Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2=[N:6][N:7]([CH2:9][C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[N:12](C(OC(C)(C)C)=O)[N:11]=3)[N:8]=[C:4]2[C:3]=1[O:28][C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[C:31]([C:36]#[N:37])[C:30]=1[Cl:38]>C(O)(C(F)(F)F)=O>[Cl:38][C:30]1[C:29]([O:28][C:3]2[C:4]3[C:5](=[N:6][N:7]([CH2:9][C:10]4[C:18]5[C:13](=[N:14][CH:15]=[CH:16][CH:17]=5)[NH:12][N:11]=4)[N:8]=3)[CH:26]=[CH:27][C:2]=2[Cl:1])=[CH:34][C:33]([Cl:35])=[CH:32][C:31]=1[C:36]#[N:37]
Reactant: CC(C)(C)OC(=O)n1nc(Cn2nc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4Cl)c3n2)c2cccnc21
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3nn(Cc4n[nH]c5ncccc45)nc23)c1Cl
Reaction time: 0.33 h

Procedure:
tert-butyl 3-{[5-chloro-4-(2,5-dichloro-3-cyanophenoxy)-2H-1,2,3-benzotriazol-2-yl]methyl}-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (100 mg, 0.175 mmol) was dissolved in TFA (5 mL) at room temperature. After 20 minutes, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse phase chromatography eluting with 30-95% MeCN/H2O+0.1% TFA. The product fractions were concentrated under reduced pressure to yield the title compound. 1H NMR (DMSO-d6) δ 13.80 (s, 1H), 8.44 (d, J=2.9 Hz, 1H), 7.99 (d, J=2.2 Hz), 7.95 (m, 1H), 7.93 (d, J=9.2 Hz, 1H), 7.62 (d, J=9.2 Hz, 1H), 7.35 (d, J=2.3 Hz, 1H), 7.16 (dd, J=8.0 Hz, J=4.6 Hz, 1H), 6.30 (s, 2H). HRMS (M+1)=470.0076.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C[Si]([C:23]#[C:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([CH:32]=1)[C:30]#[N:31])(C)C.I[C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][OH:38]>O1CCCC1.C(N(CC)CC)C.[Br-].[Zn+2].[Br-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:38][CH2:37][C:36]1[CH:35]=[C:34]([C:23]#[C:24][C:25]2[CH:26]=[N:27][CH:28]=[C:29]([CH:32]=2)[C:30]#[N:31])[CH:41]=[CH:40][CH:39]=1
Reactant: OCc1cccc(I)c1
Reactant: C[Si](C)(C)C#Cc1cncc(C#N)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1cncc(C#Cc2cccc(CO)c2)c1
Temperature: 55 °C
Yield: 48.7 %

