Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:13](=[O:17])[O:14]2)=[CH:9][CH:8]=1)(=O)=O.[C:28]([OH:31])#[C:29][CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.Cl>O1CCOCC1.CC#N.CC#N.Cl[Pd]Cl.O>[OH:31][CH2:28][C:29]#[C:30][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:13](=[O:17])[O:14]2)=[CH:9][CH:8]=1
Reactant: COc1ccc(-c2cc3ccc(OS(=O)(=O)C(F)(F)F)cc3oc2=O)cc1
Reactant: CC#CO
Agent: Cl[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CC#N
Product: COc1ccc(-c2cc3ccc(C#CCO)cc3oc2=O)cc1

Procedure:
6.90 g (17.2 mmol) of 3-(4-methoxyphenyl)-2-oxo-2H-chromen-7-yl trifluoromethanesulfonate, 1.5 ml (25.4 mmol) of propyn-1-ol, 12.0 g (36.8 mmol) of caesium carbonate, 150 mg (0.578 mmol) of bis(acetonitrile)palladium(II) chloride and 800 mg (1.68 mmol) of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl are left to stir at 60° C. for 3 h in 100 ml of dioxane, added to 400 ml of water and acidified using 2 N hydrochloric acid. The aqueous phase is extracted three times with ethyl acetate, and the combined org. phases are washed with water and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is filtered through silica gel with toluene/ethyl acetate (4:1). Crystallisation of the crude product from toluene/ethyl acetate (10:1) gives 7-(3-hydroxyprop-1-ynyl)-3-(4-methoxyphenyl)chromen-2-one as yellow crystals.
Reaction SMILES: C(OC([N:8]([CH2:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[NH:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[N:40]([CH3:41])[N:39]=[N:38][N:37]=2)[CH:31]=1)=[O:28])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=O)(C)(C)C.Cl>O1CCOCC1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][CH2:9][NH:8][CH2:19][C@@H:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]2[NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]3[N:40]([CH3:41])[N:39]=[N:38][N:37]=3)[CH:31]=2)=[O:28])=[CH:13][CH:14]=1
Reactant: Cn1nnnc1-c1cccc(NC(=O)N[C@@H]2CCCC[C@H]2CN(CCCc2ccc(F)cc2)C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1nnnc1-c1cccc(NC(=O)N[C@@H]2CCCC[C@H]2CNCCCc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.6 %

Procedure:
The product of Step j (90 mg) and 4N HCl in dioxane (50 mL) were mixed and stirred at room temperature for 3 hours. The reaction was stripped on the rotary evaporator and restripped twice from isopropanol on the rotary evaporator to yield 76 mg of a glass. MS (ESI) detects (M+H)+=466.3.
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[N:16]([CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:15]=2[CH2:37][CH2:38][NH2:39])[CH3:11])=[CH:6][CH:5]=1.[Cl:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[S:48](Cl)(=[O:50])=[O:49]>>[CH:24]([N:16]1[C:17]2[C:22](=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:14]([CH2:13][CH2:12][N:10]([CH3:11])[C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:2])=[O:40])=[CH:9][CH:8]=2)=[C:15]1[CH2:37][CH2:38][NH:39][S:48]([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=1[Cl:41])(=[O:50])=[O:49])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: COC(=O)c1ccc(N(C)CCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: CN(CCc1c(CCNS(=O)(=O)c2ccccc2Cl)n(C(c2ccccc2)c2ccccc2)c2ccc(Cl)cc12)c1ccc(C(=O)O)cc1
Yield: 96 %

Procedure:
The intermediate from example 146 step 7 was treated with 2-chlorobenzenesulfonyl chloride according to the procedure in Example 87 step 2 to generate the desired product in 96% yield.
Reaction SMILES: [I:1]I.[Cl:3][C:4]1[CH:5]=[C:6]([Cl:14])[C:7]2[O:11][C:10]([CH3:12])=[CH:9][C:8]=2[CH:13]=1.[N+]([O-])([O-])=O.[Na+]>C(O)(=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([Cl:14])[C:7]2[O:11][C:10]([CH3:12])=[C:9]([I:1])[C:8]=2[CH:13]=1
Reactant: Cc1cc2cc(Cl)cc(Cl)c2o1
Reactant: II
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1oc2c(Cl)cc(Cl)cc2c1I
Temperature: 85 °C
Reaction time: 6 h

