Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C@:8]2([CH3:26])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:9]2)[C:5]([F:27])=[CH:4][CH:3]=1.[C:28]([C:30]1[CH:31]=[CH:32][C:33]([C:36](O)=[O:37])=[N:34][CH:35]=1)#[N:29].C(N(C(C)C)CC)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CCOC(C)=O.C(=O)(O)[O-].[Na+]>[C:28]([C:30]1[CH:31]=[CH:32][C:33]([C:36]([NH:1][C:2]2[N:7]=[C:6]([C@:8]3([CH3:26])[CH2:13][C@@H:12]([C:14]([F:17])([F:15])[F:16])[O:11][C:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[N:9]3)[C:5]([F:27])=[CH:4][CH:3]=2)=[O:37])=[N:34][CH:35]=1)#[N:29]
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2nc(N)ccc2F)C[C@@H](C(F)(F)F)O1
Reactant: N#Cc1ccc(C(=O)O)nc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2nc(NC(=O)c3ccc(C#N)cn3)ccc2F)C[C@@H](C(F)(F)F)O1
Temperature: 25 °C
Yield: 146.2 %

Procedure:
To a solution of tert-butyl ((4S,6S)-4-(6-amino-3-fluoropyridin-2-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)carbamate (7k, 0.101 mg, 0.13 mmol) in EtOAc (4 mL) was added 5-cyano-2-pyridinecarboxylic acid (0.042 mg, 0.28 mmol, Aldrich), di-isopropylethylamine (0.09 mL, 0.51 mmol), and 1-propanephosphonic acid cyclic anhydride (0.18 mL, 0.28 mmol, 50 wt. % solution in ethyl acetate, Alfa-Aesar). The reaction mixture was stirred at room temperature for 2 hs. The reaction was diluted with saturated aqueous sodium bicarbonate and extracted with EtOAc (10 mL). The organic layer was washed sequentially with water and brine and dried over sodium sulfate. The solution was concentrated under reduced pressure and the crude material was purified via silica gel flash chromatography (gradient 0-30% EtOAc in hexanes) to afford the title compound as a white solid (0.097 g, 0.19 mmol, 72% yield). MS m/z=523.2 [M+H]+. Calculated for C23H22F4N6O4: 522.4
Reaction SMILES: CO.C1COCC1.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:17][C@H:16]2[C:18]([O:20]C)=[O:19])=[CH:11][CH:10]=1.[OH-].[Na+]>O>[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]2[CH2:17][C@H:16]2[C:18]([OH:20])=[O:19])=[CH:13][CH:14]=1
Reactant: COC(=O)[C@@H]1C[C@H]1c1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Nc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
To a 25 mL RB flask fitted with magnetic stirrer was charged 5 mL of methanol: and 5 mL of THF. To the stirred solvent, was added methyl (1R,2R)-2-(4-aminophenyl)cyclo propane carboxylate (1 g, 5.23 mmol) and NaOH (0.627 g, 15.69 mmol) in water (3 mL). The resulting solution was stirred at RT for 3 h. After completion of the reaction (reaction monitored by TLC), solvent was removed under reduced pressure. The RM was diluted with 3 mL of water, cooled to 0° C., then acidified to pH 3 with 1N HCl, and extracted with ethyl acetate (50 mL×2). The organic layer was washed water (50 mL), and saturated brine solution (30 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as white color solid (0.9 g, yield: 97.2%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([OH:23])=[C:14]([C:20](O)=[O:21])[N:15]=[C:16]2[Cl:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:30])[C@@H:27]([CH3:29])[NH2:28]>>[CH3:24][O:25][C:26](=[O:30])[C@H:27]([NH:28][C:20]([C:14]1[N:15]=[C:16]([Cl:19])[C:17]2[C:12]([C:13]=1[OH:23])=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:18]=2)=[O:21])[CH3:29]
Reactant: O=C(O)c1nc(Cl)c2cc(OCc3ccccc3)ccc2c1O
Reactant: COC(=O)[C@@H](C)N
Product: COC(=O)[C@@H](C)NC(=O)c1nc(Cl)c2cc(OCc3ccccc3)ccc2c1O