Procedure:
Add a 1 M solution of tetrabutylammonium fluoride in THF (3.33 mL, 3.33 mmol) to a solution of 5-trimethylsilanylethynyl-nicotinonitrile, (prepared as described in PREPARATION 3), (0.801 g, 4.00 mmol), in tetrahydrofuran (8.3 mL) and triethylamine (3.34 mL). After 5 min add zinc (II) bromide (1.56 g, 5.99 mmol), 3-iodobenzyl alcohol (0.42 mL, 3.33 mmol), and tetrakis(triphenylphosphine)palladium (0) (269 mg, 0.233 mmol). Heat to 55° C. for 2 h, cool to room temperature, and filter through diatomaceous earth. Purify by silica gel chromatography, eluting with 80:20 to 60:40 (1:1 hexanes:dichloromethane):ethyl acetate, to give the title compound as a yellow crystalline solid (380 mg, 49%).
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]21[O:29][C:21]1=[N:22][CH:23]=[C:24]([C:26]([OH:28])=O)[CH:25]=[C:20]1[CH2:19]2.[NH2:30][C@H:31]1[CH2:36][C@@H:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@@H:34]([CH3:43])[N:33]([CH2:44][C:45]([F:48])([F:47])[F:46])[C:32]1=[O:49].Cl.N[C@H]1C[C@@H](C2C=CC=CC=2)[C@@H](C)N(CC(F)(F)F)C1=O.C(N(CC)C(C)C)(C)C.Cl.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:43][C@H:34]1[N:33]([CH2:44][C:45]([F:48])([F:46])[F:47])[C:32](=[O:49])[C@@H:31]([NH:30][C:26]([C:24]2[CH:25]=[C:20]3[CH2:19][C:3]4([C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:18])[CH3:16])[C:2]4=[O:1])[O:29][C:21]3=[N:22][CH:23]=2)=[O:28])[CH2:36][C@H:35]1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: C[C@@H]1[C@H](c2ccccc2)C[C@H](N)C(=O)N1CC(F)(F)F
Reactant: C[Si](C)(C)CCOCN1C(=O)C2(Cc3cc(C(=O)O)cnc3O2)c2cccnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1[C@H](c2ccccc2)C[C@H](NC(=O)c2cnc3c(c2)CC2(O3)C(=O)N(COCC[Si](C)(C)C)c3ncccc32)C(=O)N1CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2′-oxo-1′-((2-(trimethylsilyl)ethoxy)methyl)-1′,2′-dihydro-3H-spiro[furo[2,3-b]pyridine-2,3′-pyrrolo[2,3-b]pyridine]-5-carboxylic acid, (described in Intermediate 5) (0.095 g, 0.23 mmol), (3S,5S,6R)-3-amino-6-methyl-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-2-one, (described in Intermediate 1) (0.098 g, 0.35 mmol), N,N-diisopropylethylamine (0.12 mL, 0.69 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.065 g, 0.35 mmol) and HOBT (0.015 g, 0.12 mmol) in DMF (3 mL) was stirred initially at 0° C. for 15 min, then gradually warmed to 23° C. and stirred for 3 h. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 50% ethyl acetate in petroleum ether to give the title compounds as a 1:1 mixture of isomers. MS: m/z=682.5 (M+1).
Reaction SMILES: C([Sn](CCCC)(CCCC)[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)CCC.I[C:24]1[CH:25]=[N:26][N:27](C(OC(C)(C)C)=O)[C:28](=[O:30])[CH:29]=1.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([O:7][CH2:6][C:24]2[CH:25]=[N:26][NH:27][C:28](=[O:30])[CH:29]=2)=[CH:13][CH:12]=1
Reactant: CCCC[Sn](CCCC)(CCCC)COc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)n1ncc(I)cc1=O
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=c1cc(COc2ccc(Cl)cc2)cn[nH]1
Temperature: 110 °C
Reaction time: 2 h
Yield: 34.1 %

Procedure:
A mixture of tributyl((4-chlorophenoxy)methyl)stannane (29.5 mg, 0.068 mmol), tert-butyl 4-iodo-6-oxopyridazine-1(6H)-carboxylate (20 mg, 0.062 mmol) and bis(triphenylphosphine)palladium(II)chloride (2.18 mg, 3.10 μmol) in toluene (1.0 mL) under nitrogen in a sealed tube was stirred at 110° C. for 2 hours. After removal of the precipitate, the filtrate was concentrated and dissolved in CH2Cl2 (3.0 mL). After addition of TFA (1.0 mL, 12.98 mmol), the solution was stirred at RT for 15 min before being concentrated. The crude product was purified by prep-HPLC (C18 column/Water:MeOH:TFA 90:10:0.1 to 10:90:0.1 gradient) to give 5-((4-chlorophenoxy)methyl)pyridazin-3(2H)-one 8B (5.0 mg, 33% yield). 1H NMR (400 MHz, THF-D8) δ ppm 5.99 (1H, d, J=1.76 Hz), 5.55 (2H, d, J=8.78 Hz), 5.27 (2H, d, J=9.03 Hz), 5.08 (1H, d, J=1.51 Hz), 3.24 (2H, s).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH:15]=2)[C:10]([CH3:24])=[C:9]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:38][C:39]#[N:40]>CC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:38][C:39]#[N:40])=[CH:19][CH:18]=3)[CH:15]=2)[C:10]([CH3:24])=[C:9]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(-c2ccccc2)n(Cc2ccccc2)c2cc(-c3ccc(O)cc3)ccc12
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c(-c2ccccc2)n(Cc2ccccc2)c2cc(-c3ccc(OCC#N)cc3)ccc12

