Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C@@H:19]4[O:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]4)=[CH:15][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[ClH:32].CCOCC>O1CCOCC1>[ClH:32].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]([C@@H:19]4[O:24][CH2:23][CH2:22][NH:21][CH2:20]4)=[CH:17][CH:18]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(-c3n[nH]c(-c4ccc(F)cc4)n3)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Fc1ccc(-c2nc(-c3ccc([C@H]4CNCCO4)cc3)n[nH]2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
(S)-tert-Butyl 2-(4-(5-(4-fluorophenyl)-1H-1,2,4-triazol-3-yl)phenyl)morpholine-4-carboxylate (28 mg, 0.066 mmol) was dissolved in dioxane (0.5 ml) and a solution of HCl in dioxane (4M, 0.2 ml, 0.79 mmol) was added. The reaction mixture was stirred at 60° C. for 2 h. After cooling ether (2 ml) was added and the solid was filtered off. It was washed with ether and dried in vacuo to afford (S)-2-(4-(5-(4-fluorophenyl)-1H-1,2,4-triazol-3-yl)phenyl)morpholine hydrochloride (26 mg, 99%) as a white solid. MS (ISP): 325.2 ([M+H]+).
Reaction SMILES: [CH3:1][S:2][CH:3]([C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)[C:4]([O:6]C)=[O:5].[OH-].[K+].O.S(=O)(=O)(O)O>COCCOC>[CH3:1][S:2][CH:3]([C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: COC(=O)C(SC)c1ccsc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: CSC(C(=O)O)c1ccsc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.1 %

Procedure:
Methyl α-methylthio(3-thienyl)acetate (5.045 g) was dissolved in 60 ml of 1,2-dimethoxyethane, and 20 ml of a 2N aqueous solution of potassium hydroxide was added. The mixture was stirred at room temperature for 3 hours and 10 minutes. To the reaction mixture were added 30 ml of water and 6 ml of 3N sulfuric acid. The mixture was extracted three times with 50 ml of diethyl ether. The ethereal layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Recrystallization of the residue from benzene/n-hexane afforded 3.291 g of α-methylthio(3-thienyl)acetic acid as pale yellow crystals having a melting point of 73.5 to 74.0° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[CH2:12][NH:11][CH:10]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]2([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])[C:18]#[N:19])[CH:5]=[CH:6][CH:7]=1.Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C)C=O>[C:34]([O:33][C:31](=[O:32])[CH2:30][N:11]1[CH2:12][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])[C@:9]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])([C:18]#[N:19])[C@@H:10]1[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)CC1NCC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C[C@@H]1N(CC(=O)OC(C)(C)C)C[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 66 h
Yield: 66.2 %

Procedure:
To a solution of rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-2-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (2.5 g, 5.9 mmol) in N,N-dimethylformamide (50 mL) was added tert-butyl bromoacetate (2.5 g, 12.8 mmol) and Cs2CO3 (5 g, 15.4 mmol). The reaction mixture was stirred at room temperature for 66 h. Water was added. The mixture was extracted with ethyl acetate. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water twice, dried over MgSO4, then concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:10) to give rac-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetic acid tert-butyl ester as a white foam (2.1 g, 66%).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@H:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17]1.[Br:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33](O)[N:32]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:30][C:31]1[N:32]=[C:33]([O:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][C@H:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH2:17]2)[CH:34]=[CH:35][CH:36]=1
Reactant: Oc1cccc(Br)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H](O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H](Oc2cccc(Br)n2)C1
Reaction time: 18 h
Yield: 29.9 %

Procedure:
A solution of 0.473 mL (2.4 mmol) of diisopropylazodicarboxylate in 2 ml of tetrahydrofuran was added dropwise to a mixture of 454 mg (2.0 mmol) of tert-butyl (1S,3S)-3-hydroxycyclohexylcarbamate, 418 mg (2.40 mmol) of 2-bromo-6-hydroxypyridine and 629.5 mg (2.4 mmol) of triphenylphosphine in 5 ml of tetrahydrofuran at 0-5° C. The mixture was stirred for 18 hours. The mixture was concentrated, the residue purified via silica gel chromatography using a gradient of ethyl acetate in heptane to afford 222 mg (30%) of tert-Butyl (1S,3R)-3-(6-bromopyridin-2-yloxy)cyclohexylcarbamate. ESI MS m/z 370.9 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C:14](O)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].S(C)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1CO
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.7 %

