Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([CH3:16])=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CN=C1.[C:22]1(=[O:27])[CH2:26][CH2:25][CH:24]=[CH:23]1>CO.O>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[C:23]2[C:22](=[O:27])[CH2:26][CH2:25][CH:24]=2)=[CH:6][C:7]([CH3:16])=[C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:9]=1
Reactant: O=C1C=CCC1
Reactant: Cc1cc(C=O)c(Cl)nc1-c1ccccc1
Agent: c1c[nH]cn1
Solvent: CO
Solvent: O
Product: Cc1cc(C(O)C2=CCCC2=O)c(Cl)nc1-c1ccccc1
Yield: 93 %

Procedure:
The clear solution of 2-Chloro-5-methyl-6-phenylnicotinaldehyde (10 mmol, 2.31 g) and imidazole (10 mmol) in 50 ml. of MeOH was slowly charged with 50 ml. of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclopenten-1-one (10.2 mmol., 0.88 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl3 thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 93% yield (2.84 g).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][C:27]=1[CH3:38].[Cl:39][C:40]1[C:41]([C:50]([F:53])([F:52])[F:51])=[N:42][N:43]([CH2:46][C:47](O)=[O:48])[C:44]=1[CH3:45]>>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][N:35]([C:47](=[O:48])[CH2:46][N:43]3[C:44]([CH3:45])=[C:40]([Cl:39])[C:41]([C:50]([F:53])([F:52])[F:51])=[N:42]3)[CH2:34][CH2:33]2)=[CH:28][C:27]=1[CH3:38]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: Cc1cc(N2CCNCC2)ccc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1cc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)ccc1Br

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Bromo-3-methylphenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.38 (d, 1H), 7.01 (s, 1H), 6.78 (d, 1H), 5.38 (s, 2H), 3.60 (m, 4H), 3.26 (m, 2H), 3.16 (m, 2H), 2.28 (s, 3H), 2.19 (s, 3H) ppm; MS (ES) M+H expected=479.0, found=478.9.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.N1C=CC=CC=1>ClCCl>[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][S:2]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8]3)(=[O:4])=[O:3])=[CH:18][CH:17]=1
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Reactant: NCc1ccc(F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1Cc2cc(S(=O)(=O)NCc3ccc(F)cc3)ccc2N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
A suspension of 5-chlorosulfonyl-2-oxindole (5.0 g), 4-fluorobenzylamine (3.0 mL) and pyridine (3.5 mL) in dichloromethane (30 mL) was stirred at room temperature for 4 hours. The precipitate was filtered, washed with dichloromethane and dried to give 5.8 g (84%) of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid-4-fluoro-benzylamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][CH3:15])[N:11]([CH2:16][C:17]([O:19]CC2C=CC=CC=2)=[O:18])[CH2:10][C@H:9]1[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][CH3:15])[N:11]([CH2:16][C:17]([OH:19])=[O:18])[CH2:10][C@H:9]1[CH3:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)O
Reaction time: 8 h
Yield: 78.1 %

Procedure:
Pd/C (10%, 810 mg) was added to a solution of (2R,5S)-4-benzyloxycarbonylmethyl-5-ethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (2.8 g, 7.6 mmol) in MeOH (50 mL). The suspension was stirred overnight under H2. and catalyst was removed via filtration through Celite and the filtrate was evaporated in vacuo to give the title compound (1.7 g) as a pale yellow solid. 1H NMR (DMSO-d6): 4.41-3.89 (1H, m), 3.89-3.64 (1H, m), 3.37-3.21 (1H, m), 3.21-3.05 (2H, m), 2.71-2.55 (2H, m), 2.54-2.42 (3H, m), 1.45-1.36 (9H, m), 1.16 (3H, d), 0.83 (3H, t). MS: [M+H]+=287.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:26][CH3:27])[C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH2:14][C@H:13]1[C:23]([OH:25])=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:29][C:30]([F:34])([F:33])[CH2:31][NH2:32].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl.C(OCC)(=O)C>[F:29][C:30]([F:34])([F:33])[CH2:31][NH:32][C:23]([CH:13]1[CH2:14][C:15]2[C:20](=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[N:12]1[C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:26][CH3:27])=[O:25]