Procedure:
The desired product was prepared using a procedure similar to step 5 of example 3. Thus, 4-(1-benzyl-3-methyl-2-phenyl-1H-indol-6-yl)-phenol (0.291 g, 0.747 mmol) was reacted with K2CO3 (0.124 g, 0.896 mmol) and bromoacetonitrile (0.107 g, 0.896 mmol) in acetone (5 ml) to give the product (0.284 g, 0.663 mmol, 89%) as a white solid, mp 146-150° C. 1H NMR (DMSO-d6) δ 2.20 (s, 3H), 5.15 (s, 2H), 5.36 (s, 2H), 6.82 (d, J=7.0 Hz, 2H), 7.08-7.17 (m, 5H), 7.32-7.47 (m, 4H), 7.45 (t, J=6.7 Hz, 2H), 7.57-7.63 (m, 4H); [ESI(+)], m/z 429 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[C:13]2[O:12][CH:11]([CH2:14][NH2:15])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>>[CH2:29]([O:28][C:26](=[O:27])[NH:15][CH2:14][CH:11]1[CH2:10][C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:13]=2[O:12]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)c1cccc2c1OC(CN)C2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cccc2c1OC(CNC(=O)OCc1ccccc1)C2
Yield: 96.1 %

Procedure:
Treatment of (±)-1-(7-tert-butyl-2,3-dihydro-1-benzofuran-2-yl)methanamine (3.25 g, 13.4 mmol) with diisopropylethylamine (4.34 g, 33.6 mmol) and benzyl chloroformate (2.64 g, 15.5 mmol) generally according to the procedure described for Intermediate 12 gave 4.37 g (96%) of (±)-benzyl(7-tert-butyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate as a white solid. mp 73-76° C.; Anal. Calcd. for C21H25NO3 C, 74.31; H, 7.42; N, 4.13. Found C, 74.95; H, 7.51; N, 4.18. Chiral HPLC separation of (±)-benzyl(7-tert-butyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralcel OJ, ethanol) provided two fractions. Fraction 1 (Rt=9.100 min, Chiralcel OJ, ethanol); Fraction 2 (Rt=14.428 min, Chiralcel OJ, ethanol).
Reaction SMILES: I[C:2]1[C:3]([CH3:17])=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[C:6]=1[CH3:7].CC1(C)C(C)(C)OB([C:26]2[CH:35]=[CH:34][C:29]([NH:30][C:31](=[O:33])[CH3:32])=[CH:28][CH:27]=2)O1>>[OH:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([N:5]2[C:6]([CH3:7])=[C:2]([C:26]3[CH:35]=[CH:34][C:29]([NH:30][C:31](=[O:33])[CH3:32])=[CH:28][CH:27]=3)[C:3]([CH3:17])=[N:4]2)=[CH:9][CH:10]=1
Reactant: Cc1nn(-c2ccc(CCO)cc2)c(C)c1I
Reactant: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CC(=O)Nc1ccc(-c2c(C)nn(-c3ccc(CCO)cc3)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 12 from 2-[4-(4-iodo-3,5-dimethyl-1H-pyrazol-1-yl)phenyl]ethanol (step 2 of Example 11) and 4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acetanilide: MS (EI) m/z 385 [M]+, 1H-NMR (CDCl3) δ 7.44-7.26 (8H, m), 3.92-3.90 (2H, br), 3.08 (3H, s), 2.94 (2H, t, J=6.6 Hz), 2.32 (3H, s), 2.29 (3H, s).
Reaction SMILES: C([O:5][C:6](=[O:16])[CH2:7][C@@H:8]([CH2:14][NH2:15])[CH2:9][C@H:10]([CH3:13])[CH2:11][CH3:12])(C)(C)C.C[C@H](CC)C[C@@H]1CNC(=O)C1.Cl>>[NH2:15][CH2:14][C@@H:8]([CH2:9][C@H:10]([CH3:13])[CH2:11][CH3:12])[CH2:7][C:6]([OH:16])=[O:5]
Reactant: CC[C@@H](C)C[C@H](CN)CC(=O)OC(C)(C)C
Agent: CC[C@@H](C)C[C@@H]1CNC(=O)C1
Agent: Cl
Product: CC[C@@H](C)C[C@H](CN)CC(=O)O
Temperature: 50 °C

