Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH2:24][C:25]1[C:34]2[O:35][C:36]3([C:46]([CH3:48])([CH3:47])[C:45]4[C:40](=[CH:41][CH:42]=[C:43]([O:49][CH3:50])[CH:44]=4)[N:39]3[CH3:51])[CH:37]=[N:38][C:33]=2[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1>>[CH:24]([C:25]1[C:34]2[O:35][C:36]3([C:46]([CH3:47])([CH3:48])[C:45]4[C:40](=[CH:41][CH:42]=[C:43]([O:49][CH3:50])[CH:44]=4)[N:39]3[CH3:51])[CH:37]=[N:38][C:33]=2[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1)=[O:23]
Reactant: COc1ccc2c(c1)C(C)(C)C1(C=Nc3c(c(CO)cc4ccccc34)O1)N2C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Product: COc1ccc2c(c1)C(C)(C)C1(C=Nc3c(c(C=O)cc4ccccc34)O1)N2C

Procedure:
This compound is prepared according to the method employed for Example 1, from 0.42 g (1 mmol) of Dess-Martin reactant and 0.39 g (1 mmol) of 5'-hydroxymethyl-5-methoxy-1,3,3-trimethylspiro[indoline-2,3'-[3H]-naphtho[2,1-b][1,4]oxazine].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH:22]4[CH2:24][CH2:23]4)=[CH:20][C:19]([CH:25]4[CH2:27][CH2:26]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:3]=1.[CH2:32]([C@@H:34]1[CH2:38][O:37][C:36](=[O:39])[NH:35]1)[CH3:33]>>[CH:22]1([C:21]2[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:35]5[C@H:34]([CH2:32][CH3:33])[CH2:38][O:37][C:36]5=[O:39])=[CH:3][C:4]=4[S:28]([CH3:31])(=[O:30])=[O:29])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=[C:19]([CH:25]3[CH2:27][CH2:26]3)[CH:20]=2)[CH2:24][CH2:23]1
Reactant: CC[C@@H]1COC(=O)N1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Product: CC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C3CC3)CC2)c(S(C)(=O)=O)c1
Yield: 25.6 %

Procedure:
By reaction and treatment in the same manner as in Example 111 and using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl]methanone (400 mg) described in Preparation Example 89 and (R)-4-ethyloxazolidin-2-one (91.3 mg) described in Preparation Example 26, the title compound (109.5 mg) was obtained.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][N:25]=1.C(N(CC)CC)C.Cl.C([O-])(O)=O.[Na+]>CN(C)C=O>[O:21]=[C:15]1[CH:14]([N:8]2[CH2:7][C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][C:24]([C:23]([F:34])([F:22])[F:33])=[N:25][CH:26]=4)[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)nc1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3cc(CNC(=O)c4ccc(C(F)(F)F)nc4)ccc3C2=O)C(=O)N1
Reaction time: 1 h
Yield: 52.8 %

