Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([Cl:12])=[CH:7][CH:6]=2.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.N1C=CC=CC=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH3:14])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([Cl:12])=[CH:7][CH:6]=2
Reactant: Oc1cc(Cl)cc2cc(Cl)ccc12
Reactant: COc1ccccc1B(O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccccc1Oc1cc(Cl)cc2cc(Cl)ccc12
Yield: 38 %

Procedure:
A solution of 3,6-dichloronaphthalen-1-ol (1.0 equiv), 2-methoxyphenylboronic acid (1.5 equiv), Cu(OAc)2 (1.3 equiv), pyridine (5.0 equiv), and 4 Å MS in dry DCM (3.0 mL) was stirred at room temperature for 48 h. The reaction was filtered, concentrated by rotary evaporation, and purified by column chromatography to give 3,6-dichloro-1-(2-methoxyphenoxy)naphthalene (25) (38%). 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J=12.0 Hz, 1H), 7.73 (d, J=4.0 Hz, 1H), 7.44 (dd, J=12.0, 4.0 Hz, 1H), 7.40 (s, 1H), 7.10-7.06 (m, 2H), 7.02 (dd, J=3.4, 1.2 Hz, 1H), 6.96 (d, J=1.2 Hz, 1H), 6.54 (d, J=4.0 Hz, 1H), 3.80 (s, 3H), GC-MS (ES) for C17H12Cl2O2 [M]+ 318.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH3:13])[CH:5]=O.[CH3:14][C:15]([C:17]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=1)=[O:16].[OH-].[Na+]>CO>[OH:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:14]/[C:15]([C:17]2[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=2)=[O:16])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCOc1ccc(C=O)cc1O
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCOc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)cc1O
Yield: 60.7 %