Procedure:
The mixture of amine 117 and lactam 118 was treated with 6N HCl and the solution warmed to 50° C. for 17 hours then cooled to room temperature and concentrated. The resultant oil was subjected to ion-exchange chromatography (Dowex, strongly acidic resin) using 5% ammonium hydroxide to give a cream solid which was recrystallized from methanol/ethyl acetate to give (3S, 5R)-3-aminomethyl-5-methyl-heptanoic acid, example 10. MS, m/z (relative intensity): 174 [M+H, 100%]. Anal. Calcd for C19H19N1O2. C, 62.39; H, 11.05; N, 8.08. Found: C, 62.23; H, 11.33; N, 7.89.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C([O:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17](=[O:34])[C:18]([CH3:33])=[C:19]([CH:23]3[CH2:28][CH2:27][N:26]([C:29](=[O:32])[CH2:30][CH3:31])[CH2:25][CH2:24]3)[O:20]2)=[CH:15][CH:14]=1)C=C.O>CN(C)C=O>[Br:1][C:22]1[C:13]([OH:12])=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19]([CH:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:32])[CH2:30][CH3:31])[CH2:25][CH2:24]1)=[C:18]([CH3:33])[C:17]2=[O:34]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=CCOc1ccc2c(=O)c(C)c(C3CCN(C(=O)CC)CC3)oc2c1
Solvent: O
Solvent: CN(C)C=O
Product: CCC(=O)N1CCC(c2oc3c(Br)c(O)ccc3c(=O)c2C)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.9 %

Procedure:
N-Bromosuccinimide (171 mg, 0.96 mmol) was added to a solution of 7-hydroxy-3-methyl-2-(1-propanoylpiperidin-4-yl)-4H-chromen-4-one (304 mg, 0.96 mmol) obtained in Example 31-3 in N,N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane/methanol=98/2→67/33) to obtain 204 mg of the title compound (yield: 54%).
Reaction SMILES: CC([OH:4])C.CC1(C)O[C@H](CN2C=CC(N[C:18](=[O:38])[C@@H:19]([N:24]3[CH2:28][C:27]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])=[CH:26][C:25]3=[O:37])[CH2:20][CH:21]([CH3:23])[CH3:22])=N2)CO1.Cl.C(OC)(C)(C)C>O>[Cl:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[O:29][C:27]1[CH2:28][N:24]([C@@H:19]([CH2:20][CH:21]([CH3:22])[CH3:23])[C:18]([OH:38])=[O:4])[C:25](=[O:37])[CH:26]=1
Reactant: CC(C)O
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: Cl
Solvent: O
Solvent: COC(C)(C)C
Product: CC(C)C[C@@H](C(=O)O)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 27.5 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
To a 200-L glass-lined reactor was charged with 42.7 kg of 2-propanol and 13.6 kg (27.0 mol) of ((S)-2-[4-(2-Chlorophenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide. The suspension was stirred at 25-30° C. until the solids dissolved. After adjusting the batch temperature to <15° C., 59.5 kg of 2.0N hydrochloric acid was added over 3.5 h while maintaining a batch temperature of 9-17° C. The mixture was warmed to 18 to 23° C. and stirred for 5.5 h. HPLC analysis at 2 h indicated the reaction was complete. The reaction mixture was transferred into a 500 L glass-lined reactor and diluted with 28.6 kg of purified water and 166.1 kg of methyl tert-butyl ether. The aqueous phase was separated and the organic phase was washed with 1.0N sodium hydroxide solution, 10.7 wt % sodium chloride solution, and 1.0 wt % sodium chloride solution subsequently. The organic phase was transferred into a 200 L glass-line reactor. Solvents were removed by distillation in vacuo at 10-26° C. to a volume of ca. 27 L. The resulting oil was diluted with 107.6 kg of ethanol and solvents were removed by distillation in vacuo at 12-30° C. to afford 19.85 kg (10.04 kg corrected by wt %, 80.4% of yield) of (S)-2-[4-(2-Chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl-1H-pyrazol-3-yl]-amide in ethanol. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.3 Hz, 3 H), 0.94 (d, J=6.3 Hz, 3 H), 1.33-1.50 (m, 1 H), 1.49-1.67 (m, 1 H), 1.68-1.85 (m, 1 H), 3.16-3.32 (m, 2 H), 3.70-3.93 (m, 2 H), 4.09 (m, J=13.6, 3.6 Hz, 1H), 4.21 (d, J=18.4 Hz, 1H), 4.61 (d, J=18.4 Hz, 1 H), 4.71 (t, J=5.6 Hz, 1 H), 4.79 (s, 1 H), 4.88 (dd, J=10.6, 4.8 Hz, 1 H), 4.94 (d, J=5.1 Hz, 1 H), 6.41 (d, J=1.5 Hz, 1 H), 7.37 (t, J=7.5 Hz, 1 H), 7.46 (t, J=7.5 Hz, 1 H), 7.50-7.56 (m, 2 H), 7.65 (d, J=7.5 Hz, 1 H), 10.78 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7]/[C:8](=[CH:13]\[C:14]3[CH:19]=[CH:18][C:17]([S:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)/[C:9]2=[O:12])=[CH:5][C:4]=1[N:25]1[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]1.CN1CCNCC1.C(=O)([O-])[O-].[Cs+].[Cs+].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>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([S:20][C:21]([F:24])([F:22])[F:23])=[CH:16][CH:15]=3)[C:9]2=[O:12])=[CH:5][C:4]=1[N:25]1[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]1
Reactant: COc1cc2c(cc1N1CCN(C)CC1)C/C(=C\c1ccc(SC(F)(F)F)cc1)C2=O
Agent: [Pd]
Agent: CN1CCNCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1N1CCN(C)CC1)CC(Cc1ccc(SC(F)(F)F)cc1)C2=O
Temperature: 110 °C

