mole) of (Z)-2-(2-tritylamino-4-thiazolyl)-2-(hydroxyimino)acetic acid benzhydryl ester and after adding thereto 2.76 g of a powder of potassium carbonate and 1.7 g (0.0225 mole) of of chloroacetonitrile, the mixture was allowed to react overnight at room temperature. After the reaction was over, the reaction mixture was poured into 150 ml of ice water, the product was extracted first with 150 ml of ethyl acetate and then with 100 ml of ethyl acetate. The organic layers were collected, and washed twice with 50 ml of water and then with 10 ml of a saturated aqueous sodium chloride solution. The ethyl acetate layer obtained was dried over anhydrous magnesium sulfate, and the solvent was distilled off to provide a caramel. To the caramel was added 100 ml of ethyl ether to powder the caramel. 11.5 g (yield: 90.7%) of (Z)-2-(cyanomethyloxyimino)-2-(2-tritylamino-4-thiazolyl)acetic acid benzhydryl ester was obtained. ##STR15##
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([C:23]([N:25]([CH3:62])[C@@H:26]([C@@H:58]([CH3:61])[CH2:59][CH3:60])[C@H:27]([O:56][CH3:57])[CH2:28][C:29]([N:31]3[CH2:35][CH2:34][CH2:33][C@H:32]3[C@H:36]([O:54][CH3:55])[C@@H:37]([CH3:53])[C:38]([NH:40][C@H:41]([C:49]([O:51]C)=[O:50])[CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:39])=[O:30])=[O:24])[CH:20]([CH3:22])[CH3:21])=O)C3C(=CC=CC=3)C=2C=CC=1.[OH-].[Li+].O.Cl>C1COCC1>[CH3:55][O:54][C@@H:36]([C@@H:32]1[CH2:33][CH2:34][CH2:35][N:31]1[C:29](=[O:30])[CH2:28][C@@H:27]([O:56][CH3:57])[C@@H:26]([N:25]([CH3:62])[C:23](=[O:24])[C@H:19]([CH:20]([CH3:21])[CH3:22])[NH2:18])[C@@H:58]([CH3:61])[CH2:59][CH3:60])[C@@H:37]([CH3:53])[C:38]([NH:40][C@H:41]([C:49]([OH:51])=[O:50])[CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:39]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O)OC)N(C)C(=O)[C@@H](N)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a stirring solution of #113 (2.10 g, 2.46 mM) in 10 mL of THF, lithium hydroxide (228 mg, 5.16 mM) was added followed by 3 mL of water. The reaction was allowed to stir at room temperature for 2 hours. The reaction was acidified though the addition of 1 M HCl and then concentrated in vacuo. The resulting white solid was taken up in 20 mL of acetonitrile and mL of water. The aqueous layer removed and the organic layer was washed once with water. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Ethyl acetate (20 mL) was then added and the crude solid was allowed to stir for 30 minutes, before being filtered to yield a white solid #250 (1.42 g, 94%). LC-MS (Protocol Q): m/z 619.5 [M+H+], retention time=1.10 minutes. HPLC (Protocol A at 45° C.) m/z 619.4 [M+H+], retention time=6.732 minutes.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[C@:13]12[CH2:21][C@H:20]1[C:22]1[CH:30]=[C:29]2[C:25]([C:26]([C:31]3[CH:36]=[CH:35][C:34]([N:37]4[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]4)=[CH:33][CH:32]=3)=[N:27][NH:28]2)=[CH:24][CH:23]=1.[CH:43](=O)[CH3:44]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:43]([N:40]1[CH2:41][CH2:42][N:37]([C:34]2[CH:33]=[CH:32][C:31]([C:26]3[C:25]4[C:29](=[CH:30][C:22]([C@H:20]5[C@@:13]6([C:12]7[C:16](=[CH:17][CH:18]=[C:10]([O:9][CH3:8])[CH:11]=7)[NH:15][C:14]6=[O:19])[CH2:21]5)=[CH:23][CH:24]=4)[NH:28][N:27]=3)=[CH:36][CH:35]=2)[CH2:38][CH2:39]1)[CH3:44]
Reactant: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(-c4ccc(N5CCNCC5)cc4)n[nH]c3c1)C(=O)N2
Reactant: CC=O
Solvent: O=C(O)C(F)(F)F
Product: CCN1CCN(c2ccc(-c3n[nH]c4cc([C@@H]5C[C@@]56C(=O)Nc5ccc(OC)cc56)ccc34)cc2)CC1
Yield: 7.2 %