Procedure:
A suspension of 1.7 mmol of pulverized iodine in 10 ml of glacial acetic acid is admixed with 3 mmol of 5,7-dichloro-2-methylbenzofuran [42969-57] and with 0.3 mmol of sodium nitrate. The mixture is stirred at 85° C. for 6 hours. If necessary further sodium nitrate is added after 1 hour. The reaction mixture is cooled to room temperature and quenched with 10% sodium hydrogen sulphite solution, and tert-butyl methyl ether is added. The phases are separated and the aqueous phase is extracted with tert-butyl methyl ether (3×). The combined organic phases are washed with brine, dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60F) on the basis of the Rf value.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[O:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH:5]1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1.C(N(CC)CC)C.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37].O>C1COCC1>[Cl:25][C:20]1[CH:19]=[C:18]([CH:5]2[CH:4]([CH2:3][CH2:2][NH:1][C:36](=[O:37])[CH2:35][O:34][CH3:33])[O:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]2)[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: COCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCOC(CCN)C(c2ccc(Cl)c(Cl)c2)C1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC(=O)NCCC1OCCN(C(=O)OC(C)(C)C)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (6RS,7RS)-7-(2-aminoethyl)-6-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (140 mg) obtained in Example 484, step A in THF (3.0 ml) were added triethylamine (0.150 ml) and methoxyacetyl chloride (0.066 ml) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (157 mg).
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:5][CH:4]=1)=[CH2:2].B1C2CCCC1CCC2.[OH-:30].[Na+].OO>C1COCC1.O>[OH:30][CH2:2][CH2:1][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:5][CH:4]=1
Reactant: C=Cc1ccc(NC(=O)OC(C)(C)C)c2ccccc12
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(CCO)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.2 %

Procedure:
To a solution of tert-butyl 4-vinylnaphthalen-1-ylcarbamate (31) (0.83 g, 3.08 mmol) in THF (10 mL) was added 9-BBN (0.5M in THF, 9.9 mL, 4.95 mmol) dropwise under nitrogen at 0° C. The mixture was warmed to RT and stirred for 16 hr. Water (1 mL), aqueous NaOH solution (3M, 10.0 mL, 30 mmol) and hydrogen peroxide (35% in water, 8.0 mL) were added. The reaction mixture was warmed to 50° C. and stirred for 2 hr and was then extracted with ethyl acetate. The ethyl acetate extract was washed with water and brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 10-60% ethyl acetate in isohexane, gradient elution) to afford the title compound (32) (0.763 g, 86%); m/z 288 (M+H)+, (ES+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([I:13])[C:8]([CH3:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:14][C:15]([F:24])([F:23])[C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>>[I:13][C:7]1[C:8]([CH3:12])=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][N:3]=[C:2]2[NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[C:16]([C:15]([F:14])([F:23])[F:24])[CH:17]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc2c(Cl)nccc2c1I
Product: Cc1ccc2c(Nc3cccc(C(F)(F)F)c3)nccc2c1I
Temperature: 140 °C
Reaction time: 0.33 h
Yield: 49.9 %