Reactant: NCC(F)(F)F
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(OC)cc2C[C@H]1C(=O)O
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(OC)cc2CC1C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-(N-t-Butoxycarbonyl-2(S)-aminobutyryl)-5-methoxy-indoline-2(S)-carboxylic acid (0.38 g, 1 mmol) and 2,2,2-trifluoroethylamine hydrochloride (0.271 g, 2.0 mmol) were dissolved in dried dichloromethane (20 ml) under nitrogen at 0° C., and triethylamine (0.7 ml, 5 mmol) was added followed by bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.509 g, 2 mmol). The temperature was allowed to rise to room temperature and the mixture was stirred at room temperature for 24 hours, then filtered. The filtrate was concentrated under vacuum to give a brown solid which was columned on silica gel using 7:3 petroleum spirit:ethyl acetate as eluent to provide a white solid as the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([CH2:25]O)[NH:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:24])[CH2:15][C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=2[CH3:23])[CH2:10][CH2:9]1)=[O:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)C(C)C)(C)C.C(Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(#N)C.C(OCC)(=O)C.O.ClCCl>[CH3:23][C:17]1[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:16]=1[CH2:15][C:14]([N:11]1[CH2:10][CH2:9][CH:8]([C:6]2[O:7][CH2:25][CH:4]([C:3]([O:2][CH3:1])=[O:27])[N:5]=2)[CH2:13][CH2:12]1)=[O:24]
Reactant: COC(=O)C(CO)NC(=O)C1CCN(C(=O)Cc2cc(C)ccc2C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1COC(C2CCN(C(=O)Cc3cc(C)ccc3C)CC2)=N1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of N-[[1-[(2,5-dimethylphenyl)acetyl]-4-piperidinyl]carbonyl]-DL-serine methyl ester (i.e. the product of Example 9, Step C) (2.59 g, 6.88 mmol) in 25 mL of dry acetonitrile and 7 mL of dry dichloromethane was added triphenylphosphine (2.71 g, 10.32 mmol) and then N,N-diisopropylethylamine (1.6 g, 12.38 mmol). The reaction mixture was stirred until homogeneous, and carbon tetrachloride (1.59 g, 10.32 mmol) was added dropwise over 5 minutes. The reaction mixture was stirred for 2.5 h at room temperature, cooled to 0° C. and diluted with 50 mL of ethyl acetate followed by 15 mL of saturated aqueous sodium bicarbonate solution. The mixture was stirred for 10 minutes, poured into 40 mL of water, and the organic layer was separated, washed with brine, dried over MgSO4 and concentrated under reduced pressure to give 6 g of a yellow oil. The oil was purified by flash chromatography on silica gel using 50-100% of ethyl acetate in hexanes to give 900 mg of the title compound. 360 mg of starting amide was also recovered from the reaction mixture.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O.[CH3:59][O:60][C:61](=[O:85])[CH:62]=[CH:63][CH:64]([NH2:84])[CH2:65][C:66]1[C:74]2[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=2)[N:68]([CH2:75][CH:76]=[CH:77][C:78]2[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=2)[CH:67]=1>C1COCC1>[CH3:59][O:60][C:61](=[O:85])[CH:62]=[CH:63][C@H:64]([NH:84][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:65][C:66]1[C:74]2[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=2)[N:68]([CH2:75][CH:76]=[CH:77][C:78]2[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=2)[CH:67]=1
Reactant: COC(=O)C=CC(N)Cc1cn(CC=Cc2ccccc2)c2ccccc12