Procedure:
To a solution of 105 (75 mg, 0.174 mol) and N-methyl piperazine (20.9 mg, 0.209 mol) in toluene 15 mL was added cesium carbonate (113.3 mg, 0.348 mol). The reaction was degassed and purged with nitrogen for 10 min. Pd2(dba)3 (7.96 mg, 0.0087 mol) and BINAP (10.8 mg, 0.0174 mol) was added and again degassed and purged with nitrogen for another 10 min. The reaction was heated to 110° C. overnight under sealed conditions. The reaction was diluted with chloroform and filtered through celite bed. The organic layer was concentrated to get the crude compound 106 and was purified through flash chromatography by using 100-200 mesh silica gel eluting the compound at 5% methanol in chloroform as brown coloured solid 6-methoxy-5-(4-methylpiperazin-1-yl)-2-(4-((trifluoromethyl)thio)benzyl)-2,3-dihydro-1H-inden-1-one 106. 1HNMR (400 MHz, CDCl3) δ ppm 7.57 (d, 2H), 7.28 (bs, 2H), 7.20 (s, 1H), 6.90 (s, 1H), 3.91 (s, 3H), 3.70 (bs, 4H), 3.35 (d, 2H), 2.99 (bs, 5H), 2.73 (bs, 3H); MS (ESI) m/z 451.0 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:22]=[CH:21][C:8]([O:9][CH:10]2[CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]2)=[CH:7][C:6]=1C)[CH3:3].N1CC(OC2C=CC(CN(C)C)=C(C)C=2)C1.CNC.[Cl:43]C1C=C(O)C=CC=1C=O>>[NH:12]1[CH2:13][CH:10]([O:9][C:8]2[CH:21]=[CH:22][C:5]([CH2:4][N:2]([CH3:3])[CH3:1])=[C:6]([Cl:43])[CH:7]=2)[CH2:11]1
Reactant: O=Cc1ccc(O)cc1Cl
Reactant: Cc1cc(OC2CN(C(=O)OC(C)(C)C)C2)ccc1CN(C)C
Agent: CNC
Agent: Cc1cc(OC2CNC2)ccc1CN(C)C
Product: CN(C)Cc1ccc(OC2CNC2)cc1Cl
Yield: 10 %