Procedure:
To a stirred mixture of 3-(5-Aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (1.00 g, 3.20 mmol) and 6-trifluoromethylnicotinoyl chloride (0.65 g, 3.10 mmol) in N,N-dimethylformamide (25 mL), was added triethylamine (0.88 mL, 6.20 mmol) at room temperature under nitrogen. After 1 h, 1N aq. HCl (50 mL) was added and the mixture was stirred for 10 min. The mixture was neutralized with sat. aq. NaHCO3. The product was isolated by filtration, washed with water (50 mL) and dried overnight in vacuo to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-6-trifluoromethyl-nicotinamide as a white solid (0.73 g, 51% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 2.39 min (97.69%); mp: 240-242° C.; 1H NMR (DMSO-d6) δ 1.92-2.12 (m, 1H), 2.29-2.44 (m, 1H), 2.54-2.70 (m, 1H), 2.81-3.09 (m, 1H), 4.32 (d, J=17.4 Hz, 1H), 4.45 (d, J=17.6 Hz, 1H), 4.65 (d, J=5.7 Hz, 2H), 5.11 (dd, J=5.0, 13.1 Hz, 1H), 7.51 (d, J=7.9 Hz, 1H), 7.59 (s, 1H), 7.71 (d, J=7.7 Hz, 1H), 8.07 (d, J=8.1 Hz, 1H), 8.40-8.60 (m, 1H), 9.22 (s, 1H), 9.56 (t, J=5.8 Hz, 1H), 10.98 (s, 1H); 13C NMR (DMSO-d6) δ 22.49, 31.21, 42.87, 47.14, 51.60, 120.60 (q, J=2.9 Hz), 121.41 (q, J=272 Hz), 122.23, 123.00, 127.20, 130.54, 132.78, 137.49, 142.45, 143.13, 148.1 (q, J=34 Hz), 149.02, 163.74, 167.89, 170.98, 172.85; LCMS: MH=447; Anal Calcd for C21H17N4O4F3+0.25H2O: C, 55.94; H, 3.91; N, 12.43. Found: C, 55.97; H, 3.49; N, 12.28.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[C@@H:11]2[CH2:12][CH2:13][CH2:14][C@@H:10]2[C:9](=[O:15])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]2[CH:23]=[CH:24][CH:25]=[CH:26][C:6]1=2)=[O:4].[C:27]1(=[O:33])[O:32][C:30](=[O:31])[CH:29]=[CH:28]1.CCCCCC>C1(C)C(C)=CC=CC=1>[CH2:16]([N:8]1[C:9](=[O:15])[C@H:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[N:5]([C:3](=[O:4])[CH2:2][NH:1][C:27](/[CH:28]=[CH:29]\[C:30]([OH:32])=[O:31])=[O:33])[C:6]2[CH:26]=[CH:25][CH:24]=[CH:23][C:7]1=2)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1C=CC(=O)O1
Reactant: NCC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Solvent: CCCCCC
Solvent: Cc1ccccc1C
Product: O=C(O)/C=C\C(=O)NCC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Temperature: 25 °C
Yield: 78.2 %

