Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:8][N:9]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16][N:15]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+:29]([C:32]1[CH:40]=[CH:39][C:35]([CH2:36][CH2:37]Br)=[CH:34][CH:33]=1)([O-:31])=[O:30].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[C:22]([CH2:21][N:15]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10][N:9]([CH2:8][C:1]([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2])[CH2:20][CH2:19][N:18]([CH2:37][CH2:36][C:35]2[CH:34]=[CH:33][C:32]([N+:29]([O-:31])=[O:30])=[CH:40][CH:39]=2)[CH2:17][CH2:16]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]
Reactant: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCNCC1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(CCc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 24 h
Yield: 68.3 %

Procedure:
A solution of compound (20) (1.56 g, 3.89 mmol), 4-nitrophenethyl bromide (1.79 g, 7.78 mmol), anhydrous K2CO3 (1.61 g, 11.67 mmol) and KI (1.94 g, 11.67 mmol) dissolved in dry toluene (150 ml) was stirred for 24 hours. The solvent was evaporated from the reaction mixture under reduced pressure, and CH2Cl2 (250 ml) was added thereto. The resultant brown slurry was filtered through a celite pad, and washed with CH2Cl2 (2×30 ml). The solvent was evaporated from the combined filtrate under reduced pressure. The residue thus obtained was purified via alumina (basic) column chromatography using EtOAc/methanol (10:2) as an eluent to provide compound (25) as a yellow oil (1.46 g, 68% yield).
Reaction SMILES: [CH:1]#[C:2][C@@H:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].I[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C.CCN(CC)CC>[OH:9][C@@H:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:2]#[C:1][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Reactant: C#C[C@@H](O)CCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCC[C@H](O)C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, (S)-(−)-1-octyn-3-ol (61 mg, 0.53 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (150 mg, 0.41 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and Cul (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 18 h to yield (S)-(Z)-1,3-dihydro-4-(3-hydroxy-1-octynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 101 mg, 68%).
Reaction SMILES: Cl[CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:12][C:5]=2[NH:4][C:3]1=[O:19].[N-:20]=[N+:21]=[N-:22].[Na+]>CS(C)=O>[N:20]([CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:12][C:5]=2[NH:4][C:3]1=[O:19])=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1Nc2cc(-c3ccccc3)ccc2CCC1Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NC1CCc2ccc(-c3ccccc3)cc2NC1=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
A mixture comprising 0.93 g (3.42 mmol) of 3-chloro-8-phenyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one obtained in the Synthesis Example A-5, 0.27 g (4.18 mmol) of sodium azide and 15 ml of dimethyl sulfoxide was stirred at 80° C. for 3 hours. After further adding 0.05 g of sodium azide and stirring for 30 minutes, the reaction mixture was added to ice water. The crystals were collected by filtration and dried under reduced pressure to thereby give 0.77 g of the title compound. Yield 81%.
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21].CC1(C)C(C)(C)OB([C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)O1>>[NH2:35][C:34]1[CH:36]=[CH:37][C:31]([C:2]2[C:3]([F:22])=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3=[O:21])=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(N)cc3)c(F)cn2c1=O
Yield: 93.9 %

Procedure:
Ethyl 8-(4-amino-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (500 mg, 1.54 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline (439 mg, 2.00 mmol). Purification by flash silica column chromatography (CH2Cl2:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (550 mg, 93%). ESI-MS m/z: 381 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([NH2:11])[CH:9]=[CH:10][C:2]1=2.F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[N+:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:11][C:8]1[CH:9]=[CH:10][C:2]2[O:1][CH2:6][CH2:5][O:4][C:3]=2[CH:7]=1)([O-:21])=[O:20]
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=[N+]([O-])c1ccccc1Nc1ccc2c(c1)OCCO2
Temperature: 120 °C
Reaction time: 10 h
Yield: 67.2 %

