Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])=[O:6].[Br:19][CH2:20][C:21](Br)=[O:22].C(OCC)C>C(OCC)(=O)C>[CH3:1][N:2]([C:21](=[O:22])[CH2:20][Br:19])[C:3]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:4]=1[C:5](=[O:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13]
Reactant: O=C(Br)CBr
Reactant: CNc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CN(C(=O)CBr)c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 56 g of 2-methylamino-2',5-dichlorobenzophenone in 400 cc of ethyl acetate there are added an equal volume of ice and then 23 cc of bromoacetylbromide. After stirring overnight at room temperature, 300 cc of ethyl ether are added. The solvent layer is decanted, washed with 2N caustic soda, and then washed with water until neutral. It is then dried over sodium sulfate, filtered, and evaporated to dryness. The residue is treated with petroleum ether and then recrystallized from ethyl acetate. In this way there are obtained 65 g of crytals; yield: 81%.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][CH:8]=2)[C:5]([NH2:22])=[N:4][CH:3]=1.C([O-])(=O)C.[K+].Cl[C:29]1[N:30]=[C:31]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][C@@H:47]2[CH3:52])[C:32]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][C:33]=2[N:34]=1.C(#N)C>O.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>[NH2:22][C:5]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([C:29]3[N:30]=[C:31]([N:46]4[CH2:51][CH2:50][O:49][CH2:48][C@@H:47]4[CH3:52])[C:32]4[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][C:33]=4[N:34]=3)=[CH:11][CH:12]=2)[C:2]([CH3:1])=[CH:3][N:4]=1
Reactant: Cc1cnc(N)n1-c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CCN(C(=O)OC(C)(C)C)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cnc(N)n1-c1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Temperature: 25 °C

Procedure:
Step 3—Synthesis of compound wh: 5-Methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-amine (0.164 g, 0.000548 mol), Tetrakis(triphenylphosphine)palladium(0) (0.0931 g, 0.0000806 mol) Sodium carbonate (0.0887 g, 0.000837 mol) and Potassium acetate (0.1061 g, 0.001081 mol) were combined, nitrogen purged three times, added (S)-tert-butyl 2-chloro-4-(3-methylmorpholino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (0.219 g, 0.000594 mol) in dry Acetonitrile (4.60 mL, 0.0881 mol) and deoxygenated Water (2.80 mL, 0.155 mol) and the reaction was microwaved on 200 watts, 120° C. for 30 minutes on a CEM microwave. The reaction mixture was cooled to room temperature, diluted with water, extracted three times with 10% MeOH in dichloromethane, dried over Magnesium sulfate, filtered, concentrated, chromatographed through silica gel (120 g, 0-5% MeOH in dichloromethane), and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.38 (t, J=8.8, 2H), 7.53 (d, J=8.7, 2H), 6.62 (d, J=1.0, 1H), 5.41 (s, 2H), 4.52 (t, J=15.6, 2H), 4.16 (d, J=6.7, 1H), 3.89 (d, J=10.8, 1H), 3.72-3.57 (m, 5H), 3.45 (dd, J=17.3, 7.1, 2H), 2.68 (d, J=6.6, 2H), 1.99 (d, J=0.9, 3H), 1.45 (d, J=7.9, 9H), 1.27 (d, J=6.6, 3H). LC/MS-m/z+506.3 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[C:17](Br)=[C:16]([CH3:24])[CH:15]=1)=[O:12])[CH3:2].[C:26]([O:30][C:31](=[O:54])[NH:32][C:33]([C:35]1[S:36][C:37]([S:52][CH3:53])=[C:38]([S:40]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45](B(O)O)[CH:44]=2)(=[O:42])=[O:41])[CH:39]=1)=[NH:34])([CH3:29])([CH3:28])[CH3:27].C([O-])([O-])=O.[Na+].[Na+].C(O)C>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.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]1[CH:15]=[C:16]([CH3:24])[C:17]([C:47]2[CH:46]=[CH:45][CH:44]=[C:43]([S:40]([C:38]3[CH:39]=[C:35]([C:33]([NH:32][C:31]([O:30][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:54])=[NH:34])[S:36][C:37]=3[S:52][CH3:53])(=[O:41])=[O:42])[CH:48]=2)=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=1)=[O:12])[CH3:2]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(B(O)O)c1
Reactant: CCOC(=O)CCCCCNC(=O)Nc1cc(C)c(Br)c([N+](=O)[O-])c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCNC(=O)Nc1cc(C)c(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 37 %