Procedure:
A mixture of (3aR*,10aS*)-4-(aminoacetyl)-9-benzyl-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta [e][1,4]diazepin-10(1H)-one (420 mg, 1.2 mmol) and maleic anhydride (118 mg, 1.2 mmol) was stirred for 30 minutes in xylene at 140° C. The reaction mixture was left standing for cooling at room temperature, to which was added hexane (5 mL). The resulting solid was collected by filtration, which was recrystallized from chloroform-ethanol-diethyl ether to give 420 mg (yield 78%) of the titled compound, m.p. 207°-209° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1>C(O)C.C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1
Reactant: COC(=O)CC[C@H](NC(=O)c1ccc(OCc2ccccc2)cc1)C(=O)OC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)CC[C@H](NC(=O)c1ccc(O)cc1)C(=O)OC
Temperature: 22 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
To a solution of 5.0 g of N-(4-benzyloxybenzoyl)-L-glutamic acid dimethyl ester in 175 ml ethanol and 25 ml ethyl acetate were added 0.6 g of 5% Pd/C. The mixture was shaken under a hydrogen atmosphere (3 atm) at 22° C. for 3 hours. The reaction mixture was then filtered through Celite and evaporated to an oil which was dissolved in ethyl acetate and, again, filtered through Celite. The filtrate was evaporated to give 3.8 g of the title compound as an oil: 300-MHz 1H NMR (CDCl3) δ2.10-2.21 (m, 1H), 2.24-2.38 (m, 1H), 2.41-2.58 (m, 2H), 3.65 (s, 3H), 3.79 (s, 3H), 4.76-4.85 (m, 1H), 6.86 (d, J=9 Hz, 2H), 7.11 (d, J=10 Hz, 1H), 7.67 (d, J=9 Hz, 2H), 7.78 (bs, 1H).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[C:2]([O:4]C)=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1.C[O-].[Na+].Cl>CO>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH2:17][C:2](=[O:4])[C:1]([O:7][CH3:8])=[O:6])=[CH:12][CH:11]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: COC(=O)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=O)CC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dimethyl oxalate (15.27 g, 0.129 mol) and 4′-chloroacetophenone (20.0 g, 0.129 mol) were charged to a 500 mL round-bottom flask, with provisions made for magnetic stirring, and diluted with methanol (300 mL). Sodium methoxide (25% in methanol, 70 mL) was added in one portion. The reaction was stirred at room temperature for 16 hours. The reaction became an insoluble mass during this time. The solid was mechanically broken up, then concentrated hydrochloric acid (70 mL) was added, and the white suspension was stirred vigorously at room temperature for sixty minutes. The suspension was cooled to 0° C. and held for 30 minutes. The solid was filtered, and the filter cake was washed with cold water (100 mL). Upon drying, methyl 4-[4-(chloro) phenyl]-2,4-dioxobutanoate was obtained (16.94 g, 54.4%) as the enol: 1H NMR (CDCl3/300 MHz) 7.94 (d. J=8.66 Hz, 2H), 7.48 (d, J=8.66 Hz, 2H), 7.04 (s, 1H), 3.95 (s, 3H), 3.48 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]#[C:21][CH2:22][CH2:23]O)=[CH:16][CH:15]=3)=[CH:12][S:11][C:4]=2[NH:5][C:6](=[O:10])[C:7]=1[C:8]#[N:9].C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:37]=[N+:38]=[N-:39].[Na+]>CN(C=O)C>[N:37]([CH2:23][CH2:22][C:21]#[C:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[C:3]3[C:2]([OH:1])=[C:7]([C:8]#[N:9])[C:6](=[O:10])[NH:5][C:4]=3[S:11][CH:12]=2)=[CH:15][CH:16]=1)=[N+:38]=[N-:39]
Reactant: N#Cc1c(O)c2c(-c3ccc(C#CCCO)cc3)csc2[nH]c1=O
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1c(O)c2c(-c3ccc(C#CCCN=[N+]=[N-])cc3)csc2[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxy-3-[4-(4-hydroxy-but-1-ynyl)-phenyl]-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carbonitrile (0.23 g, 0.7 mmol) in 5 mL DMF was added triethylamine (0.28 mL, 2 mmol), followed by MsCl (85 μL, 1 mmol). The mixture was stirred at rt for 2 hr, after which NaN3 (0.36 g, 5.6 mmol) was added, and heated to 90° C. overnight. Solvent was removed in vacuo and purified via reverse phase HPLC to afford the titled compound. MS (ESI) m/e 360 (M−H)+; 1H NMR (300 MHz, DMSO-d6): δ 2.76 (t, J=6.61 Hz, 2H), 3.52 (t, J=6.44 Hz, 2H), 6.67 (s, 1H), 7.29 (d, J=8.48 Hz, 2H), 7.44 (d, J=8.48 Hz, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[C:4]([CH3:12])[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1>>[CH3:11][C:6]1[CH:5]=[C:4]([CH3:12])[N:3]=[C:2]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=2)[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Nc1ccc(CCO)cc1
Reactant: Cc1cc(C)c([N+](=O)[O-])c(Cl)n1
Product: Cc1cc(C)c([N+](=O)[O-])c(Nc2ccc(CCO)cc2)n1
Temperature: 150 °C
Yield: 79.6 %

Procedure:
A mixture of 2-chloro-4,6-dimethyl-3-nitropyridine (step 2, 1.3 g, 7.0 mmol) and 4-aminophenylethyl alcohol (1.4 g, 10.2 mmol) was placed in a sealed tube and heated at 150° C. for 3 h. The reaction mixture was cooled and purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (2:1) to afford 1.6 g (80%) of the title compound as orange solids: 1H-NMR (CDCl3) δ 9.55 (1H, br.s), 7.57 (2H, d, J=8.4 Hz), 7.20 (2H, d, J=8.4 Hz), 6.52 (1H, s), 3.84 (2H, t, J=6.4 Hz), 2.85 (2H, t, J=6.4 Hz), 2.54 (3H, s), 2.42 (3H, s).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].Cl[C:13]1[CH:22]=[C:21]([Cl:23])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:24][CH3:25])[CH:19]=2)[N:14]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[Cl:23][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:24][CH3:25])[CH:19]=2)[N:14]=[C:13]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:22]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: COc1ccc2nc(Cl)cc(Cl)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc2nc(-c3ccc(C#N)cc3)cc(Cl)c2c1
Temperature: 100 °C