Procedure:
5.9 g (39 mmol) of 2,3-dihydrobenzo[b]1,4-dioxin-6-amine and 5.0 g (35 mmol) of 2-fluoronitrobenzene were dissolved in N-methylpyrrolidone (70 mL) and 20.8 g (150 mmol) of potassium carbonate was added thereto. The solvent was heated with stirring for 10 hours at 120° C. The reaction mixture was poured into water, and extracted with ethyl acetate. The extracted organic layer was washed with water, 10% hydrochloric acid, water, and a saturated aqueous solution of sodium chloride in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (developing solvent: ethyl acetate:hexane=1:4), to obtain 6.4 g (yield: 66%) of N-(2-nitrophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-amine as a red liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[N+:23]([O-])=O)[C:14]2=[O:26])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[Cl-].[NH4+].O>[Fe].ClCCl>[NH2:23][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:20]=1[CH:21]=[CH:22][N:13]([CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:9]([O:11][CH3:12])=[O:10])[C:14]2=[O:26]
Reactant: COC(=O)C(c1ccc(Cl)cc1)n1ccc2c([N+](=O)[O-])cccc2c1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(c1ccc(Cl)cc1)n1ccc2c(N)cccc2c1=O
Temperature: 80 °C

Procedure:
A round bottom flask was charged with methyl 2-(4-chlorophenyl)-2-(5-nitro-1-oxoisoquinolin-2(1H)-yl)acetate (4.2 g, 0.011 mol) ethanol (60 mL, 1 mol) and ammonium chloride (6 g, 0.1 mol) in water (60 mL, 3 mol) was added and the reaction heated at 80° C. and iron (2 g, 0.04 mol) was added in four portions 5 minutes apart. The reaction was heated for another 1 h at that temperature and cooled to room temperature and poured into 200 ml dichloromethane and extracted. The solvent was removed to obtain the product as a light brown solid. MS m/z=343.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[C:16]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]#[C:27][CH3:28])=[C:22]([C:29]([F:32])([F:31])[F:30])[CH:21]=3)=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:5][CH:4]=1.[H][H]>CO.[Pt]>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[C:16]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH3:28])=[C:22]([C:29]([F:32])([F:31])[F:30])[CH:21]=3)=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: CC#Cc1ccc(NC(=O)c2cccnc2NCc2ccc(OC)nc2)cc1C(F)(F)F
Agent: [Pt]
Solvent: CO
Product: CCCc1ccc(NC(=O)c2cccnc2NCc2ccc(OC)nc2)cc1C(F)(F)F

Procedure:
A solution of 2-[(6-methoxypyrid-3-yl)methylamino]-N-[4-propynyl-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide (Example 30; 1.87 g, 4.25 mmol) in methanol (100 mL) is hydrogenated at atmospheric pressure over 5% platinum on carbon (0.4 g) at 22° C. The calculated amount of hydrogen is taken up in 13 hours. The mixture is then filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by recrystallisation from dichloromethane—hexane to give the title compound as a colourless crystalline solid, m.p. 51-61° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl-].[CH3:12][O:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2:34][C:35]1[C:40]([C:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[O:49][CH3:50])=O)=[CH:39][C:38]([Br:51])=[CH:37][N:36]=1>C1COCC1>[Br:51][C:38]1[CH:39]=[C:40]([C:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[O:49][CH3:50])=[CH:12][O:13][CH3:14])[C:35]([NH2:34])=[N:36][CH:37]=1
Reactant: COc1ccccc1C(=O)c1cc(Br)cnc1N
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=C(c1ccccc1OC)c1cc(Br)cnc1N
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 84.8 %

Procedure:
Into a 50 ml flame-dried round bottomed flask were added potassium bis(trimethylsilyl)amide (832 mg, 39.2 mmol) and anhydrous THF (10 ml). The slurry was cooled to 0° C. for 5 minutes under nitrogen, then (methoxymethyl)triphenylphosphonium chloride (1.53 g, 4.47 mmol) was added. The resulting red-orange solution was stirred at room temperature for 45 min, then a solution of (2-amino-5-bromo-pyridin-3-yl)-(2-methoxy-phenyl)-methanone (601 mg, 1.95 mmol in 10 ml THF) was added all at once. The reaction was stirred under nitrogen for 4 hours then quenched by addition of a saturated aqueous solution of ammonium chloride (25 ml). Ethyl acetate (100 ml) was added, and the layers were separated. The aqueous fraction was extracted three times with ethyl acetate, and the combined organic fractions were washed with brine, dried (Na2SO4), filtered and concentrated to give a brown, sticky oil. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes gave 554 mg (84%) of 5-bromo-3-[2-methoxy-1-(2-methoxy-phenyl)-vinyl]-pyridin-2-ylamine as a mixture of E- and Z-isomers.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][C:26]=2[NH2:31])O1>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:31][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:25]=1[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=1
Reactant: Cc1nc(Cl)cc(NC(=O)OC(C)(C)C)n1
Reactant: CC1(C)OB(c2ccncc2N)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1nc(NC(=O)OC(C)(C)C)cc(-c2ccncc2N)n1
Yield: 26 %

