Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].F[C:10]1[CH:15]=[CH:14][C:13]([S+:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1.[OH-].[Na+].[CH2:31]([SH:35])[CH2:32][CH2:33][CH3:34]>ClCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[CH2:31]([S:35][C:10]1[CH:15]=[CH:14][C:13]([S+:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCCS
Reactant: Fc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Br-]
Solvent: ClCCl
Product: CCCCSc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
26.7 g of 4-fluorophenyl diphenylsulfonium trifluoromethanesulfonate was dissolved in 200 g of dichloromethane in a reaction flask, in which the atmosphere was replaced with nitrogen. 200 g of 10 wt % sodium hydroxide aqueous solution, 5.8 g of tetra-n-butylammonium bromide, and 6.71 g of n-butanethiol were added. The mixture was stirred for 30 minutes at room temperature and transferred to a separatory funnel, shaken, and allowed to stand still. The water layer was removed. After the addition of 300 ml of distilled water, the mixture was shaken and allowed to stand still. The water layer was removed. The resulting dichloromethane solution was dried with anhydrous magnesium sulfate, filtered, and dried using an evaporator. After evaporating dichloromethane from the dried solution, the residual liquid was dried under reduced pressure to obtain 17.8 g of 4-n-butylthiophenyl diphenylsulfonium trifluoromethanesulfonate.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]2[C:7]=1[C:8](=[O:33])[N:9]([C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=1)[CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:10]2)=[O:4].[CH3:34][NH:35][CH3:36].Cl>CC#N.CCOCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:35]([CH3:36])[CH3:34])=[C:7]2[C:11]=1[CH2:10][N:9]([C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=1)[CH2:17][S:18]([CH3:21])(=[O:19])=[O:20])[C:8]2=[O:33]
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3c(Cl)ccc(NC(=O)CCl)c3C2=O)ccc1OC
Reactant: CNC
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3c(Cl)ccc(NC(=O)CN(C)C)c3C2=O)ccc1OC
Temperature: 70 °C

Procedure:
To a solution of (1S)-2-chloro-N-{7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide (400 mg, 0.78 mmol) in CH3CN (10 ml) was added dimethylamine (2N in MeOH, 1.6 ml, 3.2 mmol). The mixture was heated at 70° C. for 2 hrs. The reaction mixture was concentrated on rota-vap and extracted with water (50 ml) and EtOAc (50 ml). The organic layer was washed with water (50 ml), brine (25 ml), dried over Na2SO4 and concentrated. The resulted oil was purified by chromatography to give an oil which was stirred with HCl in ether (3 ml) to give (1S)-N-{7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-2-dimethylamino-acetamide; hydrochloride as a white solid (300 mg, 68% yield): mp, 198–200° C.; 1H NMR (DMSO-d6) δ 1.32 (t, J=7.5 Hz, 3H, OCH2CH3), 2.87 (s, 6H, N(CH3)2), 3.04 (s, 3H, CH3), 3.74 (s, 3H, CH3), 3.94–4.16 (m, 4H, OCH2CH3+NCHH+CHHSO2), 4.36–4.50 (m, 3H, CHHSO2+CH2NCO), 4.73 (d, J=18 Hz, 1H, CHHN), 5.85–5.91 (m, 1H, NCH), 6.98 (s, 2H, Ar), 7.05 (s, 1H, Ar), 7.69 (d, J=8 Hz, 1H, Ar), 8.18 (d, J=8 Hz, 1H, Ar), 10.21 (bs, 1H, HCl); 10.45 (s, 1H, NHCO); 13C NMR (DMSO-d6) δ 15.17, 23.25, 41.51, 43.86, 46.03, 49.41, 53.88, 56.00, 58.52, 64.41, 112.50, 112.80, 120.23, 121.25, 123.33, 130.22, 133.21, 134.72, 140.60, 148.55, 149.46, 154.53, 167.02, 180.13. Anal Calcd for C24H31Cl2N3O6S+0.41 H2O: C, 50.78; H, 5.65; N, 7.40. Found: C, 50.81; H, 5.55; N, 7.18; H2O, 1.30.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:23]=[CH:22][C:16]([C:17]([O:19]CC)=[O:18])=[CH:15][CH:14]=3)[CH:9]=2)=[CH:6][N:5]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[N:3]=1.[OH-].[K+]>CO>[OH:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:22][CH:23]=3)[CH:9]=2)=[CH:6][N:5]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[N:3]=1
Reactant: CCOC(=O)c1ccc(-c2cc(-c3cnc(-c4ccccn4)nc3O)on2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(-c2cc(-c3cnc(-c4ccccn4)nc3O)on2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 39.5 %