Procedure:
Followed Scheme 2, Step 1 starting from 4-cyanophenylboronic acid and 2,4-dichloro-6-methoxyquinoline, where the solvent used was DMF, and the catalyst used was Pd(PPh3)4. The mixture was heated to 100° C. for 3 h, allowed to cool, and then poured into ice water. The resulting solid was isolated by filtration, washed with water, and dried followed by recrystallization from methanol to give the desired product.
Reaction SMILES: [NH2:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]=[CH:10][C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12.C(=O)([O-])O.[Na+].CC(C)=O.[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH2:36][C:37](Cl)=[O:38]>O>[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH2:36][C:37]([NH:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]=[CH:10][C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12)=[O:38]
Reactant: Cn1nnnc1C=CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(Cl)Cc1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cn1nnnc1C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: 25 °C
Yield: 101.1 %

Procedure:
In 40 ml of water were dissolved 416 mg of 7-amino-3-(1-methyl-1H-tetrazol-5-yl)vinyl-3-cephem-4-carboxylic acid and 660 mg of sodium hydrogencarbonate. To the solution was added 10 ml of acetone and further added dropwise with stirring at 0°-5° C., 20 ml of an acetone solution containing 323 mg of 2-thienylacetyl chloride. The mixture was stirred for 30 minutes under ice-cooling and for additional 3 hours at room temperature. The acetone was distilled off at room temperature under reduced pressure. The residual solution was washed with ether, adjusted to pH 2.0 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with an aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The ethyl acetate was removed under reduced pressure, and, upon washing the residue with ether, there was obtained 590 mg of 7-(2-thienylacetamido)-3-(1-methyl-1H-tetrazol-5-yl)vinyl-3-cephem-4-carboxylic acid.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>O>[OH:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Oc1cccc2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(Oc1ccccc1)c1ccc2ccccc2c1O
Reaction time: 0.25 h
Yield: 59.6 %