Procedure:
Method 26 was followed using tert-butyl 6-chloro-2-methylpyrimidin-4-ylcarbamate (1.0 equiv.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (3.0 equiv.), Pd(dppf)Cl2-DCM (0.10 equiv.) in DME/2M Na2CO3 (3:1, 0.07M) at 80° C. for 30 min. Purification via SiO2 column chromatography eluting with EtOAc afforded tert-butyl 6-(3-aminopyridin-4-yl)-2-methylpyrimidin-4-ylcarbamate in 26% yield. LCMS (m/z): 302.1 (MH+); LC Rt=2.23 min.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[F:10][CH2:11][CH2:12]I.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:10][CH2:11][CH2:12][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: FCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCF)cc1
Temperature: 70 °C

Procedure:
A mixture of commercially available 4-hydroxybenzaldehyde (2.000 g; 16.40 mmol), 1-fluoro-2-iodoethane (2.849 g; 16.40 mmol), and K2CO3 (4.527 g; 32.80 mmol) in anh. DMF (30 ml) was heated to 70° C., under nitrogen, for 2.5 h. After cooling to rt, the reaction mixture was filtered over a pad of celite. Et2O was added and the organic layer was washed with water, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 4-(2-fluoroethoxy)benzaldehyde as a yellow oil. LC-MS (conditions A): tR=0.58 min.; no ionisation.
Reaction SMILES: P([O-])(O)(O)=O.[Na+].Cl([O-])=[O:8].[Na+].[C:11]([O:14][C@@H:15]1[C@@H:56]([O:57][C:58](=[O:60])[CH3:59])[C@H:55]([O:61][C:62](=[O:64])[CH3:63])[C@@H:54]([C:65]([O:67][CH3:68])=[O:66])[O:53][C@H:16]1[O:17][C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]2[C@@H:27]([CH2:28][CH2:29][C@H:30]([O:38][C:39](=[O:41])[CH3:40])[C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[C:26](=[O:42])[N:25]2[C:43]2[CH:48]=[CH:47][C:46]([C:49]#[C:50][CH:51]=[O:52])=[CH:45][CH:44]=2)=[CH:20][CH:19]=1)(=[O:13])[CH3:12].CC(=C)C>O1CCOCC1>[C:11]([O:14][C@@H:15]1[C@@H:56]([O:57][C:58](=[O:60])[CH3:59])[C@H:55]([O:61][C:62](=[O:64])[CH3:63])[C@@H:54]([C:65]([O:67][CH3:68])=[O:66])[O:53][C@H:16]1[O:17][C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]2[C@@H:27]([CH2:28][CH2:29][C@H:30]([O:38][C:39](=[O:41])[CH3:40])[C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[C:26](=[O:42])[N:25]2[C:43]2[CH:48]=[CH:47][C:46]([C:49]#[C:50][C:51]([OH:8])=[O:52])=[CH:45][CH:44]=2)=[CH:20][CH:19]=1)(=[O:13])[CH3:12]
Reactant: COC(=O)[C@H]1O[C@@H](Oc2ccc([C@@H]3[C@@H](CC[C@H](OC(C)=O)c4ccc(F)cc4)C(=O)N3c3ccc(C#CC=O)cc3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: [O-][Cl+][O-]
Agent: C=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)[C@H]1O[C@@H](Oc2ccc([C@@H]3[C@@H](CC[C@H](OC(C)=O)c4ccc(F)cc4)C(=O)N3c3ccc(C#CC(=O)O)cc3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 1.5 h