Procedure:
To a mixture of compound 37-m (300 mg, crude) in MeOH (10 mL) was added a solution of 20% KOH (10 mL). The mixture was stirred at 50° C. for 2 h. The reaction mixture was filtered. The filtrate was concentrated and the aqueous solution was extracted with DCM, and acidified by concentrated HCl to adjust to about pH 2-3. The solid was filtered and washed with water to afford compound 37-1 (110 mg, 73% for two steps) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.827-8.821 (s, 1H), 8.722 (s, 1H), 8.456-8.431 (m, 1H), 8.103-8.035 (m, 2H), 7.733-7.694 (m, 1H), 7.630 (s, 1H), LC-MS (ESI): 361 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[CH2:5].[Mg].II.[O:9]=[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1>O1CCCC1.[Cl-].[NH4+]>[C:19]([O:18][C:16]([N:13]1[CH2:12][CH2:11][C:10]([CH2:5][CH2:4][CH:3]=[CH2:2])([OH:9])[CH2:15][CH2:14]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: C=CCCBr
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.5 %

Procedure:
To a mixture of 4-bromobut-1-ene (10.9 g, 0.08 mol) and magnesium turnings (4.8 g, 0.2 mol) in dry tetrahydrofuran (80 mL) was added a crystal of iodine and the mixture was stirred at room temperature until complete reaction had occurred. To this mixture was added tert-butyl 4-oxopiperidine-1-carboxylate (7.7 g, 0.039 mol) in tetrahydrofuran (20 mL) at 0° C. After 1 h at 0° C., and 3 h at room temperature the reaction mixture was diluted with ammonium chloride solution and extracted with ethyl acetate. After drying over Na2SO4, the solvent was removed in vacuo and the residue was purified via flash chromatography with 25% ethyl acetate/hexane to afford the title compound 16B (3.63 g) as an oil. 1H NMR (CHLOROFORM-d) δ 5.84 (d, J=6.7 Hz, 1H), 4.89-5.11 (m, 2H), 3.16 (br. s., 2H), 2.16 (d, J=9.4 Hz, 2H), 1.48-1.66 (m, 6H), 1.45 (s, 9H).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].Cl[C:8]1[N:9]=[N+:10]([O-:22])[C:11]2[C:21]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[CH:15]=[CH:14][C:12]=2[N:13]=1>COCCOC>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:8]1[N:9]=[N+:10]([O-:22])[C:11]2[C:21]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: CN(C)CCN
Reactant: [O-][n+]1nc(Cl)nc2ccc3c(c21)CCCC3
Solvent: COCCOC
Product: CN(C)CCNc1nc2ccc3c(c2[n+]([O-])n1)CCCC3
Yield: 73.1 %

