Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=O.[NH2:24][CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.C(O)(=O)C.O>CCO>[N:29]1[CH:30]=[CH:31][C:26]([CH2:25][NH:24][C:3]([C:5]2[N:6]=[CH:7][C:8]3[C:9](=[O:23])[N:10]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:11]=[CH:12][C:13]=3[C:14]=2[OH:15])=[O:2])=[CH:27][CH:28]=1
Reactant: NCc1ccncc1
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(NCc1ccncc1)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 79 °C
Yield: 65.7 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (40 mg, 0.13 mmol) and 4-(aminomethyl)-pyridine (0.050 mL, 0.45 mmol) in 2 mL of EtOH was heated at 79° C. for 4 h. Acetic acid (0.1 mL) and water (3 mL) were added, and the resulting suspension was allowed to come to r.t. The solid was isolated by filtration and dried under high vacuum to afford 33 mg of the title compound as a light yellow solid. MS: (+) m/z 386.40 (M+1).
Reaction SMILES: [CH2:1]([N:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)[C:10](N(OC)C)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOC(C)=O>[CH2:27]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)[CH:10]=[O:11])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CON(C)C(=O)[C@H](Cc1ccc(C(F)(F)F)cc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C[C@H](Cc1ccc(C(F)(F)F)cc1)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
To a 500 mL round-bottomed flask was added (S)-2-(dibenzylamino)-N-methoxy-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide (6.22 g, 13.6 mmol), THF (100 mL), and lithium aluminum hydride (1.0 M solution in THF (27.3 mL, 27.3 mmol)), dropwise at 0° C. After 30 minutes, TLC (2:1 hexanes:EtOAc) showed that no starting material remained. The mixture was quenched by dropwise addition of water (6.82 mL), 2 N NaOH (6.82 mL), and water (9.83 mL). The solids were removed by filtration through a medium scintered glass funnel. The filtrate was dried over sodium sulfate and evaporated. The residue was taken up in EtOAc (200 mL) and washed with brine (50 mL). The organic layer was dried over sodium sulfate and evaporated to provide (S)-2-(dibenzylamino)-3-(4-(trifluoromethyl)phenyl)propanal (4.51 g, 83.3% yield) as a light yellow oil. LCMS (ES+) m/z=398.2. 1H NMR (400 MHz, CDCl3) δ ppm 2.96 (dd, J=13.89, 5.67 Hz, 1H) 3.18 (dd, J=13.89, 7.43 Hz, 1H) 3.52-3.55 (m, 1H) 3.66-3.72 (m, 2H) 3.82-3.88 (m, 2H) 7.21-7.33 (m, 12H) 7.50 (d, J=8.02 Hz, 2H) 9.74 (s, 1H).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][N:10]3[C:13]([Sn](CCCC)(CCCC)CCCC)=[CH:14][N:15]=[C:9]3[N:8]=2)[CH:5]=[N:4][CH:3]=[N:2]1.Br[C:30]1[N:35]=[C:34]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:33]=[CH:32][CH:31]=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>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][N:10]3[C:13]([C:30]4[N:35]=[C:34]([C:36]5[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=5)[CH:33]=[CH:32][CH:31]=4)=[CH:14][N:15]=[C:9]3[N:8]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(Cn3cncn3)ccn12
Reactant: Brc1cccc(-c2cccnc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: c1cncc(-c2cccc(-c3cnc4nc(Cn5cncn5)ccn34)n2)c1