Procedure:
To a 500-mL, three-neck, nitrogen-purged flask were added 28.8 g (0.20 mole) of 1-naphthol and 90 mL of toluene. To this stirred slurry was added 26.6 g (0.20 mole) of anhydrous aluminum chloride in portions over five minutes. The temperature of the mixture rose to 40°-50° C. during this addition. The orange slurry was heated to reflux, then 32.0 g (0.204 mole) of phenyl chloroformate was added over a period of 30 minutes. After this addition, the mixture was refluxed for 30 minutes then cooled to 30°-40° C. To the red reaction mixture was added 100 mL of water while holding the temperature at 35°-50° C. This addition is very exothermic initially, and ice bath cooling is used. During addition of the remaining water, the bath is lowered or removed in order to avoid cooling below 35° C. After this addition, 20 mL of 32% hydrochloric acid was added quickly at 35° -50° C. The mixture was stirred for 15 minutes, then the layers are allowed to separate. The lower (aqueous) layer was discarded. The top layer was washed (at 40°-50° C.) successively with: two 100-mL portions of 10% hydrochloric acid and two 100-mL portions of 40°-50° C. water. The solvent was then stripped off under vacuum (150-200 mm) to a pot temperature of 90° C. To the resulting amber liquid was added 120 mL of isopropyl alcohol at 70° C. The solution was cooled slowly to 0°-5° C. After stirring at 0°-5° C. for one hour, the slurry was filtered and the solids washed with three 25-mL portions of 0°-5° C. isopropyl alcohol. The yellow solids were air dried at 40° C. to give 31.5 g (59.7%) of phenyl 1-hydroxy-2-naphthoate.
Reaction SMILES: [CH2:1]([N:4]1[C:16]2[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:2][CH3:3].CN([CH:26]=[O:27])C.O=P(Cl)(Cl)Cl>O>[CH2:1]([N:4]1[C:16]2[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][C:13]([CH:26]=[O:27])=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:2][CH3:3]
Reactant: CN(C)C=O
Reactant: CCCn1c2ccccc2c2cccc(-c3ccccc3)c21
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCCn1c2ccccc2c2cc(C=O)cc(-c3ccccc3)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a 500 ml, three neck round bottom flask equipped with mechanical stirrer, thermometer, and addition funnel were added N-propylphenylcarbazole (56g, 0.2 mol) (prepared as described in the procedure used to prepare Compound (6)) and DMF (300 ml). The flask was placed in an ice/salt bath. When the temperature inside the flask reached 0° C., POCl3 (21 ml, 0.22 mol) was added slowly by the addition funnel. The inside temperature was not allowed to rise above 5° C. during the addition of the POCl3. When the addition of POCl3 was completed, the flask was placed on a steam bath for 2 hr. The flask was cooled to room temperature, then added slowly to a large excess of water (2 liters in a 4.5 liter beaker). The solution was stirred at room temperature for 3 hr, the solid was filtered off, washed repeatedly with water, and followed by washing with ethanol (20 ml). The product was recrystallized once from THF/water and dried at 60° C. in a vacuum oven for 6 hr. to produce 50 g (79% yield) of N-propylphenyl-3-formylcarbazole. 1H-N MR and IR spectra confirmed the structure of the product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:15]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:9]=[N:8]1>CC(O)=O.[Rh]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:15]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]=2[N:9]=[N:8]1
Reactant: c1ccc(-n2nnc3cnccc32)nc1
Agent: [Rh]
Solvent: CC(=O)O
Product: c1ccc(-n2nnc3c2CCNC3)nc1
Reaction time: 2 h

Procedure:
1-Pyridin-2-yl-1H-[1,2,3]-triazolo[4,5-c]pyridine (23 mg, 0.12 mmol) in HOAc (14 mL) was hydrogenated at 50 bar using Rh/C as catalyst on the H-cube apparatus with a flow rate of 1 ml/min and looped with product recycling for 2 hrs. Reaction was concentrated then partially purified on 12 g SiO2 with 0-10% NH3 MeOH/CH2Cl2. Used without further purification in next reaction. MS (ESI): mass calcd. for C10H11N5, 201.2. m/z found, 202.2 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 8.49 (ddd, J=4.9, 2.0, 0.9 Hz, 1H), 8.18-8.10 (m, 1H), 7.90 (ddd, J=8.3, 7.4, 1.9 Hz, 1H), 7.36-7.27 (m, 1H), 4.12 (t, J=1.4 Hz, 2H), 3.31-3.12 (m, 4H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][C:7]2[CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=[CH:16][C:6]1=2.O.NN>CCO.[Pd]>[NH2:17][C:14]1[CH:15]=[CH:16][C:6]2[N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][C:7]=2[CH:13]=1
Reactant: COCCN1C(=O)CCCc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: COCCN1C(=O)CCCc2cc(N)ccc21
Yield: 54 %