Procedure:
A solution of (R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (Example 15 g, 18.5 g, 80.7 mmol) in anhydrous THF (44.4 mL) was cooled to 0° C. BH3.Me2S (44.4 mL, 88.8 mmol) was added drop wise over 15 minutes. After complete addition, the mixture was allowed to warm to room temperature, and stirring was continued for 18 hours. The mixture was quenched with water, and extracted with ethyl acetate. The organic extract was dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was flash chromatographed on silica gel (35% ethyl acetate in hexanes) to provide (R)-tert-butyl-2-(hydroxymethyl)piperidine-1-carboxylate as a white solid (14.2 g, 82%). MS 116 (MH+-boc)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.O.[NH2:20][NH2:21]>C(O)C>[NH:20]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1)[NH2:21]
Reactant: Fc1cccc(Oc2ccc(C(F)(F)F)cc2)n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1cccc(Oc2ccc(C(F)(F)F)cc2)n1
Temperature: 40 °C
Yield: 47.8 %

Procedure:
Next, a reaction flask was loaded with 2-fluoro-6-(4-trifluoromethylphenoxy)pyridine (8.0 g) and ethanol (60 ml), and heated up to 40° C. with stirring. To this mixture, hydrazine monohydrate (7.6 g) was dropwise added in 30 minutes. The temperature of the mixture was raised to the reflux temperature, followed by stirring for 20 hours. Thereafter, the heating was stopped, and the reaction mixture was cooled, followed by filtration to remove insoluble components. The filtrate was condensed by an evaporator to give 2-hydrazino-6-(4-trifluoromethylphenoxy)pyridine (4.0 g).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[CH:4]=[C:5]([OH:13])[N:6]=[CH:7]2.[CH3:14][Zn]C.C1(C)C=CC=CC=1.[NH4+].[Cl-]>C1COCC1.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>[F:12][C:9]1[CH:10]=[CH:11][C:2]([CH3:14])=[C:3]2[C:8]=1[CH:7]=[N:6][C:5]([OH:13])=[CH:4]2
Reactant: Oc1cc2c(Br)ccc(F)c2cn1
Reactant: C[Zn]C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(F)c2cnc(O)cc12

Procedure:
A solution of 5-Bromo-8-fluoroisoquinolin-3-ol (76.5 mg, 0.316 mmol), 2.0 M of dimethylzinc in toluene (0.40 mL, 0.80 mmol), and Pd(PPh3)4 (22 mg, 0.019 mmol) in THF in a microwave reactor tube was heated in the microwave reactor to 80° C. for 60 min. The reaction solution was poured into sat. aq. NH4Cl, and the resulting mixture was extracted with DCM (3×25 mL). The combined DCM extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was triturated with Et2O. The resulting light greenish-yellow solid was washed with Et2O and dried in vacuo to give the title compound as light greenish-yellow solid. It was used in the next step without further purification. MS(ES+): m/z=178.17 (100) [MH+]. HPLC: tR=2.36 min (polar—5 min, ZQ2).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=O)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:20][C@@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[CH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([N:28]3[CH2:29][CH2:30][CH2:31][C@H:27]3[CH2:26][N:22]3[CH2:23][CH2:24][CH2:25][C@H:21]3[CH3:20])=[O:19])=[CH:15][CH:16]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure B′ starting from 4′-methanesulfonyl-biphenyl-4-carboxylic acid (CAS 16734-98-8) and 2-(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (M+H) 427.2
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:29])=[N:4][S:5][C:6]=1[NH:7][C:8](=[O:28])[C:9]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:19][C:18]=2[CH:27]=1)=[CH:10][N:11]([CH3:13])C.Cl.[CH2:31](N)C>O1CCCC1.O>[Cl:1][C:2]1[C:3]([CH3:29])=[N:4][S:5][C:6]=1[NH:7][C:8](=[O:28])[C:9]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([CH2:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[N:19][C:18]=2[CH:27]=1)=[CH:10][NH:11][CH2:13][CH3:31]
Reactant: Cc1nsc(NC(=O)C(=CN(C)C)c2ccc3oc(CC(C)(C)C)nc3c2)c1Cl
Reactant: CCN
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCNC=C(C(=O)Nc1snc(C)c1Cl)c1ccc2oc(CC(C)(C)C)nc2c1
Temperature: 60 °C
Yield: 85.4 %