Procedure:
The title compound was synthesized according to the method of Example A96B, using (1R*,2S*)-5′-methoxy-2-(3-(4-(piperazin-1-yl)phenyl)-1H-indazol-6-yl)spiro [cyclopropane-1,3′-indolin]-2′-one 2,2,2-trifluoroacetate (40 mg, 0.069 mmol) and acetaldehyde (6.0 uL, 0.140 mmol). The crude reaction mixture was concentrated under reduced pressure to dryness, and purified by preparative HPLC to give the title compound as a white solid (3.0 mg, 7.0%); 1H NMR (400 MHz, CD3OD) δ 7.91 (d, J=8.6 Hz, 1H), 7.87 (d, J=8.5 Hz, 2H), 7.49 (s, 1H), 7.17 (d, J=8.6 Hz, 2H), 7.02 (d, J=8.8 Hz, 1H), 6.82 (d, J=8.5 Hz, 1H), 6.60 (d, J=8.9 Hz, 1H), 5.60 (s, 1H), 4.02-4.92 (m, 2H), 3.74-3.64 (m, 2H), 3.38-3.22 (m, 5H), 3.28 (s, 3H), 3.14-3.05 (m, 2H), 2.26-2.22 (m, 1H), 2.20-2.16 (m, 1H), 1.41 (t, J=7.2 Hz, 3H); MS ESI [M+H]+ 494.3, calcd for [C30H31N5O2+H]+ 494.26.
Reaction SMILES: Cl[CH2:2][C:3]([SiH2:7][CH:8]([O:11][CH3:12])[O:9][CH3:10])=[CH:4][CH2:5]Cl>[Zn].C1COCC1>[CH3:10][O:9][CH:8]([SiH2:7][C:3]([CH:4]=[CH2:5])=[CH2:2])[O:11][CH3:12]
Reactant: COC(OC)[SiH2]C(=CCCl)CCl
Agent: [Zn]
Solvent: C1CCOC1
Product: C=CC(=C)[SiH2]C(OC)OC
Yield: 70.4 %

Procedure:
While 3.5 g (35×1.5 mmols) of Zn powder and 15 ml of THF were agitated, 8.0 g (35 mmols) of 1,4-dichloro-2-(dimethoxymethyl)silyl-2-butene was added. The mixture was heated under reflux for 2 hours, and then treated in the same manner as in Example 1 to obtain 3.9 g of 2-(dimethoxymethyl)silyl-1,3-butadiene.
Reaction SMILES: [OH:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=O)=[CH:4][CH:3]=1>CS(O)(=O)=O.[Cl-].[Na+].O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]2[C:8]3[C:9](=[CH:10][CH:11]=[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]4=3)[C:18]3[C:19]2=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)=[CH:26][CH:27]=1
Reactant: COc1ccc(C2=C(C(=O)c3ccc(O)cc3)c3ccccc3CC2)cc1
Agent: CS(=O)(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2c(c1)C(c1ccc(O)cc1)c1c-2ccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 15 g portion of 4-(4-hydroxybenzoyl)-3-(4-methoxyphenyl)-1,2-dihydronaphthalene was dissolved in 200 g of methanesulfonic acid under nitrogen, and was stirred overnight at ambient temperature. Then the suspension was poured over 200 g of ice and the mixture was added to 100 ml of brine, which was in turn extracted with 300 ml of ethyl acetate. The organic extract was then washed with 100 ml of water, with 100 ml of saturated aqueous sodium bicarbonate solution, and again with 20 ml of brine. The organic extract was concentrated and the residue was digested with hot isopropanol. The digestion mixture was cooled overnight to obtain 3.2 g of the desired product. That product was recrystallized from ethyl acetate to obtain 2.74 g of the desired product in pure form. The product was identified by its field desorption mass spectrum m/e 338 (calc'd m/e 338) and its NMR spectrum.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[C:8]([C:10]([CH3:14])([CH3:13])[CH2:11][CH3:12])[CH:7]=[CH:6][C:5]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=1[N+:26]([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:26][C:17]1[CH:18]=[C:19]([C:22]([F:23])([F:24])[F:25])[CH:20]=[CH:21][C:16]=1[O:15][C:5]1[CH:6]=[CH:7][C:8]([C:10]([CH3:13])([CH3:14])[CH2:11][CH3:12])=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:29]
Reactant: CCC(C)(C)c1ccc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])c(C(=O)OC)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC(C)(C)c1ccc(Oc2ccc(C(F)(F)F)cc2N)c(C(=O)OC)c1
Reaction time: 3 h