Reactant: O=C(O)CCCCCCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C=C[C@@H](Cc1cn(CC=Cc2ccccc2)c2ccccc12)NC(=O)CCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
A solution of 7-phenylheptanoic acid (87 mg, 0.422 mmol), BOP (205 mg, 0.464 mmol) and DIPEA (65.38 mg, 88 μL, 0.506 mmol) in THF (2.5 mL) was stirred for 10 min. To this was added a solution of the trifluoroacetic acid salt of 4-amino-5-[1-(3-phenyl-allyl)-1H-indol-3-yl]-pent-2-enoic acid methyl ester (200 mg, 0.422 mmol) and DIPEA (163 mg, 220 μL, 1.27 mmol) in THF (2.5 mL). The mixture was stirred overnight at room temperature. The solvent was removed and the crude material subject to column chromatography (50% EtOAc/petroleum ether, Rf 0.66) to afford the title compound (133 mg, 55%). 1H NMR (CDCl3) δ 7.58 (1H, d, J=8.1 Hz), 7.36-7.09 (12H, m), 7.02-6.95 (2H, m), 6.45 (1H, d, J=15.78 Hz), 6.29 (1H, dt, J=5.63, 15.78 Hz), 5.82 (1H, d, J=15.69 Hz), 5.52 (1H, d, J=8.25 Hz), 5.01-5.09 (1H, m), 4.82 (2H, d, J=5.49 Hz), 3.66 (3H, s), 3.12 (1H, dd, J=6.35, 14.69 Hz), 3.04 (1H, dd, J=6.17, 14.69 Hz), 2.55 (2H, t, J=7.69 Hz), 2.07 (2H, t, J=7.64 Hz), 1.59-1.46 (4H, m), 1.25-1.23 (4H, m). 13C NMR (CDCl3) δ 172.5, 166.6, 148.1, 142.7, 136.4, 136.1, 132.5, 128.6, 128.4, 128.2, 127.9, 126.5, 125.6, 124.6, 120.8, 122.0, 119.5, 118.8, 109.8, 109.2, 51.6, 50.2, 48.3, 36.7, 35.8, 31.2, 29.9, 29.0, 28.9, 25.4. ISMS: 549 (M+H).
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[S:13][C:12]=2[C:11]([CH:23]=O)=[CH:10][CH:9]=1)[CH3:2].C(O)=O.[OH-].[Na+].[CH3:32][NH:33]C=O>>[CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[S:13][C:12]=2[C:11]([CH2:23][NH:33][CH3:32])=[CH:10][CH:9]=1)[CH3:2]
Reactant: CNC=O
Reactant: CCN(CC)CCCNc1ccc(C=O)c2sc3ccccc3c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CCN(CC)CCCNc1ccc(CNC)c2sc3ccccc3c(=O)c12

Procedure:
A solution of 1-[[3-(diethylamino)propyl]amino]-9-oxothioxanthen-4-carboxaldehyde (3.3 g, 8.96 mmol) and 3 g of formic acid in 50 mL of N-methylformamide was allowed to reflux for 2 h. The mixture was basified with 5 mL of a 5N sodium hydroxide solution and extracted into chloroform (3×150ml). The organic layer was dried over sodium sulfate, concentrated in vacuo, and a crude oil was dissolved in a 3N aqueous HCl solution (50 ml) and heated on a steam bath for 3 h. The above mixture was cooled, basified with 30 mL of 35% NaOH, extracted into chloroform (3×150 ml), the organic layer dried over sodium sulfate and concentrated in vacuo to afford a brown oil. The brown oil was purified by flash chromatography (silica gel; 5% triethylamine/Et2O then 5% Et3N/EtOAc, then triethylamine/methanol/EtOAc (5:5:90)) to afford 1.1 g of 1-[[3-(diethylamino)-propyl]amino]-4-(methylaminomethyl)thioxanthen-9-one, as a clear orange gum. The above gum was converted into the corresponding dihydrochloride by treatment with 6N HCl in ether to afford 1.04 g of the dihydrochloride·3/2 hydrate as a yellow powder, m.p. 222°-224° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]#[CH:19])=[CH:10][C:9]=1[CH3:20])[CH3:6])[CH3:2].[Cl:23][C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:22])[C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]#[C:19][C:27]2[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=2)=[CH:10][C:9]=1[CH3:20])([CH3:21])[CH3:6])[CH3:2]
Reactant: C#CCCCOc1ccc(OC(C)(C)C(=O)OCC)c(C)c1
Reactant: Clc1ccc(I)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCCC#Cc2ccc(Cl)cc2)cc1C

Procedure:
In analogy to the procedure described in example 13B], 2-methyl-2-(2-methyl-4-pent-4-ynyloxy-phenoxy)-propionic acid ethyl ester (example 13A]) and 1-chloro-4-iodo-benzene gave the title compound as a yellow viscous oil.