Procedure:
A mixture of 3-hydroxy-4-propoxybenzaldehyde (0.8 g, 4.4 mmol), 3,4,5-trimethoxyacetophenone (0.934 mg, 4.4 mmol) and 50% w/v of aqueous sodium hydroxide (7.0 ml, 0.089 mol) in methanol (10 ml) at room temperature for 18 h. The orange solid isolated by filtration was washed sequentially with cold methanol and ether and finally dried in a vacuum dessicator. Purification was achieved using column chromatography (SiO2, petroleum:ether (40:60 v/v) with an increasing gradient of ethyl acetate) which gave 0.995 g (60%) of a yellow solid. 1H-NMR (CDCl3) δ 7.7 (d, 1H), 7.2 (m, 4H), 7.1 (dd, 3H), 6.9 (d, 1H), 5.7 (s, 1H), 4.1 (t, 2H), 3.9 (s×2, 9H), 1.9 (m, 2H), 1.1 (t, 3H). 13C-NMR (CDCl3) δ 189.1, 153.1, 148.3, 146.0, 144.7, 142.4, 133.7, 128.4, 122.9, 119.8, 112.7, 111.4, 106.1, 70.6, 60.9, 56.4, 22.4, 10.4. Mass Spectrum m/e (M+1) 373. Anal. Calcd. for C21H24O6: C, 67.73; H, 6.5. Found C, 68.01; H, 6.72.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][C:8]([CH3:12])=[C:7]([NH2:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.F[C:15]1[C:20]([C:21]2[N:26]=[CH:25][N:24]=[C:23]3[NH:27][N:28]=[CH:29][C:22]=23)=[CH:19][CH:18]=[CH:17][N:16]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CO>C1COCC1.CC(O)=O>[NH:27]1[C:23]2=[N:24][CH:25]=[N:26][C:21]([C:20]3[C:15]([NH:13][C:7]4[C:6]5[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:11]=5[CH:10]=[CH:9][C:8]=4[CH3:12])=[N:16][CH:17]=[CH:18][CH:19]=3)=[C:22]2[CH:29]=[N:28]1
Reactant: Fc1ncccc1-c1ncnc2[nH]ncc12
Reactant: Cc1ccc2c(Cl)nccc2c1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc2c(Cl)nccc2c1Nc1ncccc1-c1ncnc2[nH]ncc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-chloro-6-methylisoquinolin-5-amine (414 mg, 2147 μmol) and 4-(2-fluoropyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (420 mg, 1952 μmol) in THF (20 ml) was sonicated until all solid became a fine powder. Lithium bis(trimethylsilyl)amide, 1.0 M solution in THF (6831 μl, 6831 mmol) was then added (all solids were dissolved and color changed) The mixture was stirred at rt overnight. The mixture was poured into a mixture of MeOH (20 ml) and AcOH (2 ml) and then solvent was removed in vacuo. 2 M NH3/MeOH (30 ml) was added and then solvent was removed in vacuo. The product was purified by flash chromatography eluting with MeOH/DCM (0-5%) to give N-(3-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)pyridin-2-yl)-1-chloro-6-methylisoquinolin-5-amine. MS Found (ESI pos. ion) m/z 388 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6](Cl)=[O:7].[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C>C(Cl)Cl>[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:6](=[O:7])[CH2:5][O:4][C:3]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:2]=1[Cl:1])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: O=C(Cl)COc1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)NCCCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCNC(=O)COc1ccc(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
11 g of 2,4-dichlorophenoxy-acetic acid chloride in solution in 40 ml of methylene chloride were added without exceeding 25° C. to a mixture of 8.6 g of N-(tert-butoxycarbonyl)-1,4-diamino-butane, 120 ml of methylene chloride and 7 ml of triethylamine and the mixture was stirred for 30 minutes, then concentrated to dryness under reduced pressure. The residue was taken up in 200 ml of tetrahydrofuran and the insoluble part was filtered off. The filtrate was evaporated to dryness under reduced pressure to obtain 18.53 g of crude product melting at 107° C. which was crystallized from 740 ml of isopropyl ether to obtain 17.43 g of the expected product melting at 110° C. 5.39 g were chromatographed on silica (eluant: hexane-ethyl acetate (6-4)) to obtain 4.48 g of the sought product melting at 114° C.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.Br[C:17]([C:24]1[CH:29]=[C:28]([Cl:30])[N:27]=[C:26]([Cl:31])[CH:25]=1)([CH3:23])[CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20]>CCCCCC.O1CCCC1>[Cl:31][C:26]1[CH:25]=[C:24]([C:17](=[CH2:23])[CH2:18][C:19]([Cl:20])([Cl:21])[Cl:22])[CH:29]=[C:28]([Cl:30])[N:27]=1
Reactant: CC(Br)(CC(Cl)(Cl)Cl)c1cc(Cl)nc(Cl)c1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C(CC(Cl)(Cl)Cl)c1cc(Cl)nc(Cl)c1
Temperature: -75 °C
Reaction time: 2 h

Procedure:
To a dried tetrahydrofuran solution of 4.03 g of 2,2,6,6-tetramethylpiperidine under N2 was added 17.8 ml of 1.6M n-butyllithium in hexane. The solution was cooled to -75° C. and a concentrated solution of 4-(1-bromo-3,3,3-trichloro-1-methylpropyl)-2,6-dichloropyridine in tetrahydrofuran was added to maintain ≤-65° C. The mixture was stirred at -65° C. for two hours and quenched with 20 mls of water. The organics were extracted with ether, dried (MgSO4), and concentrated in vacuo. The crude product was purified via high pressure liquid chromatography, yielding 5 g (68%), m.p. 66°-67.5° C.
Reaction SMILES: Cl[C:2]1[C:3]2[N:17]=[CH:16][CH:15]=[CH:14][C:4]=2[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:7]=1.[CH3:18][C@H:19]1[NH:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]1>C(Cl)Cl>[CH3:18][C@H:19]1[N:24]([C:2]2[C:3]3[N:17]=[CH:16][CH:15]=[CH:14][C:4]=3[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[N:6][N:7]=2)[CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:20]1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Clc1nnc(-c2ccccc2)c2cccnc12
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1nnc(-c2ccccc2)c2cccnc12
Temperature: 130 °C