Procedure:
An aqueous solution (0.1 mL) of sodium dihydrogenphosphate (9.00 mg, 0.065 mmol) and sodium chlorite (5.00 mg, 0.055 mmol) was added to a solution of 10c (37.0 mg, 0.046 mmol) in tert-butyl alchohol (0.4 mL), dioxane (0.2 mL) and isobutylene (˜0.1 mL) at room temperature. After 1.5 h, the reaction mixture was concentrated in vacuo and the crude residue triturated repeatedly with ethyl acetate. The organic washings were dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound 10d.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[C:28]([NH:32][S:33]([C:36]1[C:37]([C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[C:44]([F:49])[CH:43]=2)=[CH:38][CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34])([CH3:31])([CH3:30])[CH3:29]>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:15])[NH:48][C:45]1[CH:46]=[CH:47][C:42]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[S:33](=[O:35])(=[O:34])[NH:32][C:28]([CH3:29])([CH3:30])[CH3:31])=[CH:43][C:44]=1[F:49])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(N)c(F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(NC(=O)C2CCCN2C(=O)OC(C)(C)C)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.6 g, 7.4 mmol) was dissolved in 40 mL dry diethyl ether under Ar, cooled in an ice water bath, added dry pyridine (3 mL, 37.2 mmol) followed by the dropwise addition of oxalyl chloride (1.6 mL, 18.6 mmol). A precipitate forms immediately. The reaction was stirred vigorously at 0° C. for one hour, then at ambient temperature for one hour. Added 50 mL diethyl ether, filtered off solids washing with diethyl ether. Concentrated the filtrates to an off-white oil. Redissolved oil in 40 mL dry DCM under Ar, cooled to 0° C., added 3 mL pyridine followed by 4′-amino-3′-fluoro-biphenyl-2-sulfonic acid tert-butylamide (2 g, 6.2 mmol). The reaction was allowed to warm to ambient temperature, stirred for 3 hours then concentrated. Redissolved in 250 mL EtOAc, washed with 10% citric acid (2×100 mL), water (3×100 mL), brine (100 mL), dried with MgSO4, filtered and concentrated. Purified on a silica gel column eluted with 30% moving to 50% EtOAc in hexanes. Combined and concentrated pure fractions to yield title compound as a white solid. (1.4 g, 42%) APCI (AP−): 518.2 (M−H)−.
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([O:9][CH:10]([C:16]2[CH:21]=[CH:20][C:19]3[O:22][CH2:23][O:24][C:18]=3[CH:17]=2)[C:11]([O:13]CC)=[O:12])=[C:7]([CH2:27][CH2:28][CH3:29])[CH:6]=1)([O:3][CH3:4])=[O:2].[OH-].[Na+].C(Cl)Cl.CO.[NH4+].[OH-]>CO>[C:1]([C:5]1[CH:26]=[CH:25][C:8]([O:9][CH:10]([C:16]2[CH:21]=[CH:20][C:19]3[O:22][CH2:23][O:24][C:18]=3[CH:17]=2)[C:11]([OH:13])=[O:12])=[C:7]([CH2:27][CH2:28][CH3:29])[CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: CCCc1cc(C(=O)OC)ccc1OC(C(=O)OCC)c1ccc2c(c1)OCO2
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCCc1cc(C(=O)OC)ccc1OC(C(=O)O)c1ccc2c(c1)OCO2
Yield: 96.4 %

