Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[H-].[Na+].Cl[CH2:23][C:24]1[O:25][CH:26]=[CH:27][CH:28]=1.C(#N)C.O>C1COCC1.C(OCC)(=O)C.O>[Br:1][C:2]1[C:3](=[O:19])[N:4]([CH2:23][C:24]2[O:25][CH:26]=[CH:27][CH:28]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)[nH]1
Reactant: ClCc1ccco1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1ccco1
Temperature: 68 °C

Procedure:
To a room temperature suspension of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (330.0 mg, 1.00 mmol)) and NaH (48.0 mg, 2.0 mmol) in THF (3.0 mL) was added 2-(chloromethyl)furan (461 mg, 3.97 mmol). The resulting suspension was stirred and heated to 68° C. for 9 hours until complete consumption of starting material by LCMS analysis. The reaction mixture was then diluted with ethyl acetate (400 mL), water washed (3×200 mL). The resulting organic extract was separated, Na2SO4 dried, and concentrated. The resulting dark residue was subjected to SiO2 chromatography with ethyl acetate/hexanes (4:6) to furnish a solid. 1H NMR (300 MHz, d4-MeOH) δ 7.62 (app q, J=8.4 Hz, 1H), 7.46 (s, 1H), 7.06 (app t, J=8.7 Hz, 2H), 6.51 (s, 1H), 6.41-6.37 (m, 2H), 5.37 (s, 2H), 5.32 (s, 2H), 2.61 (s, 3H); LC/MS C-18 column, tr32 2.63 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 410 (M+H). ES-HRMS m/z 410.0177 (M+H calcd for C18H15BrF2NO3 requires 410.0198).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[CH3:12][C:13]1([CH2:16]OC2C=CC=CC=2NC(=O)C2C=CC=CC=2)[CH2:15][O:14]1>>[CH3:7][NH:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[O:1][CH2:12][C:13]1([CH3:16])[CH2:15][O:14]1
Reactant: CNC(=O)c1ccccc1O
Reactant: CC1(COc2ccccc2NC(=O)c2ccccc2)CO1
Product: CNC(=O)c1ccccc1OCC1(C)CO1

Procedure:
was prepared from 2-hydroxy-N-methylbenzamide (prepared according to Cohen et al, J. Am. Chem. Soc., 1998, 20, 6277-6286.) according to the method described for N-{2-[(2-methyl-2-oxiranyl)methoxy]phenyl}benzamide.
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:6]=2[CH2:5][CH2:4]1)[CH3:2].Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]([CH3:31])([CH3:30])[CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[C:19]([Cl:32])=[CH:18][N:17]=1>>[Cl:32][C:19]1[C:20]([NH:22][C:23]([CH3:31])([CH3:30])[CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[N:21][C:16]([NH:14][C:11]2[CH:12]=[CH:13][C:6]3[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:9][CH2:8][C:7]=3[CH:10]=2)=[N:17][CH:18]=1
Reactant: CCN1CCc2ccc(N)cc2CC1
Reactant: CC(C)(CNS(C)(=O)=O)Nc1nc(Cl)ncc1Cl
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(NC(C)(C)CNS(C)(=O)=O)n3)cc2CC1

Procedure:
N-{2-[5-Chloro-2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-2-methyl-propyl}-methanesulfonamide was prepared from 3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and N-[2-(2,5-dichloro-pyrimidin-4-ylamino)-2-methyl-propyl]-methanesulfonamide in an analogous manner to Example 306. Product isolated as a white foam (22 mg, 10%). LCMS (m/e) 467 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.93 (s, 1H), 7.26-7.18 (m, 2H), 7.05 (d, 1H, J=7.9 Hz), 6.93 (s 1H), 5.95-5.80 (m, 1H), 5.13 (s, 1H), 3.47 (d, 2H, J=5.8 Hz), 2.97-2.88 (m, 4H), 2.78 (s, 3H), 2.72-2.58 (m, 4H), 2.59 (q, 2H, J=7.1 Hz), 1.50 (s, 6H), 1.12 (t, 3H, J=7.1 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([CH:21]([CH3:26])[CH2:22][C:23]([OH:25])=[O:24])=[N:19][CH:20]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].S(=O)(=O)(O)O.[CH3:32]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([CH:21]([CH3:26])[CH2:22][C:23]([O:25][CH3:32])=[O:24])=[N:19][CH:20]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CO
Reactant: CC(CC(=O)O)c1ccc(NC(=O)Cc2ccc([N+](=O)[O-])c(O)c2)cn1
Agent: O=S(=O)(O)O
Product: COC(=O)CC(C)c1ccc(NC(=O)Cc2ccc([N+](=O)[O-])c(O)c2)cn1