Procedure:
Methyl-2-(nitro-4-trifluoromethylphenoxy)-5-(1,1-dimethylpropyl)benzoate (2.5 g, 0.006 mol) was mixed in ethyl acetate (50 mL) and a palladium on carbon catalyst (600 mg) was added under argon. This mixture was hydrogenated at 50 psi for 3 h. The mixture was filtered through Celite® and washed with methanol and ethyl acetate. The solvents were evaporated to yield the title compound. 1H NMR (250 MHz, CDCl3) δ7.84 (d, 1H), 7.44 (dd, 1H), 7.03 (d, 1H), 684-6.97 (m, 2H), 6.72 (d, 1H), 4.22 (s, 2H), 3.81 (s, 3H), 1.55-1.72 (m, 2H), 1.29 (s, 6H), 0.60-0.77 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([Cl:13])[N:7]=[C:6]1Cl.[C:16]([O:20][C:21](=[O:29])[NH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17].CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:15])[CH2:4][N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([Cl:13])[N:7]=[C:6]1[N:26]1[CH2:25][CH2:24][CH:23]([NH:22][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:29])[CH2:28][CH2:27]1
Reactant: COC(=O)Cn1c(Cl)nc(Cl)c(Cl)c1=O
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(Cl)c(Cl)c1=O
Reaction time: 8 h
Yield: 64.6 %

Procedure:
To a solution of (2,4,5-trichloro-6-oxo-6H-pyrimidin-1-yl)-acetic acid methyl ester (6.0 g, 22.4 mmol) and piperidin-4-yl-carbamic acid tert-butyl ester (4.9 g, 24.4 mmol) in DMF (50 mL) was added DIPEA (5.7 g, 44.3 mmol) dropwise at RT, and the mixture was stirred overnight. The reaction mixture was diluted with water (500 mL), and the solids were collected by filtration. The solids were then dissolved in DCM (100 mL), washed with water (100 mL, 3×), washed with brine (100 mL), dried (Na2SO4) and concentrated. The residue was purified by silica chromatography (1:2 to 1:1, DCM:PE) to give 6.3 g of the title product (64%). 1H NMR (400 MHz, CDCl3): δ 1.22-1.34 (m, 2H), 1.45 (s, 9H), 1.97-2.03 (m, 2H), 2.96-3.09 (m, 2H), 3.68-3.69 (m, 1H), 3.75 (s, 3H), 4.42-4.44 (m, 3H), 4.84 (s, 2H). [M+H] Calc'd for C17H24Cl2N4O5, 435. Found, 435.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[CH3:37][S:38]([CH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)(=[O:40])=[O:39]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:47]3[CH2:48][CH2:49][N:44]([CH2:43][CH2:42][CH2:41][S:38]([CH3:37])(=[O:39])=[O:40])[CH2:45][CH2:46]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:31])([CH3:30])[C:32]#[N:33])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(3-methanesulfonyl-propyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxy-phenyl)-2-methyl-propionitrile was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12j) and 1-(3-methanesulfonyl-propyl)-piperazine (example 16e) in an analogous manner as described in example 25. LR-MS: 710.4 [(M+H)+]
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+].CO.[Cl-].[NH4+]>C1COCC1>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: O=[N+]([O-])c1ccc2c(c1)C(O)CCC2
Reaction time: 1 h

Procedure:
7-Nitro-3,4-dihydro-2H-naphthalen-1-one (2.0 g, 10 mmol) was dissolved in THF (50 mL) and NaBH4 (0.95 g, 25 mmol) was added. MeOH (50 mL) was then added dropwise over 5 minutes and the reaction mixture was stirred for one hour. Saturated ammonium chloride was then added to the reaction mixture, and the resulting mixture was extracted three times with ethyl acetate. The organic solutions were combined and washed with brine, dried (Na2SO4) and concentrated to give 7-nitro-1,2,3,4-tetrahydronaphthalen-1-ol. Yield 1.83 g (95%). LCMS (ESI): calc. C10H11NO3=193; obs. M+H=194.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](Cl)=[O:25]>>[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:25]
Reactant: O=C(Cl)c1ccco1
Reactant: CCN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CCN1CCC(c2c[nH]c3ccc(NC(=O)c4ccco4)nc23)CC1