Procedure:
A 25 mL round bottom flask was charged with 6-[3-(4-bromo-3-methyl-5-nitro-phenyl)-ureido]-hexanoic acid ethyl ester (110 mg, 0.264 mmol, Example 278: step a), {[4-(3-dihydroxyboranyl-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (234 mg, 0.529 mmol, Example 140: step a), aqueous Na2CO3 (2M, 1.06 mL, 2.12 mmol), ethanol (1.06 mL, anhydrous) and toluene (2.11 mL, anhydrous). A stir bar was added, the solution was degassed for 10 min, and Pd(PPh3)4 (76 mg, 65.8 μmol) was added. The reaction mixture was stirred under Ar at 80° C. for 5 hrs, then cooled to rt. The solvents were removed in vacuo. The residue was diluted in EtOAc, washed with brine, and dried over magnesium sulfate. Removal of solvents in vacuo followed by preparative TLC (50–100% EtOAc/hexanes) afforded the title compound as a brown oil (74 mg, 37%). ESI-MS (m/z): Calcd. for C33H41N5O9S3: 748.2 (M+1); found: 747.8.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>O1CCOCC1.O>[CH3:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:7][C:8]=1[N+:13]([O-:15])=[O:14]
Reactant: Cc1ccc(OCCCBr)cc1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(OCCCN2CCOCC2)cc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
A solution of the 4-(3-bromo-propoxy)-1-methyl-2-nitro-benzene V-h (500 mg, 1.82 mmol) in dry dioxane (30 mL) was treated with K2CO3 (1.01 g, 7.28 mmol) and morpholine (319 μl, 3.65 mmol) and heated to 100° C. for 6 h. The cooled mixture was diluted with water and extracted with DCM. The combined organics were dried (MgSO4), filtered and evaporated before purification by column chromatography (SiO2; eluting with 2% EtOH in DCM) to afford the desired product as a yellow-orange oil V-i (356 mg, 70%). 1H NMR (300 MHz, CDCl3) δ 7.51 (d, J=2.7 Hz, 1H), 7.21 (d, J=8.5 Hz, 1H), 7.05 (dd, J=8.5, 2.7 Hz, 1H), 4.06 (t, J=6.3 Hz, 2H), 3.79-3.66 (m, 4H), 2.49 (dt, J=9.0, 5.1 Hz, 9H), 2.07-1.88 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[S:13][C:14](C(O)=O)=[CH:15][C:4]=2[NH:3]1>C(O)(=O)C>[S:13]1[C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:2](=[O:1])[NH:3][C:4]=2[CH:15]=[CH:14]1
Reactant: O=C(O)c1cc2c(s1)Oc1ccccc1C(=O)N2
Solvent: CC(=O)O
Product: O=C1Nc2ccsc2Oc2ccccc21
Temperature: 25 °C
Yield: 79 %