Procedure:
Using similar protocols as described in Examples 20A, 20B and 20C employing dimethylamine and 2-chloro-4-hydroxybenzaldehyde as starting material afforded 0.13 g (10%) of 47A as an oil. 1H NMR (500 MHz, CDCl3): δ 2.26 (s, 6H), 3.45 (s, 2H), 3.78 (m, 2H), 3.92 (m, 2H), 4.96 (m, 1H), 6.65 (d, 1H), 6.76 (d, 1H), 7.27 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([N+:11]([O-])=O)[CH:5]=1.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([NH2:11])[CH:5]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(F)c(N)c1
Yield: 88.7 %

Procedure:
Stir mixture of 4-fluoro-3-nitro-benzoic acid methyl ester (5.30 g, 26.6 mmol) and palladium (5% on carbon, 5.66 g, 2.66 mmol, Aldrich Chemical Co.) in ethanol (0.2 M). Carefully introduce hydrogen (balloon) and stir the reaction for 24 h. Filter the reaction mixture through a glass-fiber filter and wash the filter cake with ethanol. Concentrate the filtrate to afford the title compound (4.00 g, 23.6 mmol, 89%): MS (m/z): 170 (M+1).
Reaction SMILES: [ClH:1].Cl.[CH:3]1(NC(C2C3C=C(C4C([Cl:24])=CN=C(NCCC5CCN(C)CC5)N=4)SC=3C=CC=2)=O)CC1.[CH:35]1([NH:38][C:39]([C:41]2[C:49]3[CH:48]=[C:47]([C:50]4[C:55]([Cl:56])=[CH:54][N:53]=[C:52]([NH:57][CH2:58][CH2:59][CH2:60][N:61]5[C@H:66]([CH3:67])[CH2:65][NH:64][CH2:63][C@@H:62]5[CH3:68])[N:51]=4)[S:46][C:45]=3[CH:44]=[CH:43][CH:42]=2)=[O:40])[CH2:37][CH2:36]1>>[ClH:24].[ClH:56].[ClH:1].[CH:35]1([NH:38][C:39]([C:41]2[C:49]3[CH:48]=[C:47]([C:50]4[C:55]([Cl:56])=[CH:54][N:53]=[C:52]([NH:57][CH2:58][CH2:59][CH2:60][N:61]5[CH:62]([CH3:68])[CH2:63][N:64]([CH3:3])[CH2:65][CH:66]5[CH3:67])[N:51]=4)[S:46][C:45]=3[CH:44]=[CH:43][CH:42]=2)=[O:40])[CH2:37][CH2:36]1
Reactant: CN1CCC(CCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Reactant: C[C@@H]1CNC[C@H](C)N1CCCNc1ncc(Cl)c(-c2cc3c(C(=O)NC4CC4)cccc3s2)n1
Agent: Cl
Product: CC1CN(C)CC(C)N1CCCNc1ncc(Cl)c(-c2cc3c(C(=O)NC4CC4)cccc3s2)n1

Procedure:
Using the method of 2-{5-chloro-2-[2-(1-methylpiperidin-4-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide di-hydrochloride, the title compound is synthesized from 2-{5-chloro-2-[3-(2,6-cis-dimethylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide as a yellow solid. ES+(m/z) 513 (35Cl) and 515 (37Cl) [M(free base)+H].
Reaction SMILES: [Na].[C:2]([O:6][C:7]([NH:9][C@H:10]1[C@@H:15]([C:16]([O:18][CH3:19])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].C[O-].[Na+].[Cl-].[NH4+]>CO>[C:2]([O:6][C:7]([NH:9][C@H:10]1[C@H:15]([C:16]([O:18][CH3:19])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:8])([CH3:5])([CH3:4])[CH3:3]
Reactant: COC(=O)[C@H]1CCCC[C@H]1NC(=O)OC(C)(C)C
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)[C@@H]1CCCC[C@H]1NC(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 64.1 %

