Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[C:4]([S:6][CH3:7])=[CH2:5].C(OC(=C)C(O)=O)C.[CH2:17]([N:24]([CH2:30]OC)[CH2:25][Si](C)(C)C)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C:4]1([S:6][CH3:7])[CH2:5][CH2:25][N:24]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:30]1)=[O:8]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=C(SC)C(=O)OC
Agent: C=C(OCC)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(SC)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-ethoxyacrylate 2-Methylsulfanyl-acrylic acid methyl ester 6BP (136 g, 1.03 mol) and benzyl-methoxymethyl-trimethylsilanylmethyl-amine 7BP (290 g, 1.22 mol) in dichloromethane (2.7 L ml) was added at 0° C. a solution of trifluoroacetic acid (26 mL, 0.3 mol). The resulting solution was warmed to room temperature and stirred for one overnight. The crude product was purified by column chromatography on silica gel eluting with a solution of ethyl acetate in hexane (1:4) to give 1-benzyl-3-methylsulfanyl-pyrrolidine-3-carboxylic acid methyl ester 8BP (131 g, 47%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:15][C:16]1[C:25]([CH3:26])=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[CH3:27].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([NH:15][C:16]1[C:17]([CH3:27])=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][C:25]=1[CH3:26])=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1C(F)(F)F
Reactant: COC(=O)c1cc(C)c(N)c(C)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C)c(NC(=O)c2cc(Br)ccc2C(F)(F)F)c(C)c1
Reaction time: 0.17 h
Yield: 40.2 %

Procedure:
To a solution of 5-bromo-2-(trifluoromethyl)benzoic acid (1.00 g, 0.00371 mol) in CH2Cl2 (15 mL) at room temperature are added methyl 4-amino-3,5-dimethylbenzoate (0.46 g, 0.00260 mol, see preparation 12) and triethylamine (1.10 ml, 0.00743 mol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 6.00 ml, 0.00929 mol) is added via syringe and stirred at room temperature. After 14 hours, the reaction mixture is diluted with water and extracted with dichloromethane. The organic layers are combined and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) with 10-15% EtOAc to give the title compound as an off-white solid (0.45 g, 27.67%).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][CH2:22][NH:23][C:24]1[N:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([C:32]2[CH:33]=[C:34]([C:38]([CH3:43])([CH3:42])[C:39]([OH:41])=O)[CH:35]=[CH:36][CH:37]=2)[CH:25]=1.[CH2:44]([S:46]([NH2:49])(=[O:48])=[O:47])[CH3:45]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][CH2:22][NH:23][C:24]1[N:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([C:32]2[CH:33]=[C:34]([C:38]([CH3:43])([CH3:42])[C:39]([NH:49][S:46]([CH2:44][CH3:45])(=[O:48])=[O:47])=[O:41])[CH:35]=[CH:36][CH:37]=2)[CH:25]=1
Reactant: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Reactant: CCS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCS(=O)(=O)NC(=O)C(C)(C)c1cccc(-c2cc(NCCc3ccc(Cl)cc3Cl)nc(OC)n2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
N-(3-dimethylaminopropyl)-N-ethylcarbodimide hydrochloride (44 mg, 0.23 mmol) is added to a stirred ice cold solution of 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid (100 mg, 0.22 mmol), ethanesulfonamide (25 mg, 0.23 mmol) and 4-Dimethylaminopyridine (27 mg, 0.22 mmol) in dry DCM under nitrogen atmosphere. The ice bath is removed and the reaction mixture is stirred overnight at 60° C. The volatiles are removed under reduced pressure, the residue is dissolved in ethyl acetate, washed with 0.1 N HCl, brine and water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue is purified by chromatography (SiO2 packed column), eluting with EtOAc/DCM to afford ethanesulfonic acid [2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionyl]-amide [67 mg, Example 95(a)]. LCMS: RT=2.49 minutes, MS: 551, 553 (M+H).
Reaction SMILES: C([Cl:4])(=O)C.[Cl:5][C:6]1[CH:28]=[C:27]([C:29]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([OH:39])[CH:34]=2)=[O:30])[CH:26]=[C:25]([Cl:40])[C:7]=1[C:8]([NH:10][C@H:11]([C:21]([O:23][CH3:24])=[O:22])[CH2:12][NH:13]C(OC(C)(C)C)=O)=[O:9]>CO>[ClH:4].[NH2:13][CH2:12][C@@H:11]([C:21]([O:23][CH3:24])=[O:22])[NH:10][C:8](=[O:9])[C:7]1[C:6]([Cl:5])=[CH:28][C:27]([C:29]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([OH:39])[CH:34]=2)=[O:30])=[CH:26][C:25]=1[Cl:40]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1c(Cl)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)[C@H](CN)NC(=O)c1c(Cl)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Product: Cl
Reaction time: 0.17 h
Yield: 97 %