Procedure:
To the degassed solution of 7-([1,2,4]triazol-1-ylmethyl)-3-tributylstannylimidazo[1,2-α]pyrimidine was added 6-bromo-2,3′-bipyridine (prepared according to Example 49) (0.39 g, 1.65 mmol) and tetrakis(triphenylphosphine)palladium(0) (173 mg, 0.10 mmol) and the mixture heated at reflux for 3 h. The crude reaction was adsorbed onto silica and purified by chromatography on silica gel eluting with a dichloromethane, methanol, aqueous ammonia (33%) mixture in the volume ratios of 90:5:0.5 respectively to give 6-[7-([1,2,4]triazol-1-ylmethyl)imidazo[1,2-α]pyrimidin-3-yl]-2,3′-bipyridine as a hygroscopic solid following crystallisation from dichloromethane/ethyl acetate. Addition of an excess of 1M HCl in ether to a solution of the product in a methanol/ether solvent mixture gave 50 mg of the dihydrochloride salt as a white solid: δH (360 MHz, CDCl3) 5.62 (2H, s), 6.96 (1H, d, J 7), 7.47 (1H, dd, J 4.7 and 4.7), 7.66 (1H, d, J 7.7), 7.78 (1H, d, J 7.9), 7.91 (1H, t, J 9), 8.05 (1H, s), 8.23-8.27 (1H, m), 8.36 (1H, s), 8.41 (1H, s), 8.71-8.72 (1H, m), 9.25 (1H, s), 10.30 (1H, d, J 7.2); m/z (ES+) 355 (M++H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([CH3:16])=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4].[CH3:17][O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22][CH:21]=1>>[CH3:17][O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:2]([CH3:1])[C:3](=[O:4])[C:5]3=[C:9]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[O:8][N:7]=[C:6]3[CH:16]=2)=[CH:22][CH:21]=1
Reactant: CNC(=O)c1c(C)noc1-c1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Product: COC(=O)c1ccc(-c2cc3noc(-c4ccccc4)c3c(=O)n2C)cc1

Procedure:
This compound is obtained using 3-methyl-5-phenyl-isoxazole-4-carboxylic acid methylamide and 4-formyl-benzoic acid methyl ester in 15% as a beige solid. Mass spectrum: m/z (M+H)+: 361.2
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.O1CCN([C:17]2[CH2:21][CH2:20][CH2:19][CH:18]=2)CC1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9](=[O:10])[C:18]3[CH2:19][CH2:20][CH2:21][C:17]=3[C:4]=2[CH:3]=1
Reactant: C1=C(N2CCOCC2)CCC1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c2ccc(F)cc2c2c1CCC2
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-fluorophenylisocyanate (5.0 g, 36.5 mmol) in chloroform (25 ml) is mixed with 1-morpholino-1-cyclopentene (5.5 ml, 36.5 mmol) and refluxed for 15 minutes. The batch is concentrated by evaporation and purified by column chromatography (SiO2) with ethyl acetate-hexane: 7.6 g (94%) of cyclopentanone-2-carboxylic acid-(4-fluorophenyl)amide, 1H-NMR (DSC842). The amide is stirred in concentrated sulfuric acid (30 ml) for 30 minutes at 100° C. The batch is poured onto ice water and filtered. The filter residue is recrystallized from ethanol: 2.02 g (29%) of product.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:4]([O:6][CH3:7])=[O:5].CCN(CC)CC.[C:24](Cl)(=[O:34])[O:25][CH2:26][C:27]([CH3:33])([CH3:32])[CH2:28][CH2:29][CH:30]=[CH2:31]>C1COCC1>[CH3:14][C:13]([CH3:16])([O:12][C:10](=[O:11])[NH:9][CH2:8][CH:3]([C:4]([O:6][CH3:7])=[O:5])[NH:2][C:24](=[O:34])[O:25][CH2:26][C:27]([CH3:33])([CH3:32])[CH2:28][CH2:29][CH:30]=[CH2:31])[CH3:15]
Reactant: C=CCCC(C)(C)COC(=O)Cl
Reactant: COC(=O)C(N)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCCC(C)(C)COC(=O)NC(CNC(=O)OC(C)(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
To a stirring solution of 381 mg of methyl 2-amino-3-(tert-butoxycarbonylamino)propanoate hydrochloride, and 1 mL of Et3N in 10 mL of anhydrous THF, was added 1.5 mmol of 2,2-dimethylhex-5-enyl carbonochloridate. The resulting mixture was stirred at rt overnight, then concentrated. The residue was subject to column chromatography on silica gel with heptanes/EtOAc (v/v 7/1) as eluent, giving 500 mg colorless oil (90%). 1HNMR (400 MHz, CDCl3) d 5.82 (m, 1H), 5.64 (br s, 1H), 5.02 (dd, 1H, J=13.2, 1.8 Hz), 4.95 (d, 1H, J=8.2 Hz), 4.83 (br s, 1H), 4.39 (br d, 1H, J=6.0 Hz), 3.83 (br s, 2H), 3.80 (s, 3H), 2.55 (m, 2H), 2.02 (m, 2H), 1.43 (s, 9H), 1.35 (m, 2H), 0.91 (s, 6H).
Reaction SMILES: [F:1][CH2:2][CH2:3]Br.[Cl:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]([F:13])[C:7]=1[C:14]1[C:23](=[O:24])[NH:22][C:17]2=[N:18][CH:19]=[CH:20][N:21]=[C:16]2[C:15]=1[O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[Cl:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]([F:13])[C:7]=1[C:14]1[C:23](=[O:24])[N:22]([CH2:3][CH2:2][F:1])[C:17]2=[N:18][CH:19]=[CH:20][N:21]=[C:16]2[C:15]=1[O:25][C:26](=[O:31])[C:27]([CH3:28])([CH3:30])[CH3:29]
Reactant: CC(C)(C)C(=O)Oc1c(-c2c(F)ccc(F)c2Cl)c(=O)[nH]c2nccnc12
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Oc1c(-c2c(F)ccc(F)c2Cl)c(=O)n(CCF)c2nccnc12
Temperature: 120 °C

