Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=2)[C:15](=[O:24])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C=O.[C:38]([BH3-])#N.[Na+].CCOC(C)=O>CC(O)=O>[C:1]([O:5][C:6](=[O:35])[C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH:14]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=2)[C:15](=[O:24])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=2)[CH3:38])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(NC(C(=O)Nc2ccc(I)cc2)c2ccc(C(C)(C)C)cc2)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CN(c1ccc(C(=O)OC(C)(C)C)cc1)C(C(=O)Nc1ccc(I)cc1)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Yield: 105.5 %

Procedure:
4-{[(4-tert-Butyl-phenyl)-(4-iodo-phenylcarbamoyl)-methyl]-amino}-benzoic acid tert-butyl ester (110 mg, 0.19 mmol) was dissolved in 2 mL of HOAc. paraformaldehyde (51 mg, 0.57 mmol) and sodium cyano-borohydride (36 mg, 0.57 mmol) were then added and heated to 40 C for 1 h. Cooled to RT, EtOAc (20 mL) was added and extracted water (20 mL). The organic layer was washed again with water (20 mL), dried over sodium sulfate, filtered and the organic layer was removed under reduced pressure to give a white solid (120 mg, 100%). 1H NMR showed the compound to be very clean and sufficient for the following step. LCMS (M+1=599.4)
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.[NH2:29][C@H:30]([CH3:33])[CH2:31][OH:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[OH:32][CH2:31][C@H:30]([NH:29][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:10][C:9]([C:4]2[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[O:28])=[CH:20][CH:21]=1)[CH3:33]
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Reactant: C[C@@H](N)CO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N[C@H](C)CO)cc1

Procedure:
In analogy to example 207, step 2, 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (example 207, step 1) was coupled with (R)-2-aminopropan-1-ol using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as an off-white solid, MS (ESI+): m/z=433.3 [M+H]+.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][S:10](=[O:15])(=[O:14])[N:11]([CH3:13])[CH3:12])=[CH:5][CH:4]=1.[ClH:16]>CCOC(C)=O.CCCCCC>[Cl:16][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][S:10](=[O:15])(=[O:14])[N:11]([CH3:13])[CH3:12])=[CH:5][CH:4]=1
Reactant: Cl
Reactant: CN(C)S(=O)(=O)Oc1ccc(CO)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CN(C)S(=O)(=O)Oc1ccc(CCl)cc1