Procedure:
A solution of acidic methanol was prepared by adding acetyl chloride (25 mL, 351.6 mmol) to cooled (˜0° C.) methanol (200 mL) and stirring for 10 min. This solution was added to N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]-carbonyl]benzoyl]-3-[[(1,1-dimethylethoxy)carbonyl]amino]-L-alanine, methyl ester (8.64 g, 16.0 mmol) and the resulting solution was stirred at room temperature for 16 h. The solvent was evaporated to give 3-amino-N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-L-alanine, methyl ester hydrochloride (7.40 g, 97%) as a cream-colored foam.
Reaction SMILES: [NH2:1][OH:2].[CH2:3]([N:5]([CH2:22][CH3:23])[C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[N:9]=[C:8]([CH2:18][CH3:19])[C:7]=1[C:20]#[N:21])[CH3:4]>CS(C)=O>[CH2:22]([N:5]([CH2:3][CH3:4])[C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[N:9]=[C:8]([CH2:18][CH3:19])[C:7]=1/[C:20](=[N:1]/[OH:2])/[NH2:21])[CH3:23]
Reactant: NO
Reactant: CCc1nn(-c2ccc(O)cc2)c(N(CC)CC)c1C#N
Solvent: CS(C)=O
Product: CCc1nn(-c2ccc(O)cc2)c(N(CC)CC)c1/C(N)=N/O
Temperature: 160 °C
Yield: 32.7 %

Procedure:
Hydroxylamine (50 wt % solution in water, 0.45 mL, 7.3 mmol) was added to 5-(diethylamino)-3-ethyl-1-(4-hydroxyphenyl)-1H-pyrazole-4-carbonitrile (16 mg, 0.06 mmol) dissolved in DMSO (1 mL) in a microwave vial. The reaction was heated at 160° C. in the microwave for 30 min. Purification using preparative HPLC gave (Z)-5-(diethylamino)-3-ethyl-N′-hydroxy-1-(4-hydroxyphenyl)-1H-pyrazole-4-carboximidamide (6.22 mg, 35%). Identification of the title compound by 1II-NMR showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. ES/MS m/z: 318.29 (M+H), 316.32 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.40 (m, 2H), 6.90 (m, 2H), 2.96 (q, 4H, J=7.2 Hz), 2.65 (q, 2H, J=7.4 Hz), 1.19 (t, 3H, J=7.4 Hz) and 0.95 (t, 6H, J=7.2 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:16][C:17]1[CH:18]=[CH:19][C:20]([Sn](CCCC)(CCCC)CCCC)=[N:21][CH:22]=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.C1(C)C=CC=CC=1>[CH3:16][C:17]1[CH:18]=[CH:19][C:20]([C:2]2[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=2)[C:7]([O:9][CH3:10])=[O:8])=[N:21][CH:22]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cn1
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C(=O)OC)cc(-c2ccc(C)cn2)c1
Temperature: 25 °C