Reaction SMILES: [N:1]#[C:2][NH2:3].[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]=[C:12]=[S:13]>>[C:2]([NH:3][C:12]([NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[F:4])=[S:13])#[N:1]
Reactant: N#CN
Reactant: Fc1ccccc1N=C=S
Product: N#CNC(=S)Nc1ccccc1F

Procedure:
Cyanamide and 2-fluorophenyl isothiocyanate were processed as described in Example 44A to provide the desired product which was used without further purification.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH2:37][C:38](Cl)=[O:39]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([C:38](=[O:39])[CH2:37][C:33]3[S:32][CH:36]=[CH:35][CH:34]=3)[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:30][CH:31]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)Cc1cccs1
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc(F)c(C(=O)OC)c3)cc2)cc1
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)Cc3cccs3)c3ccc(F)c(C(=O)OC)c3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure B using methyl 5-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2-fluorobenzoate and 2-thiophenacetyl chloride as a pink oil (92%). 1H NMR (CDCl3, 300 MHz) δ 7.61 (dd, J=6.2, 2.5 Hz, 1H), 7.44 (m, 4H), 7.17 (m, 5H), 7.07 (m, 1H), 6.97-6.88 (m, 2H), 6.70 (d, J=3.0 Hz, 1H), 4.90 (s, 2H), 3.94 (s, 31), 3.65 (s, 2H), 2.63 (t, J=7.5 Hz, 2H), 1.61 (m, 2H), 1.37 (m, 2H), 0.94 (t, J=7.4 Hz, 3H). M1(ESI): 540.1. HPLC, Rt: 5.72 min (Purity: 99.2%).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O>C1C=CC=CC=1>[O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][Cl:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccccc1Oc1ccccc1
Solvent: c1ccccc1
Product: ClCc1ccccc1Oc1ccccc1
Yield: 109.7 %

Procedure:
Into a three-necked 500 ml round-bottom flask are charged 25 g (0.125 mole) of o-phenoxy benzyl alcohol and 200 ml of benzene. To this solution is added 18 g (0.15 mole) of thionyl chloride dropwise with stirring. The reaction mixture is then heated to reflux for four hours. Solvent and excess thionyl chloride are removed under vacuum to give 30 g of product.
Reaction SMILES: [CH2:1]([N:8]1[CH:17]=[C:16](Br)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:19]3[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=3[CH3:29])[C:22]([O:24][CH3:25])=[O:23])[CH:14]=2)[C:9]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][N:32]([CH:39]1CCCCC1)[CH:33]1CCC[CH2:35][CH2:34]1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C(=O)C>[CH2:1]([N:8]1[CH:17]=[C:16]([CH2:35][CH2:34][CH2:33][N:32]([CH3:39])[CH3:31])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:19]3[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=3[CH3:29])[C:22]([O:24][CH3:25])=[O:23])[CH:14]=2)[C:9]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C1CCCCC1)C1CCCCC1
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(=O)n(Cc4ccccc4)cc(Br)c3c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(C)c(-c2ccc3c(=O)n(Cc4ccccc4)cc(CCCN(C)C)c3c2)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of the product from step i) (170 mg), tetrabutylammonium chloride (10 mg), Pd-118 (24 mg) and N-methyldicyclohexylamine (0.12 mL) in N,N-dimethylacetamide (3 mL) was evacuated and flushed with nitrogen (×3) before the addition of allyl alcohol (0.05 mL). The resultant solution was stirred under nitrogen at 70° C. for 2 hours. The reaction mixture was cooled to room temperature and dilute hydrochloric acid (1N, 2 mL) was added, followed by dichloromethane (10 mL). The resulting suspension was filtered and the filtrate was washed with water (2×5 mL). The organic phase was separated and treated with dimethylamine hydrochloride (0.181 g) followed by sodium triacetoxyborohydride (0.157 g). The mixture was then stirred at room temperature for 30 minutes. The reaction mixture was filtered and poured directly onto a silica column (10 g) (eluting with 3% methanol in dichloromethane) to afford the sub-titled compound (0.12 g).