Procedure:
To a solution of 1-chloro-5-iodo-6-methylisoquinoline (0.400 g, 1.32 mmol) in EPA (5.00 ml), charged to a 5 mL microwave reaction vessel, 3-(trifluoromethyl)aniline (0.329 ml, 2.64 mmol) was added. The reaction mixture was stirred at 140° C. for 20 min. The resulting ppt was collected by filtration and washed with excess IPA. The solid was dried under vacuum to give 5-iodo-6-methyl-N-(3-(trifluoromethyl)phenyl)isoquinolin-1-amine (0.282 g, 50.0% yield) as a pale solid. MS (M+H)+ 429.
Reaction SMILES: [CH2:1]([CH:3]1[O:8][C:7]2[CH:9]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([CH3:27])([CH3:26])[C:22]([O:24][CH3:25])=[O:23])=[N:17][CH:18]=3)[CH:11]=[CH:12][C:6]=2[NH:5][CH2:4]1)[CH3:2].N1C=CC=CC=1.[Cl:34][C:35](Cl)([O:37]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Cl:34][C:35]([N:5]1[CH2:4][CH:3]([CH2:1][CH3:2])[O:8][C:7]2[CH:9]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([CH3:26])([CH3:27])[C:22]([O:24][CH3:25])=[O:23])=[N:17][CH:18]=3)[CH:11]=[CH:12][C:6]1=2)=[O:37]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCC1CNc2ccc(-c3ccc(OCC(C)(C)C(=O)OC)nc3)cc2O1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC1CN(C(=O)Cl)c2ccc(-c3ccc(OCC(C)(C)C(=O)OC)nc3)cc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A solution of methyl 3-(5-(2-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)pyridin-2-yloxy)-2,2-dimethylpropanoate B-10 (248.0 mg, 0.60 mmol) and dry pyridine (97.0 μL, 1.20 mmol) in anhydrous methylene chloride (3.0 mL) was added dropwise to a solution of triphosgene (71.2 mg, 0.24 mmol) in anhydrous methylene chloride (3.0 mL) at −20° C. under an atmosphere of argon. The reaction mixture was allowed to warm to room temperature over 30 mins and was stirred for 3 h at room temperature. It was then successively diluted with methylene chloride (25 mL), quenched with a 1 N aqueous solution of hydrogen chloride (1.0 mL), diluted with water (10 mL) and decanted. The aqueous layer was extracted with methylene chloride (3×30 mL); the combined extracts were washed with a 1 N aqueous solution of hydrogen chloride (20 mL), brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The light pink solid methyl 3-(5-(4-(chlorocarbonyl)-2-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)pyridin-2-yloxy)-2,2-dimethylpropanoate B-11 (265.0 mg, Yield=100%) was used for the next step without purification and stored at −20° C. under an atmosphere of nitrogen. MS (ESI) [M+1]+ 433.
Reaction SMILES: [C:1]([Si:5]([CH3:31])([CH3:30])[O:6][CH2:7][C@@H:8]([C@@H:17]1[C@@H:21]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)[CH2:20][NH:19][CH2:18]1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:32][C:33]1[N:38]=[N:37][CH:36]=[C:35]([C:39](O)=[O:40])[CH:34]=1>>[C:1]([Si:5]([CH3:31])([CH3:30])[O:6][CH2:7][C@@H:8]([C@@H:17]1[C@@H:21]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)[CH2:20][N:19]([C:39]([C:35]2[CH:34]=[C:33]([CH3:32])[N:38]=[N:37][CH:36]=2)=[O:40])[CH2:18]1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](Oc1ccc(Cl)cn1)[C@H]1CNC[C@@H]1c1ccc(F)c(F)c1
Reactant: Cc1cc(C(=O)O)cnn1
Product: Cc1cc(C(=O)N2C[C@H]([C@H](CO[Si](C)(C)C(C)(C)C)Oc3ccc(Cl)cn3)[C@@H](c3ccc(F)c(F)c3)C2)cnn1

Procedure:
The titled compound was prepared following a general procedure I for amidation between 2-{(R)-2-(tert-butyl-dimethyl-silanyloxy)-1-[(3R,4S)-4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethoxy}-5-chloro-pyridine and 6-Methyl-pyridazine-4-carboxylic acid . ES-MS m/e: 589.1 (M+H+).
Reaction SMILES: [C:1]1([N:10]2[CH2:14][CH2:13][C@H:12]([NH:15][C:16]([C:18]3[N:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][N:19]=3)=[O:17])[CH2:11]2)[C:2]2[N:3]([CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:5][N:6]=1>CO.[Pd]>[CH2:24]([C:21]1[CH:20]=[N:19][C:18]([C:16]([NH:15][C@H:12]2[CH2:13][CH2:14][N:10]([C:1]3[C:2]4[N:3]([CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:5][N:6]=3)[CH2:11]2)=[O:17])=[N:23][CH:22]=1)[CH3:25]
Reactant: C=Cc1cnc(C(=O)N[C@H]2CCN(c3nccn4cccc34)C2)nc1
Agent: [Pd]
Solvent: CO
Product: CCc1cnc(C(=O)N[C@H]2CCN(c3nccn4cccc34)C2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 208.3 %

Procedure:
To a solution of (S)—N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)-5-vinylpyrimidine-2-carboxamide (0.04 g, 0.12 mmol, 1 eq) in 1 mL of MeOH was added 10% Pd/C (0.013 g, 0.01 mmol, 0.1 eq). The reaction mixture was equipped with a H2 balloon and stirred for 1 hr at room temperature. The contents were filtered and the purified by HPLC to afford (S)-5-ethyl-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide (0.009 g, 0.25 mmol, 22%). 1H NMR (400 MHz, CD3OD) δ 8.80 (s, 2 H), 7.76 (m, 1 H), 7.71 (d, J=5.8 Hz, 1 H), 7.54 (s, 1 H), 6.92 (dd, J=2.6, 4.4 Hz, 1 H), 6.84 (d, J=5.5 Hz, 1 H), 5.00-3.60 (br, 5 H), 2.81 (q, J=7.4 Hz, 2 H), 2.65-2.30 (br, 2 H), 1.33 (t, J=7.4 Hz, 3 H); MS: (ES) m/z calculated for C17H18N6O [M+H]+337.2, found 337.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([O:18][CH:19]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.ClC1C=CC=CC=1C(OC1CNC1)C1C=CC(Cl)=CC=1>>[F:29][C:26]([F:27])([F:28])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH:19]([O:18][CH:16]1[CH2:17][NH:14][CH2:15]1)[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1
Reactant: COc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccccc2C(F)(F)F)cc1
Agent: Cl
Agent: Clc1ccc(C(OC2CNC2)c2ccccc2Cl)cc1
Product: COc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Yield: 28.9 %