Procedure:
A mixture of dimethyl 5-bromoisophthalate (1.0 g, 3.66 mmol), 5-methyl-2-(tributylstannyl)pyridine (1.5 mL, 4.5 mmol), tetrakis(triphenylphosphine)palladium(0) (200 mg, 0.17 mmol), and toluene (10 mL) under nitrogen was subjected to microwave irradiation at 120° C. for 2 hour. The mixture was cooled to room temperature and the precipitate was collected via filtration and rinsed with hexane to afford a white solid which was the desired product. The filtrate was purified via flash chromatography to afford another crop of the desired product (0.8 g in total). LC-MS: 286.3 [M+1]+; 1H NMR (400 MHz, CDCl3): 8.84 (d, J=1.6 Hz, 2H), 8.71 (t, J=1.6 Hz, 1H), 8.56 (t, J=0.8 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.61 (dd, J=2.0, 8.1 Hz, 1H), 3.98 (s, 6H), 2.41 (s, 3H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]([CH3:26])[C@H:19]([C:23](O)=[O:24])[CH:20]([CH3:22])[CH3:21])=[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.[CH3:27][O:28][C@@H:29]([C@@H:38]([N:43]([CH3:51])[C:44](=[O:50])[C@H:45]([CH:47]([CH3:49])[CH3:48])[NH2:46])[C@@H:39]([CH3:42])[CH2:40][CH3:41])[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1>CC1CCCO1>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([N:18]([CH3:26])[C@H:19]([C:23]([NH:46][C@H:45]([C:44]([N:43]([C@@H:38]([C@@H:39]([CH3:42])[CH2:40][CH3:41])[C@H:29]([O:28][CH3:27])[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])[CH3:51])=[O:50])[CH:47]([CH3:49])[CH3:48])=[O:24])[CH:20]([CH3:21])[CH3:22])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](N)C(C)C
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OCC1c2ccccc2-c2ccccc21
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Solvent: CC1CCCO1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reaction time: 0.17 h
Yield: 108.4 %

Procedure:
To a mixture of N-[(9H-fluoren-9-ylmethoxy)carbonyl]-N-methyl-L-valine (19.54 g, 55.29 mmol, 1.3 eq.) and #6 (15.25 g, 42.54 mmol, 1 eq.) in 2-methyltetrahydrofuran (152 mL, 0.28 M) was added 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (9.71 g, 55.3 mmol, 1.3 eq.). After 10 minutes, N-methylmorpholine (6.6 mL, 60 mmol, 1.4 eq.) was slowly added, while keeping the internal temp below 25° C. The reaction was stirred for 4 hours and was then quenched by the addition of water (50 mL). After stirring for 15 minutes, the aqueous layer was separated and back-extracted with 2-methyltetrahydrofuran (50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (100 mL), then were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting yellow foam was purified by silica gel chromatography (Gradient: 5% to 35% ethyl acetate in heptane) to give #7 (32 g, 97%). 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ 7.89 (d, J=7.4 Hz, 2H), 7.62 (d, J=7.4 Hz, 2H), 7.41 (br dd, J=7.4, 7.4 Hz, 2H), 7.29-7.34 (m, 2H), 4.52-4.69 (br m, 1H), 3.70-3.82 (br m, 1H), 3.22 and 3.25 (2 br s, total 3H), 2.94 and 2.96 (2 br s, total 3H), 2.78 and 2.81 (2 br s, total 3H), 2.11-2.23 (m, 1H), 1.90-2.10 (m, 2H), 1.68-1.83 (br m, 1H), 1.40 (s, 9H), 1.21-1.33 (br m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Cl:26])[C:5]2[C:10]([C:11]#[C:12][CH2:13][OH:14])=[CH:9][N:8]([CH2:15][C:16]3[C:21]([CH3:22])=[C:20]([O:23][CH3:24])[C:19]([CH3:25])=[CH:18][N:17]=3)[C:6]=2[N:7]=1.Cl.[CH3:28][N:29]([CH2:31][C:32](Cl)=[O:33])[CH3:30].C1(C)C=CC=CC=1>N1C=CC=CC=1>[NH2:1][C:2]1[N:3]=[C:4]([Cl:26])[C:5]2[C:10]([C:11]#[C:12][CH2:13][O:14][C:32](=[O:33])[CH2:31][N:29]([CH3:30])[CH3:28])=[CH:9][N:8]([CH2:15][C:16]3[C:21]([CH3:22])=[C:20]([O:23][CH3:24])[C:19]([CH3:25])=[CH:18][N:17]=3)[C:6]=2[N:7]=1
Reactant: COc1c(C)cnc(Cn2cc(C#CCO)c3c(Cl)nc(N)nc32)c1C
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1c(C)cnc(Cn2cc(C#CCOC(=O)CN(C)C)c3c(Cl)nc(N)nc32)c1C