Procedure:
2-Fluoroethyl bromide was added to a mixture of 2,2-dimethyl-propionic acid 7-(2-chloro-3,6-difluoro-phenyl)-6-oxo-5,6-dihydro-pyrido[2,3-b]pyrazin-8-yl ester (Example 1.3) (0.20 g), potassium carbonate (0.207 g) and potassium iodide (catalytic amount) in N,N-dimethylformamide (10 ml). The reaction mixture was heated in the microwave for 20 minutes at 120° C. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 1:1) to give Compound No. C9 of Table C as a yellow solid (0.103 g).
Reaction SMILES: BrC[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[F:15][C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1>>[Cl:14][C:11]1[CH:12]=[CH:13][C:4]([CH2:3][O:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([F:15])[CH:17]=2)=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: Oc1cccc(F)c1
Reactant: COC(=O)c1cc(Cl)ccc1CCBr
Product: COC(=O)c1cc(Cl)ccc1COc1cccc(F)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from methyl 2-(bromoethyl)-5-chlorobenzoate and 3-fluorophenol:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4](O)=[O:5].CC[N:17]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.N>O1CCCC1>[NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH2:17])=[O:5]
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cc(N)c(C(N)=O)cc1OC
Temperature: 7.5 °C
Yield: 60.3 %

Procedure:
Into a 1-L 3-necked round-bottom flask, was placed 2-amino-4,5-dimethoxybenzoic acid (20 g, 101.43 mmol, 1.00 equiv), tetrahydrofuran (400 mL), EDC.HCl (39 g, 203.44 mmol, 2.01 equiv) and HOBt (27.5 g, 203.52 mmol, 2.01 equiv). This was followed by the addition of 4-methylmorpholine (20.6 g, 203.96 mmol, 2.01 equiv) dropwise with stirring at 5-10° C. To this was added ammonia (30 mL) dropwise with stirring at 5-10° C. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 300 mL of ethyl acetate. The resulting mixture was washed with 1×300 mL of brine. The aqueous layer was extracted with 5×100 mL of ethyl acetate and the organic layers combined. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 12 g (crude, 61.2% yield) of 2-amino-4,5-dimethoxybenzamide as a yellow solid. MS (ESI) m/z 197 [M+H]+
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[NH2:26]>CCOC(C)=O>[CH3:33][O:32][C:28]1[CH:27]=[C:25]([NH:26][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:11][CH:10]=3)[N:3]=2)[CH:24]=[C:23]([O:22][CH3:21])[C:29]=1[O:30][CH3:31]
Reactant: Clc1cncc(Oc2ccc(-c3ccccc3)cc2)n1
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: CCOC(C)=O
Product: COc1cc(Nc2cncc(Oc3ccc(-c4ccccc4)cc3)n2)cc(OC)c1OC
Yield: 63 %