Procedure:
8-chloro-5-phenylpyrido[3,2-d]pyridazine 71 (374 mg, 1.548 mmol) and (R)-tert-butyl 3-methylpiperazine-1-carboxylate (1240 mg, 6.19 mmol) were combined in a reaction vial and heated to 130° C. for 3 h. After cooling to room temperature, the resulting solid was dissolved in 100 mL of CH2Cl2 and washed with 1×10 mL of saturated NaHCO3, followed by 1×10 mL of brine. The combined organic layers were dried over MgSO4, filtered and concentrated. Purification by column chromatography afforded pure (R)-tert-butyl 3-methyl-4-(5-phenylpyrido[3,2-d]pyridazin-8-yl)piperazine-1-carboxylate 74. 1H-NMR (400 MHz, CDCl3): δ 9.08 (dd, J=4.3, 1.6 Hz, 1H), 8.32 (dd, J=8.2, 1.6 Hz, 1H), 7.70 (m, 2H), 7.67 (dd, J=8.6, 4.3 Hz, 1H), 7.53 (m, 3H), 4.70 (m, 1H), 4.30-3.67 (series of m, 2H), 3.66 (ddd, J=13.3, 12.1, 3.5 Hz, 1H), 3.35 (m, 2H), 1.51 (s, 9H), 1.36 (br d, J=6.3 Hz, 3H). MS 405.2 (calc'd) 406.1 (M+H, found).
Reaction SMILES: [CH2:1]([C:3]1[S:39][C:6]2[N:7]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=4)=[CH:27][CH:26]=3)[C:8](=[O:23])[N:9]([CH2:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=O)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].[C:40]([O:43][CH2:44][CH2:45]P(OCC)(OCC)=O)(=[O:42])[CH3:41].[H-].[Na+].O>C1COCC1>[C:37]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:7]2[C:6]3[S:39][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=3[C:10](=[O:11])[N:9]([CH2:12]/[C:13](/[C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)=[CH:41]/[C:40]([O:43][CH2:44][CH3:45])=[O:42])[C:8]2=[O:23])=[CH:30][CH:29]=1)#[N:38]
Reactant: CCOP(=O)(CCOC(C)=O)OCC
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(/Cn1c(=O)c2cc(CC)sc2n(Cc2ccc(-c3ccccc3C#N)cc2)c1=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of 4′-{[6-ethyl-3-[2-(4-methoxyphenyl)-2-oxoethyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (1.0 g), (diethoxyphosphoryl)ethyl acetate (0.56 ml) in THF (20 ml) was added NaH (0.1 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give ethyl (2E)-4-[1-[(2′-cyanobiphenyl-4-yl)methyl]-6-ethyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl]-3-(4-methoxyphenyl)but-2-enoate (1.0 g, 88%). This was dissolved in dimethyl sulfoxide (5 mL), and the mixture was added to a mixture of hydroxylammonium chloride (1.15 g), sodium hydrogencarbonate (1.40 g) and dimethyl sulfoxide (20 mL), which had been stirred at 40° C. for 30 min in advance. The reaction mixture was stirred at 90° C. for 16 hr, diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.32 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.30 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a stereoisomer mixture (0.078 g, 13%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([CH2:9][C:10]1([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12][CH2:11]1)#[N:8].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(OCC)C>[NH2:8][CH2:7][CH2:9][C:10]1([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1(CC#N)CCCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NC1(CCN)CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
To a suspension of 8.48 g (223.63 mmol) of lithium aluminum hydride in 687 ml of diethyl ether at 0° C. was added dropwise 16.7 g (74.54 mmol) of tert-butyl 1-(cyanomethyl)cyclopentylcarbamate dissolved in 344 ml of diethyl ether. The resulting mixture was stirred at 0° C. under nitrogen atmosphere for 1 h. The reaction mixture was diluted with 100 ml of diethyl ether at 0° C. and treated with excess of a saturated aqueous solution of sodium sulfate. Further solid sodium sulfate was added and the organic phase was filtered to remove salts. The solvent was evaporated to dryness to give 13.83 g of product as an oil.
Reaction SMILES: [Li+].[OH-].O.[CH3:4][N:5]([C@@H:13]([CH2:18][CH:19]=[CH2:20])[C:14]([O:16]C)=[O:15])[C:6](=[O:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>C1COCC1>[CH3:4][N:5]([C@@H:13]([CH2:18][CH:19]=[CH2:20])[C:14]([OH:16])=[O:15])[C:6](=[O:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: C=CC[C@@H](C(=O)OC)N(C)C(=O)CCCCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CC[C@@H](C(=O)O)N(C)C(=O)CCCCC
Yield: 96 %