Procedure:
A solution of 3-[2-amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo [2,3-d]pyrimidin-5-yl]-prop-2-yn-1-ol (see example 1, 177 mg, 0.48 mmol) in anhydrous pyridine (3 mL) was treated with N,N-dimethylamino-acetyl chloride hydrochloride (113 mg, 0.72 mmol) at rt for 30 min. Addition of toluene (10 mL) caused the formation of a sticky pellet. The toluene solution was discarded, and the pellet was partitioned between water and DCM. The DCM layer was concentrated, and purified by flash chromatography (EtOAc/DCM/Et3N 33:66:1, gradually adding MeOH (0-2%)) to afford the title compound. tR=4.51 min. 1H NMR (CDCl3) δ 8.23 (s, 1H), 7.14 (s, 1H), 5.31 (s, 2H), 5.00 (s, 2H), 4.98 (s, 2H), 3.76 (s, 3H), 3.25 (s, 2H), 2.38 (s, 6H), 2.28 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[S:32][CH:33]=[CH:34][N:35]=1)[S:7]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[CH:20]2[CH2:24][CH2:23][CH2:22][N:21]2[CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:11]=1)(=[O:9])=[O:8].[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43]>C(Cl)Cl>[F:45][C:44]([F:47])([F:46])[C:42]([OH:48])=[O:43].[O:28]1[CH2:29][CH2:30][CH:25]([N:21]2[CH2:22][CH2:23][CH2:24][CH:20]2[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:17]=2[CH:18]=[CH:19][C:10]([S:7]([NH:6][C:31]2[S:32][CH:33]=[CH:34][N:35]=2)(=[O:8])=[O:9])=[CH:11]3)[CH2:26][CH2:27]1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(C4CCCN4C4CCOCC4)cccc3c2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1nccs1)c1ccc2c(C3CCCN3C3CCOCC3)cccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-(2,4-dimethoxybenzyl)-5-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-2-yl)-N-(thiazol-2-yl)naphthalene-2-sulfonamide (0.038 g, 0.065 mmol) was dissolved in DCM (1 mL) and TFA (0.1 ml, 1.298 mmol) was added. The reaction was stirred for 30 minutes at room temperature. The reaction was concentrated, triturated with diethyl ether, and filtered. The solids were washed with diethyl ether and vacuum dried overnight to afford 5-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-2-yl)-N-(thiazol-2-yl)naphthalene-2-sulfonamide 2,2,2-trifluoroacetate as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=12.79 (br. s., 1H), 9.65 (br. s., 1H), 8.55 (br. s., 1H), 8.43 (d, J=9.1 Hz, 1H), 8.27 (d, J=7.2 Hz, 1H), 8.04 (d, J=7.3 Hz, 1H), 7.91 (d, J=8.9 Hz, 1H), 7.82-7.72 (m, 1H), 7.27 (d, J=4.6 Hz, 1H), 6.85 (d, J=4.5 Hz, 1H), 5.61 (d, J=6.1 Hz, 1H), 3.91-3.68 (m, 5H), 3.63-3.45 (m, 3H), 3.13 (t, J=11.3 Hz, 3H), 2.71-2.57 (m, 2H), 2.20 (br. s., 2H), 1.98 (br. s., 1H), 1.84 (d, J=10.5 Hz, 1H), 1.65 (br. s., 2H), 1.51 (br. s., 1H). m/z (ESI) 444.2 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:13])[CH3:12])=[C:7]([S:14](=[O:17])(=[O:16])[NH2:15])[CH:6]=1)=[O:4].[CH2:18]([NH:20][C:21]([NH:23][CH2:24][CH3:25])=[S:22])[CH3:19]>>[ClH:1].[CH2:24]([N:23]1[C:3]([C:5]2[CH:10]=[CH:9][C:8]([CH:11]([CH3:13])[CH3:12])=[C:7]([S:14](=[O:17])(=[O:16])[NH2:15])[CH:6]=2)([OH:4])[CH2:2][S:22][C:21]1=[N:20][CH2:18][CH3:19])[CH3:25]
Reactant: CC(C)c1ccc(C(=O)CCl)cc1S(N)(=O)=O
Reactant: CCNC(=S)NCC
Product: CCN=C1SCC(O)(c2ccc(C(C)C)c(S(N)(=O)=O)c2)N1CC
Product: Cl

