Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC([N:20]1[CH2:29][CH2:28][C:23]2([O:27][CH2:26][CH2:25][O:24]2)[CH:22]([CH2:30][CH:31]([CH3:41])[C:32]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:33])[CH2:21]1)=O)C1C=CC=CC=1>CO.[Pd]>[CH2:8]([N:20]1[CH2:29][CH2:28][C:23]2([O:24][CH2:25][CH2:26][O:27]2)[CH:22]([CH2:30][CH:31]([CH3:41])[C:32]([NH:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:33])[CH2:21]1)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(CC1CN(C(=O)OCc2ccccc2)CCC12OCCO2)C(=O)Nc1ccccc1
Reactant: O=CCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(CC1CN(CCc2ccccc2)CCC12OCCO2)C(=O)Nc1ccccc1
Yield: 92 %

Procedure:
Phenylacetaldehyde (0.87 mL, 7.40 mmol) was added to a solution of (8-benzyloxycarbonyl-1,4-dioxa-8-aza-spiro[4.5]-decane-6-ylmethyl)-N-phenylpropionamide (96) in MeOH (49.4 mL, 0.03M) in a hydrogenation flask. 20% Pd/C (0.53 g) was added, and the mixture was shaken under 40 psi H2 until the consumption of H2 ceased and the reaction was judged complete by TLC (3.5 h). The crude reaction mixture was passed through a column of Celite, concentrated in vacuo, and purified by flash column chromatography (60:38:2::Hexanes:CH2Cl2:2N NH3 in EtOH) to obtain pure (8-phenethyl-1,4-dioxa-8-aza-spiro[4.5]-decane-6-ylmethyl)-N-phenylpropionamide (97) (0.59 g, 92%). 1H NMR (CDCl3): 7.42-7.12 (10H, m), 4.08 (1H, dd, J=13.4, 9.5 Hz), 3.96-3.77 (4H, m), 3.65 (1H, broad d, J=10.9 Hz), 2.92-2.80 (1H, m), 2.80-2.64 (3H, m), 2.64-2.51 (2H, m), 2.33 (2H, broad t, J=10.3 Hz) 2.20-1.94 (3H, m), 1.72 (1H, dt, J=13.3, 13.2, 3.7 Hz), 1.58 (1H, ddd, J=13.1, 10.9, 4.3 Hz), 1.03 (3H, t, J=7.4 Hz) ppm. LRMS: 408.86.
Reaction SMILES: C([O:9][CH2:10][C@@H:11]1[C:15]([O:17]C(=O)C)([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:28]=[CH:27][C:26]([NH:29]C(=O)C3C=CC=CC=3)=[N:25][C:24]2=[O:38])[O:12]1)(=O)C1C=CC=CC=1.CO>N>[NH2:29][C:26]1[CH:27]=[CH:28][N:23]([C@H:13]2[C:14]([F:22])([CH3:21])[C@@:15]([OH:17])([CH3:16])[CH:11]([CH2:10][OH:9])[O:12]2)[C:24](=[O:38])[N:25]=1
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2ccc(NC(=O)c3ccccc3)nc2=O)[C@]1(C)F
Agent: N
Solvent: CO
Product: CC1(F)[C@H](n2ccc(N)nc2=O)OC(CO)[C@@]1(C)O
Yield: 46 %