Procedure:
Step F (3): According to the general procedure outlined in Step A (3), a solution of LiOH/H2O (2M, 2.5 mL), was added to a mixture of (S)-methyl 2-(N-methylhexanamido)pent-4-enoate (254 mg, 1.05 mmol) in THF (2.5 mL) to afford 229 mg (96% yield) of (S)-2-(N-methylhexanamido)pent-4-enoic acid as a clear viscous oil. LC-MS (M+H)+=228.2; 1H NMR (500 MHz, CDCl3) δ ppm 0.82-0.93 (m, 3H) 1.23-1.36 (m, 4H) 1.55-1.70 (m, 2H) 2.26-2.38 (m, 2H) 2.47-2.59 (m, 1H) 2.71-2.80 (m, 1H) 2.94 (s, 3H) 4.99-5.19 (m, 3H) 5.61-5.75 (m, 1H) 5.91 (br s, 1H).
Reaction SMILES: P(Cl)(Cl)[Cl:2].[CH2:5]([O:9][P:10](OCCCC)[O:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:6][CH2:7][CH3:8]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH2:5]([O:9][P:10]([Cl:2])[O:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:6][CH2:7][CH3:8]
Reactant: CCCCOP(OCCCC)OCCCC
Reactant: ClP(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Product: CCCCOP(Cl)OCCCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 194.9 %

Procedure:
17.0 g (0.125 mole) of phosphorus trichloride is added dropwise at 5° to 10° C., with vigorous stirring, to a mixture of 62.5 g (0.25 mole) of tri-n-butylphosphite and 5.0 g of benzyltriethylammonium chloride (water content 7%). After completion of the addition, the reaction mixture is heated to room temperature and stirred for a further 8 hours at this temperature. After separation of the benzyltriethylammonium chloride by filtration there is obtained, by distillation of the filtrate under reduced pressure, 51.8 g (65% of theory, relative to phosphorus trichloride) of di-n-butylchlorophosphite, b.p. 96° to 98° C./10 Torr.
Reaction SMILES: Br[C:2]1[C:21]([Cl:22])=[CH:20][C:5]([O:6][CH2:7][CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)=[CH:4][C:3]=1[Cl:23].[CH3:24][N:25](C)C=O>[C-]#N.[Na+]>[Cl:23][C:3]1[CH:4]=[C:5]([O:6][CH2:7][CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[CH:20]=[C:21]([Cl:22])[C:2]=1[C:24]#[N:25]
Reactant: Clc1cc(OCCOc2ccc3ccccc3c2)cc(Cl)c1Br
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Na+]
Product: N#Cc1c(Cl)cc(OCCOc2ccc3ccccc3c2)cc1Cl
Temperature: 155 °C

Procedure:
A mixture of 2-[2-(4-bromo-3,5-dichlorophenoxy)ethoxy]naphthalene (3.28 g) in dimethylformamide (10 mL) and cuprous cyanide (0.833 g) was heated under argon at 155° C. for four hours. The cooled mixture was diluted with aqueous 10% sodium cyanide solution (100 mL) and extracted twice with dichloromethane. The organic solutions were washed in turn with aqueous 10% sodium cyanide solution and water, dried (Na2SO4), filtered and evaporated to give 2.2 g of crude 2,6-dichloro-4-[2-(2-naphthalenyloxy)ethoxy]benzonitrile. A portion crystallized from dichloromethanediethyl ether provide pure colorless material, mp 156°-158° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][C:16]([C:22]([NH2:24])=[O:23])=[C:15]2Cl.C(O)(=O)C.C(O)C>C(O)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:15]2[C:14]3[C:19](=[CH:20][CH:21]=[C:12]([O:11][CH3:10])[CH:13]=3)[N:18]=[CH:17][C:16]=2[C:22]([NH2:24])=[O:23])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(F)ccc1N
Reactant: COc1ccc2ncc(C(N)=O)c(Cl)c2c1
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2ncc(C(N)=O)c(Nc3ccc(F)cc3C)c2c1
Temperature: 25 °C