Procedure:
A mixture of N-(4-chloro-3-methylisothiazol-5-yl)-α-[(dimethylamino)methylene]-[2-(2,2-dimethylpropyl)benzoxazol-5-yl]acetamide (0.20 g, 0.00046 mole) [from Example 5] and ethylamine hydrochloride (0.0225 g, 0.0028 mole) in tetrahydrofuran (4 ml) and water (1 ml) was heated for 24 hours at 60° C. The mixture was cooled to room temperature, the solvent was evaporated in vacuo and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic extract was dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. Further purification by flash column chromatography, eluting with ethyl acetate:hexane at 2:3 by volume, gave N-(4-chloro-3-methylisothiazol-5-yl)-α-[(ethylamino)methylene]-[2-(2,2-dimeth-ylpropyl)benzoxazol-5-yl]acetamide as a colourless solid (0.17 g). Analysis by 1H NMR showed the product comprised a mixture of E- and Z-isomers.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][C@@H:24]1[C@H:28]2[N:29]([C:34](=[O:59])[C@@H:35]([NH:41][C:42](=[O:58])[C:43]3[CH:48]=[CH:47][C:46]([N:49]4[CH2:54][CH2:53][N:52]([CH:55]([CH3:57])[CH3:56])[CH2:51][CH2:50]4)=[CH:45][CH:44]=3)[CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:30][C@@H:31]([O:32][CH3:33])[C@H:27]2[O:26][CH2:25]1>ClCCl>[CH:55]([N:52]1[CH2:51][CH2:50][N:49]([C:46]2[CH:45]=[CH:44][C:43]([C:42]([NH:41][C@@H:35]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:34]([N:29]3[CH2:30][C@@H:31]([O:32][CH3:33])[C@H:27]4[O:26][CH2:25][C:24](=[O:23])[C@@H:28]34)=[O:59])=[O:58])=[CH:48][CH:47]=2)[CH2:54][CH2:53]1)([CH3:57])[CH3:56]
Reactant: CO[C@@H]1CN(C(=O)[C@H](CC(C)(C)C)NC(=O)c2ccc(N3CCN(C(C)C)CC3)cc2)[C@H]2[C@@H]1OC[C@@H]2O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CO[C@@H]1CN(C(=O)[C@H](CC(C)(C)C)NC(=O)c2ccc(N3CCN(C(C)C)CC3)cc2)[C@@H]2C(=O)CO[C@@H]21
Reaction time: 18 h