Procedure:
To a solution of the above 1-(2-methoxy-ethyl)-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one in EtOH (10 mL) was sequentially added 10% Pd/C (120 mg) and hydrazine-monohydrate (1 mL). The solution was warmed to reflux for 2.5 h, cooled, filtered through celite, and repeatedly evaporated from toluene to remove residual hydrazine. The residue was recrystallized from EtOAc/heptane to afford transparent prisms of 7-amino-1-(2-methoxy-ethyl)-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (345 mg, 54%) that had the following properties: mp: 134-135° C.; LC/MS (ESI+): 235 (M+H); 1H-NMR (CDCl3, 400 MHz): δ 7.08 (d, J=8.4, 1H), 6.60 (d, J=8.4, 1H), 6.51 (s, 1H), 4.20 (br s, 1H), 3.65 (m, 2H), 3.53 (m, 2H), 3.28 (s, 3H), 2.60 (br s, 1H), 2.27 (m, 2H), 1.58 (m, 3H).
Reaction SMILES: C(N(CC)CC)C.O=C1CCC(=O)N1[O:15][C:16](=O)[CH2:17][C:18]#[N:19].[NH:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28]2[CH:33]=[CH:32][N:31]=[C:30]([NH:34][C:35]3[C:36](=[O:41])[NH:37][CH:38]=[CH:39][CH:40]=3)[N:29]=2)[CH2:22]1>ClCCl>[O:15]=[C:16]([N:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28]2[CH:33]=[CH:32][N:31]=[C:30]([NH:34][C:35]3[C:36](=[O:41])[NH:37][CH:38]=[CH:39][CH:40]=3)[N:29]=2)[CH2:22]1)[CH2:17][C:18]#[N:19]
Reactant: O=c1[nH]cccc1Nc1nccc(N[C@@H]2CCCNC2)n1
Reactant: N#CCC(=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CCC(=O)N1CCC[C@@H](Nc2ccnc(Nc3ccc[nH]c3=O)n2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 13.5 %

Procedure:
Triethylamine (33 μL, 0.24 mmol) and 3-[(2,5-dioxopyrrolidin-1-yl)oxy]-3-oxopropane nitrile (prepared as described in BE875054(A1), 51 mg, 0.28 mmol) were added to a solution of (R)-3-(4-(piperidin-3-ylamino)pyrimidin-2-ylamino)pyridin-2(1H)-one (Preparation 19c, 67 mg, 0.23 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at ambient temperature for 24 hours and solvent was evaporated. Water was added and the mixture was extracted with dichloromethane. The organic layer was dried (MgSO4), evaporated under reduced pressure and the residue was purified by reverse phase chromatography (C-18 silica from Waters©, water/acetonitrile/methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to give the title compound (11 mg, 12%) as a solid.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([SH:6])[CH3:5].[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10](F)[CH:9]=1.O>CS(C)=O>[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10]([S:6][CH:4]([CH3:5])[CH3:3])[CH:9]=1
Reactant: CC(C)S
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)Sc1cc(Br)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (32.87 g) in dimethyl sulfoxide (600 ml) was added 2-propanethiol (41.73 ml) at ° C. under nitrogen atmosphere and stirred at room temperature for 1 hour. The reaction mixture was cooled with ice bath and added 4-bromo-2-fluorobenzoic acid (60 g). The reaction mixture was stirred at 70° C. for 1.5 hours and then cooled to room temperature. The mixture was poured into water (3 l) and washed with hexane (600 ml). The water layer was acidified with concentrated hydrochloric acid and then the resulting white solid was collected by filtration. The white solid was dried at 60° C. to give 4-bromo-2-(isopropylthio)benzoic acid (75.49 g).
Reaction SMILES: [Br:1][C:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:20][CH2:19]3)=[CH:10][CH:9]=2)[C:4]([SH:7])=[N:5][N:6]=1.Br[C:22]([CH3:31])([CH3:30])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:1][C:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:20][CH2:19]3)=[CH:10][CH:9]=2)[C:4]([S:7][C:22]([CH3:31])([CH3:30])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[N:5][N:6]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: Sc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Yield: 75.4 %

Procedure:
A solution of 5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol (prepared as described above; 500 mg, 1.444 mmol) and tert-butyl 2-bromo-2-methylpropanoate (270 μL, 1.444 mmol) and diisopropylethylamine (755 μL, 4.332 mmol) in DMF (3 mL) was heated at 60° C. for 20 hours. The mixture was then concentrated, diethyl ether (15 mL) was added and the mixture was sonicated until all solids dissolved. The solution was then washed with HCl with (1N, 10 mL) and extracted with diethyl ether (2×15 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to afford tert-butyl 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoate as a light brown foam (532 mg, 75% yield).