Procedure:
To a nitrogen flushed 5 L 3 neck round bottom flask equipped with a mechanical stirrer, a dropping funnel, and a nitrogen inlet was charged with 697.3 g (1.68 mol) of the crude product of Step A and 2 L of methanol. 500 mL of 5.0N (1.5 eq) aqueous sodium hydroxide was added over a 20-minute period via an addition funnel. The reaction mixture was stirred at room temperature for an additional 1 hr at which point TLC analysis (CH2Cl2 -MeOH-NH4OH 90:10:1) indicated that the starting material had been consumed. The reaction mixture neutralized with 420 mL of 6N HCl, and the bulk of the organic solvent was removed in vacuo. The residue was dissolved in ether and extracted with a combination of aqueous NaOH and NaHCO3. The aqueous layer was extracted with ether and the combined organic layer was washed with aqueous NaHCO3. The aqueous layer was acidified with HCl and extracted with ether. The ether solution was dried with magnesium sulfate, filtered, and concentrated to afford 708.9 g (theoretical 625 g) of the title compound as a viscous orange oil. NMR indicated that it was ca. 85% product by weight (15% ether) thus providing a corrected yield of 602.6 g (96.4% yield)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[F:51][C:52]([F:66])([F:65])[C:53]1[CH:58]=[CH:57][C:56]([C:59]2[CH2:60][CH2:61][NH:62][CH2:63][CH:64]=2)=[CH:55][CH:54]=1>CN(C)C=O>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[C:9]([C:10]([N:62]2[CH2:61][CH:60]=[C:59]([C:56]3[CH:57]=[CH:58][C:53]([C:52]([F:51])([F:65])[F:66])=[CH:54][CH:55]=3)[CH2:64][CH2:63]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(OCC(F)(F)F)c(C(=O)O)c1
Reactant: FC(F)(F)c1ccc(C2=CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(OCC(F)(F)F)c(C(=O)N2CC=C(c3ccc(C(F)(F)F)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 0.17 mmol 5-methanesulfonyl-2-(2,2,2-trifluoro-ethoxy)-benzoic acid in 0.75 ml dimethylformamide, 0.19 mmol TBTU, 0.855 mmol N-ethyldiisopropylamine and 0.205 mmol 4-(4-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine were successively added. The reaction was then stirred at RT for 45 min., concentrated in vacuo and purified by column chromatography (SiO2, 10 g, heptane, ethylacetate 0 to 100%), to give the title compound. MS (m/e): 508.6 (MH+, 100%)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.Br[CH2:13][CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].C(OC([O-])=O)([O-])=O.[K+].[K+]>CN(C=O)C.O>[Si:17]([O:16][CH2:15][CH2:14][CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1)([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: COc1cc(O)ccc1C=O
Agent: O=C([O-])OC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OCCCO[Si](C)(C)C(C)(C)C)ccc1C=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.9 %

Procedure:
The mixture of 4-hydroxy-2-methoxybenzaldehyde (10.0 g), (3-bromopropoxy)-tert-butyldimethylsilane (25.0 g), and potassium dicarbonate (13.6 g) in DMF (100 mL) was stirred at RT for 5 h. The mixture was diluted with water and extracted with EtOAc. And the combined organic solutions were washed with water and brine, dried and concentrated. The residue was purified by silica gel chromatography eluting with hexane/EtOAc to give 21.3 g of the subtitle compound as a yellow oil [as a mixture with (3-bromopropoxy)-tert-butyldimethylsilane].
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[CH:8]=2)[N:3]=1.[CH3:29][O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>N1C=CC=CC=1>[CH3:29][O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([N:1]([C:35](=[O:36])[C:34]2[CH:38]=[CH:39][C:31]([O:30][CH3:29])=[CH:32][CH:33]=2)[C:2]2[C:11]([C:12]#[N:13])=[C:10]([NH:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([N:22]4[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]4)[CH:8]=3)[N:3]=2)=[O:36])=[CH:33][CH:32]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CN1CCN(c2ccc3nc(N)c(C#N)c(NCc4ccccc4)c3c2)CC1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)N(C(=O)c2ccc(OC)cc2)c2nc3ccc(N4CCN(C)CC4)cc3c(NCc3ccccc3)c2C#N)cc1
Temperature: 0 °C

Procedure:
To the solution of 0.6 g of 2-amino-3-cyano-4-benzylamino-6-(4-methylpiperazino)quinoline in 2 mL of pyridine, 0.6 mL of 4-methoxybenzoyl chloride is added under stirring and cooling. The reaction mixture is stirred at 80° C. for 8 hours, and then poured onto 5 mL of ice-water. The precipitated material is filtered off, washed twice with 3 mL of water. After drying 0.63 g of the title compound is obtained, m.p.: 176° C.
Reaction SMILES: [OH:1][CH:2]([CH3:6])[C:3]([OH:5])=[O:4].CC(C)([O-])C.[K+].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1>CN(C=O)C>[OH:1][CH:2]([CH3:6])[C:3]([O:5][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)=[O:4]
Reactant: COc1ccc(CCl)cc1
Reactant: CC(O)C(=O)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)C(C)O)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a stirred solution of DL -2 hydroxypropionic acid (9.0 g, 100 mmole) in 100 ml dry DMF was added potassium tert-butoxide (12.34 g, 110 mmole) and the mixture was stirred for one hour at 60° C. 4-methoxybenzyl chloride (18.8 g 120 mmole) was added and the mixture was stirred for eight hours at 60° C. The mixture was evaporated under reduced pressure and 250 ml ethyl acatate was added. The organic phase was washed four times with water. The organic phase was dried with sodium sulfate and concentrated in vacuo. Yield: 16.8 g