Procedure:
A mixture of 4-fluoro-2-methylaniline (0.025 mmol), 6-methoxy-4-chloro-3-quinolinecarboxamide (0.025 mmol), 50 μl 20% Acetic acid/Ethanol and 250 μl ethanol was refluxed for four hours. After cooling to room temperature the solvent was removed in vacuu.
Reaction SMILES: [OH:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4](=[O:16])[C:3]=1[C:17]([NH:19][CH2:20][C:21]([O:23]CC)=[O:22])=[O:18].[Cl:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:28]=1[CH2:29]Br.C(=O)([O-])[O-].[Na+].[Na+].Cl>CN(C)C=O>[Cl:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:28]=1[CH2:29][N:7]1[C:2]([OH:1])=[C:3]([C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])[C:4](=[O:16])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]1=[O:8]
Reactant: Clc1cccc(Cl)c1CBr
Reactant: CCOC(=O)CNC(=O)c1c(O)[nH]c(=O)n(Cc2ccccc2)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CNC(=O)c1c(O)n(Cc2c(Cl)cccc2Cl)c(=O)n(Cc2ccccc2)c1=O
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 11.2 %

Procedure:
A mixture of ethyl N-{[6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycinate (example 11a, 388 mg, 1.12 mmoles), 2,6-dichlorobenzyl bromide (295 uL, 1.23 mmoles) and sodium carbonate (330 mg, 3.1 mmoles) in dimethylformamide (6.0 mL) was stirred under argon at 100° C. for 2.5 hours. The mixture was cooled, poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The ester was hydrolysed by stirring in a mixture of ethanol (3 mL) and 1 molar sodium hydroxide solution (3 mL) for 3 hours. The mixture was acidified and extracted with ethyl acetate. Purification by preparative HPLC (acetonitrile-water—0.1% TFA, 20-100%) and crystallization from ethanol-water gave the title compound (60 mg, 11%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.12 (br. s., 1 H), 10.02 (br. s., 1 H), 7.42 (d, 2 H), 7.22-7.35 (m, 6 H), 5.30 (s, 2 H), 5.01 (s, 2 H), 4.12 (d, J=5.81 Hz, 2 H).
Reaction SMILES: [CH2:1]([N:3]([CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)[C:4]1[C:5]([CH3:17])=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7](O)=[O:8])[CH3:2].Cl.[NH2:26][CH2:27][C:28]1[C:29](=[O:38])[NH:30][C:31]([CH3:37])=[CH:32][C:33]=1[CH2:34][CH2:35][CH3:36].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O>[CH2:1]([N:3]([CH:18]1[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]1)[C:4]1[C:5]([CH3:17])=[C:6]([CH:10]=[C:11]([C:13]([F:15])([F:14])[F:16])[CH:12]=1)[C:7]([NH:26][CH2:27][C:28]1[C:29](=[O:38])[NH:30][C:31]([CH3:37])=[CH:32][C:33]=1[CH2:34][CH2:35][CH3:36])=[O:8])[CH3:2]
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Reactant: CCN(c1cc(C(F)(F)F)cc(C(=O)O)c1C)C1CCN(C)CC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(C(F)(F)F)cc(N(CC)C2CCN(C)CC2)c1C
Temperature: 23 °C
Reaction time: 20 h
Yield: 22.4 %