Procedure:
N,N-Dimethyl-1,2-ethanediamine (0.12 mL, 1.0 mmol) was added to a stirred solution of chloride 171 (83 mg, 0.4 mmol) in DME (20 mL) and the solution stirred at reflux temperature for 3 h. The solvent was evaporated and the residue partitioned between DCM (50 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 172 (84 mg, 84%) as a yellow solid: mp (MeOH) 151-153° C.; 1H NMR δ 7.31-7.36 (m, 2H, H-5, H-6), 5.75 (br s, 1H, NH), 3.51-3.55 (m, 2H, CH2N), 3.45-3.49 (m, 2H, CH2), 2.72-2.83 (m, 2H, CH2), 2.57 (br dd, J=6.0, 5.8 Hz, 2H, CH2N), 2.29 [s, 6H, N(CH3)2], 1.75-1.82 (m, 4H, 2×CH2); 13C NMR δ 158.4, 149.8, 137.4, 134.7, 132.4, 129.1, 123.5, 57.7, 45.0 (2), 38.6, 30.7, 29.3, 23.1, 21.6. Anal. calcd for C15H21N5O.½CH3OH: C, 61.4; H, 7.6; N, 23.1. Found: C, 61.2; H, 7.4; N, 23.4%.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](OC(=O)C)(=O)[CH3:14]>>[CH3:12][O:11][C:10]1[C:2]2[N:1]=[C:13]([CH3:14])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(C(=O)O)c1N
Reactant: CC(=O)OC(C)=O
Product: COc1cccc2c(=O)oc(C)nc12
Temperature: 140 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
To a 100 mL round-bottomed flask, 2-amino-3-methoxybenzoic acid (10.1 g, 60.4 mmol) and acetic anhydride (50 ml, 530 mmol) were added to give a suspension. The mixture was heated to 140° C. with stirring for 180 min. The reaction mixture was cooled to room temperature and concentrated to provide 8-methoxy-2-methyl-4H-benzo[d][1,3]oxazin-4-one (11.51 g, 100%): 1H NMR (400 MHz, DMSO-d6) δ 7.59 (dd, J=6.9, 2.3 Hz, 1H), 7.52-7.42 (m, 2H), 3.89 (s, 3H), 2.39 (s, 3H); HPLC: RT=0.795 min (H2O/MeOH with TFA, Sunfire C18 2.5 μm, 2.1×30 mm, gradient=2 min, wavelength=220 nm); MS(ES): m/z=292 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15][C:16]3[C:24]4[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=4)[NH:18][C:17]=3[CH3:26])[CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:28]1[CH:29]=[N:30][N:31]([CH2:33][CH3:34])[CH:32]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15][C:16]3[C:24]4[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=4)[N:18]([C:28]4[CH:29]=[N:30][N:31]([CH2:33][CH3:34])[CH:32]=4)[C:17]=3[CH3:26])[CH:10]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2cccc(Sc3c(C)[nH]c4cc(Cl)ccc34)c2)CC1
Reactant: CCn1cc(Br)cn1
Product: CCOC(=O)C1(c2cccc(Sc3c(C)n(-c4cnn(CC)c4)c4cc(Cl)ccc34)c2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: 1-[3-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-cyclopropanecarboxylic acid ethyl ester and 4-bromo-1-ethylpyrazole.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].Cl[CH2:37][CH2:38][N:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[N:13]([CH2:37][CH2:38][N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7]
Reactant: Cc1ccccc1N1C(=O)NC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Reactant: ClCCN1CCCC1
Product: Cc1ccccc1N1C(=O)N(CCN2CCCC2)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=597.1 (M+H+), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione and 1-(2-chloroethyl)-pyrrolidine.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][C:7]1([C:12]2([CH:15]=O)[CH2:14][CH2:13]2)[O:11][CH2:10][CH2:9][O:8]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)C>[CH:15]([C:12]1([C:7]2([CH3:6])[O:8][CH2:9][CH2:10][O:11]2)[CH2:13][CH2:14]1)=[CH2:1]
Reactant: CC1(C2(C=O)CC2)OCCO1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Product: C=CC1(C2(C)OCCO2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
44.6 g of methyltriphenylphosphonium bromide in 700 ml of diethyl ether is introduced, and 50 ml of n-butyllithium solution (2.5 M in hexane) is added in drops at 0° C. under nitrogen. It is stirred for 1 more hour at room temperature and then 9.5 g of 7 in 10 ml of diethyl ether is added. After 1 hour, the reaction solution is quenched with sodium chloride solution, extracted with ethyl acetate, washed with sodium chloride solution, dried on sodium sulfate, and the solvent is removed. The residue is chromatographed on silica gel with ethyl acetate/hexane, whereby 5.4 g of title compound 8 is obtained as a colorless oil.
Reaction SMILES: [CH2:1]([C:7]1[S:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:15]([O:21][C:22]1[CH:28]=[CH:27][C:25](O)=[C:24]([C:29]#[N:30])[C:23]=1[C:31]#[N:32])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CC=CN=2)CCCC1>C1COCC1>[CH2:1]([C:7]1[S:11][C:10]([C:12]([O:14][C:25]2[CH:27]=[CH:28][C:22]([O:21][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:23]([C:31]#[N:32])[C:24]=2[C:29]#[N:30])=[O:13])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(C(=O)O)s1
Reactant: CCCCCCOc1ccc(O)c(C#N)c1C#N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1ccc(N2CCCC2)nc1
Solvent: C1CCOC1
Product: CCCCCCOc1ccc(OC(=O)c2ccc(CCCCCC)s2)c(C#N)c1C#N
Yield: 53.2 %