Procedure:
To a stirring solution of compound 120 (0.801 g, 3.07 mmol) in acetic acid (30 mL) was added mercuric oxide (red) (0.664 g, 3.07 mmol) and the reaction mixture was stirred at reflux for 8 hours. The mixture was then cooled to room temperature and poured into ice-cold water (75 mL). The resulting solid was filtered and triturated in ethanol to afford title compound 121 (0.527 g, 79%) as a beige solid. LRMS (ESI): (calc) 217.02 (found) 217.9 (MH)+. 1H NMR (DMSO-d6) δ (ppm): 10.45 (s, 1H), 7.80 (d, J=7.6 Hz, 1H), 7.59 (t, J=7.2 Hz, 1H), 7.33 (t, J=7.4 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 6.99 (d, J=6.1 Hz, 1H), 6.63 (d, J=6.1 Hz, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][C@@H:11]([O:15][C:16]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)=[O:17])[C@@H:12]([NH2:14])[CH3:13])[CH:6]=[CH:7][C:8]=1[Cl:9].C(N(CC)CC)C.[Si]([O:42][CH:43]1[CH2:49][C:48](=[O:50])[O:47][C:45](=[O:46])[CH2:44]1)(C(C)(C)C)(C)C>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][C@@H:11]([O:15][C:16]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)=[O:17])[C@@H:12]([NH:14][C:48]([CH2:49][CH:43]([OH:42])[CH2:44][C:45]([OH:47])=[O:46])=[O:50])[CH3:13])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: C[C@H](N)[C@@H](Cc1ccc(Cl)c(Cl)c1)OC(=O)c1ccc2ccccc2c1
Reactant: CC(C)(C)[Si](C)(C)OC1CC(=O)OC(=O)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)CC(O)CC(=O)O)[C@@H](Cc1ccc(Cl)c(Cl)c1)OC(=O)c1ccc2ccccc2c1
Reaction time: 8 h
Yield: 71.1 %

Procedure:
129 mg of (1S, 2R)-3-(3,4-dichlorophenyl)-1-methyl-2-(2-naphthoyloxy)propylamine hydrochloride and 120 μl of triethylamine were dissolved in 15 ml of methylene chloride, and 82 mg of 3-(tert-butyldimethylsilyloxy)glutaric anhydride was added thereto with stirring under cooling with ice. The mixture was stirred at room temperature for 3 hours. The reaction solution was extracted by an addition of 1N hydrochloric acid and methylene chloride. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and the solvent was distilled off under reduced pressure. The residue was dissolved in a liquid mixture of 10 ml of tetrahydrofuran and 5 ml of 1N hydrochloric acid, and the solution was left to stand at room temperature overnight. The reaction solution was extracted by an addition of water and ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent is separated by filtration, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel thin layer chromatography (Kieselgel™ 60F254, Art 5744, manufactured by Merck Co.; chloroform/methanol=6/1) to obtain 112 mg (yield: 71%) of the above-identified compound as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:30]#[C:31][Si](C)(C)C)[CH:27]=[CH:26][C:25]=3[S:36]([CH3:39])(=[O:38])=[O:37])[C:5]2=[CH:4][CH:3]=1.[F-].[K+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:30]#[CH:31])[CH:27]=[CH:26][C:25]=3[S:36]([CH3:39])(=[O:38])=[O:37])[C:5]2=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#Cc1ccc(S(C)(=O)=O)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Agent: [F-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(S(C)(=O)=O)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1

Procedure:
In a manner similar to the method described in example 214f, racemic (2′S,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-methylsulfonyl-5-(2-trimethylsilanyl-ethynyl)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′-dione reacted with KF in methanol to give the title compound. MS (M+H+) 539
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][C@H:9]2[CH2:14][CH2:13][C@@H:12]([O:15][C:16]3[CH:25]=[C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:23]=[C:22]4[C:17]=3[N:18]=[CH:19][CH:20]=[N:21]4)[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[C:32](=O)([O-])[O-:33].[Cs+].[Cs+].CO>C1(C)C=CC=CC=1.[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+].CC1C=CC(OC)=C(P(C(C)(C)C)C(C)(C)C)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C>[CH3:32][O:33][C:2]1[CH:3]=[N:4][C:5]([NH:8][C@H:9]2[CH2:14][CH2:13][C@@H:12]([O:15][C:16]3[CH:25]=[C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:23]=[C:22]4[C:17]=3[N:18]=[CH:19][CH:20]=[N:21]4)[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Brc1cnc(N[C@H]2CC[C@@H](Oc3cc(N4CCOCC4)cc4nccnc34)CC2)nc1
Agent: Cl[Pd+]
Agent: C=C[CH2-]
Agent: COc1ccc(C)c(-c2c(C(C)C)cc(C(C)C)cc2C(C)C)c1P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1cnc(N[C@H]2CC[C@@H](Oc3cc(N4CCOCC4)cc4nccnc34)CC2)nc1
Temperature: 100 °C
Yield: 63.6 %