Procedure:
A solution of ((2R,4R)-3-acetoxy-5-(4-benzamido-2-oxopyrimidin-1(2H)-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.22 g, 0.42 mmol) in methanolic ammonia (25% w/w 15 ml) was stirred at room temperature for overnight. Completion of the reaction mixture monitored by thin-layer chromatography and methanol was removed under reduced pressure. Water added to the crude and extracted with ethyl acetate and the organic layer was dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 15% methanol in dichloromethane to elude title compound (0.047 g). Yield: 46%; 1H-NMR: 1H NMR (300 MHz, CDCl3): δ 7.40 (dd, 1H, J1=7.5 Hz, J2=7.5 Hz), 7.25-7.17 (bs, 2H), 6.23 (d, 1H, J=23.4 Hz), 5.72 (d, 1H, J=7.5 Hz), 5.53 (s, 1H), 4.79 (t, 1H), 4.11-4.09 (m, 1H), 3.49-3.45 (m, 2H), 1.29-1.19 (m, 6H); ES Mass: [M+1]+ 274 (100%), [M+2]+ 275 (60%); IR cm−: 3459, 2927, 2855, 2274, 1635, 1028, 938, 724, 471.
Reaction SMILES: Cl.[OH:2][CH2:3][C@H:4]1[CH2:8][C@H:7]([CH3:9])[CH2:6][NH:5]1.[C:10](#[N:13])[CH:11]=[CH2:12]>>[OH:2][CH2:3][C@H:4]1[CH2:8][C@H:7]([CH3:9])[CH2:6][N:5]1[CH2:12][CH2:11][C:10]#[N:13]
Reactant: C[C@@H]1CN[C@@H](CO)C1
Reactant: C=CC#N
Agent: Cl
Product: C[C@H]1C[C@H](CO)N(CCC#N)C1

Procedure:
(2R,4S)-4-Methylpyrrolidine-2-carboxylic acid described in J. Chem. Soc. C, pp. 514-522 (1971) is reacted with di-tert-butyl dicarbonate to give (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylic acid. (2R,4S)-1-tert-Butoxycarbonyl-4-methylpyrrolidine-2-carboxylic acid is reacted with methyl iodide in the presence of potassium carbonate in acetonitrile solvent to give methyl (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylate. Methyl (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylate is reduced with lithium borohydride to give (2R,4S)-1-tert-butoxycarbonyl-2-hydroxymethyl-4-methylpyrrolidine. (2R,4S)-1-tert-Butoxycarbonyl-2-hydroxymethyl-4-methylpyrrolidine is reacted with 4N hydrogen chloride-dioxane to give (2R,4S)-2-hydroxymethyl-4-methylpyrrolidine hydrochloride. (2R,4S)-2-Hydroxymethyl-4-methylpyrrolidine hydrochloride is reacted with acrylonitrile to give 3-[(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]propionitrile. In the same manner as in Example 1b (e) and using 3-[(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]propionitrile and N,N-diethyl-2,3-dimethylbenzamide, 3-(2-(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]ethyl)-5-methyl-2H-isoquinolin-1-one is obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)=[O:2].C(=O)(O)[O-].[Na+].[NH:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23]([O:25]C(C)(C)C)=[O:24]>C(Cl)Cl>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:18]2[CH2:22][CH2:21][CH2:20][C@H:19]2[C:23]([OH:25])=[O:24])(=[O:11])=[O:10])=[CH:5][CH:4]=1)=[O:2]
Reactant: O=Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Yield: 59.9 %

Procedure:
To a vigorously stirred solution of 4-formylbenzenesulfonyl chloride (1 g, 5 mmol) in DCM (10 mL), was added saturated aqueous sodium bicarbonate solution (10 mL), followed by tert-butyl(2S)-pyrrolidine-2-carboxylate (856 mg, 5 mmol). The organic phase was passed through a hydrophobic frit, and the solvent was removed in vacuo. The crude material was purified by silica gel column chromatography, eluting with 0-100% EtOAc in isohexane, to afford the title compound as a colourless gum (849 mg, 60%).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([C:15]3[CH:24]=[C:23]4[C:18]([CH2:19][CH2:20][NH:21][CH2:22]4)=[CH:17][CH:16]=3)[N:12]=[C:11]([NH2:25])[N:10]=2)[CH2:5][CH2:4]1.F[C:27]1[N:32]=[CH:31][C:30]([C:33]2[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=2)=[CH:29][CH:28]=1>>[NH2:25][C:11]1[N:12]=[C:13]([C:15]2[CH:24]=[C:23]3[C:18]([CH2:19][CH2:20][N:21]([C:27]4[N:32]=[CH:31][C:30]([C:33]5[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=5)=[CH:29][CH:28]=4)[CH2:22]3)=[CH:17][CH:16]=2)[CH:14]=[C:9]([N:6]2[CH2:5][CH2:4][N:3]([CH3:2])[CH2:8][CH2:7]2)[N:10]=1
Reactant: N#Cc1ccc(-c2ccc(F)nc2)cc1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(c3ccc(-c5ccc(C#N)cc5)cn3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared from 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt and 4-(6-fluoropyridin-3-yl)benzonitrile using procedures analogous to those for Example 14. Analytic LCMS (M+H)+: m/z=503.4.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([CH:24]=1)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:9]=1.Cl.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1>>[CH3:25][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=2)=[CH:24][C:6]=1[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[N:11]=[C:10]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:9]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: Cc1ccc(N)cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1
Agent: Cl
Product: Cc1ccc(NC(=O)c2cccnc2)cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1

Procedure:
The title compound was prepared from a mixture of 4-(5-amino-2-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (20 mg, 0.058 mmol) and nicotinoyl chloride hydrochloride (10 mg, 0.058 mmol) similar to Example 139 and isolated as a tan solid (13 mg, 47%). 1H NMR (DMSO-d6):
Reaction SMILES: [Mg].[Br:2][C:3]1[CH:8]=[C:7]([CH2:9]Br)[CH:6]=[CH:5][C:4]=1[F:11].II.C[O:15][C:16]([C:18]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1)=O>C(OCC)C.O1CCCC1>[Br:2][C:3]1[CH:8]=[C:7]([CH2:9][C:16]([C:18]2[N:19]=[CH:20][CH:21]=[CH:22][C:23]=2[C:24]([O:26][CH3:27])=[O:25])=[O:15])[CH:6]=[CH:5][C:4]=1[F:11]
Reactant: COC(=O)c1cccnc1C(=O)OC
Reactant: Fc1ccc(CBr)cc1Br
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1cccnc1C(=O)Cc1ccc(F)c(Br)c1
Temperature: 25 °C

Procedure:
A mixture of magnesium turnings (880 mg, 37 mmol) and 2-bromo-4-(bromomethyl)-1-fluorobenzene (1.0 g, 3.7 mmol) in anhydrous diethyl ether (15 ml) was treated with a piece of iodine. The mixture was then heated to gentle reflux until the color of the mixture disappeared, after which the heating continued for additional hour. The suspension was cooled to room temperature, and cannulated into a solution of dimethylpyridine-2,3-dicarboxylate (1.0 g, 5.1 mmol) in tetrahydrofuran (50 ml) at −78° C. The reaction mixture was maintained at the same temperature for 30 minutes, and was quenched with addition of water. After warming up to room temperature, the reaction mixture was partitioned between ethyl acetate and brine. The organic phase was washed with brine and concentrated. The residue was purified by flash chromatography (15% ethyl acetate in hexane) to provide the title compound. MS (DCI/NH3) m/z 353 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](O)=[O:14])=[C:10]([CH:16]=O)[CH:9]=2)=[CH:4][CH:3]=1.O.[NH2:19][NH2:20].Cl.C([O-])(O)=O.[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[C:13](=[O:14])[NH:19][N:20]=[CH:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=Cc1cc(-c2ccc(Cl)cc2)sc1C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=c1[nH]ncc2cc(-c3ccc(Cl)cc3)sc12
Temperature: 82 °C
Yield: 72.7 %

Procedure:
To a stirred solution of 5-(4-chlorophenyl)-3-formylthiophene-2-carboxylic acid (3 g, 0.011 mol) in ethanol (30 ml) was added hydrazine hydrate (0.65 ml, 0.013 mol) in small drops. To this was added conc. HCl (1.8 ml, 0.058 mol) in a dropwise manner and heated to 82° C. for 2 days. The reaction mixture was allowed to cool down and 10% NaHCO3 (5 ml) was added slowly until pH=8. The solid was filtered, washed with water (200 ml) and dried to afford 2.1 g (71%) of the title compound. Rf=0.5 (CHCl3:MeOH, 8:2). 1H NMR (400 MHz, DMSO-d6) δ 12.98 (bs, 1H), 8.39 (s, 1H), 7.98 (s, 1H), 7.88 (d, 2H, J=8.6 Hz), 7.59 (d, 2H, J=8.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([O:25]C)=O)=[CH:14][C:12]=2[N:13]=1.[F:28][C:29]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:30]=1[NH2:31].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:27][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([NH:31][C:30]3[CH:32]=[CH:33][C:34]([C:36]([F:37])([F:38])[F:39])=[CH:35][C:29]=3[F:28])=[O:25])=[CH:14][C:12]=2[N:13]=1
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cncc3Cl)[nH]c2c2c1OC(C)(C)C2
Reactant: Nc1ccc(C(F)(F)F)cc1F
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC1(C)Cc2c(c(C(=O)Nc3ccc(C(F)(F)F)cc3F)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Yield: 36.8 %

Procedure:
The title compound was prepared following the procedure described for Example-137 by using methyl 2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylate (Step-1 of Intermediate-3, 0.100 g, 0.245 mmol), 2-fluoro-4-(trifluoromethyl)aniline (0.064 g, 0.357 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL), dry toluene (5.0 mL) at room temperature to afford 0.050 g of the desired product. 1HNMR (DMSO-d6): δ 1.57 (s, 6H), 3.11 (s, 2H), 7.31 (s, 1H), 7.62 (d, J=8.1 Hz, 1H), 7.81 (d, J=11.4 Hz, 1H), 8.46 (s, 2H), 8.70 (t, J=8.4 Hz, 1H), 10.23 (s, 1H), 11.03 (br s, 1H), 11.60 (br s, 1H); MS [M+H]+: 552.33.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=N[CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.BrC1C=CC=[C:28]([F:32])C=1>>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:28]([F:32])[CH:19]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(NC(=O)c2nc(C)ccc2Nc2cccnc2)ccn1
Reactant: Fc1cccc(Br)c1
Product: Cc1cc(NC(=O)c2nc(C)ccc2Nc2cccc(F)c2)ccn1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide (example 5) in accordance with the general method of example 20 using 1-Bromo-3-fluorobenzene instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow crystalline solid, MS (ISP): m/e=337.3 (M+H+).
Reaction SMILES: COC(=O)NC(C(N1CCCC1C1NC(C2C=CC(C3C=CC(C4NC(C5CCCN5[C:46](=[O:56])[CH:47]([NH:51][C:52]([O:54][CH3:55])=[O:53])[CH:48]([CH3:50])[CH3:49])=NC=4)=CC=3)=CC=2)=CN=1)=O)CCC(F)(F)F.[CH3:58][O:59][C:60](=[O:105])[NH:61][CH:62]([C:71]([N:73]1[CH2:77][CH2:76][CH2:75][CH:74]1[C:78]1[NH:79][C:80]([C:83]2[CH:88]=[CH:87][C:86]([C:89]3[CH:94]=[CH:93][C:92]([C:95]4[NH:96][C:97]([CH:100]5[CH2:104][CH2:103][CH2:102][NH:101]5)=[N:98][CH:99]=4)=[CH:91][CH:90]=3)=[CH:85][CH:84]=2)=[CH:81][N:82]=1)=[O:72])[CH2:63][CH2:64][O:65][CH2:66][C:67]([F:70])([F:69])[F:68]>>[CH3:55][O:54][C:52](=[O:53])[NH:51][CH:47]([C:46]([N:101]1[CH2:102][CH2:103][CH2:104][CH:100]1[C:97]1[NH:96][C:95]([C:92]2[CH:93]=[CH:94][C:89]([C:86]3[CH:87]=[CH:88][C:83]([C:80]4[NH:79][C:78]([CH:74]5[CH2:75][CH2:76][CH2:77][N:73]5[C:71](=[O:72])[CH:62]([NH:61][C:60]([O:59][CH3:58])=[O:105])[CH2:63][CH2:64][O:65][CH2:66][C:67]([F:70])([F:68])[F:69])=[N:82][CH:81]=4)=[CH:84][CH:85]=3)=[CH:90][CH:91]=2)=[CH:99][N:98]=1)=[O:56])[CH:48]([CH3:50])[CH3:49]
Reactant: COC(=O)NC(CCC(F)(F)F)C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1
Reactant: COC(=O)NC(CCOCC(F)(F)F)C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5)[nH]4)cc3)cc2)[nH]1
Product: COC(=O)NC(CCOCC(F)(F)F)C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1
Yield: 45 %

Procedure:
This compound was made in 45% yield by the same procedure as (4,4,4-Trifluoro-1-{2-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-butyl)-carbamic acid methyl ester, using [1-(2-{5-[4′-(2-Pyrrolidin-2-yl-3H-imidazol-4-yl)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-3-(2,2,2-trifluoroethoxy)-propyl]-carbamic acid methyl ester as the starting material. LCMS-ESI+: calculated for C41H49F3N8O7: 822.87; observed [M+1]+: 823.45. 1H-NMR: 400 MHz, (CD3OD) δ: 7.82-7.72 (m, 4H), 7.69-7.65 (m, 4H), 7.38-7.32 (m, 2H), 5.22-5.16 (m, 2H), 4.65-4.61 (m, 1H), 4.26-4.21 (m, 1H), 4.04-3.84 (m, 6H), 3.72-3.48 (m, 8H), 2.39-1.98 (m, 10H), 1.88-1.78 (m, 1H), 1.01-0.89 (m, 6H) ppm.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.C1C=C(Cl)C=C(C(OO)=[O:23])C=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:14][O:13][C:11]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][N+:2]([O-:23])=[CH:1]2)=[O:12]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1cccc2cnccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cccc2c[n+]([O-])ccc12
Temperature: 25 °C
Yield: 63.5 %

Procedure:
Methyl isoquinoline-5-carboxylate (5.8 g, 31.0 mmol) obtained in Step (3) above and dichloromethane (60 mL) were mixed and stirred. The reaction solution was added with mCPBA (8.02 g, 46.2 mmol) and stirred for about 5 hours at 50° C. The reaction mixture was cooled to room temperature and adjusted to have a pH value in a range of 9˜10 by adding a saturated aqueous sodium bicarbonate. The reaction mixture was diluted with dichloromethane, and washed with a saturated aqueous sodium bicarbonate solution and saline. The organic layer thus obtained was dried over anhydrous sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (4 g, 63.5%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:31][CH3:32])=[C:16]([CH:22]4[CH2:25][N:24]([C@H:26]([CH3:30])[C:27]([OH:29])=O)[CH2:23]4)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)[N:51]([CH3:53])[CH3:52])C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CNC>CN(C=O)C.CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:31][CH3:32])=[C:16]([CH:22]4[CH2:25][N:24]([C@H:26]([CH3:30])[C:27]([N:51]([CH3:53])[CH3:52])=[O:29])[CH2:23]4)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN([C@H](C)C(=O)O)C1
Agent: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN([C@H](C)C(=O)N(C)C)C1
Reaction time: 1 h
Yield: 61.7 %

Procedure:
To a solution of (2R)-2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)propanoic acid (4 mg, 0.009 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (4 mg, 0.009 mmol) in DMF (0.3 mL) at room temperature was added triethylamine (4 μL, 0.03 mmol) and dimethylamine hydrochloride (0.9 mg, 0.01 mmol). The reaction mixture was stirred for 1 h, then diluted with methanol and purified by preparative RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (2.7 mg, 63%). The product was isolated as a single diastereomer. LCMS calculated for C24H33ClN7O2 (M+H)+: m/z=486.2; Found: 486.1. 1H NMR (300 MHz, DMSO-d6): δ□ 8.09 (s, 1H), 7.23 (s, 1H), 6.18 (m, 1H), 3.78 (m, 3H), 3.50 (s, 3H), 3.01 (s, 3H), 3.0-2.9 (m, 3H), 2.77 (s, 3H), 2.54 (s, 3H), 2.06 (s, 3H), 1.67 (d, 3H), 0.98 (d, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15]([OH:17])=O)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:22]([N:24]([CH2:31][CH3:32])[CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[CH3:23]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15]([N:28]3[CH2:29][CH2:30][CH:25]([N:24]([CH2:31][CH3:32])[CH2:22][CH3:23])[CH2:26][CH2:27]3)=[O:17])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCN(CC)C1CCNCC1
Reactant: O=C(O)c1ccccc1Nc1ccnc2cc(Br)ccc12
Product: CCN(CC)C1CCN(C(=O)c2ccccc2Nc2ccnc3cc(Br)ccc23)CC1

Procedure:
2-(7-Bromo-4-quinolylamino)benzoic acid is converted to the acid chloride which is reacted with 4-diethylamino piperidine as in Example 1 to give the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:7])[C:3]([CH3:6])([OH:5])[CH3:4].N1C=CN=C1.[CH3:13][C:14]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C(Cl)Cl>[Si:17]([O:5][C:3]([CH3:6])([CH3:4])[C@@H:2]([NH2:1])[CH3:7])([C:14]([CH3:16])([CH3:15])[CH3:13])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@H](N)C(C)(C)O
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C[C@H](N)C(C)(C)O[Si](C)(C)C(C)(C)C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a solution of (S)-3-amino-2-methylbutan-2-ol (4 g, 38.8 mmol) and imidazole (5.20 g, 77.7 mmol) in CH2Cl2 (50 mL) was added TBSCl (8.7 g, 57.7 mmol) at 0° C. The mixture was stirred overnight. The mixture was washed with brine. The organic phase was separated and concentrated to give (S)-3-(tert-butyldimethylsilyloxy)-3-methylbutan-2-amine (8.4 g, 100%), which was used for the next step without purification. 1H NMR (CDCl3): 0.00 (s, 6H), 0.73 (s, 9H), 1.08 (s, 3H), 1.12 (d, 3H), 1.21 (s, 3H), 2.83 (q, 1H), 4.08 (brs, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+].O>[Fe].C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Reaction time: 3 h
Yield: 90 %

Procedure:
(4-Nitro-benzyl)-carbamic acid tert-butyl ester (6.34 g, 25.1 mmol), iron powder (6.5 g, 116 mmol), ammonium formate (13.0 g, 206 mmol), H2O (75 mls), and toluene (75 mls) were combined and heated to reflux. After 3 hrs the reaction mixture was allowed to cool and filtered through Celite with thorough washing with EtOAc. The filtrate was transferred to a separatory funnel and the phases separated. The organic phase was further washed with H2O (1×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo to give (4-amino-benzyl)-carbamic acid tert-butyl ester (5.02 g, 90% yield). LC/MS Calcd for [M+H]+ 223.1, found 167.1 (minus t-butyl).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1ccc(CBr)cc1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Product: Cc1ccc(COc2ccc(Cl)c([N+](=O)[O-])c2)cc1

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 1-Bromomethyl-4-methyl-benzene using the conditions described in Example 10C to provide 1-Chloro-4-(4-methyl-benzyloxy)-2-nitro-benzene which was treated sequentially using the procedures from Examples 10D and 10E to provide the title product.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].[CH2:18](O)[CH3:19]>>[F:5][C:6]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:7]=1[C:8]([O:10][CH2:18][CH3:19])=[O:9]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc([N+](=O)[O-])ccc1F
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Under ice-cooling, thionyl chloride (8.02 mL) was added dropwise to ethanol (200 mL), and 2-fluoro-5-nitrobenzoic acid (13.81 g) was added. This mixture was stirred at 80° C. for 4 hrs. and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (15.77 g) as a pale-yellow oil.
Reaction SMILES: O.[SH:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[CH2:7][CH2:8][C:9]([OH:11])=O>C1(C)C(C)=CC=CC=1>[SH:2][CH2:3][CH2:4][N:5]1[C:6](=[O:12])[CH2:7][CH2:8][C:9]1=[O:11]
Reactant: O=C(O)CCC(=O)NCCS
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1CCC(=O)N1CCS
Temperature: 140 °C
Yield: 100.2 %

Procedure:
In a 100 cm3 reactor fitted with a water separator (Dean Stark) there is heated to a temperature of 140° C. a mixture, stirred under an inert atmosphere, of 20 g of N-(2-mercapto ethyl) succinamic acid in 50 cm3 of xylene. After about 5 hours of reaction, the theoretical amount of water (2 cm3) is removed. The xylene is then distilled under reduced pressure. The crude product is dried and 18 g of a pasty product are obtained which slowly crystallizes at ambient temperature, its characteristics being the same as those of the product prepared following the procedures in section (a) immediately above.