Procedure:
Dess-Martin periodinane (2.82 g, 6.66 mmol) was added to a stirred solution of N—((S)-1-((3R,3aR,6R,6aS)-3-hydroxy-6-methoxydihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1yl)benzamide (1.72 g, 3.33 mmol) in dichloromethane (65 mL) under an atmosphere of argon. The mixture was stirred for 18 hours then diluted with dichloromethane (300 mL). The organic phase was washed with aqueous sodium hydroxide solution (1M, 100 mL) then the aqueous extracted with dichloromethane (150 mL). The organic layer was washed with aqueous sodium hydroxide solution (1M, 100 mL) then brine (150 mL), then dried (Na2SO4), filtered and reduced in vacuo to give 4-(4-isopropylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aS)-6-methoxy-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide a pale yellow solid (1.408 g, 82%). TLC (Rf=0.45, MeOH:CH2Cl2 1:19), analytical HPLC main peak, Rt=10.39 min., HPLC-MS 515.3 [M+H]+, 533.3 [M+H2O+H]+, 1051.6 [2M+Na]+; [□]D22−31.08° (c=3.7, CHCl3); δH (500 MHz, CDCl3) 0.99 (9H, s, C(CH3)3), 1.08 (6H, d, J=6.52 Hz, NCH(CH3)2), 1.68-1.74 (2H, m, CH2C(CH3)3), 2.65 (4H, brt, J=5.04 Hz, CH2NCH(CH3)2), 2.67-2.73 (1H, m, NCH(CH3)2), 3.29 (4H, brt, J=5.05 Hz, CH2CH2NCH(CH3)2), 3.49 (3H, s, OCH3), 3.61 (1H, dd, 5.35 Hz, NCH2CHOCH3), 4.00-4.04 (1H, m, CHOCH3), 4.09 (1H, d, J=16.89 Hz, OCH2C═O), 4.20 (1H, d, J=16.93 Hz, OCH2C═O), 4.27 (1H, dd, 5.88 Hz, NCH2CHOCH3), 4.74 (1H, d, J=6.86 Hz, OCH2(C═O)CH), 4.91 (1H, dd, 4.28 Hz, OCHCHOCH3), 4.94-5.00 (1H, m, CHCH2C(CH3)3), 6.61 (1H, d, J=8.69 Hz, NH), 6.84 (2H, brd, J=8.95 Hz, aromatic CH), 7.65 (2H, brd, J=8.91 Hz, aromatic CH); δC (125 MHz, CDCl3) 18.53 (NCH(CH3)2), 29.75/29.80 (C(CH3)3), 30.75/30.77 (C(CH3)3), 46.53 (CH2C(CH3)3), 47.02 (NCH2CH2NCH(CH3)2), 48.24 (CHCH2C(CH3)3), 48.43 (NCH2CH2NCH(CH3)2), 49.76 (NCH2CHOCH3), 54.49 (NCH(CH3)2), 58.23 (OCH3), 60.49 (OCH2C(═O)CH), 71.45 (OCH2C═O), 78.84 (CHOCH3), 80.25 (OCHCHOCH3), 114.01/114.10/128.49 and 129.83 (aromatic CH), 123.08 (aromatic quaternary), 153.55 (aromatic quaternary), 166.69 (NHC═O), 173.53 (CH2NC═O), 207.93 (ketone C═O).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH2:6][CH2:5]2.CN(C)[CH:20]=[O:21].C(OCC)C.[Cl-].[NH4+]>O1CCCC1>[CH:20]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH2:6][CH2:5]2)=[O:21]
Reactant: Brc1ccc2c(c1)CCC2OC1CCCCO1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)CCC2OC1CCCCO1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
8.1 g of 5-bromo-1-(tetrahydropyran-2-yloxy)indane was dissolved in 100 ml of anhydrous tetra-hydrofuran under a nitrogen atmosphere. To the solution was dropwise added 20 ml of a 1.5N n-butyllithium-hexane solution at -65° C. in 10 minutes. The resulting mixture was stirred at the same temperature for 5 minutes. Thereto was added 2.3 ml of anhydrous N,N-dimethylformamide. The reaction mixture was heated to room temperature and added to a mixture of 100 ml of ice water, 100 ml of diethyl ether and 2 g of ammonium chloride. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: toluene/ethyl acetate=15/1) to obtain 6.5 g of 5-formyl-1-(tetrahydropyran-2-yloxy)indane.
Reaction SMILES: [OH:1][C:2]([C:18]([F:21])([F:20])[F:19])([CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])([CH3:9])[CH3:8])[C:3]([OH:5])=O.S(Cl)(Cl)=O.[NH2:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:32](=[O:33])[O:31][CH2:30]2>CC(N(C)C)=O>[OH:1][C:2]([C:18]([F:21])([F:20])[F:19])([CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])([CH3:9])[CH3:8])[C:3]([NH:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:32](=[O:33])[O:31][CH2:30]2)=[O:5]
Reactant: Nc1ccc2c(c1)COC2=O
Reactant: COc1ccccc1C(C)(C)CC(O)(C(=O)O)C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: COc1ccccc1C(C)(C)CC(O)(C(=O)Nc1ccc2c(c1)COC2=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
400 mg of 2-hydroxy-4-(2-methoxyphenyl)-4-methyl-2-trifluoromethyl-valeric acid is mixed in 5 ml of dimethylacetamide at 0° C. with 0.23 ml of thionyl chloride. After 30 minutes of stirring at 0° C., 390 mg of 5-aminophthalide in 2 ml of dimethylacetamide is added, and the mixture is stirred for another 4 hours at this temperature. Then, ice water is added, extracted with ethyl acetate, and after drying (Na2SO4), the crude product is chromatographed on silica gel. With hexane/ethyl acetate (50:50), the title compound is obtained in a crystalline state, flash point 134-135° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1N2CN3CN(C2)CN1C3.C(O)(=[O:28])C.[Cl-].[Na+]>C(Cl)(Cl)Cl.O>[Cl:9][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]=1[CH:2]=[O:28]
Reactant: Clc1cccc(-c2ccccc2)c1CBr
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=Cc1c(Cl)cccc1-c1ccccc1