Procedure:
As shown in step 6-ix of Scheme 6, to a mixture 5-bromo-N-((cis)-4-((7-morpholinoquinoxalin-5-yl)oxy)cyclohexyl)pyrimidin-2-amine (75 mg, 0.155 mmol), cesium carbonate (101 mg, 0.309 mmol), allylpalladium(II) chloride dimer (0.28 mg, 0.0015 mmol), RockPhos (2.17 mg, 0.0046 mmol) and MeOH (9.9 mg, 12.5 μL, 0.31 mmol) in toluene (2 mL) was flushed with nitrogen gas and heated to 100° C. for 18 hours. The reaction mixture was iluted with EtOAc, filtered though a layer of diatomaceous earth, and concentrated under reduced pressure. Purification by medium pressure silica gel chromatography (0-8% MeOH/DCM gradient) yielded 5-methoxy-N-((cis)-4-((7-morpholinoquinoxalin-5-yl)oxy)cyclohexyl)pyrimidin-2-amine (compound 134, 43 mg): 1H-NMR (300 MHz, CDCl3) δ 8.70 (d, J=1.9 Hz, 1H), 8.63 (d, J=1.9 Hz, 1H), 8.07 (s, 2H), 6.96 (d, J=2.5 Hz, 1H), 6.92 (d, J=2.5 Hz, 1H), 5.01 (d, J=8.1 Hz, 1H), 4.80 (q, J=5.6, 4.2 Hz, 1H), 4.03-3.87 (m, 5H), 3.80 (s, 3H), 3.42-3.27 (m, 4H), 2.29-2.10 (m, 2H), 1.99-1.82 (m, 6H).
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:22])/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].C(OC(=O)C)C>[CH:1]1([NH:7][C:8](=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(/C=C/C=C/c1ccc2c(c1)OCO2)NC1CCCCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(CCCCc1ccc2c(c1)OCO2)NC1CCCCC1
Yield: 83.9 %

Procedure:
To 5-(3,4-methylenedioxy phenyl)-2E,4E-pentadienoic acid cyclohexyl amide (300 mg) was added 5% Pd/C (30 mg) and hydrogenated the contents at 30 psi for 1 hr. The solution was filtered and rotary evaporated to yield a white solid. Recrystallisation from ethylacetate and petroleum spirit yielded pure white crystals (255 mg, yield 84%). m.p. 145.4° C.-146.3° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C.O>[C:12]1([CH:11]2[CH2:9][C:8](=[O:10])[C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=3)[O:1]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1ccccc1O
Solvent: CCO
Solvent: O
Product: O=C1CC(c2ccccc2)Oc2ccccc21
Yield: 40.5 %

Procedure:
A mixture of 1-(2-hydroxyphenyl)ethanone (30 g, 220 mmol), benzaldehyde (23.3 g, 220 mmol) and borax (84 g, 220 mmol) in ethanol (180 mL) and H2O (300 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O, and extracted with ether. The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated. The residue was purified by column to give 2-phenylchroman-4-one (20 g, 40%).
Reaction SMILES: [CH3:1][C:2]([OH:8])([CH3:7])[C:3]#[C:4][CH2:5][OH:6].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].O>C1COCC1>[CH3:16][S:17]([O:6][CH2:5][C:4]#[C:3][C:2]([OH:8])([CH3:7])[CH3:1])(=[O:19])=[O:18]
Reactant: CC(C)(O)C#CCO
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(O)C#CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-methylpent-2-yne-1,4-diol (Synthesis 2001. 1013.) (1.00 g) in THF (40 mL) were added triethylamine (1.85 mL) and methanesulfonyl chloride (0.69 mL). The reaction mixture was stirred at room temperature overnight under a nitrogen atmosphere, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.57 g).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]([NH:10]C(=O)OC(C)(C)C)([CH3:9])[CH3:8])[S:4][N:3]=1.O>Cl.C(OCC)(=O)C>[CH3:8][C:7]([NH2:10])([C:5]1[S:4][N:3]=[C:2]([CH3:1])[N:6]=1)[CH3:9]
Reactant: Cc1nsc(C(C)(C)NC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nsc(C(C)(C)N)n1
Yield: 87.7 %