Procedure:
0.50 g (2.36 mM) of 5-hexylthiophene-2-carboxylic acid (M.W.: 212), 0.58 g (2.36 mM) of 2,3-dicyanohydroquinone monohexyl ether (M.W.: 244) and 20 ml of THF were mixed and stirred. To the mixture, 0.49 g (2.36 mM) of dicyclohexylcarbodiimide (M.W.: 206) and 0.05 g of pyrrolidinopyridine were added, followed by stirring overnight at room temperature. After the reaction, the reaction mixture was subjected to filtration and the filtrate was subjected to distillation to obtain a crude product. The crude product was purified by silica gel column chromatography with the use of benzene and recrystallized from ethanol to obtain 0.55 g of an objective product (yield: 53.4%).
Reaction SMILES: O[CH:2]([NH:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[C:3]([F:6])([F:5])[F:4].P(Cl)(Cl)[Cl:18]>P(Cl)(Cl)(Cl)=O.CCCCCCC>[Cl:18][CH:2]([NH:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: ClP(Cl)Cl
Reactant: O=C(NC(O)C(F)(F)F)c1ccc(Cl)cc1
Solvent: CCCCCCC
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(NC(Cl)C(F)(F)F)c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
A mixture of N-(1-hydroxy-2,2,2-trifluoroethyl)-4-chlorobenzamide (2.53 g, 0.01 mol) in phosphorus oxychloride (2 mL) is treated with phosphorus trichloride (1.57 g, 0.012 mol), heated to and held at 80° C. for 30 minutes, and concentrated in vacuo to obtain a residue. The residue is dissolved in hot heptane, decanted from the waxy phosphorus products, and crystallized to give the title product as a white crystalline solid (2.43 g, 89.3% yield): mp 119.0-121.0° C.; IR (Nujol) 3266, 1668 cm−1; 1H NMR (CDCl3) δ7.76 and 7.46 (AB with fine splitting, ArH), 6.86 (d, J=8.5 Hz, NH, moves to 10.24 in DMSO-d6), 6.55(m, CH); 19F NMR δ−77.7(d, J=5 Hz).
Reaction SMILES: [F:1][C:2]([F:22])([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=1)[CH2:3][NH:4][CH2:5][C:6]([N:8]([CH3:10])[CH3:9])=[O:7].C=O.[C:25](O)(=O)C>C1COCC1>[F:1][C:2]([F:22])([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=1)[CH2:3][N:4]([CH3:25])[CH2:5][C:6]([N:8]([CH3:10])[CH3:9])=[O:7]
Reactant: CC(=O)O
Reactant: CCCCOc1cccc(C(F)(F)CNCC(=O)N(C)C)c1
Agent: C=O
Solvent: C1CCOC1
Product: CCCCOc1cccc(C(F)(F)CN(C)CC(=O)N(C)C)c1
Reaction time: 1 h
Yield: 65 %

Procedure:
107.5 mg (0.34 mmol) of the free base of 2-[2,2-difluoro-2-(3-butoxyphenyl)-ethylamino]-N,N-dimethyl-acetamide (see Example 1-1) are dissolved in dry THF (10 mL). To this solution, formaldehyde (36.5% water solution, 52.1 μL; 0.69 mmol), acetic acid (2.5 mL), and MP-CNBH3 (2.3 mmol/g; 325 mg; 0.75 mmol) are added sequentially. After stirring 1 hour the reaction is completed. After further stirring for 1.5 hours, the reaction mixture is evaporated. The crude residue is flash-chromatographed on silica gel using DCM/MeOH (99.5/0.5) as an eluant. 73.1 mg (65%) of pale yellow fluid 2-{[2,2-difluoro-2-(3-butoxyphenyl)-ethyl]-methylamino}-N,N-dimethyl-acetamide are obtained.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH2:9][CH2:10][NH:11][C:5]2=[N:4][CH:3]=1.Cl.[CH2:23]([N:25]([CH2:40][CH3:41])[CH2:26][CH2:27][NH:28][C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)=[O:30])[CH3:24]>>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[CH2:12][N:8]1[CH2:9][CH2:10][NH:11][C:5]2[N:4]=[CH:3][C:2]([C:34]3[CH:35]=[CH:36][C:31]([C:29]([NH:28][CH2:27][CH2:26][N:25]([CH2:40][CH3:41])[CH2:23][CH3:24])=[O:30])=[CH:32][CH:33]=3)=[N:7][C:6]1=2
Reactant: CCN(CC)CCNC(=O)c1ccc(B(O)O)cc1
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(Br)nc32)c1Cl
Agent: Cl
Product: CCN(CC)CCNC(=O)c1ccc(-c2cnc3c(n2)N(Cc2c(F)ccc(F)c2Cl)CCN3)cc1