Procedure:
A stirred solution of 2-bromomethyl-3-chloro-[1,1'-biphenyl] (18.7 g, 0.067 mole) and hexamethylenetetraamine (9.3 g, 0.067 mole) in 200 ml of chloroform was heated at reflux for 221/2 hours. The reaction mixture was cooled and the solvent evaporated under reduced pressure to give a residue. To the residue was added 250 ml of a 1:1 solution of concentrated acetic acid:water. The mixture was heated at reflux for approximately 22 hours, then cooled. The mixture was saturated with sodium chloride and extracted with four 200 ml portions of methylene chloride. The extracts were combined, washed with saturated aqueous sodium chloride solution, followed by saturated aqueous sodium bicarbonate solution, and dried over anhydrous potassium carbonate. The mixture was filtered and the filtrate evaporated under reduced pressure to give a residue. The residue was subjected to column chromatography on silica gel, elution first with toluene:n-heptane (9:1), followed by toluene:methylene chloride (1:1), and finally methylene chloride to give 3-chloro-[1,1'-biphenyl]-2-carboxaldehyde (3.4 g) as an oil.
Reaction SMILES: N[C:2]1[C:3]([CH3:20])=[C:4]([CH:12]=[C:13]([CH3:19])[C:14]=1[C:15]([O:17][CH3:18])=[O:16])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[I:21]CI.N(OCCC(C)C)=O>C1COCC1.[Cu]I>[I:21][C:2]1[C:3]([CH3:20])=[C:4]([CH:12]=[C:13]([CH3:19])[C:14]=1[C:15]([O:17][CH3:18])=[O:16])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: ICI
Reactant: COC(=O)c1c(C)cc(C(=O)OC(C)(C)C)c(C)c1N
Agent: [Cu]I
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: COC(=O)c1c(C)cc(C(=O)OC(C)(C)C)c(C)c1I
Temperature: 25 °C
Yield: 48.4 %