Procedure:
5.5 g of 2-chloro-4'isopropyl-3'-sulfamoylacetophenone and 2.2 g of 1,3-diethylthio urea were reacted and worked up as prescribed in Example 12. Colorless solid body, decomposition beginning at 96° C, γC=N 1610 cm-1.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[N:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[C:19]([F:20])=[CH:18][C:17](B2OC(C)(C)C(C)(C)O2)=[C:16]([F:30])[CH:15]=1>>[Cl:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[N:5]=[CH:4][CH:3]=2)=[C:16]([F:30])[CH:15]=1
Reactant: COC(=O)c1c(Cl)ccnc1C
Reactant: CC1(C)OB(c2cc(F)c(Cl)cc2F)OC1(C)C
Product: COC(=O)c1c(-c2cc(F)c(Cl)cc2F)ccnc1C
Yield: 24 %

Procedure:
Prepared as described in Example 16, Part D by carrying out a Suzuki coupling between methyl 4-chloro-2-methylnicotinate (prepared as described in Example 14, Part A) and 2-(4-chloro-2,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (prepared as described in Example 16, Part A-Part C) to afford methyl 4-(4-chloro-2,5-difluorophenyl)-2-methylnicotinate (3 g, 4.13 mmol, 24% yield) as a brown oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.60 (d, J=5.2 Hz, 1H), 7.36 (m, 1H), 7.20 (m, 2H), 3.74 (s, 3H), 2.49 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([Cl:11])[N:10]=[C:6]2[C:5]([C:12]([OH:14])=O)=[CH:4][C:3]=1Cl.[CH2:16]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][NH2:27])[CH2:22][CH2:21]1)[CH2:17][CH2:18][CH3:19]>>[NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([Cl:11])[N:10]=[C:6]2[C:5]([C:12]([NH:27][CH2:26][CH:23]2[CH2:24][CH2:25][N:20]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:21][CH2:22]2)=[O:14])=[CH:4][CH:3]=1
Reactant: CCCCN1CCC(CN)CC1
Reactant: Nc1c(Cl)cc(C(=O)O)c2nc(Cl)cn12
Product: CCCCN1CCC(CNC(=O)c2ccc(N)n3cc(Cl)nc23)CC1

Procedure:
The title compound was prepared according to the procedure described in the step 3 in EXAMPLE 5 using 5-amino-2-chloroimidazo[1,2-a]pyridine-8-carboxylic acid (EXAMPLE 25, Step 3) and 1-(1-butyl-4-piperidinyl)methanamine (EXAMPLE 1, METHOD A, Step 5).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([OH:28])=[C:4]([C:29]([O:31][CH3:32])=[O:30])[C:3]=1[C:33]([O:35][CH3:36])=[O:34].C(=O)([O-])[O-].[K+].[K+].[CH2:43](Br)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C)C=O.CC(C)=O>[C:44]1([CH2:43][O:28][C:5]2[C:6]3[C:11](=[C:10]([O:12][CH2:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:9]=[CH:8][C:7]=3[O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:2]([O:1][CH2:33][C:3]3[CH:4]=[CH:5][CH:6]=[CH:11][CH:2]=3)=[C:3]([C:33]([O:35][CH3:36])=[O:34])[C:4]=2[C:29]([O:31][CH3:32])=[O:30])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1c(C(=O)OC)c(O)c2c(OCc3ccccc3)ccc(OCc3ccccc3)c2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1c(C(=O)OC)c(OCc2ccccc2)c2c(OCc3ccccc3)ccc(OCc3ccccc3)c2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 10.00 g of dimethyl 1,4-dihydroxy-5,8-bis(phenylmethoxyl)-2,3-naphthalene dicarboxylate prepared in Step 2A-b above, 12.00 g of potassium carbonate and 8.0 mL of benzyl bromide in 100 mL of dimethyl formamide and 200 mL of acetone was stirred at room temperature for 2 days. The reaction was filtered. The filtrate was then concentrated and the solid was washed with mixed solvent of ethyl acetate and petroleum ether to give 12.50 g of the title compound as a yellow solid.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[C:8]2[CH:9]=[CH:10][CH2:11][O:12][C:13]=2[CH:14]=[CH:15][CH:16]=1)=[O:6]>CO.O>[O:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:7]([C:5]([OH:6])=[O:4])[C:8]=2[CH:9]=[CH:10][CH2:11]1
Reactant: COC(=O)c1cccc2c1C=CCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc2c1C=CCO2
Temperature: 55 °C
Reaction time: 3 h