Procedure:
Sodium metal (0.14 g, 6.1 mmol) was placed into a flame dried flask under nitrogen atmosphere and cooled to 0° C. 10 mL of freshly distilled methanol was added and the mixture stirred until all the sodium dissolved. An amount of 25 (2.00 g, 7.7 mmol) was dissolved in 10 mL of freshly distilled methanol and transferred to NaOMe solution via cannula. The solution was refluxed under nitrogen for 5.5 h, cooled to rt and acidified with 0.5 M aqueous 0.5 M ammonium chloride (18 mL, 9 mmol). The methanol was removed under reduced pressure, and the resulting solid collected by filtration to yield 1.27 g of desired product.
Reaction SMILES: FC1C=CC([C@@H](N)C)=CC=1.N1C(Cl)=NC(Cl)=NC=1Cl.[OH-].[NH4+].[Cl:22][C:23]1[N:28]=[C:27]([NH2:29])[N:26]=[C:25]([NH:30][C@H:31]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH3:32])[N:24]=1.[NH2:40][CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=1.C(NC(C)C)(C)C>C1COCC1>[Cl:22][C:23]1[N:28]=[C:27]([NH2:29])[N:26]=[C:25]([NH:30][C@H:31]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH3:32])[N:24]=1.[F:39][C:36]1[CH:37]=[CH:38][C:33]([C@@H:31]([NH:30][C:25]2[N:24]=[C:23]([NH:40][CH2:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=3)[N:28]=[C:27]([NH2:29])[N:26]=2)[CH3:32])=[CH:34][CH:35]=1
Reactant: NCCc1ccccn1
Agent: C[C@H](N)c1ccc(F)cc1
Agent: C[C@H](Nc1nc(N)nc(Cl)n1)c1ccc(F)cc1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[C@H](Nc1nc(N)nc(NCCc2ccccn2)n1)c1ccc(F)cc1
Yield: 144.8 %

Procedure:
The 4-Chloro-N2-[(1S)-1-(4-fluorophenyl)ethyl]-1,3,5-triazine-2,6-diamine used was prepared from (1S)-1-(4-Fluorophenyl)ethylamine (resolved by the procedure of Takenaka, S. et al. J. Chem. Soc., Perkins Trans. 2 1978, 95-99), cyanuric chloride and ammonium hydroxide according to the procedure outlined in the first two steps of Scheme 3 and by the procedure as described in Examples 14 and 15. A stirred solution of 4-Chloro-N2-[(1S)-1-(4-fluorophenyl)ethyl]-1,3,5-triazine-2,6-diamine (1.15 g, 4.30 mmol), 2-(2-aminoethyl)pyridine (0.58 g, 4.73 mmol), diisopropylamine (20 ml), and THF (10 ml) was heated at reflux for 18 hours and then concentrated under reduced pressure. The yellow residue was taken up in CH2Cl2 and washed with H2O and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica, eluting with 3% MeOH/CH2Cl2 to afford N2-[(1S)-1-(4-Fluorophenyl)ethyl]-N4-[2-(2-pyridinyl)ethyl]-1,3,5-triazine-2,4,6-triamine (free base) as a pale tan foam (1.10 g, 72%). 1H NMR (CDCl3) δ 8.51 (s, 1H), 7.56 (t, 1H), 7.31 (s, 2H), 7.08 (m, 1H), 6.97 (m, 3H), 5.88-5.44 (b m, 1H), 5.42-5.19 (b m, 1H), 5.15 (m, 1H), 4.95 (b s, 2H), 3.72 (d, 2H), 3.20-2.81 (b m, 2H), 1.47 (d, 3H). HPLC-MS (C-18, MeOH/H2O/TFA linear gradient elution, 5 ml/min, 220 nm): 1 peak at 0.84 minutes; MS (ES+) obs. m/z 353.83. A stirred solution of N2-[(1S)-1-(4-Fluorophenyl)ethyl]-N4-[2-(2-pyridinyl)ethyl]-1,3,5-triazine-2,4,6-triamine was treated with 10 mL of 1 N HCl in Et2O and allowed to stand at ambient temperature for 30 minutes. The mixture was concentrated by rotary evaporation to afford the titled compound as a pale white fine powder. LC/MS (C-18, MeOH/H2OTFA linear gradient elution, 5 ml/min, 220 nm): 1 peak at 0.86 minutes; MS (ES+) obsd m/z=354.26. MP=161° C.