Procedure:
A solution of tert-butyl 2-(3-methyl-1,2,4-thiadiazol-5-yl)propan-2-ylcarbamate (0.15 g, 0.58 mmol) in saturated hydrochloride in ethyl acetate (10 mL) was stirred at room temperature for 1 h. Then water (20 mL) was added. The water phase was washed with ethyl acetate (2×20 mL). Then the water phase was adjusted with sodium hydroxide solution (2 M) to pH=9˜10 and extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated to give product (0.08 g, 87%) as yellow oil; MS (EI): m/e 231.1 [M+H]+.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([NH2:36])[CH2:32][CH2:33][O:34][CH3:35]>>[CH3:35][O:34][CH2:33][CH2:32][C:31]1[N:36]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:2][CH2:3][S:4][CH2:5][CH2:6]3)=[O:8])[CH2:10]2)[O:27][N:30]=1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Reactant: COCCC(N)=NO
Product: COCCc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1

Procedure:
According to General Method 6A, 600 mg (1.43 mmol) of the compound from Example 25A and 232 mg (1.58 mmol) of N′-hydroxy-3-methoxypropanimidamide were reacted Yield: 398 mg (53% of theory)
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH2:8][CH3:9])[CH:7]=1.N([O-])=O.[Na+].NC(N)=O.[ClH:21]>O.[Cu]Cl>[Cl:21][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH2:8][CH3:9])[CH:7]=1
Reactant: Cl
Reactant: CCc1cc(N)ccc1[N+](=O)[O-]
Agent: Cl[Cu]
Agent: NC(N)=O
Agent: O=N[O-]
Solvent: O
Product: CCc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 46 %

Procedure:
1.66 g (10 mmol) of 5-amino-1-ethyl-2-nitrobenzene (2) are dissolved in a 60° C. mixture of 5 ml of conc. HCl and 25 ml H2O and cooled rapidly in an ice bath. At a temperature below 5° C., diazotisation is carried out with 760 mg (11 mmol) of sodium nitrite in 10 ml of H2O. After 10 minutes, a pinch of urea from a spatula is added and the mixture stirred for another 5 minutes in the ice bath. This reaction mixture is poured into an 80° C. solution of 1.5 g of copper(I) chloride in 10 ml of conc. HCl and 5 ml H2O which results in considerable evolvement of gas. The solution is held at this temperature for another 30 min. After cooling, the reaction solution is extracted three times with 50 ml each of EE and the combined organic phases washed with 50 ml each of NaOH and H2O. After drying over Na2SO4, concentration by means of a rotary evaporator is carried out. The crude product is placed on silica gel and purified by flash chromatography (40 g of silica gel, 3.5×13 cm, LM: PE). 863 mg (4.6 mmol, 46%) of (6) are obtained as a yellow oil.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9](F)[C:10]([F:21])=[C:11]([N:15]4[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]4)[C:12]=3[F:14])[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1.[NH3:27]>C(O)C>[NH2:27][C:9]1[C:10]([F:21])=[C:11]([N:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)[C:12]([F:14])=[C:13]2[C:8]=1[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5][N:4]2[CH:1]1[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCNCC3)c(F)c(F)c2c1=O
Reactant: N
Solvent: CCO
Product: Nc1c(F)c(N2CCNCC2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1