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:9]2[N:10]=[C:11](N)[S:12][C:8]=2[CH:7]=[CH:6][CH:5]=1.Cl.C([CH2:17][O:18][C:19]1[C:20]([F:29])=[C:21]([C:26]([NH2:28])=[O:27])[C:22]([F:25])=[CH:23][CH:24]=1)#N>O.COCCO.CCO>[Cl:3][C:4]1[C:9]2[N:10]=[C:11]([CH2:17][O:18][C:19]3[C:20]([F:29])=[C:21]([C:26]([NH2:28])=[O:27])[C:22]([F:25])=[CH:23][CH:24]=3)[S:12][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: N#CCOc1ccc(F)c(C(N)=O)c1F
Reactant: Nc1nc2c(Cl)cccc2s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: COCCO
Solvent: O
Product: NC(=O)c1c(F)ccc(OCc2nc3c(Cl)cccc3s2)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
(Method K) A solution of KOH (15.15 g, 270 mmol, 20 equiv.) in H2O (25 ml) was added to a solution of 4-chloro-1,3-benzothiazol-2-amine (2.5 g, 13.5 mmol, 1 equiv.) in 2-methoxy-ethanol (25 ml) and the reaction mixture was heated under reflux overnight. After cooling at r.t., the mixture was diluted with H2O (200 ml), acidified with 5N HCl solution to pH 4 and extracted with CH2Cl2 (3×150 ml). The combined organic extracts were washed with brine (100 ml), dried (Na2SO4) and concentrated under reduced pressure to dryness, to give 1.5 g (70% yield). From this crude residue, 167 mg (assuming 1.05 mmol), were mixed with 3-(cyanomethoxy)-2,6-difluorobenzenecarboxamide (150 mg, 0.7 mmol) and the mixture was stirred at 120° C., in a pre-heated oil bath, under N2, for 2 h. EtOH (2 ml) was added and the reaction mixture was heated for a further 2 h. After cooling at r.t., the solid was filtered, washed with EtOH and re-crystallised from EtOAc/pentane, to give the desired product as a pale yellow solid, 62 mg (25% yield on second step). HPLC-MS (method 1): m/z 355 [M+H]+, Rt=3.75 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:4]=1[CH2:5][N:18]1[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]1
Reactant: COc1cc([N+](=O)[O-])ccc1C=O
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COc1cc([N+](=O)[O-])ccc1CN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round bottom flask or vial containing 2-methoxy-4-nitro-benzaldehyde (1.0 g, 5.5 mmol), add dichloroethane (40 mL), 1-methylpiperazine (1.0 ml, 8.3 mmol), and sodium triacetoxyborohydride (3.5 g, 16.5 mmol). Stir at room temperature overnight. Quench with saturated aqueous NaHCO3 and extract with CH2Cl2 (1×) and EtOAc (2×). Combine the organic portions, dry over MgSO4, filter, and concentrate under vacuum. Purify the residue by flash chromatography on silica gel using a gradient of MeOH (0.005% NH4OH)/CH2Cl2 (5% to 10%) to give the title compound. MS (ES+) 266.0 (M+1)+. 1H NMR (CDCl3): δ 7.80 (dd, J=8 Hz, 2 Hz, 1H), 7.66 (d, J=2 Hz, 1H), 7.56 (J=8 Hz, 1H), 3.89 (s, 3H), 3.58 (s, 2H), 2.52 (br. 4H), 2.45 (br, 2H), 2.28 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:42])/[CH:21]=[CH:22]/[C:23]2[C:31]3[C:26](=[CH:27][C:28]([CH:32]=O)=[CH:29][CH:30]=3)[N:25](COCC[Si](C)(C)C)[N:24]=2)[CH2:16][CH2:15]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[CH:32][C:28]1[CH:27]=[C:26]2[C:31]([C:23](/[CH:22]=[CH:21]/[C:20]([N:17]3[CH2:16][CH2:15][N:14]([CH3:13])[CH2:19][CH2:18]3)=[O:42])=[N:24][NH:25]2)=[CH:30][CH:29]=1