Procedure:
To a stirred solution of 3-[ethyl(1-methylpiperidin-4-yl)amino]-2-methyl-5-(trifluoromethyl)benzoic acid (crude material, 680 mg, 1.97 mmol) and 3-(aminomethyl)-6-methyl-4-propyl-1,2-dihydropyridin-2-one HCl salt (642 mg, 2.96 mmol) in DMSO (7 mL) was added PyBOP (1.85 g, 3.55 mmol) and hunig base (764 mg, 5.91 mmol). The reaction mixture was stirred at 23° C. for 20 hours. The reaction mixture was quenched with water and resulting precipitate was collected. The solid was purified by silica gel column chromatography (NH—SiO2 ethylacetate/MeOH=20/1) to give the titled compound as a white solid (224 mg, 22% yield). 1H-NMR (400 MHz, CDCl3) δppm; 7.31 (s, 1H), 7.26 (s, 1H), 7.16 (m, 1H), 5.94 (s, 1H), 4.55 (d, J=5.9 Hz, 2H), 3.08 (q, J=7.0 Hz, 2H), 2.82 (m, 2H), 2.66-2.73 (m, 3H), 2.33 (s, 3H), 2.24 (s×2, 6H), 1.79-1.98 (m, 2H), 1.67-1.75 (m, 4H), 1.59-1.66 (m, 2H), 1.02 (t, J=7.2 Hz, 3H), 0.84 (t, J=7.0 Hz, 3H); MS (ES) [M−H] 505.2; HPLC 98.1% purity.
Reaction SMILES: [N:1]1([C:6]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:9]=3[S:8](=[O:20])(=[O:19])[N:7]=2)[CH:5]=[CH:4]N=C1.[CH2:21](N)CC>>[CH2:5]([NH:1][C:6]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:9]=2[S:8](=[O:20])(=[O:19])[N:7]=1)[CH2:4][CH3:21]
Reactant: O=C(O)c1ccc2c(c1)S(=O)(=O)N=C(n1ccnc1)N2
Reactant: CCCN
Product: CCCNC1=NS(=O)(=O)c2cc(C(=O)O)ccc2N1

Procedure:
3-(Imidazol-1-yl)-4H-1,2,4-benzothiadiazine-7-carboxylic acid 1,1-dioxide was treated with propylamine according to the general procedure Method A to give the title compound; m.p. >310° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[OH2:15]>OS(O)(=O)=O>[NH2:1][C:2]1[C:6]([C:7]([NH2:8])=[O:15])=[CH:5][N:4]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:3]=1
Reactant: N#Cc1cn(-c2ccccc2)nc1N
Reactant: O
Agent: O=S(=O)(O)O
Product: NC(=O)c1cn(-c2ccccc2)nc1N

Procedure:
3-amino-1-phenyl-1H-pyrazole-4-carbonitrile (0.34 g, 1.846 mmol) was stirred in 95% H2SO4 (10 mL) at 50° C. for 3 hours. Room temperature was attained, water was added and the products extracted into EtOAc (×3). The aqueous phase was neutralised with 2 N NaOH and the products extracted into DCM (×2) followed by 20% MeOH-DCM (×4). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was triturated in EtOAc to give 3-amino-1-phenyl-1H-pyrazole-4-carboxamide as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5].[CH3:18][Mg]Br.Cl>C(OCC)C>[NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])([OH:5])[CH3:18]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: C[Mg]Br
Agent: Cl
Solvent: CCOCC
Product: CC(O)(c1cc(Cl)ccc1N)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 5 g of 2-amino-2′,5-dichlorobenzophenone dissolved in 100 ml of diethyl ether, at −30° C., are added 12.5 ml of 3M methylmagnesium bromide solution, and the mixture is maintained at room temperature for 18 hours. 6 ml of 3M methylmagnesium bromide solution are added and the mixture is left at room temperature for 1 hour. The resulting mixture is hydrolysed with 2M hydrochloric acid solution and washed with water. The organic phase is dried over anhydrous sodium sulfate to give 4.3 g of the expected product.
Reaction SMILES: C([N:8]1[C:12]([C:13]2[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=2[NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[N:11][N:10]=[N:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[OH-].[Pd+2].[OH-]>[CH3:20][O:19][C:18]1[C:13]([C:12]2[NH:8][N:9]=[N:10][N:11]=2)=[C:14]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:15]=[CH:16][CH:17]=1
Reactant: COc1cccc(NS(=O)(=O)c2ccccc2)c1-c1nnnn1Cc1ccccc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COc1cccc(NS(=O)(=O)c2ccccc2)c1-c1nnn[nH]1
Yield: 61.2 %

Procedure:
A mixture of N-[2-(1-benzyl-1H-tetrazol-5-yl)-3-methoxyphenyl]-benzenesulfonamide (Intermediate 12, 0.104 g), ammonium formate (0.45 g) and palladium hydroxide (0.01 g) in ethanol (10 mL) was heated at reflux for 72 hours. The reaction mixture was filtered through celite and the filtrate was evaporated under vacuum. The residue was purified by flash chromatography on silica, eluting with a mixture of DCM and methanol. The fractions containing the desired product were combined and evaporated to give the title compound as a colorless solid (0.05 g).