Procedure:
Beginning with 0.015 gm (0.061 mMol) 5-amino-3-(1-ethylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.008 mL (0.080 mMol) furoyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: N1C2OCC(N)C=2C=CN=1.CO[N:13]=[C:14]1[C:22]2[C:17](=[N:18][C:19]([CH3:25])=[CH:20][C:21]=2[O:23][CH3:24])[O:16][CH2:15]1>>[CH3:24][O:23][C:21]1[CH:20]=[C:19]([CH3:25])[N:18]=[C:17]2[O:16][CH2:15][CH:14]([NH2:13])[C:22]=12
Reactant: CON=C1COc2nc(C)cc(OC)c21
Agent: NC1COc2nnccc21
Product: COc1cc(C)nc2c1C(N)CO2

Procedure:
This compound was prepared using a method analogous to that of 5,6-dihydrofuro[2,3-c]pyridazin-5-amine (A.2.3.4), 4-methoxy-6-methylfuro[2,3-b]pyridin-3(2H)-one O-methyl oxime replacing furo[2,3-c]pyridazin-5(6H)-one O-methyl oxime;
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:20][C@@H:10]([O:11]C2C=CC(OC)=CC=2)[C@H:9]([N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])[C@@H:8]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:7]1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(=[O:3])[CH3:2].[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>C(#N)C.O.C(OCC)(=O)C>[C:1]([O:4][CH2:5][C@H:6]1[O:20][CH:10]([OH:11])[C@H:9]([N:21]2[C:22](=[O:31])[C:23]3=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]3[C:25]2=[O:26])[C@@H:8]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C@@H:7]1[O:40][CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(O[C@@H]2O[C@H](COC(C)=O)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2N2C(=O)c3ccccc3C2=O)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CC(=O)OC[C@H]1OC(O)[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 81.4 %

Procedure:
Compound 22 (9.0 g, 14.1 mmol) was dissolved in acetonitrile:water (4:1, 400 ml). Ammonium cerium (IV) nitrate (20.1 g, 36.7 mmol) was added thereto, and the mixture was stirred vigorously for 40 minutes at room temperature. The reaction mixture was diluted with ethyl acetate, washed successively with water, saturated aqueous sodium hydrogencarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica, gel column chromatography (toluene:ethyl acetate=2.5:1) to obtain Compound 23 (6.1 g, 81%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:16]([CH3:17])[C:15]2[C:14]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]=[CH:22]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[N:30]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=1)=[C:31]=[O:32].[NH4+].[Cl-]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH:16]([CH3:17])[C:15]2[C:14]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:31](=[O:32])[NH:30][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:40])([F:42])[F:41])[CH:34]=3)[CH:23]=[CH:22]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CC1c2c(ncnc2Oc2ccc3[nH]ccc3c2)CN1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC1c2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)CN1C(=O)OC(C)(C)C
Reaction time: 0.17 h