Procedure:
The entitled compound was prepared from 7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazine and 4-{[2-(Diethylamino)ethyl]carbamoyl}benzeneboronic acid hydrochloride using Suzuki coupling conditions as described in Scheme 1.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]([O:15]C)=O.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1>C(O)C.O>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:23][C:13]([C:3]2[C:4](=[O:12])[NH:5][C:6]3[C:11]([C:2]=2[OH:1])=[N:10][CH:9]=[CH:8][CH:7]=3)=[O:15])=[CH:20][CH:19]=1
Reactant: COC(=O)c1c(O)c2ncccc2[nH]c1=O
Reactant: NCc1ccc(F)cc1
Solvent: O
Solvent: CCO
Product: O=C(NCc1ccc(F)cc1)c1c(O)c2ncccc2[nH]c1=O
Temperature: 100 °C

Procedure:
A mixture of methyl 4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.2 g, 0.91 mmol) and 4-fluorobenzyl amine (Aldrich, 0.31 mL, 2.72 mmol) in absolute ethanol (5 mL) was heated to 100° C. for 6 hours. A thick paste formed. The reaction was diluted with water and the solids collected. The crude material was purified by preparative reverse phase HPLC eluting with a gradient of 5-95% acetonitrile/water (0.1% TFA). The product precipitated from the column fractions was collected to afford the desired product as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:39])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:37][CH3:38])=[C:12]([NH:15][C:16]3[NH:21][C:20]4=[N:22][CH:23]=[CH:24][C:19]4=[C:18]([NH:25][C:26]4[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[C:27]=4[C:28]([NH2:30])=[O:29])[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].Cl[C:41]1N=C(NC2C=C(F)C=C(F)C=2C(N)=O)C2C=CN(S(C3C=CC(C)=CC=3)(=O)=O)C=2N=1.CN.CN(CC(N1C2C(=CC(OC)=C(N)C=2)CC1)=O)C>O1CCCC1>[CH3:1][N:2]([CH3:39])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:37][CH3:38])=[C:12]([NH:15][C:16]3[NH:21][C:20]4=[N:22][CH:23]=[CH:24][C:19]4=[C:18]([NH:25][C:26]4[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[C:27]=4[C:28]([NH:30][CH3:41])=[O:29])[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: COc1cc2c(cc1Nc1nc(Nc3cc(F)cc(F)c3C(N)=O)c3ccnc-3[nH]1)N(C(=O)CN(C)C)CC2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cc(F)cc(F)c4C(N)=O)nc(Cl)nc32)cc1
Agent: CN
Agent: COc1cc2c(cc1N)N(C(=O)CN(C)C)CC2
Solvent: C1CCOC1
Product: CNC(=O)c1c(F)cc(F)cc1Nc1nc(Nc2cc3c(cc2OC)CCN3C(=O)CN(C)C)[nH]c2nccc1-2
Yield: 12 %

Procedure:
In a manner analogous to General Protocol III, 2-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-4,6-difluorobenzamide was prepared from 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-4,6-difluorobenzamide (0.3 g, 0.63 mmol), 2.0M methyl amine in tetrahydrofuran, and 1-[(dimethylamino)acetyl]-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine (0.19 g, 0.75 mmol) to afford the title compound (0.043 g, 12% over 3 steps) as an off-white solid. ESIMS (M+H)+=551. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.19 (s, 6 H) 2.79 (d, J=4.58 Hz, 3 H) 3.08 (t, J=8.24 Hz, 2 H) 3.10 (s, 2 H) 3.72 (s, 3 H) 4.11 (t, J=8.24 Hz, 2 H) 6.20-6.22 (m, 1 H) 6.78-6.87 (m, 1 H) 6.90-6.96 (m, 2 H) 7.74 (s, 1 H) 8.46 (s, 2 H) 8.51-8.55 (m, 1 H) 10.75 (s,1 H), 11.28 (bs, 1 H).
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8]C)=[O:7])=O.C[O-].[Na+].Cl>CN(C)C=O.CO>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([C:14]2[O:13][C:4]3[C:5]([C:6]([OH:8])=[O:7])=[CH:10][CH:11]=[CH:12][C:3]=3[CH:1]=2)=[CH:16][CH:17]=1)([O-:23])=[O:22]
Reactant: COC(=O)c1cccc(C=O)c1OCc1ccc([N+](=O)[O-])cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(O)c1cccc2cc(-c3ccc([N+](=O)[O-])cc3)oc12
Reaction time: 0.17 h
Yield: 59.8 %