Procedure:
A solution of NaOH (7.26 mmol) in a mixture of MeOH (5.4 mL) and water (12.1 mL) is added to 2H-chromene-5-carboxylic acid methyl ester (4.84 mmol). The mixture is stirred at 55° C. for 3 h, partially concentrated in vacuo to remove MeOH and made acidic by addition of aq. HCl (1.0M). The desired carboxylic acid precipitates and is collected by filtration. 1H-NMR (DMSO-d6): δ=4.75 (bs, 2H); 5.99-6.05 (m, 1H); 6.98 (d, J=7.78 Hz, 1H); 7.19 (t, J=7.78 Hz, 1H); 7.25 (d, J=10.3 Hz, 1H); 7.40 (d, J=7.78 Hz, 1H); 13.0 (bs, 1H).
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.[C:11](Cl)(=[O:14])[CH:12]=[CH2:13].Cl>C(=O)(O)[O-]>[C:11]([C:2]1[N:3]=[C:4]2[C:8]([NH:7][CH:6]=[N:5]2)=[C:9]([NH2:10])[N:1]=1)(=[O:14])[CH:12]=[CH2:13]
Reactant: Nc1ncnc2nc[nH]c12
Reactant: C=CC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Product: C=CC(=O)c1nc(N)c2[nH]cnc2n1
Reaction time: 1 h

Procedure:
Adenine (0.27 g, 0.002 mole) was dissolved in 7 ml of bicarbonate buffer (pH 8), cooled to 0°-4° C., and acrylic acid chloride (1.1 g, 0.01 mole) was added with intense stirring for 1 hour. The solution was acidified with 1 M HCl until pH 6 was obtained, the solvent was evaporated in vacuum and the formed white precipitate was recrystallized from dimethyl sulfoxide. The yield of the AAD was 70%. The IR spectra displayed no absorption bands at 1650 cm-1 (bending vibrations of NH2 groups); however, absorption bands appeared at 1680 (amide-1), 1540 (amide-II), and 1290 (amide-III). These data confirm that a compound of AAD having the above formula was prepared.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([O:14][CH3:15])=[O:13])=[N:8][NH:9]2)=[CH:5][CH:4]=1.[C:18](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[CH3:18][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:11]=2)[C:7]([C:12]([O:14][CH3:15])=[O:13])=[N:8]1
Reactant: COC(=O)c1n[nH]c2cc(C(F)(F)F)ccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)c1nn(C)c2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
To an acetonitrile (5 ml) solution of methyl 6-(trifluoromethyl)-1H-indazole-3-carboxylate (300 mg, 1.2 mmol) were added potassium carbonate (1.0 g, 7.4 mmol) and iodomethane (350 mg, 2.5 mmol) at room temperature respectively. The mixture was stirred at room temperature for 4 hours. The solid was removed by filtration and washed with acetonitrile. The filtrate was concentrated in vacuo. After being filtered off, the filtrate was concentrated under reduced pressure, the residue was applied to a silica gel chromatography column and eluted with a hexane/ethyl acetate=4/1 to furnish 239 mg (75% yield, major product) of the title as a white solid;
Reaction SMILES: [NH3:1].Cl[C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:7][N:8]=1>O1CCCC1>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[N:5]=[N:4][C:3]([NH2:1])=[N:8][CH:7]=2)=[CH:10][CH:11]=1
Reactant: N
Reactant: Fc1ccc(-c2cnc(Cl)nn2)cc1
Solvent: C1CCOC1
Product: Nc1ncc(-c2ccc(F)cc2)nn1
Temperature: 50 °C

Procedure:
Ammonia gas was bubbled through a solution of 3-chloro-6-(4-fluorophenyl)-1,2,4-triazine (600 mg, 0.0029 mol) in tetrahydrofuran (8 mL) for 5 min at −40° C. The reaction mixture was sealed and heated at 50° C. for 2 hours. The mixture was concentrated under reduced pressure to yield the desired product (550 mg) which was directly used in the next step without further purification. LCMS: (M+H)=209.1.