Procedure:
Using Method EE with 2-chloro-6-[(4-phenyl)-phenyl-oxy]-pyrazine (110 mg, 0.39 mmol) and 3,4,5-trimethoxyaniline (84 mg, 0.46 mmol), and purification by column chromatography (AcOEt), the title compound was obtained (105 mg). Yield: 63%. 1H NMR (250 MHz, DMSO-d6) δ 3.38 (s, 6H, [CH3O]3+5), 3.52 (s, 3H, [CH3O]4), 6.81 (s, 2H, Harom2′+6′), 7.29 (d, 2H, Harom 3+5, J=8.6 Hz), 7.36-7.53 (m, 1H, Harom4″), 7.68 (d, 2H, Harom 2″+6″, J=7.9 Hz), 7.71 (d, 2H, Harom 2+6, J=8.7 Hz), 7.81 (s, 1H, HPz 5), 7.98 (s, 1H, HPz 3), 9.58 (s, 1H, NH). m/z: 430.2 [(M+H)+, calcd for C25H23N3O4 429.2].
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:28]([C:31]1[CH:36]=[C:35]([CH:37]([CH3:39])[CH3:38])[CH:34]=[C:33]([CH:40]([CH3:42])[CH3:41])[C:32]=1[S:43](Cl)(=[O:45])=[O:44])([CH3:30])[CH3:29]>>[CH:28]([C:31]1[CH:36]=[C:35]([CH:37]([CH3:38])[CH3:39])[CH:34]=[C:33]([CH:40]([CH3:42])[CH3:41])[C:32]=1[S:43]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:25]([OH:27])=[O:26])[NH:18][C:16]([O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:17])(=[O:45])=[O:44])([CH3:29])[CH3:30]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)NCCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c(C(C)C)c1
Yield: 34 %

Procedure:
Nα-(9-fluorenylmethoxycarbonyl)-L-lysine was reacted with 2,4,6-triisopropylbenzenesulfonyl chloride under the conditions used in example 2 giving 34% of the title compound.
Reaction SMILES: [C:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]([CH3:19])(O)[CH3:17])=[CH:10][CH:9]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].BrC1C=[CH:25][C:24]([CH:27]=[CH:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:31][CH:30]=2)=[CH:23]C=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[NH4+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1(C)C=CC=CC=1.[OH-].[Na+].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.[Cu]I>[C:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:19]=[CH:23][C:24](/[CH:27]=[CH:28]/[C:29]3[CH:30]=[CH:31][C:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:33][CH:34]=3)=[CH:25][CH:17]=2)=[CH:10][CH:9]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)c1ccc(C=Cc2ccc(Br)cc2)cc1
Reactant: CC(C)(O)C#Cc1ccc(C(=O)OC(C)(C)C)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CC[N+](CC)(CC)Cc1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(C#Cc2ccc(/C=C/c3ccc(C(=O)OC(C)(C)C)cc3)cc2)cc1

Procedure:
A mixture of 13.02 g of 4-(4-carbo-tert.-butoxyphenyl)-2-methyl-3-butyn-2-ol, 17.97 g of 4-bromo-4'-carbo-tert.-butoxystilbene, 0.93 g of triphenylphosphine. 0.34 g of benzyltriethylammonium chloride, 175 mg of bis(triphenylphosphine)palladium(II) chloride and 175 mg of copper(I) iodide in 70 ml of toluene and 36 ml of 5,5N NaOH is vigorously stirred under reflux for 48 hours. After the addition of 250 ml of saturated ammonium chloride solution, the reaction product is extracted with methylene chloride, dried and concentrated by evaporation.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[CH3:22][C:23]1([CH2:27][NH:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[CH2:26][NH:25][CH2:24]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:25]4[CH2:26][C:23]([CH2:27][NH:28][C:29](=[O:34])[C:30]([F:32])([F:33])[F:31])([CH3:22])[CH2:24]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC1(CNC(=O)C(F)(F)F)CNC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC1(CNC(=O)C(F)(F)F)CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Yield: 99.5 %