Procedure:
(RS) 3-{5-[2-(3-hydroxy-4-nitrophenyl)-acetylamino]-pyridin-2-yl}-butanoic acid (2.1 g, Reference Example 26) in methanol (80 mL) was treated with concentrated sulphuric acid (0.5 mL). The mixture was heated at reflux temperature for 24 hours, then cooled, then concentrated to low volume and then diluted with ethyl acetate. This solution was washed with 5% aqueous sodium bicarbonate, then with water, then dried over magnesium sulphate and then evaporated to give the title compound (2.0 g) as an oil.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:25][C:21]1[CH:20]=[C:19]([N:18]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[N:11]=[C:10]2[C@@H:8]([NH2:7])[CH3:9])[CH:24]=[CH:23][CH:22]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccnc2n1-c1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)c1nc2cccnc2n1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
To a solution of {(S)-1-[3-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl]ethyl}carbamic acid tert-butyl ester (35 mg, 0.09 mmol) in DCM (1 mL) was added TFA (1 mL) and the mixture was stirred at RT for 3 h. The crude mixture was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to afford (S)-1-[3-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl]ethylamine as an orange oil (23 mg).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(=O)=O.N.[Li]>C(O)C>[C:1]1([OH:11])[C:10]2[CH2:9][CH:8]=[CH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2ccccc12
Agent: N
Agent: O=C=O
Agent: [Li]
Solvent: CCO
Product: Oc1cccc2c1CC=CC2

Procedure:
108 g (0.75 mol) of α-naphthol are placed in a 4 liter reactor. The round-bottomed flask is cooled in a bath of solid carbon dioxide and alcohol, and about 1 liter of liquid ammonia is introduced, whilst stirring vigorously. When the naphthol has almost dissolved, 20.9 g of lithium wire are added in small pieces and the mixture is then stirred for 1/2 hour. 170 ml of ethyl alcohol are then poured in dropwise. The round-bottomed flask is then left to warm up and nitrogen is bubbled into the mixture in order to drive off the ammonia. The grey pasty residue is taken up in 1 liter of water and the mixture is extracted 3 times with 100 ml of ether. The aqueous phase is cooled and acidified with concentrated HC1 until the pH is acid. The brown oil which has appeared is extracted 3 times with ether and the ether fraction is washed 3 times with water before being dried over magnesium sulphate. After filtration and evaporation to dryness, the solid is taken up in ether and the mixture is dried over MgSO4 in the presence of charcoal. The mixture is filtered and the filtrate is evaporated to dryness. A yellow solid is obtained. After recrystallisation, a white solid is finally obtained. Melting point=73°-74.5° C.
Reaction SMILES: CO.[SH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16].C[O-].[CH3:20][O:21][C:22]1[CH:42]=[CH:41][C:25]([CH2:26][S:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]Br)=[CH:24][CH:23]=1>CCOC(C)=O.C(O)(=O)C>[CH3:20][O:21][C:22]1[CH:42]=[CH:41][C:25]([CH2:26][S:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][S:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:24][CH:23]=1
Reactant: COc1ccc(CSCCCCCCCCCCCCBr)cc1
Reactant: O=C(O)CCCCCCCCCCCS
Agent: C[O-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(CSCCCCCCCCCCCCSCCCCCCCCCCCC(=O)O)cc1
Reaction time: 0.08 h
Yield: 48.7 %

Procedure:
Na (116 mg, 5 mmol) was dissolved it dry MeOH. 12-mercapto-1-dodecanoic acid (340 mg, 1.46 mmol)-synthesized according to JACS 115, 3458-3474, 1993—was added to the methoxide solution. After stirring with some heating for 5 min, (2) (497 mg, 1.24 mmol) was added to the reaction. The reaction became very viscous and an additional 1.75 mL of MeOH was introduced. The reaction was then left overnight. The reaction was quenched with 10% acetic acid. The paste-like reaction mixture was transferred to a 500 mL separatory funnel dissolved in equal volumes of EtOAc/Hex (1:1) and the acetic acid solution. The organic layer was separated. The aqueous layer was then extracted two more times. The combine extracts were concentrated yielding 740.3 mg (1.34 mmol) of crude product. The excess acetic acid was removed as a toluene azeotrope. The solid was crystallized from isopropyl ether giving 483 mg (71%). TLC and NMR show an impurity believed to be a disulfide side product. The material was further purified by flash chromatography eluting with CHCl3/MeOH/AA (99:0.5:0.5) yielding 334 mg (0.604 mmol, 49%) of pure product. 1H NMR (CDCl3): d 9.45 (brs, 1H, COOH), 7.23 (d, J=8.8 Hz, 2H, AA′ of AA′ BB′ aromatic system), 6.85 (d, J=8.7 Hz, 2H, BB′ of AA′ BB′ aromatic system), 3.80 (s, 3H, methoxy), 3.66 (s, 2H, benzyl), 2.50 (t, J=7.3 Hz, 4H, RCH2SCH2R), 2.40 (t, J=7.3 Hz, 2H, RSCH2R), 2.35 (t, J=7.5 Hz, 2H, RCH2COOH), 1.5-1.7 (cm, 8H, CH2 b to heteroatoms), 1.15-1.45 (cm, 30H, bulk methylenes). 13C NMR (CDCl3): d 179.5 (COOH), 129.9 (aromatic, 2C), 113.9 (aromatic, 2C), 55.2 (MeOR), 35.6 (CH2), 33.7 (CH2), 32.2 (CH2), 31.3 (CH2), 29.7 (CH2), 29.4 (CH2), 29.2 (CH2), 28.9 (CH2), 24.6 (CH2).
Reaction SMILES: [CH2:1]1[C:5]2=[C:6]3[C:7]([CH2:10][CH2:11]/[C:12]/3=[CH:13]\[CH2:14][NH:15][C:16](=[O:19])[CH2:17][CH3:18])=[N:8][CH:9]=[C:4]2[O:3][CH2:2]1>CO.[C].[Pd]>[CH2:1]1[C:5]2=[C:6]3[CH:12]([CH2:13][CH2:14][NH:15][C:16](=[O:19])[CH2:17][CH3:18])[CH2:11][CH2:10][C:7]3=[N:8][CH:9]=[C:4]2[O:3][CH2:2]1
Reactant: CCC(=O)NC/C=C1\CCc2ncc3c(c21)CCO3
Agent: [Pd]
Solvent: CO
Product: CCC(=O)NCCC1CCc2ncc3c(c21)CCO3
Temperature: 50 °C
Reaction time: 6 h
Yield: 60.2 %

Procedure:
To a solution of N-[(2E)-2-(1,2,6,7-tetrahydro-8H-cyclopenta[b]furo[3,2-d]pyridin-8-ylidene)ethyl]propanamide (65.0 mg, 0.252 mmol) in methanol (1.3 mL) was added palladium-carbon powder (13 mg), and the mixture was stirred at 50° C. for 6 hr under a hydrogen atmosphere. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=50/50→100/0) to give the title compound (39.5 mg, yield 60%).
Reaction SMILES: OCCCN1C=C(C2C=CC(N[C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=C3C=2CN(C)C3=O)C=N1.C(OP1(=O)CC2C=CC(=CC=2)NC2=NC(=C(C(F)(F)F)C=N2)NC2C=CC(=NC=2C(NC)=O)C2=CN(N=C2)CCCCO1)C.[NH2:94][C:95]1[C:96]([C:112]([NH:114][CH3:115])=[O:113])=[N:97][C:98]([C:101]2[C:102]([C:110]#[N:111])=[N:103][N:104]([CH2:106][CH2:107][CH2:108][OH:109])[CH:105]=2)=[CH:99][CH:100]=1>>[C:110]([C:102]1[C:101]([C:98]2[N:97]=[C:96]([C:112](=[O:113])[NH:114][CH3:115])[C:95]([NH:94][C:26]3[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:22][N:23]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:25]=3)=[CH:100][CH:99]=2)=[CH:105][N:104]([CH2:106][CH2:107][CH2:108][OH:109])[N:103]=1)#[N:111]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: CNC(=O)c1nc(-c2cn(CCCO)nc2C#N)ccc1N
Agent: CCOP1(=O)Cc2ccc(cc2)Nc2ncc(C(F)(F)F)c(n2)Nc2ccc(nc2C(=O)NC)-c2cnn(c2)CCCCO1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cn(CCCO)nc4C#N)nc3C(=O)NC)n2)c(OC)c1)OCC
Yield: 69 %

Procedure:
Prepared analogously to Compound 1B using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 1 E, 236 mg, 0.520 mmol) and 3-amino-6-[3-cyano-1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-N-methylpyridine-2-carboxamide (Compound 52C, 164 mg, 0.546 mmol) to afford 259 mg of the title compound (69%). 1H NMR (400 MHz, CD3OD) δ 9.17 (br. s., 1H), 8.47 (s, 1H), 8.38 (s, 1H), 7.91 (d, J=9.1 Hz, 1H), 7.68 (br. s., 1H), 7.08 (s, 1H), 6.98 (d, J=7.8 Hz, 1H), 4.52 (t, J=6.9 Hz, 2H), 4.08 (quin, J=7.3 Hz, 4H), 3.88 (s, 2H), 3.61 (t, J=6.1 Hz, 2H), 3.33-3.42 (m, 2H), 2.99 (s, 3H), 2.17 (quin, J=6.5 Hz, 2H), 1.26 (t, J=7.1 Hz, 7H). MS (ESI): m/z=718.47 [M+H]+. UPLC: tR=1.39 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([CH3:14])[NH:11][CH:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=1.CC1(C)CCCC(C)(C)N1>CN(C=O)C>[C:21]([C:20]1[CH:23]=[CH:24][C:17]([N:11]2[CH:12]([CH3:14])[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH:10]2[CH3:15])=[N:18][CH:19]=1)#[N:22]
Reactant: N#Cc1ccc(Br)nc1
Reactant: CC1CN(C(=O)OC(C)(C)C)CC(C)N1
Agent: CC1(C)CCCC(C)(C)N1
Solvent: CN(C)C=O
Product: CC1CN(C(=O)OC(C)(C)C)CC(C)N1c1ccc(C#N)cn1
Temperature: 150 °C
Yield: 34.5 %

Procedure:
The compound 3,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (250 mg, 1.1 mmol) was dissolved in dry DMF (1 mL) taken in a shield tube. To the reaction mixture was added 6-bromonicotinonitrile (210 mg, 1.1 mmol) followed by 2,2,6,6-tetramethyl piperidine (0.16 g, 1.1 mmol) and the mixture was heated to 150° C. for 5 h. Reaction mixture was cooled to room temperature. The product was extracted with EtOAc and the organic layer was washed with H2O and brine. Solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 20-25% EtOAc in petroleum ether) to afford tert-butyl 4-(5-cyanopyridin-2-yl)-3,5-dimethylpiperazine-1-carboxylate (0.12 g, yield 33%). 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=2.3 Hz, 1H), 7.64 (dd, J=9.0 Hz, J=2.3 Hz, 1H), 6.53 (d, J=9.0 Hz, 1H), 4.48 (m, 2H), 4.13-4.00 (m, 2H), 3.16-3.06 (m, 2H), 1.51 (s, 9H), 1.27 (s, 3H), 1.25 (s, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1.[NH:15]1[CH2:20][CH2:19][C:18]2([CH:25]3[CH2:26][CH:27]=[CH:28][CH:29]=[C:24]3[CH2:23][O:22][CH2:21]2)[CH2:17][CH2:16]1.[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32]>C(OCC)(=O)C>[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:15]3[CH2:16][CH2:17][C:18]4([CH:25]5[CH2:26][CH:27]=[CH:28][CH:29]=[C:24]5[CH2:23][O:22][CH2:21]4)[CH2:19][CH2:20]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: C1=CCC2C(=C1)COCC21CCNCC1
Reactant: ClCCCOc1cccc2[nH]ccc12
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: C1=CCC2C(=C1)COCC21CCN(CCCOc2cccc3[nH]ccc23)CC1

Procedure:
The title compound was prepared in similar fashion from 1-chloro-3-(1H-indole-4-oxy)propane and 1,5-dihydrospiro[4H-2-benzopyran-4,4'-piperidine]. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 69% overall yield as a foam. FDMS m/e=376 (M+ of free base).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2=[CH:16][S:17][C:18]([CH3:19])=[C:5]12)=[O:3].[N:20]1([CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][NH2:37])[CH2:31][CH2:30]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH3:19][C:18]1[S:17][CH:16]=[C:6]2[C:7](=[O:15])[NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:4]([C:2]([NH:37][CH2:36][CH2:35][N:32]3[CH2:31][CH2:30][CH:29]([CH2:28][CH2:27][CH2:26][N:20]4[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]4)[CH2:34][CH2:33]3)=[O:3])[C:5]=12
Reactant: NCCN1CCC(CCCN2CCCCC2)CC1
Reactant: Cc1scc2c1N(C(=O)Cl)c1ccccc1NC2=O
Product: Cc1scc2c1N(C(=O)NCCN1CCC(CCCN3CCCCC3)CC1)c1ccccc1NC2=O
Yield: 9 %

Procedure:
Prepared analogously to Example 1 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 2-[4-[3-(piperidin-l-yl)propyl]-piperidin-l-yl]ethanamine in a yield of 9% of theory. Colourless crystals, m.p. 170°-171° C.
Reaction SMILES: NC1N=CN=C2C=1N=CN2CC1N(C2C=CC=CC=2C)C(=O)C2C(=CC=CC=2C)N=1.[NH2:31][C:32]1[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:33]=1[C:34]([OH:36])=[O:35].[Cl:42][CH2:43][C:44](Cl)=[O:45]>>[Cl:42][CH2:43][C:44]([NH:31][C:32]1[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:33]=1[C:34]([OH:36])=[O:35])=[O:45]
Reactant: O=C(Cl)CCl
Reactant: Cc1cccc(N)c1C(=O)O
Agent: Cc1ccccc1-n1c(Cn2cnc3c(N)ncnc32)nc2cccc(C)c2c1=O
Product: Cc1cccc(NC(=O)CCl)c1C(=O)O

Procedure:
The synthetic scheme for the preparation of 2-((6-amino-9H-purin-9-yl)methyl)-5-methyl-3-o-tolylquinazolin-4(3H)-one, 1, is shown in FIG. 1. 2-amino-6-methylbenzoic acid, 1″, is reacted with 2-chloroacetyl chloride to produce the 2-(−2-chloroacetamido)-6-methylbenzoic acid, 2″. Reaction with o-toluidine and phosphoryl trichloride yields the cyclized intermediate, 3″. Further reaction with diBOC-protected adenine give the BOC protected product, 4″, which is deprotected resulting in 2-((6-amino-9H-purin-9-yl)methyl)-5-methyl-3-o-tolylquinazolin-4(3H)-one, 1.
Reaction SMILES: [OH:1][C@@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:3][C:4](OC)=[O:5].[CH3:21][NH2:22]>CO>[CH3:21][NH:22][C:4](=[O:5])[CH2:3][C@@H:2]([OH:1])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CN
Reactant: CCCCCCCCCCCCC[C@H](O)CC(=O)OC
Solvent: CO
Product: CCCCCCCCCCCCC[C@H](O)CC(=O)NC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-Methyl 3-hydroxyhexadecanoate (1.0 g) was dissolved in a solution of 40% methylamine in methanol (15 ml). This mixture was stirred at room temperature for 2 hours. The resulting crystalline solid was collected by filtration to give (S)-N-methyl-3-hydroxyhexadecanamide (0.71 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]2[CH:21]=[N:20][C:19]([Cl:22])=[C:18]([NH:23][CH2:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:17]=2)=[CH:4][C:5]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:38][CH2:39][CH2:40][CH2:41]Br>CN(C=O)C>[Cl:22][C:19]1[C:18]([NH:23][CH2:24][CH:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)=[N:17][C:16]([C:3]2[C:2]([Cl:1])=[CH:7][N:6]=[C:5]([NH:8][C@H:9]3[CH2:14][CH2:13][C@H:12]([N:15]4[CH2:41][CH2:40][CH2:39][CH2:38]4)[CH2:11][CH2:10]3)[CH:4]=2)=[CH:21][N:20]=1
Reactant: N[C@H]1CC[C@H](Nc2cc(-c3cnc(Cl)c(NCC4CCOCC4)n3)c(Cl)cn2)CC1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cnc(N[C@H]2CC[C@H](N3CCCC3)CC2)cc1-c1cnc(Cl)c(NCC2CCOCC2)n1
Temperature: 60 °C

Procedure:
To a scintillation vial containing trans-N1-(5-chloro-4-(5-chloro-6-((tetrahydro-2H-pyran-4-yl)methyl)aminopyrazin-2-yl)pyridin-2-yl)cyclohexane-1,4-diamine (12 mg, 0.027 mmol) and K2CO3 (3.67 mg, 0.027 mmol) was added DMF (1 ml) and 1,4-dibromobutane (3.15 μl, 0.027 mmol). The reaction mixture was capped and heated to 60° C. for 3 hr. The crude solution was concentrated and purified by reverse phase preparative HPLC to yield 3-chloro-6-(5-chloro-2-(trans-4-(pyrrolidin-1-yl)cyclohexylamino)pyridin-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (3.8 mg, 6.13 μmol, 23.07% yield), LCMS (m/z): 505.2 (MH+), retention time=0.64 min, and a TFA salt after lyapholization.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[O:11][CH2:12][C:13](=[O:20])[C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[F:8].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][N:28]=2)[C:23]([CH:30]=O)=[CH:22]1.C(O)C.[OH-].[Na+]>CC(O)C.Cl>[NH:21]1[C:29]2=[N:28][CH:27]=[CH:26][CH:25]=[C:24]2[C:23]([CH:30]=[C:12]2[O:11][C:10]([NH:9][C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=3)=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13]2=[O:20])=[CH:22]1
Reactant: CCOC(=O)C1=C(Nc2ccc(F)c(F)c2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccc(F)c(F)c2)OC(=Cc2c[nH]c3ncccc23)C1=O
Yield: 44.3 %

Procedure:
To a solution of ethyl 2-[(3,4-difluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.084 g, 0.30 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.041 g, 0.28 mmol) in 2-propanol (2.0 mL), 2M hydrochloric acid in ethanol (0.14 mL, 0.28 mmol) was added at ambient temperature. The mixture was refluxed for 18 h. Cooled with ice bath, aqueous 2M sodium hydroxide solution (0.13 mL, 0.26 mmol) was added dropwise to neutralize, ethanol (5.0 mL) was added and the mixture was refluxed for 1.5 h. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound as solid (0.051 g, y. 44%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([NH2:12])=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14].N1C=CC=CC=1.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[O:26]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([NH:12][C:25]([O:27][C:28]2[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=2)=[O:26])=[CH:6][C:5]=1[C:13]([F:14])([F:16])[F:15]
Reactant: COC(=O)c1cc(OC)c(N)cc1C(F)(F)F
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(OC)c(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1C(F)(F)F
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a stirred solution of 5-methoxy-4-amino-2-trifluoromethyl-benzoic acid methyl ester (552 mg, 2.22 mmol) in 6.6 mL CH2Cl2 at 0° C. under nitrogen was added pyridine (180 μL, 2.22 mmol) followed p-nitrophenyl chloroformate (448 mg, 2.22 mmol) as a solid. After stirring for 1 hour, the reaction was diluted to 30 mL with CH2Cl2 and washed 2×30 mL with 2N HCl and 1×30 mL with H2O. The organics were dried (MgSO4), filtered and concentrated to the p-nitrophenyl carbamate which was isolated as a white foam (878 mg, 96%). 1H-NMR (400 MHz, CDCl3) δ 8.57 (br s, 1H), 8.30 (d, 2H), 7.77 (br s, 1H), 7.40 (d, 2H), 7.37 (s, 1H), 4.03 (s, 3H), 3.94 (s, 3H).
Reaction SMILES: [Cl:1][C:2]([Cl:13])([Cl:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.S(Cl)([Cl:16])=O>>[Cl:1][C:2]([Cl:13])([Cl:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:16])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(C(Cl)(Cl)Cl)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(C(Cl)(Cl)Cl)cc1

Procedure:
Reaction of 4-trichloromethylbenzoic acid with thionyl chloride affords 4-trichloromethylbenzoyl chloride, which, on reaction with diethylamine, affords 4-trichloro-methyl-N,N-diethylbenzamide. Following a procedure similar to that described in Preparation 5, reaction of the latter with s-butyl lithium and reaction of the resulting lithium salt with sulfur dioxide followed by sodium hydroxylamine-O-sulfonate affords 4-trichloromethyl-2-aminosulfonyl-N,N-diethylbenzamide, which, on heating in glacial acetic acid, affords 6-trichloromethylsaccharin.