Procedure:
In the same manner as described in Example 13, 1-cyclopropyl-5,6,8-trifluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was allowed to react with ammonia in ethanol in a sealed tube to give 5-amino-1-cyclopropyl-6,8-difluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 263°-264° C.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([C@H:23]2[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]2)[C:14]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[CH:6]=1.[Cl:32][C:33]1[N:34]=[N:35][C:36](Cl)=[CH:37][CH:38]=1.[H-].[Na+].C(OCC)(=O)C>CN(C=O)C>[CH3:31][C:2]([CH3:30])([CH3:1])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([C:14]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[C@H:23]2[CH2:28][CH2:27][C@H:26]([O:29][C:36]3[N:35]=[N:34][C:33]([Cl:32])=[CH:38][CH:37]=3)[CH2:25][CH2:24]2)[CH:6]=1
Reactant: CC(C)(C)C#Cc1cc(N(C(=O)[C@H]2CC[C@H](C)CC2)[C@H]2CC[C@H](O)CC2)c(C(=O)O)s1
Reactant: Clc1ccc(Cl)nn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)C#Cc1cc(N(C(=O)[C@H]2CC[C@H](C)CC2)[C@H]2CC[C@H](Oc3ccc(Cl)nn3)CC2)c(C(=O)O)s1
Reaction time: 0.5 h

Procedure:
A mixture of 5-(3,3-Dimethyl-but-1-ynyl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (53 mg, 0.12 mmol) and 3,6-dichloropyridazine (86 mg, 0.58 mmol) in DMF (0.5 mL) was treated with sodium hydride (58 mg, 1.4 mmol, 60% oil dispersion) in two portions. The mixture was stirred until the bubbling slowed, and was sealed and heated by microwave at 100 deg C. for 30 min. After cooling, ethyl acetate (2-3 mL) was added and the mixture was carefully quenched with citric acid (10% aqueous solution, 2-3 mL). Water was added and the mixture was extracted with ethyl acetate (2×30 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was passed through a plug of silica (10% MeOH:DCM eluent) and concentrated to yield 69 mg of 5-(3,3-Dimethyl-but-1-ynyl)-3-{(trans-4-methyl-cyclohexanecarbonyl)-[trans-4-(6-chloro-pyridazin-3-yloxy)-cyclohexyl]-amino}-thiophene-2-carboxylic acid as a black oil which was carried on without further purification.
Reaction SMILES: [CH2:1]([CH:3]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([C:28](=[O:41])[NH:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[CH:21]=1)[C:4](N1[C@@H](CC2C=CC=CC=2)COC1=O)=[O:5])[CH3:2].[OH:42]O.O.[OH-].[Li+].Cl>O.O1CCCC1>[CH2:1]([CH:3]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([C:28](=[O:41])[NH:29][CH2:30][C:31]2[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=2)[CH:21]=1)[C:4]([OH:5])=[O:42])[CH3:2]
Reactant: OO
Reactant: CCC(Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1)C(=O)O
Reaction time: 0.03 h
Yield: 20 %

Procedure:
(4S)-3-[2-ethyl-3-[4-methoxy-3-[N-[[4-(trifluoromethyl)phenyl]methyl]carbamoyl]phenyl]propionyl]-4-benzyl-2-oxazolidinone (860 mg, 1.51 mmol) was mixed with 8 ml of mixed solution of tetrahydrofuran with water (4:1 v/v), which was cooled with ice under an atmosphere of argon. Under stirring, 611 ml of 30% aqueous hydrogen peroxide was added over 2 minutes, further 101 mg of lithium hydroxide monohydrate dissolved in 2.7 ml of water was added thereto over 2 minutes. After the mixture was stirred for 1 hour under cooling with ice, sodium sulfite 7-hydrate dissolved in 4 ml of water was added, and the mixture was stirred for 5 minutes at 0° C. The reaction mixture was poured into 5% aqueous solution of hydrochloric acid, which was extracted with ethyl acetate. The extract was washed with brine, then dried over anhydrous magnesium sulfate and concentrated. The residue was crystallized by adding ethyl acetate and n-hexane to obtain 125 mg (20%) of the title compound as colorless prisms.