Procedure:
A mixture of 1 g (3.5 mmoles) of 1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 1.32 g (5.7 mmoles) of 3-methyl-3-trifluoroacetamidomethylazetidine hydrochloride and 2.3 g of triethylamine is heated under reflux in 12 ml of pyridine for 3 hours. The mixture is evaporated, water is added, and the product filtered. 1.6 g (100%) of 1-cyclopropyl-6,8-difluoro-7-(3-trifluoroacetamidomethyl-3-methyl-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are obtained, melting at 232°-7° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:6](=[O:7])[NH:5][C:3]1=[O:4].CC([O-])(C)C.[K+].Br[CH2:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:27]=[C:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[S:25][C:24]=2[S:32]([NH:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:34])=[O:33])[CH:20]=[CH:21][CH:22]=1>CS(C)=O.C(Cl)Cl>[CH3:1][N:2]1[CH2:8][C:6](=[O:7])[N:5]([CH2:16][C:17]2[CH:18]=[C:19]([C:23]3[CH:27]=[C:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[S:25][C:24]=3[S:32]([NH:35][C:36]([CH3:38])([CH3:37])[CH3:39])(=[O:33])=[O:34])[CH:20]=[CH:21][CH:22]=2)[C:3]1=[O:4]
Reactant: CC(C)Cc1cc(-c2cccc(CBr)c2)c(S(=O)(=O)NC(C)(C)C)s1
Reactant: CN1CC(=O)NC1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)Cc1cc(-c2cccc(CN3C(=O)CN(C)C3=O)c2)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of 1-methylhydantoin (33.9 mg, 0.297 mmol) in DMSO (1 mL) and t-BuOK (46.6 mg, 0.415 mmol), that had been stirred for 40 min at ambient temperature, was added a solution of 3-(3-bromomethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (87.9 mg, 0.198 mmol; see Example 1(e)) in DMSO (1 mL) dropwise. The reaction mixture was stirred for 1 h at ambient temperature and then diluted with CH2Cl2 (15 mL). The organic layer was washed with water, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by flash chromatography using EtOAc:petroleum ether (35:65) as eluent to give the sub-title compound in 54% yield as a colourless syrup (51.5 mg, 0.107 mmol).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]#[N:11])[CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH3:14][Si:15]([CH2:18][CH2:19][O:20][CH2:21]Cl)([CH3:17])[CH3:16]>CN(C=O)C>[CH3:14][Si:15]([CH3:17])([CH3:16])[CH2:18][CH2:19][O:20][CH2:21][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]#[N:11])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: N#Cc1ccc2cc[nH]c2c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2ccc(C#N)cc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
1H-Indole-6-carbonitrile (CAS #:15861-36-6) (1.47 g, 10.34 mmol) was dissolved in DMF (103 mL) and cooled to 0° C. NaH (60% in mineral oil, 0.620 g, 15.51 mmol) was added in one batch. The reaction was allowed to stir at room temperature for 15 minutes. SEMCl (2.38 mL, 13.44 mmol) was added at 0° C. and stirred for 20 minutes. The reaction was quenched with saturated ammonium chloride and then EtOAc was added. The organic layer was removed and the water layer was extracted again with EtOAc. The combined organics were washed with water, dried over MgSO4 filtered and concentrated. The resulting residue was purified via flash chromatography (0-50% EtOAc:heptanes) to obtain title compound. MS (ESI+) m/z 273.23 (M+H).
Reaction SMILES: Cl[C:2]1[C:3](=[O:23])[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C([O-])=O.[NH4+].C(OCC)(=O)C>[Pd].CO>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:4]2[C:3](=[O:23])[CH:2]=[C:7]([N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[CH:6]=[N:5]2)=[CH:20][CH:19]=1
Reactant: COc1ccc(Cn2ncc(N3CCOCC3)c(Cl)c2=O)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2ncc(N3CCOCC3)cc2=O)cc1