Reactant: COc1ccc2c(c1)CC(=O)N2
Reactant: CN1CCN(C(=O)/C=C/c2nn(COCC[Si](C)(C)C)c3cc(C=O)ccc23)CC1
Product: COc1ccc2c(c1)C(=Cc1ccc3c(/C=C/C(=O)N4CCN(C)CC4)n[nH]c3c1)C(=O)N2
Yield: 9.7 %

Procedure:
The synthetic method followed that described in Example A66 starting from 5-methoxyoxindole (10 mg, 0.0583 mmol) and (E)-3-(3-(4-methylpiperazin-1-yl)-3-oxoprop-1-enyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (25 mg, 0.0.0583 mmol) to give 2.5 mg of the title compound as an 85:15 mixture of (E)/(Z) isomers. 1H NMR (400 MHz, CD3OD) 8.95, 7.80 (s, 1H), 8.21-8.16 (m, 1H), 7.97-7.87 (m, 2H), 7.59 (d, J=7.52 Hz, 1H), 7.45 (d, J=15.7 Hz, 1H), 7.32, 7.22 (s, 1H), 6.85 (s, 2H), 3.84, 3.63 (s, 3H), 3.90-3.75 (m, 4H), 2.62-2.48 (br. s, 4H), 2.34 (s, 3H); MS ESI 444.2 [M+H]+, calcd for [C25H25N5O3+H]+ 444.20.
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3](O)=[O:4].[CH:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1.C1(C)C(C)=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[NH:14]([C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:3](=[O:4])[C:2]([OH:1])([CH3:7])[CH3:6])=[CH:19][CH:20]=1)[C:11]1[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=1
Reactant: Nc1ccc(Nc2ccccc2)cc1
Reactant: CC(C)(O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(C)(O)C(=O)Nc1ccc(Nc2ccccc2)cc1
Yield: 772.4 %

Procedure:
A 500 milliliter resin pot was charged with 52 grams (0.05 moles) of α-hydroxy isobutyric acid from Example 1, 77.3 grams (0.42 moles) p-aminodiphenylamine, 1 gram p-toluene sulfonic acid and 140 mls. of xylene under a nitrogen blanket. A Dean-Stark water separator and a condenser was attached to the resin pot and the mixture was heated to vigorous reflux with H2O being removed as it was formed. After 3 hours of reflux the heat was removed and the product was allowed to crystallize in the resin pot under nitrogen. The product was broken up, washed with toluene, filtered and dried to obtain 104.4 grams (92% yield) of N-(4-anilinophenyl)-2-hydroxyisobutyramide with a melting point of 171°-174° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][CH:17]([NH:21]C(=O)OC(C)(C)C)[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][CH:17]([NH2:21])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:29][CH:30]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CC(NC(=O)OC(C)(C)C)CC4)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cn2ncc3c4c(cnc32)CC(N)CC4)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.4 %

Procedure:
To a solution of tert-butyl 3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolin-7-ylcarbamate (3.0 g, 8.8 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (10 mL). The reaction was stirred at room temperature for 3 hours. The solvent was then removed under reduced pressure to give an oily residue that was triturated in diethyl ether to give a solid. The solid was filtered, washed with diethyl ether and dried under reduced pressure to give the desired product 3-(4-methoxy-benzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolin-7-ylamine (TFA salt) as a brown solid (2.1 g, 92%). 1H NMR (400 MHz, DMSO-d6) δ 8.08 (bs, 2H), 8.07 (s, 1H), 8.02 (s, 1H), 7.161 (d, 2H, J=8.4 Hz), 6.84 (d, 2H, J=8.8 Hz), 5.53 (s, 2H), 3.69 (s, 3H), 3.67-3.52 (m, 1H) 3.23 (dd, J=4.4, 16 Hz, 1H), 3.16-3.04 (m, 2H), 2.930 (dd, J=9.6, 15.6 Hz, 1H), 2.19-2.29 (m, 1H), 1.85-1.98 (m, 1H). LCMS [M+H]: 309.