Procedure:
To a solution of 4-(1H-Indol-5-yloxy)-5-methyl-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (400 mg, 1.092 mmol) in THF (10 mL) at 0° C., sodium hydride (74.2 mg, 1.856 mmol, 60% in mineral oil) is added. After 10 min, 1-isocyanato-3-trifluoromethyl-benzene (0.314 ml, 2.183 mmol) is added and the reaction is allowed to reach rt. After 2 h, a saturated solution of NH4Cl in water (5 mL) is added. The organics are extracted with EtOAc (×3), dried and evaporated to give the crude 5-methyl-4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester. MS (ESI) m/z 554.9 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].[CH3:37][N:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]([CH2:47][NH2:48])=[CH:39]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:23]([NH:48][CH2:47][C:40]1[C:41]2[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:38]([CH3:37])[CH:39]=1)=[O:24]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: Cn1cc(CN)c2ccccc21
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCc2cn(C)c3ccccc23)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with C-(1-methyl-1H-indol-3-yl)-methylamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:26])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[CH:13][C:12]=1[CH3:25].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:26])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][C:12]=1[CH3:25]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
To a stirred solution of tert-butyl 4-[N′-(2-fluorophenyl)ureido]-3-methylphenylacetate (1.25 g, 3.49 mmol) in CH2Cl2 (10 ml) was added TFA (10 ml) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to a small volume and poured into ice-H2O. The resulting precipitate was collected under a reduced pressure and the crude solid was recrystallized from MeOH—CHCl3-IPE to give 4-[N′-(2-fluorophenyl)ureido]-3-methylphenylacetic acid (830 mg, 79%) as white needles. 1H-NMR (DMSO-d6) δ 2.23 (s, 3 H), 3.47 (s, 2 H), 6.96–7.30 (m, 5 H), 7.74–7.76 (m, 1 H), 8.17–8.20 (m, 1 H), 8.33 (s, 1 H), 8.94 (s, 1 H), 12.27 (br s, 1 H); Anal. Calcd for C16H15FN2O3: C, 63.57; H, 5.00; N, 9.27; F, 6.28. Found: C, 63.28; H, 5.00; N, 9.14; F, 6.43.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:13]1(C(=O)CCC)C=CC=CC=1>>[CH2:1]([C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:13]
Reactant: CCCC(=O)c1ccccc1
Reactant: Cc1[nH]cnc1-c1ccccc1
Product: CCc1[nH]cnc1-c1ccccc1

Procedure:
The compound is synthesized using the methods described in examples 269C and 103D starting from 1-phenylbutan-1-one.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:8][C:9](=[O:21])[NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][C:18]([O-:20])=[O:19])=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl.C(O)(=O)C>CO>[CH3:1][C:2]1[C:3]([NH:8][C:9](=[O:21])[NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][C:18]([OH:20])=[O:19])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1NC(=O)Nc1ccccc1CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cccnc1NC(=O)Nc1ccccc1CC(=O)O
Reaction time: 16 h

Procedure:
A solution of methyl 4-(2-(3-methylpyridylureido)phenylacetate (1 eq.) in methanol was treated with 1 N NaOH (2 eq.). The reaction was stirred for 16 h, then acidified carefully with 1 N HCl to pH 7 then with acetic acid to pH 3. The product was filtered and washed with methanol then ether to give 4-(2-(3-methylpyridylureido)phenylacetic acid: 1H NMR (CD3SOCD3, 300 MHz, ppm) 11.97 (s, 1H), 8.64 (brs, 1H), 8.31 (s, 1H), 7.69 (m, 1H), 7.62 (d, 8.4 Hz, 2H), 7.33 (d, 8.4 Hz, 2H), 7.09 (m, 1H), 3.62 (s, 2H), 2.38 (s, 3H); m/z 286.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:11][CH:12]([F:28])[C:13]1[CH:14]=[C:15]2[C:20](=[N:21][C:22]=1[CH:23]([O:26][CH3:27])[O:24][CH3:25])[NH:19][CH2:18][CH2:17][CH2:16]2.[C:29]1([O:35][C:36](=O)[O:37]C2C=CC=CC=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[F:28][CH:12]([F:11])[C:13]1[CH:14]=[C:15]2[C:20](=[N:21][C:22]=1[CH:23]([O:24][CH3:25])[O:26][CH3:27])[N:19]([C:36]([O:35][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:37])[CH2:18][CH2:17][CH2:16]2
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Reactant: COC(OC)c1nc2c(cc1C(F)F)CCCN2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(OC)c1nc2c(cc1C(F)F)CCCN2C(=O)Oc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of LHMDS in THF (1.6M, 6.64 ml, 10.63 mmol) was added drop wise to a solution of 6-(difluoromethyl)-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 101, 1.7 g, 6.25 mmol) and diphenylcarbonate (1.41 g, 6.57 mmol) in THF (20 ml) at −78° C. The reaction mixture was stirred for 30 minutes at −78° C., then for 18 h at room temperature, partitioned between saturated aqueous NH4Cl and DCM, extracted DCM (2×), dried over Na2SO4 and evaporated. The residue was preabsorbed onto isolate and purified by normal phase chromatography using a 40 g RediSep® silica column, eluting with a gradient from heptane to 50% EtOAc in heptane. Product containing fractions were combined and evaporated to give the title compound as a white solid. (UPLC-MS 7) tR 1.19 min; ESI-MS 379.4 [M+H]+.