Procedure:
To a mixture of 4-chloro-2-(4-methoxybenzyl)-5-(morpholin-4-yl)pyridazin-3(2H)-one (8.56 g, 25.50 mmol) and 10% Pd/C catalyst (1.45 g) in methanol (105 ml) was added ammonium formate (3.70 g, 58.7 mmol), and the mixture was refluxed under argon with TLC monitoring (ethyl acetate). Further portions of ammonium formate were added until the starting material was completely consumed. The catalyst was filtered off and washed with methanol, then the solvent was evaporated under reduced pressure. The residue was taken up in water (30 ml) and extracted with dichloromethane (4×40 ml). The combined extracts were washed with water, dried (Na2SO4) and evaporated. The crude product was purified by crystallization from ethanol (95%).
Reaction SMILES: Cl.[CH:2]1([N:5]2[C:14]3[C:9](=[CH:10][C:11]([F:29])=[C:12]([N:16]4[CH2:20][CH2:19][CH:18]([NH:21]C(OC(C)(C)C)=O)[CH2:17]4)[C:13]=3[Cl:15])[C:8](=[O:30])[C:7]([C:31](=[O:37])[CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:6]2)[CH2:4][CH2:3]1>Cl.C(OC(=O)C)C>[ClH:15].[CH:2]1([N:5]2[C:14]3[C:9](=[CH:10][C:11]([F:29])=[C:12]([N:16]4[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17]4)[C:13]=3[Cl:15])[C:8](=[O:30])[C:7]([C:31](=[O:37])[CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:6]2)[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2c(F)cc3c(=O)c(C(=O)CS(C)(=O)=O)cn(C4CC4)c3c2Cl)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)CC(=O)c1cn(C2CC2)c2c(Cl)c(N3CCC(N)C3)c(F)cc2c1=O
Reaction time: 0.5 h
Yield: 201.1 %

Procedure:
5.4 g of the compound obtained from Example 32 was dissolved in 10% HCl-ethylacetate solution, and then stirred for 30 minutes. The resulting solid was filtered, and then dried to obtain 4.49 g of the object compound
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[O:18][C:19]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29][CH2:30][NH:31][CH2:32][C:33]5[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=5)[C:20]=4[C:21]=3[CH3:22])=[CH:11][C:9]=2[CH:10]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:22][C:21]1[C:20]2[C:23]([O:27][CH2:28][CH2:29][CH2:30][NH:31][CH2:32][C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)=[CH:24][CH:25]=[CH:26][C:19]=2[O:18][C:17]=1[CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:8]2[O:7][C:6]([CH2:4][OH:3])=[CH:10][C:9]=2[CH:11]=1
Reactant: CCOC(=O)c1cc2cc(OCc3oc4cccc(OCCCNCc5cccnc5)c4c3C)ccc2o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(COc2ccc3oc(CO)cc3c2)oc2cccc(OCCCNCc3cccnc3)c12
Reaction time: 0.33 h

Procedure:
To a solution of the compound in Example 36 (10 mg, 0.02 mmol) in THF was added LiAlH4 (1.5 mg) at 0° C. After stirring for 20 min., the reaction was quenched by adding H2O. Silica gel column chromatography (CH2Cl2/MeOH=20/1) gave desired product as a colorless oil. (9 mg, 98%). FAB-MS: m/z 473 (MH+); 1H-NMR (CDCl3): δ 2.04 (2H, m), 2.28 (3H, s), 2.86 (2H, t, J=7.5 Hz), 3.82 (2H, s), 4.14 (2H, t, J=5.5 Hz), 4.75 (2H, s) 5.11 (2H, s), 6.59 (1H, d, J=8 Hz), 6.95(1H, d, J=2 Hz), 7.06 (1H, d, J=8 Hz), 7.12-7.19 (2H, m), 7.34 (1H, d, J=9 Hz), 7.66 (1H, d, J=8 Hz), 8.44 (1H, brd, J=4.5 Hz), 8.51 (1H, brs).