Procedure:
16.1 g of methyl 3-formyl-2-(4-nitrobenzyloxy)benzoate are dissolved in 100 ml of dimethylformamide and a solution of 5.4 g of sodium methoxide in 20 ml of methanol is added dropwise to the solution at 120° C. The mixture is stirred at the same temperature for 10 minutes. The reaction mixture is acidified with 10% hydrochloric acid and then extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. The resultant crystals are collected, washed and dried to give 8.65 g of 2-(4-nitrophenyl)benzofuran-7-carboxylic acid as pale orange powder.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([CH3:16])=[N:9][C:10]3[N:11]([N:12]=[C:13]([CH3:15])[CH:14]=3)[C:6]=2[N:5]=[CH:4][C:3]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:15][C:13]1[CH:14]=[C:10]2[N:9]=[C:8]([CH3:16])[C:7]3[C:2]([N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)=[C:3]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:4]=[N:5][C:6]=3[N:11]2[N:12]=1
Reactant: CCOC(=O)c1cnc2c(c(C)nc3cc(C)nn32)c1Cl
Reactant: CN1CCNCC1
Product: CCOC(=O)c1cnc2c(c(C)nc3cc(C)nn32)c1N1CCN(C)CC1

Procedure:
3.04 g. of 6-chloro-2,5-dimethylpyrazolo[1,5-a]-pyrido[3,2-e]pyrimidine-7-carboxylic acid, ethyl ester (0.01 mol.) and 10 ml. of N-methylpiperazine are heated at reflux temperature for 5 minutes. The excess N-methyl piperazine is removed in vacuo and the residue is treated with water. The product, 2,5-dimethyl-6-(4-methyl-1-piperazinyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylic acid, ethyl ester, crystallizes and is filtered off, yield 3.1 g. (85%), m.p. 158°-159°.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:17]([CH3:19])[CH3:18]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH:17]([CH3:19])[CH3:18])[C:3]=1[F:9]
Reactant: CC(C)Br
Reactant: Oc1cccc(Br)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)Oc1cccc(Br)c1F
Temperature: 80 °C
Reaction time: 4 h
Yield: 72.9 %

Procedure:
To a mixture of 3-bromo-2-fluoro-phenol (2 g, 10 mmol) and cesium carbonate (10 g, 40 mmol) in acetonitrile (20 mL) was added 2-bromopropane (4 mL, 50 mmol). The reaction mixture was stirred at 80° C. for 4 h. The mixture was filtered through a plug of Celite and eluted with ethyl acetate. The resulting solution was evaporated. The residue was purified by flash chromatography on silica gel and eluting with hexanes:EtOAc (1:1) to afford the title product (1.7 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([OH:13])[CH:7]=[C:8]([O:10][CH2:11][CH3:12])[CH:9]=1)[CH3:2].Br[CH:15]([C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=1)[C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:19][O:18][C:16](=[O:17])[CH:15]([C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=1)[O:13][C:6]1[CH:7]=[C:8]([O:10][CH2:11][CH3:12])[CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1
Reactant: COC(=O)C(Br)c1ccc(Br)cc1
Reactant: CCOc1cc(O)cc(OCC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOc1cc(OCC)cc(OC(C(=O)OC)c2ccc(Br)cc2)c1

Procedure:
20.0 g (110 mmol) of 3,5-diethoxyphenol and 30.7 g (99.8 mmol) of methyl bromo(4-bromophenyl)acetate are dissolved in 39 ml of 2-butanone under argon at RT, and 31.0 g (225 mmol) of potassium carbonate are added. The reaction mixture is heated under RF for 4 h. After cooling, the precipitate is filtered off with suction and washed with 2-butanone, and the filtrate is concentrated. Chromatography on silica gel 60 (mobile phase: toluene) results in 33.1 g (81% of theory) of the product.