Procedure:
7-Benzyloxy-1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid, 0.33 g, was coupled with D-Alanine methyl ester analogously to Example A-1 a). 0.246 g of off-white solid were obtained: MS-(+)-ion, M+1=415.0 amu.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]#[C:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:3])[CH3:2].[Cl:16][S:17](O)(=[O:19])=[O:18].C(Cl)(=O)C(Cl)=O>ClCCl>[C:1]([O:4][CH2:5][C:6]#[C:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([S:17]([Cl:16])(=[O:19])=[O:18])=[CH:14][CH:15]=1)(=[O:3])[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)OCC#CCOc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(=O)OCC#CCOc1ccc(S(=O)(=O)Cl)cc1
Temperature: -7.5 °C
Reaction time: 1 h

Procedure:
A 22-L reactor was equipped with a thermometer, a water condenser, a cooling bath/heating mantle, and an addition funnel, and dichloromethane (11 L) was charged. A solution of 4-phenoxy-2-butynyl acetate in dichloromethane (2.04 kg, 10 mol) was charged to the reactor, followed by 2 L of dichloromethane and the solution was cooled −5 to −10° C. Chlorosulfonic acid (0.73 L, 1.28 kg, 11 mol) was added slowly via an addition funnel maintaining temperature between −5 and 0° C. After the addition was complete, the cooling bath was removed and the reaction mixture was stirred for 1–2 h at 18–22° C. The progress of the reaction was monitored by TLC or HPLC (disappearance of starting material). DMF (155 mL, 146 g) was added portion wise. The reaction mixture was heated to reflux (38–40° C.). Oxalyl chloride (1.13 L, 1.65 kg, 13 mol) was added through an addition funnel into the boiling solution over a period of 2–3 h maintaining gentle reflux. After all the oxalyl chloride was added, reflux was continued for 1 h. The completion of reaction was checked by HPLC (less than 3% of intermediate sulfonic acid remaining). After completion, the heating was stopped and the reaction mixture was cooled to 18–22° C. and stirred for 16 h. The reaction mixture was quenched into a 50-L reactor with 5 L of cold (5 to 10° C.) water and stirred for 10–20 min while maintaining the temperature below 20° C. The organic layer was separated and the aqueous layer was extracted with (2 L) of fresh dichloromethane. The combined organic layers were washed with 4 L of sodium bicarbonate solution until pH=7–8. The dichloromethane layer was separated and concentrated in vacuo at 35–40° C. to a volume of 5 to 7 L. This solution was mixed with 3 kg of silica gel and concentrated in vacuo until a free-flowing powder was obtained. The silica gel powder was transferred to a filter funnel with a Celite bed and eluted with 22 L of isopropyl ether. The ether solution was concentrated in vacuo to yield about 3 L of a slightly viscous liquid. This residue was transferred to a 5-L reaction flask with overhead stirrer, seeded and stirred for 16–18 h at 18–22° C. Crystallization began after several hours. Stirring continued at low temperature (0 to −10° C.). The solid was filtered on Buchner funnel lined with polypropylene and washed with 2 L of cold (5° C.) IPE, then dried under vacuum (30 mm) at 18–20° C. to yield 1.1 kg (55%, HPLC strength 94.8%) of product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)=[O:16].C(N(CC)CC)C.[Cl:37][CH2:38][C:39](Cl)=[O:40]>ClCCl>[Cl:37][CH2:38][C:39]([N:6]([CH2:5][C:4]1[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:3]=1[O:2][CH3:1])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[C:15](=[O:16])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)=[O:40]
Reactant: COc1ccc(CNc2ccc(OC)cc2C(=O)c2cccc(F)c2)c(OC)c1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN(C(=O)CCl)c2ccc(OC)cc2C(=O)c2cccc(F)c2)c(OC)c1
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of {2-[(2,4-dimethoxybenzyl)amino]-5-methoxyphenyl}(3-fluorophenyl)methanone (190 mg, 0.480 mmol) in 5 mL of dichloromethane was added triethylamine (0.335 mL, 2.40 mmol), followed by chloroacetyl chloride (0.115 mL, 1.44 mmol). After 30 minutes, another portion of chloroacetyl chloride (0.115 mL, 1.44 mmol) was added, and the mixture was stirred overnight. The reaction was partitioned between EtOAc and saturated NaHCO3 solution, and the organic layer was washed with saturated NH4Cl solution and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The titled product was isolated as a brown foam (229 mg, 100% yield) which was used in the next step without further purification ESI+MS: 472.1 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:10]([O:12]C)=O)=[N:5][C:6]([Cl:9])=[CH:7][CH:8]=1.[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1>CO>[Cl:9][C:6]1[N:5]=[C:4]2[C:10](=[O:12])[N:20]([CH2:19][C:18]3[CH:21]=[CH:22][C:15]([F:14])=[CH:16][CH:17]=3)[CH2:2][C:3]2=[CH:8][CH:7]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1nc(Cl)ccc1CBr
Solvent: CO
Product: O=C1c2nc(Cl)ccc2CN1Cc1ccc(F)cc1
Yield: 71.3 %

Procedure:
A solution of methyl 3-(bromomethyl)-6-chloropicolinate (100 mg, 0.38 mmol) and 4-fluorobenzylamine (237 mg, 1.89 mmol) in MeOH (10 mL) was stirred at 15° C. overnight. After the reaction, it was filtered to afford crude 2-chloro-6-(4-fluorobenzyl)-5H-pyrrolo[3,4-b]pyridin-7(6H)-one (75 mg, yield: 72%). 1H-NMR (CDCl3, 400 MHz) δ 7.73 (d, J=8.0 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.28˜7.31 (m, 2H), 7.05 (t, J=8.4 Hz, 2H), 4.82 (s, 2H), 4.25 (s, 2H). MS (M+H)+: 277/279.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH2:18])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH2:12][C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[S:39](=[O:47])(=[O:46])[N:38]=1.ClCCl.C(OCC)(=O)C>ClCCl>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH:18][C:37]3[C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=4[S:39](=[O:46])(=[O:47])[N:38]=3)[N:13]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH2:12][C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Reactant: COc1ccc(CN2Cc3sc(N)c(C(=O)OC(C)(C)C)c3CC2CN)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(CN2Cc3sc(N)c(C(=O)OC(C)(C)C)c3CC2CNC2=NS(=O)(=O)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
To a solution of 2-amino-5-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (155 mg, 0.384 mmol) and triethylamine (59 μl, 0.423 mmol) in dichloromethane (2 ml) at 0° C., was added a solution of 3-chloro-benzo[d]isothiazole 1,1-dioxide (85.2 mg, 0.423 mmol) in dichloromethane (2 ml). The reaction mixture was stirred at 0° C. for 1 hour. The reaction was judged complete by tic (dichloromethane/ethyl acetate (1:1)). The reaction mixture was washed with water (3×20 ml), dried (MgSO4), filtered and the solvent evaporated in vacuo. The crude residue was subjected to flash chromatography using a gradient from 100% dichloromethane to dichloromethane/ethyl acetate (80/20) as eluent, which afforded 200 mg (92%) of 2-amino-5-((1,1-dioxo-1H-benzo[d]isothiazol-3-ylamino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as a foam.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:9]=[CH:10][C:5]2=[C:4]([N:17]2[CH2:23][CH:22]3[O:24][CH:19]([CH2:20][CH2:21]3)[CH2:18]2)[N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O>[CH:19]12[O:24][CH:22]([CH2:21][CH2:20]1)[CH2:23][N:17]([C:4]1[N:3]=[C:2]([C:33]3[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=3)[N:7]=[C:6]3[N:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[N:9]=[CH:10][C:5]=13)[CH2:18]2
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: Clc1nc(N2CC3CCC(C2)O3)c2cnn(-c3ccccc3)c2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(-c4ccccc4)c3n2)cc1

Procedure:
6-Chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine (2.5 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.0 mmol) are dissolved in a microwave vial in DME (18 mL). Na2CO3 (2.5 mL, 2M in water) is added along with a catalytic amount of tetrakis triphenylphosphine palladium. The mixture is heated in a sealed tube under microwave irradiation at 185 C for 40 min. The mixture is diluted with 50 mL EtOAc and washed with a saturated solution of NaHCO3 (2×50 mL). The aqueous layers are extracted with EtOAc (50 mL) and the combined organic layers are dried over MgSO4, filtered and concentrated in vacuo. Purification gives the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][NH2:11].[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][N:23]([C:26]2[S:27][C:28]([C:32](O)=[O:33])=[C:29]([CH3:31])[N:30]=2)[C:22](=[O:35])[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][NH:11][C:32]([C:28]1[S:27][C:26]([N:23]2[CH:24]=[CH:25][C:20]([O:19][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:21][C:22]2=[O:35])=[N:30][C:29]=1[CH3:31])=[O:33]
Reactant: NCc1cc2ccccc2[nH]1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1cc2ccccc2[nH]1
Yield: 22 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use (1H-indol-2-yl)methanamine in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 22% yield: 1H NMR (300 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.73 (t, J=5.6 Hz, 1H), 8.62 (d, J=8.1 Hz, 1H), 7.45-7.29 (m, 7H), 7.01-6.87 (m, 2H), 6.39 (dd, J=8.1, 2.7 Hz, 1H), 6.25-6.22 (m, 2H), 5.16 (s, 2H), 4.53 (d, J=5.6 Hz, 2H), 2.56 (s, 3H); MS (ES+) m/z 471.2 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[Cl:8][C:9]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:10]=1[CH2:11][O:12][C@H:13]1[O:18][C@@H:17]([CH2:19]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:16][CH2:15][CH2:14]1>>[Cl:8][C:9]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:10]=1[CH2:11][O:12][C@H:13]1[O:18][C@@H:17]([CH2:19][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:16][CH2:15][CH2:14]1
Reactant: c1c[nH]cn1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCC[C@@H](OCc3c(Cl)cccc3Cl)O2)cc1
Agent: [H-]
Agent: [Na+]
Product: Clc1cccc(Cl)c1CO[C@@H]1CCC[C@H](Cn2ccnc2)O1
Yield: 107 %

Procedure:
Using 103 mg of imidazole, 66 mg of 55% sodium hydride and 161 mg of cis-6-(2,6-dichlorobenzyloxy)-2-tosyloxymethyltetrahydropyran, the procedure described in Example 1(b) was repeated to give 132 mg of the title product in the form of a colourless oil.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:12][CH2:11][C:6]3(OCC[O:7]3)[CH2:5][CH2:4]2)[CH2:2]1.[OH-].[Na+].C([O-])(O)=O.[Na+]>C1COCC1.O.C(O)(C(F)(F)F)=O>[CH2:2]1[C:3]2([CH2:12][CH2:11][C:6](=[O:7])[CH2:5][CH2:4]2)[CH2:1]1
Reactant: C1COC2(CCC3(CC3)CC2)O1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCC2(CC1)CC2
Yield: 138.8 %

Procedure:
A solution of 7,10-dioxa-dispiro[2.2.4.2]dodecane (6.25 g, approx. 29 mmol) in THF (25 mL), water (20 mL) and TFA (10 mL) is stirred at it for 2 h. The mixture is neutralized by adding 2 N aq. NaOH and sat. NaHCO3 solution and extracted with diethyl ether. The organic extracts are washed with water, dried over Na2SO4, filtered and the solvent of the filtrate is removed to give spiro[2.5]octan-6-one (5.0 g) as a colourless oil containing remainders of toluene (product volatile). 1H NMR (CDCl3): δ 2.14 (t, J=6.4 Hz, 4H), 1.40 (t, J=6.4 Hz, 4H), 0.21 (s, 4H).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[I-].[Na+].Cl[CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[N:21]([CH2:34][CH2:35][CH3:36])[N:22]=[C:23]2[C:32]=1[C:31]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:25]=[C:24]2[NH2:33]>CN(C=O)C>[NH2:33][C:24]1[C:23]2=[N:22][N:21]([CH2:34][CH2:35][CH3:36])[C:20]([CH2:19][CH2:18][CH2:17][CH2:16][N:5]3[C:1](=[O:11])[C:2]4[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4]3=[O:6])=[C:32]2[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:25]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CCCCCl
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1nc2c(N)nc3ccccc3c2c1CCCCN1C(=O)c2ccccc2C1=O
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 93.8 %

Procedure:
A mixture of potassium phthalimide (6.61 g, 35.7 mmol), sodium iodide (0.669 g, 4.46 mmol) and 1-(4-chlorobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared as described in Example 46, 5.65 g, 17.8 mmol) in DMF (30 mL) was heated at 90° C. for 3 hours. The reaction mixture was allowed to cool to room temperature overnight, then was diluted with ice water (300 mL) and stirred for 10 minutes. A solid formed that was collected by filtration and dried to yield 7.14 g of 2-[4-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl]-1H-isoindole-1,3 (2H)-dione as a tan solid, mp 204-206° C. 1H-NMR (300 MHz, CDCl3) δ 7.86-7.70 (m, 5H), 7.69-7.64 (m, 1H), 7.43-7.36 (m, 1H), 7.29-7.22 (m, 1H), 5.37 (br s, 2H), 4.30 (t, J=7.3 Hz, 2H), 3.77 (t, J=6.8 Hz, 2H), 3.31-3.21 (m, 2H), 2.05-1.75 (m, 6H), 0.98 (t, J=7.4 Hz, 3H).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[C:16]([CH2:18][OH:19])[CH:15]=[C:14]([C:20]([F:23])([F:22])[F:21])[N:13]=3)[CH2:7][CH2:6]2)[O:4]CC1.Cl.O.C([O-])(O)=O.[Na+]>CC(C)=O>[OH:19][CH2:18][C:16]1[CH:15]=[C:14]([C:20]([F:22])([F:23])[F:21])[N:13]=[C:12]([O:11][CH:8]2[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]2)[CH:17]=1
Reactant: OCc1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCC(Oc2cc(CO)cc(C(F)(F)F)n2)CC1
Reaction time: 16 h

Procedure:
[2-(1,4-Dioxaspiro[4.5]dec-8-yloxy)-6-(trifluoromethyl)pyridin-4-yl]methanol was dissolved in acetone (8 mL) and 10.0 M hydrogen chloride in water (1.5 mL, 15 mmol) was added. The reaction was stirred for 16 hours and LCMS analysis showed it was mostly complete. The reaction was neutralized with NaHCO3 and partitioned between EtOAc and water. The EtOAc extracts were washed with brine, dried and evaporated in vacuo. The crude product was used in the next reaction. MS (ES): 290 (M+1)
Reaction SMILES: [C:1]([N:8]1[C@@H:12]([C:13]#[CH:14])[CH2:11][O:10]C1(C)C)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O>[C:1]([NH:8][C@@H:12]([C:13]#[CH:14])[CH2:11][OH:10])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: C#C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: C#C[C@@H](CO)NC(=O)OC(C)(C)C

Procedure:
A solution of (S)-N-Boc-2,2-dimethyl-4-ethynyl-oxazolidine (200 mg, 0.89 mmol) (Example 93A above) in a mixture of MeOH (25 mL) and water (2 mL) was treated with p-toluenesulfonic acid monohydrate (16 mg, 0.09 mmol) according to the procedure that described above in Example 104A. (Yield 120 mg, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([OH:42])=[C:18]([CH:41]=2)[NH:19][C:20](=[O:40])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=[CH:28][C:29]3[S:30][CH:31]=[C:32]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:33]=3)[CH:22]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52]>CN(C)C=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:42][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])=[C:18]([NH:19][C:20](=[O:40])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=[CH:28][C:29]4[S:30][CH:31]=[C:32]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[N:33]=4)[CH:22]=3)[CH:41]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Nc1cc(CCCS(=O)(=O)c2ccc(Cl)cc2)ccc1O)c1cccc(C=Cc2nc(-c3ccccc3)cs2)c1
Reactant: CCOC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(CCCS(=O)(=O)c2ccc(Cl)cc2)cc1NC(=O)c1cccc(C=Cc2nc(-c3ccccc3)cs2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 52 %

Procedure:
5'-[3-(4-Chlorophenylsulfonyl)propyl]-2'-hydroxy-3-[2-(4-phenyl-2-thiazolyl)vinyl]benzanilide (0.60 g, 0.98 mmol) was dissolved in dimethylformamide (6 ml), potassium carbonate (0.20 g, 1.45 mmol), a catalytically effective amount of tetrabutylammonium bromide and ethyl bromoacetate (0.13 ml, 1.17 mmol) were added in that order under ice-cooling, followed by 12 hours of stirring at room temperature. Ice-water was added to the reaction solution and the product formed was extracted twice with benzene-ethyl acetate mixed solution (1:1). The resulting organic layer was washed with 5% potassium carbonate aqueous solution and brine in that order, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent=acetone:chloroform=1:100) and crystallized from acetonitrile to give ethyl 4-[3-(4-chlorophenylsulfonyl)propyl]-2-[3-[2-(4-phenyl-2-thiazolyl)vinyl]benzoylamino]phenoxyacetate (0.36 g, 0.51 mmol, 53%) as colorless crystals.
Reaction SMILES: [SH2:1].[Br:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].C(N(CC)CC)C>N1C=CC=CC=1>[Br:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]([NH2:6])=[S:1]
Reactant: N#Cc1ccccc1Br
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: NC(=S)c1ccccc1Br
Temperature: 0 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
Gaseous hydrogen sulfide was bubbled into a stirred solution of 1.82 g (10.0 mmol) of 2-bromobenzonitrile, 13 mL of triethylamine and 10 mL of pyridine. After 4 hours, the reaction mixture was poured into 200 mL of ice-water mixture. The resultant oil slowly crystallized. The precipitate was removed by filtration, washed with water (3×) and dissolved in methylene chloride. The organic layer was separated, dried over magnesium sulfate and filtered. The filtrate was evaporated under vacuum to give 1.46 g (6.76 mmol, 68%) of the product. 1H NMR (200 MHz, CDCl3): 7.24 (m, 4H), 7.52 (dt, 1H), 8.59 (dd, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:23]=[CH:22][CH:21]=[CH:20][C:14]=2C(OCC)=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.S([O-])([O-])(=O)=O.[Na+].[Na+].C1C[O:41][CH2:40]C1>>[OH:41][CH2:40][C:20]1[CH:21]=[CH:22][N:23]=[C:13]([C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:14]=1
Reactant: CCOC(=O)c1cccnc1-c1cc(OC)c(OC)c(OC)c1
Reactant: C1CCOC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Product: COc1cc(-c2cc(CO)ccn2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl 2-(3,4,5-trimethoxyphenyl)nicotinate (27.70 g) was dissolved in THF (200 mL), and to the solution lithium aluminum hydride (3.31 g) was added at 0° C. under an argon atmosphere, and the mixture was stirred at 0° C. for 1 hour as it is. A small amount of water and then sodium sulfate were added to the reaction mixture, and the reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and the resultant crystals were recrystallized from ethyl acetate-hexane to obtain the title compound.