Procedure:
To a solution of JRL01115 (725 mg, 3.135 mmol) in dichloromethane (10 mL) at ice/water temperature was added thionyl chloride (0.35 mL, 4.703 mmol). After stirring at room temperature for 1 h, the volatiles were removed from the reaction mixture and the oil resulted co-evaporated 3 times with chloroform (3×30 mL) to give to LWO02144 as a yellow oil (767 mg, 98%); Rf 0.52 (EtOAc/hexane, 1:1), c.f. 0.19 (JRL01115); 1H (400 MHz, CDCl3) 2.99 (6H, s, NMe2), 4.58 (2H, s), 7.28 (2H AA′BB′) and 7.42 (2H, AA′BB′); LRMS (FAB+) 403.0 [18, (M+H+NBA)+], 391.2 (21), 249.9 [100, (M+H)+], 214.0 [45, (M+H—Cl)+], 113.0 (17); HRMS (FAB+) 249.02239, C9H12ClNO3S requires 249.02264. LWO02144 was very pure and hence was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[N:10][N:11]([CH2:13][CH2:14]O)[CH:12]=2)=[CH:4][CH:3]=1.FC1C=CC(C2C=N[N:32]([CH2:40]CO)[C:33]=2C2C=CN=CC=2)=CC=1.CS(Cl)(=O)=O>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[N:10][N:11]([CH2:13][CH2:14][N:32]([CH3:40])[CH3:33])[CH:12]=2)=[CH:4][CH:3]=1
Reactant: OCCn1cc(-c2ccc(F)cc2)c(-c2ccncc2)n1
Reactant: OCCn1ncc(-c2ccc(F)cc2)c1-c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CN(C)CCn1cc(-c2ccc(F)cc2)c(-c2ccncc2)n1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
4-(4-Fluorophenyl)-3-(4-pyridinyl)-1H-pyrazole-1-ethanol (or 4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazole-1-ethanol) prepared as set forth in Example 11 (1.36 g) was dissolved in 30 mL pyridine and cooled to 0° C., whereupon methanesulfonyl chloride (0.6 mL) was added. After stirring at 0° C. for 12 hours, about 20 g of ice was added, and the mixture was extracted with toluene (300 ml). After evaporation, the residue was used directly without further purification. 0.7 g of the above obtained compound was dissolved in methanol (25 mL), and dimethylamine/THF solution (4M, 2 mL) was added. The reaction mixture was refluxed for 12 hours, then evaporated to dryness. The residue was purified by chromatography (methanol/dichloromethane 1:10). A mixture (0.59 g) of 4-(4-fluorophenyl)-N,N-dimethyl-3-(4-pyridinyl)-1H-pyrazole-1-ethanamine and 4-(4-fluorophenyl)-N,N-dimethyl-5-(4-pyridinyl)-1H-pyrazole-1ethanamine were obtained. 1H NMR: consistent with the assigned structure. Mass spectrum, m/z: 311 (M+1). Anal. calc'd C18H19N4F.0.55H2O: C, 67.50; H, 6.33; N, 17.49. Found: C, 67.21; H, 6.46; N, 17.14.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1I.C([O:13][B:14](OC(C)C)[O:15]C(C)C)(C)C.C([Li])CCC.Cl>O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[B:14]([OH:15])[OH:13]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Clc1ccc(Cl)c(I)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1cc(Cl)ccc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cold (-78° C.) solution of 2,5-dichloroiodobenzene (50 g) and triisopropoxyborane (46.5 ml) in tetrahydrofuran (500 ml) was added dropwise n-butyllithium in hexane (1.69 M, 119 ml). The mixture was stirred at -78° C. for 30 minutes. The reaction mixture was poured into 2M hydrochloric acid solution (180 ml) and stirred for 10 minutes. The product was extracted with ether (200 ml) 2 times, and the organic layers were combined, washed with brine, dried over magnesium sulfate and evaporated in vacuo. To the residue was added n-hexane (60 ml) and the crystalline was collected, washed with n-hexane and dried to give 2,5-dichlorophenyl-dihydroxyborane (21.0 g).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.[C:12](O)(=[O:23])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22].C(N(C(C)C)CC)(C)C>CN(C=O)C>[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[CH:4]([NH:3][C:12](=[O:23])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])[CH2:5]2
Reactant: NC1CN2CCC1CC2
Reactant: C=CCCCCCCCCC(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCCCCCCC(=O)NC1CN2CCC1CC2
Temperature: 0 °C
Reaction time: 46 h
Yield: 23 %

Procedure:
An oven-dried 50 mL round bottom flask was charged with 3-aminoquinuclidine dihydrochloride (2 mmol), 10-undecenoic acid (2 mmol), N,N-dimethylaminopyridine (0.3 mmol), diisopropylethylamine (4 mmol), and dry DMF (15 mL). The flask was purged with argon and cooled to 0° C. in an ice bath. Dicyclohexycarbodiimide (2.2 mmol) was then add to the solution, the flask repurged with argon, and the mixture warmed to R.T. and stirred for 46 h. The reaction mixture was concentrated in vacuo and 30 ml diethyl ether added to the residue. The solid was filtered off over Celite and the organic phase concentrated in vacuo. The residue was purified by silica gel chromatography using ethyl acetate/hexanes (3:7) to afford the product as a white solid (23%). Rf=0.44. 1HNMR (400 MHz, CDCl3): δ=5.73 (m, 1H), 4.93 (dd, 1H, 3JHH=17.0 Hz, 4JHH=1.5 Hz), 4.87 (d, 1H, 3JHH=10.3 Hz), 3.71 (m, 1H), 2.10 (t, 2H, 3JHH=7.8 Hz), 1.97 (q, 2H, 3JHH=7.3 Hz), 1.85 (m, 2H), 1.54-1.68 (m, 5H), 1.02-1.34 (m, 15H) ppm. 13CNMR (400 MHz, CDCl3): δ=172.2, 139.1, 114.1, 48.6, 48.0, 37.0, 34.0, 33.7, 33.2, 29.3, 29.2, 29.0, 28.8, 25.9, 25.7, 25.5, 25.0, 24.9 ppm. HRMS-ESI: Calculated [M-C2H2]+: 266.2358. found: 266.2474.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:13]([C:15]3[C:16]([O:34][CH2:35][CH3:36])=[C:17]([C:23]4[CH:24]=[CH:25][C:26]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])=[N:27][CH:28]=4)[C:18]([CH3:22])=[C:19]([Cl:21])[CH:20]=3)[CH3:14])[N:9]=[C:10]([CH:11]=[CH2:12])[C:3]=12.Cl.O>[Pt].CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:13]([C:15]3[C:16]([O:34][CH2:35][CH3:36])=[C:17]([C:23]4[CH:24]=[CH:25][C:26]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])=[N:27][CH:28]=4)[C:18]([CH3:22])=[C:19]([Cl:21])[CH:20]=3)[CH3:14])[N:9]=[C:10]([CH2:11][CH3:12])[C:3]=12
Reactant: C=Cc1nn(C(C)c2cc(Cl)c(C)c(-c3ccc(C(=O)N(C)C)nc3)c2OCC)c2ncnc(N)c12
Agent: [Pt]
Agent: Cl
Solvent: CO
Solvent: O
Product: CCOc1c(C(C)n2nc(CC)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Reaction time: 3 h
Yield: 27.4 %

Procedure:
5-{3-[1-(4-Amino-3-vinyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide (14 mg, 0.028 mmol) and 5% platinum on carbon (14 mg) was combined in methanol (1 mL), to which was added 0.25 M hydrogen chloride in water (0.28 mL, 0.069 mmol). The suspension was hydrogenated under balloon pressure of H2 at room temperature for 3 h. The suspension was filtered and the filtrate purified on 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 (3.9 mg, 28%). The product was isolated as a racemic mixture. LCMS calculated for C26H31ClN7O2(M+H)+: m/z=508.2; Found: 508.3.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][C@H:14]3[CH2:18][O:19][CH3:20])=[O:12])[S:10][C:3]=12.[CH3:21][NH:22][C:23]([C:25]1[C:26]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][C:27]=2[S:28][C:29]=1[CH2:30][CH3:31])=[O:24].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:21][NH:22][C:23]([C:25]1[C:26]2[CH:35]=[CH:34][C:33]([O:36][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][CH2:15][C@H:14]5[CH2:18][O:19][CH3:20])=[O:12])[S:10][C:3]=34)=[CH:32][C:27]=2[S:28][C:29]=1[CH2:30][CH3:31])=[O:24]
Reactant: CCc1sc2cc(O)ccc2c1C(=O)NC
Reactant: COC[C@@H]1CCCN1C(=O)c1cc2nccc(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCc1sc2cc(Oc3ccnc4cc(C(=O)N5CCC[C@H]5COC)sc34)ccc2c1C(=O)NC
Yield: 9.8 %

Procedure:
This material was prepared by reacting 7-chloro-2-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridine 2a (155 mg, 0.5 mmole) with 2-ethyl-6-hydroxybenzo[b]thiophene-3-carboxylic acid methylamide 134d (141 mg, 0.60 mmole) and Cs2CO3 (488 mg, 1.5 mmole) in a manner analogous to that described for example 1 to give a yellow solid (25 mg, 10%). 1H NMR (DMSO-d6, 300 MHz), δ 8.59 (1H, d, J=5.56 Hz), 8.33 (1H, d, J=4.55 Hz), 8.03 (1H, s), 7.99 (1H, d, J=2.02 Hz), 7.81 (1H, d, J=8.59 Hz), 7.33 (1H, dd, J=2.27, 8.84 Hz), 6.77 (1H, d, J=5.56 Hz), 4.31 (1H, br s), 3.90–3.81 (2H, m), 3.37–3.15 (2H, m), 3.37 (3H, s), 3.00 (2H, q, J=7.41 Hz), 2.83 (3H, d, J=4.55 Hz), 2.09–1.84 (4H, m), 1.28 (3H, t, J=7.58 Hz).
Reaction SMILES: [F:1][C:2]1[C:10]2[S:9][CH:8]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]=2[C:5]([CH3:15])=[CH:4][C:3]=1[OH:16].OS(O)(=O)=O.[CH3:22]O>>[CH3:22][O:13][C:12](=[O:14])[CH2:11][C:7]1[C:6]2[C:5]([CH3:15])=[CH:4][C:3]([OH:16])=[C:2]([F:1])[C:10]=2[S:9][CH:8]=1
Reactant: CO
Reactant: Cc1cc(O)c(F)c2scc(CC(=O)O)c12
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1csc2c(F)c(O)cc(C)c12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a mixture of (7-fluoro-6-hydroxy-4-methyl-1-benzothiophen-3-yl)acetic acid (267 mg) and MeOH (8.0 mL) was added conc. H2SO4 (0.100 mL). The mixture was stirred at 80° C. for 1 h. The mixture was concentrated. The mixture was neutralized with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (255.5 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[CH2:13]([O:15][P:16]([O:20]CC)[O:17][CH2:18][CH3:19])[CH3:14]>>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[CH:12][C:3]=1[CH2:2][P:16]([O:17][CH2:18][CH3:19])([O:15][CH2:13][CH3:14])=[O:20]
Reactant: CCOP(OCC)OCC
Reactant: COC(=O)c1ccccc1CBr
Product: CCOP(=O)(Cc1ccccc1C(=O)OC)OCC
Temperature: 25 °C
Yield: 92.5 %

Procedure:
step 1—A solution of methyl 2-bromomethyl-benzoate (9.99 g, 43.6 mmol) and triethylphosphite (7.25 g, 43.6 mmol) was heated to 150° C. for 5 h. The reaction mixture as cooled to RT then purified by SiO2 chromatography to afford 11.55 g of 2-(diethoxy-phosphorylmethyl)-benzoic acid methyl ester (72)
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8]CCCC)=[O:7])=[CH:4][C:3]=1[O:15][CH2:16][CH2:17][CH2:18][CH3:19].[OH-].[Li+]>C1COCC1.CO>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCOC(=O)c1ccc(Br)c(OCCCC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOc1cc(C(=O)O)ccc1Br
Temperature: 23 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a solution of 5.1 (0.90 g, 2.7 mmol) in THF/MeOH (2/1) (18 mL), was added lithium hydroxide (6.0 mL, 6.0 mmol). The resulting mixture was stirred overnight at 23° C. and then quenched with excess 1N HCl. The mixture was then extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The crude residue was purified by combiflash (0 to 40% EtOAc/hexanes) to afford a 20.1 (0.68 g, 91% yield).
Reaction SMILES: O[CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[C:6]([CH3:14])=[C:5]([NH:15][C:16](=[O:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:4]=1[CH3:23]>C(OCC)(=O)C.CCCCCC>[CH2:2]([C:3]1[C:11]2[O:10][C:9]([CH3:12])([CH3:13])[CH2:8][C:7]=2[C:6]([CH3:14])=[C:5]([NH:15][C:16](=[O:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:4]=1[CH3:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1c2c(c(C(O)c3ccccc3)c(C)c1NC(=O)CC(C)(C)C)OC(C)(C)C2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(Cc2ccccc2)c2c(c(C)c1NC(=O)CC(C)(C)C)CC(C)(C)O2
Yield: 74 %

Procedure:
Using N-(7-(1-hydroxy(phenyl)methyl)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 355, the title compound was synthesized in the same manner as in Example 271. Yield: 74%. Melting point: 129-130° C. (ethyl acetate-hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[C:8]([CH2:13][CH3:14])=[N:7]2.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:9]1[C:8]([CH2:13][CH3:14])=[N:7][C:6]2[C:11]([N:10]=1)=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2
Reactant: CCc1nc2cccc(Cl)c2[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCc1nc2cccc(Cl)c2nc1Cl
Yield: 77.2 %

Procedure:
A thick slurry of 8-chloro-3-ethylquinoxalin-2(1H)-one (1.00 Kg, 4.79 mol) in POCl3 (2.68 L, 28.8 mol) was stirred at 100° C. for 2 h. At this time LC-MS analysis showed that the reaction was complete. After the removal of most of the POCl3 under reduced pressure, the residue was poured carefully into ice-water and neutralized with a combination of 2M aq. NaOH and saturated aq. NaHCO3. The resulting suspension was extracted with DCM (3×4 L). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The crude was purified by flash column chromatography eluting with hexane/EtOAc (30/1) to give 3,5-dichloro-2-ethylquinoxaline (840 g) as a white solid. 1H NMR (DMSO-d6) δ ppm 8.01-8.08 (m, 2H), 7.84 (t, J=8.0 Hz, 1H), 3.10-3.17 (d, J=7.3 Hz, 2H), 1.36 (t, J=7.3 Hz, 3H). Mass Spectrum (ESI) m/z=227.1 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([B:7]2[O:11][C:10]([CH3:13])([CH3:12])[C:9]([CH3:15])([CH3:14])[O:8]2)=[CH:5][CH:4]=[N:3]1.[Cl:16]N1C(=O)CCC1=O>C1COCC1>[Cl:16][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[B:7]1[O:11][C:10]([CH3:13])([CH3:12])[C:9]([CH3:15])([CH3:14])[O:8]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Solvent: C1CCOC1
Product: Cn1ncc(Cl)c1B1OC(C)(C)C(C)(C)O1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.3 g, 6.3 mmol), N-chlorosuccinimide (0.93 g, 7.0 mmol) and THF (6.6 mL) was stirred at 70° C. for 3 h. The mixture was extracted with EtOAc, dried and concentrated under reduced pressure. The sub-title compound was purified by chromatography on silica gel using 40% EtOAc in hexanes gave the desired compound, 1.456 g, 95%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)C(C)C)(C)C.[C:45]([C:47]1[CH:76]=[CH:75][C:50]([O:51][C:52]2[C:57]([C:58]([N:60]3[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]3)=[O:59])=[CH:56][CH:55]=[C:54]([O:66][C:67]3[CH:72]=[CH:71][C:70]([C:73]#[N:74])=[CH:69][CH:68]=3)[N:53]=2)=[CH:49][CH:48]=1)#[N:46]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11]([N:63]1[CH2:64][CH2:65][N:60]([C:58]([C:57]2[C:52]([O:51][C:50]3[CH:49]=[CH:48][C:47]([C:45]#[N:46])=[CH:76][CH:75]=3)=[N:53][C:54]([O:66][C:67]3[CH:68]=[CH:69][C:70]([C:73]#[N:74])=[CH:71][CH:72]=3)=[CH:55][CH:56]=2)=[O:59])[CH2:61][CH2:62]1)=[O:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: N#Cc1ccc(Oc2ccc(C(=O)N3CCNCC3)c(Oc3ccc(C#N)cc3)n2)cc1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCC(=O)N1CCN(C(=O)c2ccc(Oc3ccc(C#N)cc3)nc2Oc2ccc(C#N)cc2)CC1
Reaction time: 0.17 h

Procedure:
A solution of 3-tert-butoxycarbonylamino-propionic acid, 0.177 g (0.94 mmol), in 3 ml of DMF was added dropwise to a stirred suspension of 0.72 g (3.76 mmol) of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and hydroxybenzotriazole (HOBT) 0.508 g (3.76 mmol) in 5 ml of DMF at RT. That was followed by the addition of N,N-diisopropylethylamine (DIPEA) 0.242 g (1.88 mmol) while the temperature was maintained below 5. The mixture was stirred for 10 min and a solution of 4-[2,6-Bis-(4-cyano phenoxy)pyridine-3-carbonyl]piperazine (0.4 g, 0.94 mmol) in DMF (10 ml) was added followed by stirring overnight at RT. The reaction mixture was concentrated under reduced pressure and partitioned between water (150 ml) and ethyl acetate (150 ml) after the pH was adjusted to 2-3 with 6 N HCl. The organic phase was washed with 1 M Na2CO3 and saturated brine solution, dried over sodium sulphate and concentrated. The crude oily residue was purified by column chromatography using hexane-ethyl acetate (10:2) to afford 0.45 g of the required product. Percentage purity (LCMS): 10.3%. (M+1)=596.2 (with BOC).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[C:15]3[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=3[CH:13]=[C:12]([C:21](O)=[O:22])[CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(Cl)[Cl:27]>O=S(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[C:15]3[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=3[CH:13]=[C:12]([C:21]([Cl:27])=[O:22])[CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: ClCCl
Reactant: CC1(C)Cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)O)cc2O1
Solvent: O=S(Cl)Cl
Product: CC1(C)Cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)Cl)cc2O1
Yield: 94 %

Procedure:
4-(4-Methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (15a) (3.35 g, 9.24 mmol) was dissolved in SOCl2 (50 mL) and DCM (20 mL) and stirred at room temperature for 2 hr. The volatiles were removed to give 3.3 g of a yellow solid (94% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 1.51 (s, 6 H) 2.91 (s, 2 H) 3.06 (s, 3 H) 7.10 (d, J=8.56 Hz, 2 H) 7.30 (s, 1 H) 7.35 (s, 1 H) 7.93 (d, J=8.56 Hz, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=[CH:12][C:13]([O:15]C)=[O:14])[CH:6]=[CH:7][CH:8]=1.O.[OH-].[Li+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=[CH:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C=CC=Cc1cccc(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cccc(C=CC=CC(=O)O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of the product from step (i) (53.2 g) and lithium hydroxide monohydrate (52 g) in methanol (250 ml) and water (100 ml) was stirred at room temperature for 24 hours and partitioned between ethyl acetate and 2M HCl. The organic phase was washed with brine, dried (MgSO4), and evaporated under reduced pressure to afford an orange oil.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[C:8]([OH:15])=[N:9][C:10]([Cl:14])=[C:11]([Cl:13])[CH:12]=1.N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:15][C:8]1[C:7]([Cl:6])=[CH:12][C:11]([Cl:13])=[C:10]([Cl:14])[N:9]=1)[O:4][CH3:5]
Reactant: Oc1nc(Cl)c(Cl)cc1Cl
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Oc1nc(Cl)c(Cl)cc1Cl

Procedure:
Methyl 3,5,6-trichloro-2-pyridyl carbonate was prepared by reacting methyl chloroformate with 3,5,6-trichloro-2-pyridinol at 0° C.-5° C. in the presence of an equivalent of pyridine as acid acceptor and using methylene chloride as the reaction solvent.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[Cl-].[CH3:12][O:13][C:14]1[CH:25]=[CH:24][CH:23]=[CH:22][C:15]=1[CH:16]=[N+:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH3:12][O:13][C:14]1[CH:25]=[CH:24][CH:23]=[CH:22][C:15]=1[CH:16]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1
Reactant: COc1ccccc1C=[N+]1CCCC1
Reactant: Cn1ccc2ccccc21
Agent: [Cl-]
Product: COc1ccccc1C(c1cn(C)c2ccccc12)N1CCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-methyl-1H-indole and 1-(2-methoxy-benzylidene)-pyrrolidinium chloride.
Reaction SMILES: [NH2:1][C:2]([CH3:46])([CH3:45])[CH2:3][NH:4][C:5]([C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@@H:16]2[CH2:20][C@H:19]([N:21]3[CH:25]=[C:24]([CH2:26][OH:27])[CH:23]=[N:22]3)[C@@H:18]([OH:28])[C@H:17]2[OH:29])=[C:9]([NH:30][CH2:31][CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:8]=1)=[O:6].[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[CH2:54]([NH:56][C:57](=[O:103])NCCCNC(C1N=C2C(N=CN2[C@@H]2C[C@H](N3C=C(CO)C=N3)[C@@H](O)[C@H]2O)=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1)=O)[CH3:55]>>[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[CH2:54]([NH:56][C:57](=[O:103])[NH:1][C:2]([CH3:46])([CH3:45])[CH2:3][NH:4][C:5]([C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@@H:16]2[CH2:20][C@H:19]([N:21]3[CH:25]=[C:24]([CH2:26][OH:27])[CH:23]=[N:22]3)[C@@H:18]([OH:28])[C@H:17]2[OH:29])=[C:9]([NH:30][CH2:31][CH:32]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:8]=1)=[O:6])[CH3:55]
Reactant: CC(C)(N)CNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1
Reactant: CCNC(=O)NCCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)NC(C)(C)CNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1

Procedure:
This compound is prepared from 9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid (2-amino-2-methyl-propyl)-amide (Example 84, first step a) using a procedure analogous to that of 9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid [3-(3-ethyl-ureido)-propyl]-amide trifluoroacetate (Example 87).