Procedure:
1-tert-Butyl 4-methyl 3-amino-2,5-dimethylterephthalate (0.444 g, 1.59 mmol) was dissolved in THF (10 mL), and the mixture was sparged with nitrogen for 10 minutes. Copper (I) iodide (302 mg, 1.59 mmol) and diiodomethane (0.64 mL, 7.93 mmol) were added followed by isoamyl nitrite (0.63 mL, 4.74 mmol), and the mixture was stirred at reflux for 20 h. The mixture was cooled to ambient temperature and then was partitioned between ethyl acetate and 1N hydrochloric acid. The aqueous portion was extracted with ethyl acetate (2×). The combined organic portion was washed with brine, dried over sodium sulfate, then filtered and concentrated to provide an oil which was purified by column chromatography (silica gel, 2-10% ethyl acetate in hexanes). The clean fractions were combined and concentrated, and the residue was partitioned between ethyl acetate and 1: I saturated sodium bicarbonate solution: 1 M sodium thiosulfate. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, then filtered and concentrated to afford 1-tert-butyl 4-methyl 3-iodo-2,5-dimethylterephthalate (300 mg, 0.769 mmol, 48% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.42 (s, 1H), 3.96 (s, 3H), 2.60 (s, 3H), 2.31 (s, 3H), 1.59 (s, 9H); GCMS for C15H19IO4: 359 ([M-OCH3]+).
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:19]([C:21]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:23][CH:22]=3)=[O:20])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:31]=[C:30]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=[C:21]1[C:19]([NH:18][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH2:9][NH:8]2)=[CH:13][CH:14]=1)=[O:20]
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(NC(=O)c3c[nH]c4ccccc4c3=O)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc2c(c1)NCCC2)c1c[nH]c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
A mixture of 7-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1,2,3,4-tetrahydroquinoline-1-carboxylic acid tert-butyl ester (183) (23 mg, 0.05 mmol), TFA (1 mL) and CH2Cl2 (1 mL) was stirred at room temperature overnight. The solution was concentrated and the residue was dissolved in DMSO (1 mL) and purified by HPLC (10-99% CH3CN—H2O) to yield the product, 4-oxo-N-(1,2,3,4-tetrahydroquinolin-7-yl)-1H-quinoline-3-carboxamide (299) (7 mg, 32%). HPLC ret. time 2.18 min, 10-99% CH3CN, 5 min run; ESI-MS 320.3 m/z (MH+).
Reaction SMILES: C([N:8]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][C:11]([CH3:21])([CH3:20])[N:10]2[N:22]=[CH:23][C:24]([C:25](=[O:36])[C:26]([CH3:35])([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)[CH3:27])=[C:9]12)C1C=CC=CC=1.C(O)C.[H][H]>C1COCC1.[Pd]>[CH3:20][C:11]1([CH3:21])[N:10]2[N:22]=[CH:23][C:24]([C:25](=[O:36])[C:26]([CH3:27])([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)[CH3:35])=[C:9]2[NH:8][CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12]1
Reactant: Cc1ccc(C(C)(C)C(=O)c2cnn3c2N(Cc2ccccc2)C(c2ccccc2)CC3(C)C)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(C(C)(C)C(=O)c2cnn3c2NC(c2ccccc2)CC3(C)C)cc1
Reaction time: 1 h
Yield: 84 %

Procedure:
To 0.060 g (0.126 mmol) of 6 dissolved in 4 mL of 1:1 THF:ethanol was added 0.080 g of 10% palladium on carbon. The reaction vessel was capped with a rubber septum and charged with hydrogen via a balloon. After 1 h, the catalyst was removed via filtration and the filtrate concentrated to a cream colored solid. Purification by flash chromatography eluting with 90% hexanes/ethyl acetate gave 0.041 g (84%) of the title compound as a white solid. 1H NMR (CDCl3) δ 1.49 (s, 3H), 1.54 (s, 9H), 2.04-2.11 (m, 2H), 2.32 (s, 3H), 4.63 (dd, J=4.1, 10.7 Hz, 1H), 6.66 (s, 1H), 7.12-7.26 (m, 5H), 7.31-7.44 (m, 5H). MS Calcd.: 387; Found: 388 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:13])[CH:3]=1.[C:14](OCC)(=[O:20])[C:15](OCC)=[O:16]>>[CH3:13][C:4]1[CH:3]=[C:2]2[C:11]([NH:12][C:14](=[O:20])[C:15](=[O:16])[NH:1]2)=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(N)c(N)cc1C
Reactant: CCOC(=O)C(=O)OCC
Product: COC(=O)c1cc2[nH]c(=O)c(=O)[nH]c2cc1C
Temperature: 145 °C
Reaction time: 3 h

Procedure:
A mixture of 3.98 g of methyl 4,5-diamino-2-methylbenzoate and 40 mL of diethyl oxalate was stirred at 145° C. for 3 hours. After cooling to room temperature, the solid was collected by filtration, washed with diethyl ether, and dried under reduced pressure to obtain 4.75 g of methyl 7-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate.