Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:29])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1.Cl[S:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])(=[O:33])=[O:32]>N1C=CC=CC=1>[N:22]1[CH:21]=[C:20]([C:18]([NH:17][C:15]2[CH:16]=[C:11]([C:8]3[N:7]=[C:6]([CH:4]4[CH2:3][N:2]([S:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])(=[O:32])=[O:33])[CH2:5]4)[O:10][N:9]=3)[CH:12]=[CH:13][C:14]=2[CH3:29])=[O:19])[N:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=12
Reactant: Cc1ccc(-c2noc(C3CNC3)n2)cc1NC(=O)c1cnc2ccccn12
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(-c2noc(C3CN(S(=O)(=O)NC(=O)OC(C)(C)C)C3)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of N-(5-(5-(azetidin-3-yl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (21) (50 mg, 0.133 mmol) in anhydrous pyridine (1.5 mL) at 0° C. was added tert-butyl chlorosulfonylcarbamate (35 mg, 0.160 mmol). The reaction was stirred to room temperature for 1 hour. The reaction was quenched with water and the solvent was concentrated. The crude product tert-butyl 3-(3-(3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidin-1-ylsulfonylcarbamate (128) was purified by preparative HPLC. 1H NMR (400 MHz, d6-DMSO) δ 11.27 (s, 1H), 10.25 (s, 1H), 9.55-9.53 (m, 1H), 8.76 (s, 1H), 8.07 (d, J=1.6 Hz, 1H), 7.93-7.90 (m, 1H), 7.84 (dd, J=1.6, 8.0 Hz, 1H), 7.75-7.71 (m, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.37-7.34 (m, 1H), 4.37-4.33 (m, 5H), 2.38 (s, 3H), 1.38 (s, 9H). MS m/z 554.17 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8](Br)[CH:7]=[CH:6]2.[CH3:14][C:15]([OH:19])([C:17]#[CH:18])[CH3:16]>C(NCC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:18]#[C:17][C:15]([CH3:16])([OH:19])[CH3:14])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: COc1ccc2cc(C#CC(C)(C)O)ccc2c1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A mixture of 6-methoxy-2-bromonaphthalene (14.23 g, 60.0 mmol), copper (I) iodide (0.17 g, 0.90 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.63 g, 0.90 mmol), and 2-methyl-3-butyn-2-ol (8.7 mL, 90 mmol) in diethylamine (100 mL) was heated at reflux for 16 hours, cooled to room temperature and solvent evaporated. The residue was purified by flash chromatography using 15-25% ethyl acetate in hexane as an eluant. Drying at 80° C. for 20 minutes afforded 4-(6-methoxy-2-naphthyl)-2-methyl-3-butyn-2-ol as a light orange solid (14.4 g), mp: 118-119° C. 1HNMR (300 MHz, DMSO-d6): δ7.95 (s, 1H), 7.75-7.85 (m, 2H), 7.4 (dd, 1H, J=8.4 Hz and 1.5 Hz), 7.35 (d, 1H, J=2.4 Hz), 7.2 (dd, 1H, J=8.5 Hz and 1.5 Hz), 5.5 (s, 1H), 3.9 (s, 3H), and 1.5 ppm (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][OH:10])=[CH:4][CH:3]=1.[CH2:12](O)[CH2:13][OH:14]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:9][OH:10])[O:14][CH2:13][CH2:12][O:11]2)=[CH:6][CH:7]=1
Reactant: O=C(CO)c1ccc(F)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: OCC1(c2ccc(F)cc2)OCCO1
Yield: 71.8 %

Procedure:
The same reaction as in the synthesis of 3a was conducted from 1-(4-fluorophenyl)-2-hydroxyethanone (23.89 g, 155 mmol), ethylene glycol (42 mL, 780 mmol), p-toluenesulfonic acid monohydrate (0.5 g) and benzene (300 mL) and the resulting crude product was purified by a silica gel column chromatography (toluene:ethyl acetate=4:1) to give [2-(4-fluorophenyl)-[1,3]dioxolan-2-yl]methanol (22.05 g, 72%) as an oily product. 1H-NMR (DMSO-d6) δ: 3.51 (d, J=6.3 Hz, 2H), 3.75-3.81 (m, 2H), 3.99-4.07 (m, 2H), 4.94 (t, J=6.3 Hz, 1H), 7.13-7.19 (m, 2H), 7.42-7.47 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:7][C:6](=O)[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[S:17][CH:16]=[C:15]([C:18]#[N:19])[CH:14]=3)=[CH:12][C:3]1=2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>O>[CH3:1][C:2]1([CH3:20])[O:7][C:6](=[S:30])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[S:17][CH:16]=[C:15]([C:18]#[N:19])[CH:14]=3)=[CH:12][C:3]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cc(C#N)cs3)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Product: CC1(C)OC(=S)Nc2ccc(-c3cc(C#N)cs3)cc21

Procedure:
The title compound was prepared in a manner similar to Example 16 using 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl) thiophene-3-carbonitrile and Lawesson's reagent. The product was obtained in the form of yellow crystals: m.p. 258-259° C. 1H NMR (DMSO-d6) δ 12.3 (s, 1H), 8.54 (d, 1H, J=0.9 Hz), 7.96 (s, 1H), 7.69-7.62 (m, 2H), 7.11-7.08 (d, 1H , J=8.3 Hz), 1.69 (s, 6H); MS (ESI) m/z 299 [M−H]−; Anal. Calcd. For C15H12N2OS2.½ H2O: C, 58.0; H, 4.24; N, 9.05. Found: C, 58.33; H, 3.85; N, 8.39.
Reaction SMILES: [NH2:1][C:2]1[C:12]2[C:11](=[O:13])[NH:10][CH2:9][CH2:8][N:7](C(=O)C(F)(F)F)[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([NH:37][CH3:38])(=[O:36])=[O:35])[C:24]([Cl:39])=[CH:23][N:22]=1.Cl>C(O)(C)C.O1CCOCC1>[Cl:39][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([NH:37][CH3:38])(=[O:36])=[O:35])=[N:26][C:21]([NH:1][C:2]2[C:12]3[C:11](=[O:13])[NH:10][CH2:9][CH2:8][NH:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)=[N:22][CH:23]=1
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1cccc2c1C(=O)NCCN2C(=O)C(F)(F)F
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2cccc3c2C(=O)NCCN3)ncc1Cl
Reaction time: 0.17 h
Yield: 15.4 %

Procedure:
Into a microwave vial was placed 6-amino-1-(2,2,2-trifluoro-acetyl)-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (25 mg, 0.092 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide (27 mg, 0.082 mmol) in isopropyl alcohol (3 mL) with 4 M HCl in dioxane (˜2 drops). The mixture was subjected to microwaves at 120° C. for 10 minutes. Trace starting materials were present so the reaction mixture was resubjected to the same microwave conditions. The resulting solid was collected by filtration and washed with cold methylene chloride and dried in a vacuum oven at 50° C. overnight to give product as an off-white solid 2-[5-Chloro-2-(5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-6-ylamino)pyrimidin-4-ylamino]-N-methylbenzene-sulfonamide (6 mg, 16% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.60 (s, 1H), 9.62 (s, 1H), 9.04 (d, 1H, J=8 Hz), 8.95-8.86 (m, 3H), 8.55 (s, 1H), 7.88-7.25 (m, 4H), 6.71 (d, 1H, J=7.8 Hz), 6.52 (s, 1H), 3.46 (m, 2H), 2.84 (d, 3H), 2.5 (m, 2H); MS (m/e) 474 (M+1)
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([C:7]1[C:12]([CH2:13]O)=[CH:11][CH:10]=[CH:9][C:8]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:6]>C(Cl)Cl>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([CH2:13][Cl:3])[C:7]=2[CH2:5][CH3:6])=[CH:16][CH:17]=1
Reactant: O=S(Cl)Cl
Reactant: CCc1c(CO)cccc1-c1ccc(OC)cc1
Solvent: ClCCl
Product: CCc1c(CCl)cccc1-c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 71 %

Procedure:
After thionyl chloride (4 ml) was added to a solution of (2-ethyl-4′-methoxy-1,1′-biphenyl-3-yl)methanol (4.39 g, 17.9 mmol) obtained in Example (90-3) in methylene chloride (18 ml) under ice-cooling, the mixture was stirred at room temperature for 7 hours. The residue obtained by removing the solvent under reduced pressure was diluted with ethyl acetate and the mixture was successively washed with water, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 3′-(chloromethyl)-2′-ethyl-1,1′-biphenyl-4-yl methyl ether (3.32 g, yield: 71%).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([NH:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:34])=[C:24]([NH:26][C:27]([N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:28])[CH:25]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:34][C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:2]2[CH:10]=[C:9]([NH:11][CH2:12][C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=2)=[CH:25][C:24]=1[NH:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:28]
Reactant: NC(=O)c1cnc(Cl)cc1NCc1cccnc1
Reactant: Nc1ccc(F)c(NC(=O)N2CCCC2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: NC(=O)c1cnc(Nc2ccc(F)c(NC(=O)N3CCCC3)c2)cc1NCc1cccnc1
Yield: 22.2 %

Procedure:
A mixture of 6-chloro-4-(pyridin-3-ylmethylamino)nicotinamide (2, 27 mg, 0.1 mmoles), N-(5-amino-2-fluorophenyl)pyrrolidine-1-carboxamide (3, 34 mg, 0.15 mmoles), Pd(OAc)2 (2 mg). BINAP (15 mg), Cs2CO3 (100 mg) in dioxane (1 mL) was heated at 120° C. under microwave for 60 min. Purification with reversed phase HPLC, 6-(4-fluoro-3-(pyrrolidine-1-carboxamido)phenylamino)-4-(pyridin-3-ylmethylamino)nicotinamide (4, 10 mg) was obtained. MS found for C23H24FN7O2 as (M+H)+ 450.5, UV: λ=249.1 nm. 1H NMR: (CD3OD) δ8.50 (s, 1H), δ8.42 (d, 1H), δ8.26 (d, 1H), δ7.80 (dd, 1H), δ7.60 (dd, 1H), δ7.40 (dd, 1H), δ7.00 (dd, 1H), δ6.91 (m, 1H), δ5.88 (d, 1H), δ4.49 (s, 2H), δ3.48 (m, 4H), δ1.99 (b, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2(O)[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C1(C)C(C)=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)CO>O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:17][CH2:16][C:11]3([O:12][CH2:13][CH2:14][O:15]3)[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2cccc(F)c2)CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Solvent: OCCO
Product: Fc1cccc(C2=CCC3(CC2)OCCO3)c1
Temperature: 25 °C

Procedure:
513 g of 8-(3-fluorophenyl)-1,4-dioxaspiro[4.5]decan-8-ol, 1.8 l of xylene, 19 g of p-toluenesulfonic acid and 50 ml of ethylene glycol were boiled for 4 hours in a water separator. The reaction solution was cooled to room temperature and washed with 2×200 ml of water. The organic extracts were dried using sodium sulfate, filtered and evaporated to a residue, giving 8-(3-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:28]([Cl:29])=[C:27]([O:30][CH3:31])[CH:26]=[C:25]([Cl:32])[C:4]=1[CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:33]/[C:34](=[CH:43]\[CH:44]=[C:45](/[CH3:48])\[CH:46]=O)/[C:35](/[CH3:42])=[CH:36]/[C:37]([O:39][CH2:40][CH3:41])=[O:38].C1OC1CC>C1(C)C=CC=CC=1>[Cl:2][C:3]1[C:28]([Cl:29])=[C:27]([O:30][CH3:31])[CH:26]=[C:25]([Cl:32])[C:4]=1/[CH:5]=[CH:48]/[C:45](/[CH3:46])=[CH:44]/[CH:43]=[C:34](\[F:33])/[C:35](/[CH3:42])=[CH:36]/[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: COc1cc(Cl)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(Cl)c1Cl
Reactant: CCOC(=O)/C=C(C)/C(F)=C/C=C(\C)C=O
Agent: CCC1CO1
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C(C)/C(F)=C/C=C(C)/C=C/c1c(Cl)cc(OC)c(Cl)c1Cl
Yield: 58 %

Procedure:
A mixture of 2.36 g. (9.54 mmol) of 2,3,6-trichloro-4-methoxybenzyl triphenylphosphonium chloride and 2.0 g. (8.93 mmol) of ethyl (E,Z,E)-4-fluoro-3,7-dimethyl-8-oxo-2,4,6-octatrienoate in 200 ml. of toluene and 150 ml. of 1,2-butylene oxide was heated at 85°-90° C. under argon for 18 hours. The mixture was worked up in the usual manner and the resulting crude product was filtered through 150 g. of silica gel. Elution with methylene chloride gave 2.48 g. of a yellow crystalline substance. Recrystallization of this material from methylene chloride-isopropyl ether yielded 2.21 g. (58% yield) of ethyl (E,Z,E,E)-9-(2,3,6-trichloro-4-methoxyphenyl)-4-fluoro-3,7-dimethyl-2,4,6,8-nonatetraenoate as yellow crystals, mp. 140°-142.5° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:17])[CH:8]=[C:9]([C:11]([O:13]C)=[O:12])[CH:10]=1)=[O:4].[OH-].[Na+].Cl.NC(N)=O>>[C:3]([C:5]1[CH:6]=[C:7]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:17])[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1cc(NC(=O)Nc2ccc([N+](=O)[O-])cc2)cc(C(=O)OC)c1
Agent: Cl
Agent: NC(N)=O
Agent: [Na+]
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)Nc1cc(C(=O)O)cc(C(=O)O)c1
Reaction time: 0.5 h
Yield: 88 %

Procedure:
The urea (7.67) (100 mg, 0.27 mmol) was added to a stirred solution of sodium hydroxide (1M, 5 ml). After 0.5 h the reaction was complete by TLC examination. The reaction mixture was neutralised to pH 2 with 1M HCl, causing the urea to precipitate. The precipitate was collected by filtration, washed, dried, and recrystallised from dioxan to give the title compound 7.65 as a yellow powder (82 mg, 91%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5](=[O:30])[NH:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][C:17]3[CH2:24][CH2:23][CH2:22][C:21]4[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:20]=4[C:18]=3[N:19]=2)[CH2:10][CH2:9]1.[H-].[Na+].CCOC(C)=O.Cl>CN(C=O)C.C(Cl)(Cl)Cl.CCOCC.O>[F:29][C:27]1[CH:26]=[CH:25][C:21]2[CH2:22][CH2:23][CH2:24][C:17]3[S:16][C:15]([NH:14][CH:11]4[CH2:12][CH2:13][CH:8]([CH2:7][N:6]5[CH2:2][CH2:3][O:4][C:5]5=[O:30])[CH2:9][CH2:10]4)=[N:19][C:18]=3[C:20]=2[CH:28]=1
Reactant: O=C(NCC1CCC(Nc2nc3c(s2)CCCc2ccc(F)cc2-3)CC1)OCCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C1OCCN1CC1CCC(Nc2nc3c(s2)CCCc2ccc(F)cc2-3)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57 %

Procedure:
To a stirred solution of 2-chloroethyl-N-({4-[(9-fluoro-5,6-dihydro-4H-benzo[6,7]-cyclohepta[d][1,3]thiazol-2-yl)amino]cyclohexyl}methyl)carbamate (5.4 g, 11.95 mmol) in 100 ml anhydrous DMF was added NaH (60% in mineral oil) (0.6 g, 15.0 mmol). TLC (EtOAc) indicated that the reaction had proceeded to approximately 40% completion after 15 minutes. An additional 0.58 g (14.5 mmol) NaH (60% in mineral oil) was added and the solution was stirred at room temperature for another 15 minutes. TLC indicated the reaction was complete. The solution was poured into water (500 ml) and was extracted with EtOAc. The extract was separated and evaporated to yield a dark viscous oil. The oil was chromatographed on silica-gel eluting with 2:1 EtOAc/hexane to yield a white solid. The solid was dissolved in 40 ml CHCl3 and 10 ml 1N HCl in Et2O was added to the solution. The volatiles were removed and the resulting solid was triturated with Et2O. The solution was filtered and the slightly tan solid washed with ether and dried to yield 52% (2.83 g) of the desired product as the HCl salt: 1H-NMR (Free-base) (CDCl3) δ 1.16 (4H, m), 1.60 (1H, m), 1.80 (2H, m), 2.05 (2H, m), 2.22 (2H, m), 2.81 (4H, m), 3.12 (2H, d, J=7.3 Hz), 3.27 (1H, m), 3.57 (2H, t, J=8.2 Hz), 4.33 (2H, t, J=8.0 Hz), 5.05 (1H, d, J=7.7 Hz), 6.83 (1H, dt, J=2.7, 8.2 Hz), 7.05 (1H, m), 7.68 (1H, dd, J=2.7, 10.8 Hz). m.p. (HCl salt) 223-225° C. Anal. Calcd. For C22H27N3ClFO2S: C, 58.5; H, 6.0; N, 9.3. Found: C, 58.43; H, 6.06; N, 9.38; 416 (ESMS, MH+).
Reaction SMILES: [CH:1]1(O)[C:10]2[C:5]3[C:6](=[CH:11][CH:12]=[CH:13][C:4]=3[CH2:3][O:2]1)[CH:7]=[CH:8][CH:9]=2.C[Si]([C:19]#[N:20])(C)C.C([O-])(O)=O.[Na+]>C(#N)C>[CH:1]1([C:19]#[N:20])[C:10]2[C:5]3[C:6](=[CH:11][CH:12]=[CH:13][C:4]=3[CH2:3][O:2]1)[CH:7]=[CH:8][CH:9]=2
Reactant: OC1OCc2cccc3cccc1c23
Reactant: C[Si](C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: N#CC1OCc2cccc3cccc1c23
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1,3-Dihydrobenzo[de]isochromen-1-ol (100 mg) in acetonitrile (3 mL) at 0° C. was added Zn(II)iodide (86 mg) and suspension was stirred at 0° C. for 10 minutes. Trimethylsilyl cyanide (672 μL) was added and the reaction mixture was stirred at room temperature overnight. Solution of saturated NaHCO3 (10 mL) was added and the mixture was extracted with ethyl acetate (2×15 mL). Combined organic phases were washed with brine and dried with Na2SO4. Evaporation of solvents afforded 110 mg 1,3-dihydrobenzo[de]isochromene-1-carbonitrile that was mixed with ethylene diamine mono-p-toluenesulfonic acid salt (157 mg) and the mixture was heated to 200° C. After 3 hours the reaction mixture was cooled to room temperature and taken to mixture of dichloromethane (10 ml) and aqueous NaHCO3 (1:1 saturated solution/water). Phases were separated and aqueous phase was extracted with dichloromethane (5 mL). Combined organic phases were dried with Na2SO4 and concentrated. The evaporation residue was purified by separation method E (aq.NH3-MeOH-dichloromethane). The obtained 2-(1,3-dihydrobenzo[de]isochromen-1-yl)-4,5-dihydro-1H-imidazole was converted to the title compound using salt formation method A.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:25]C(=O)OC(C)(C)C)[C:10]([NH:12][C:13]2[N:17]([CH3:18])[N:16]=[C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH:14]=2)=[O:11])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[NH2:25][C@@H:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:10]([NH:12][C:13]1[N:17]([CH3:18])[N:16]=[C:15]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[CH:14]=1)=[O:11]
Reactant: Cn1nc(-c2ccncc2)cc1NC(=O)[C@H](Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: Cn1nc(-c2ccncc2)cc1NC(=O)[C@@H](N)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
To a 100 ml flask was added tert-butyl (S)-3-(4-fluorophenyl)-1-(1-methyl-3-(pyridin-4-yl)-1H-pyrazol-5-ylamino)-1-oxopropan-2-ylcarbamate 103.1.A (1.35 g, 3.07 mmole), 18 ml of 4N-hydrogen chloride solution in 1,4-dioxane and 9 ml of 1,4-dioxane. The reaction was stirred at room temperature for 2 hours at which time the solvent was removed by rotary evaporation. The residue was suspended in ethyl acetate, and washed successively with saturated sodium bicarbonate, water and brine. The organic layer was dried over anhydrous sodium sulfate, and concentrated in vacuo to give 103.1.B (905 mg, 87% yield) as colorless crystals.
Reaction SMILES: C([NH:18]CC=O)(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.[CH3:22][C:23]1[CH:32]=[C:31]2[C:26]([CH:27]=[CH:28][C:29]([C:33]([OH:35])=O)=[N:30]2)=[CH:25][CH:24]=1.ON1C2C=CC=CC=2N=N1.C(O)C(N)(CO)CO>ClCCl>[CH3:22][C:23]1[CH:32]=[C:31]2[C:26]([CH:27]=[CH:28][C:29]([C:33]([NH2:18])=[O:35])=[N:30]2)=[CH:25][CH:24]=1
Reactant: Cc1ccc2ccc(C(=O)O)nc2c1
Reactant: O=CCNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: NC(CO)(CO)CO
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1ccc2ccc(C(N)=O)nc2c1
Reaction time: 0.08 h
Yield: 339.2 %

Procedure:
A solution of the amine 4 (1.0 mg, 1.9 μmol, 1.0 equiv) in dichloromethane (0.1 mL) was added to 7-methylquinoline-2-carboxylic acid (2.8 μmol, 1.5 equiv) and 1-hydroxybenzotriazole (0.44 mg, 3.2 μmol, 1.7 equiv) in a vial at 23° C. The solution was stirred for 5 min, then N-cyclohexylcarbodiimide-N′-propyloxymethyl polystyrene (Argonaut Technologies, 1.13 mmol/g, 3.4 mg, 3.8 μmol, 2.0 equiv) was added in one portion at 23° C. The reaction mixture was stirred gently at 23° C. under an argon atmosphere for 16 h. PS-Trisamine (Argonaut Technologies, 4.71 mmol/g, 2.0 mg, 9.5 μmol, 5.0 equiv) was then added in one portion and the reaction mixture was stirred for a further 2 h. The mixture was filtered through Celite (0.5 cm) and concentrated in vacuo to give the 7-methylquinoline-2-carboxylic acid amide derivative (1.2 mg, 95%) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5](Cl)[C:6]([CH2:12][CH3:13])=[N:7]2.[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16]>CS(C)=O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([NH:19][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]([CH2:12][CH3:13])=[N:7]2
Reactant: CCc1nc2cccc(Br)c2nc1Cl
Reactant: CC(C)(C)N
Solvent: CS(C)=O
Product: CCc1nc2cccc(Br)c2nc1NC(C)(C)C
Temperature: 25 °C
Yield: 91.7 %

Procedure:
A solution of 5-bromo-3-chloro-2-ethylquinoxaline (312a) (131 mg, 0.48 mmol) and t-butylamine (Aldrich) (0.25 mL, 2.41 mmol) in DMSO (1.0 mL) was stirred under argon in a sealed flask at 100° C. for 17 h. The reaction mixture was then cooled to RT and partitioned between Et2O (80 mL) and saturated aq. NaHCO3 (80 mL). The organic layer was separated and sequentially washed with water (50 mL) and brine (40 mL), then dried over Na2SO4, filtered, and concentrated in vacuo to provide 8-bromo-N-(tert-butyl)-3-ethylquinoxalin-2-amine (136 mg, 0.44 mmol, 92% yield) as a yellow-orange solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.86 (1H, d, J=8.2 Hz), 7.82 (1H, dd, J=7.6, 1.2 Hz), 7.20 (1H, t, J=7.9 Hz), 4.87 (1H, br. s.), 2.84 (2H, q, J=7.4 Hz), 1.64 (9H, s), 1.42 (3H, t, J=7.4 Hz). m/z (ESI, +ve) 308.3/310.3 (M+H)+.
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[CH2:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1>CO>[CH3:1][O:2][CH2:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)Cc1cccc(CBr)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1cccc(CC(=O)O)c1
Yield: 99.2 %

Procedure:
Under an atmosphere of argon gas, to sodium methoxide (160 g), methanol (800 ml) was added with stirring. Thereto, a solution of 3-bromomethylphenylacetic acid (226 g; prepared in Reference Example 18) in methanol (3200 ml) was added. The mixture was refluxed for 20 minutes. After the temperature of mixture became to room temperature, methanol was distilled off. The residue was poured into 2N HCl. Thereto, ethyl acetate was added. The organic layer was washed by an aqueous saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated to obtain the title compound (176.3 g).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])=[O:3].[CH3:13][CH:14]([OH:19])[CH2:15][CH:16]([OH:18])[CH3:17]>>[CH3:12][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][C:2]([O:18][CH:16]([CH2:15][CH:14]([OH:19])[CH3:13])[CH3:17])=[O:3]
Reactant: CC(O)CC(C)O
Reactant: COc1ccccc1OC(=O)Cl
Product: COc1ccccc1OC(=O)OC(C)CC(C)O

Procedure:
The reaction of 2-methoxyphenol chloroformate with 2,4-pentanediol is conducted on a 0.01 mole scale employing the same conditions as described in Example III. A 1.5 g yield of the pure product is obtained as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=[O:17])[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:19]O>CCO>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[O:17][N:19]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: CCOC(=O)C(=O)CC(=O)c1cccc(F)c1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2cccc(F)c2)on1
Temperature: 80 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a solution of ethyl 4-(3-fluorophenyl)-2,4-dioxobutanoate (30.0 g, 126 mmol) in EtOH (300 mL) was added hydroxylamine hydrogen chloride (17 g, 252 mmol). The mixture was stirred at 80° C. for 1 h. The mixture was concentrated to 80 mL and diluted with H2O (100 mL). The precipitate was filtered and washed with H2O to give ethyl 5-(3-fluorophenyl)isoxazole-3-carboxylate (25.8 g, 87%). LRMS (M+H+) m/z 236.0.
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][CH:31]=[CH:30][C:4]=1[O:5][C:6]1[C:20]([O:21]C2C=CC(C#N)=CC=2)=[CH:19][C:9]2[NH:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:12][C:8]=2[CH:7]=1)#[N:2].O[C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[C:38]#[N:39]>>[C:1]([C:3]1[CH:33]=[CH:32][CH:31]=[CH:30][C:4]=1[O:5][C:6]1[C:20]([O:21][C:35]2[CH:42]=[CH:41][CH:40]=[C:37]([C:38]#[N:39])[CH:36]=2)=[CH:19][C:9]2[NH:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:12][C:8]=2[CH:7]=1)#[N:2]
Reactant: N#Cc1cccc(O)c1
Reactant: N#Cc1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2ccccc2C#N)cc1
Product: N#Cc1cccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2ccccc2C#N)c1

Procedure:
The entitled compound was obtained as a brown solid in the same method as in Example 28 or in accordance with the method or by combining it with an ordinary method but using 4-fluoro-5-(2-cyano-phenoxy)-2-nitro-phenylamine obtained in Example 28 and 3-hydroxy-benzonitrile.