Procedure:
The corresponding hydrochloride salt was prepared from 1-benzhydryl-3-[2-(trifluoromethyl)-4′-methoxybenzyloxy]azetidine (156) (7.5 mmol) using the procedure described for compound (9). Due to the presence of impurities, the salt was partitioned between aqueous base and an organic solvent, the organic phase dried (MgSO4) and evaporated to afford the desired product as a colourless oil (730 mg, 29%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([F:11])[F:10])=[CH:4][C:3]=1[CH2:12][C:13]#[N:14].[CH2:15]([OH:17])C.C=O.C1CCN2C(=NCCC2)CC1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([F:11])[F:10])=[CH:4][C:3]=1[CH:12]([CH2:15][OH:17])[C:13]#[N:14]
Reactant: CCO
Reactant: N#CCc1cc(OC(F)F)ccc1Cl
Agent: C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: N#CC(CO)c1cc(OC(F)F)ccc1Cl
Reaction time: 0.83 h
Yield: 65 %

Procedure:
A 25 mL flask with a stir bar was charged with 3.0 g (13.8 mmol) of 2-(2-chloro-5-(difluoromethoxy)phenyl)ethanenitrile, 12 mL of ethanol and 1.34 mL of 37% formaldehyde solution. The mixture was stirred and a mixture of 115 μL of 40% Triton B in methanol and 38 μL of DBU was added. After a very mild exotherm, all solids dissolved. After 50 minutes at ambient temperature, the reaction was quenched by the addition of 0.5 mL of 3 N HCL. The mixture was filtered to remove floc, diluted with 2 volumes of water and extracted with butyl chloride. The extracts were water washed and stripped to an oil. This was chromatographed on 35 g of silica gel eluting with 5%→60% EtOAc in hexane to recover 2.2 g (65% yield.) of the desired product, Rf 0.18 (silica gel, EtOAc:hexane=1:4).
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:6])[CH3:5].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:25][CH2:26][O:27][CH2:28][CH2:29][OH:30]>CN(C)C=O>[OH:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][S:1][CH2:2][CH2:3][C:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:6])[CH3:5]
Reactant: OCCOCCCl
Reactant: CC(C)(CCS)NC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(CCSCCOCCO)NC(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
The crude benzyl 4-mercapto-2-methylbutan-2-ylcarbamate (2.83 g, 10.2 mmol) from the previous reaction was dissolved into dimethylformamide (60 mL). Cesium carbonate (6.65 g, 2 equiv, 20.4 mmol) was added in one portion to the solution to give a suspension followed by 2-(2-chloroethoxy)ethanol (1.39 g, 11.2 mmol). The flask was sealed with a septum and vigorously stirred at 50° C. under nitrogen atmosphere for 16 hours. The suspension was concentrated to an oily solid residue. This material was mixed with ethyl acetate (200 mL) and water (50 mL). The layers were separated and the organic layer was washed with brine (2×50 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to a yellow oil. The crude oil was used without purification (2.23 g, 64.3%). LRMS (ESI/APCI) m/z 342 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:10]2[CH:15]=[C:14]([Cl:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[C:10]3[CH:15]=[C:14]([Cl:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(Cl)cc23)cc1OC
Product: COc1ccc(CNc2nc(-n3cncn3)nc3sc(Cl)cc23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2,6-dichloro-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-chloro-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:14])[C:6]1[CH:11]=[C:10]([Cl:12])[C:9](Cl)=[N:8][CH:7]=1)([CH3:3])[CH3:2].[CH2:15]([NH:17][CH3:18])[CH3:16]>CC(=O)OCC>[CH:1]([O:4][C:5](=[O:14])[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([N:17]([CH2:15][CH3:16])[CH3:18])=[N:8][CH:7]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1cnc(Cl)c(Cl)c1
Reactant: CCNC
Solvent: CCOC(C)=O
Product: CCN(C)c1ncc(C(=O)OC(C)C)cc1Cl
Temperature: 105 °C
Reaction time: 72 h
Yield: 90.5 %

Procedure:
A mixture of 5,6-dichloro nicotinic acid isopropyl ester (4.76 g, 22.3 mmol) and ethylmethylamine (6.88 g, 116.4 mmol) is stirred in a sealed vessel at 105° C. for 72 h. The mixture is cooled to rt, diluted with EA (300 mL) and washed with sat. aq. NaHCO3-solution (3×10 mL) followed by brine (10 mL). The org. extract is dried over MgSO4, filtered, concentrated and dried to give 5-chloro-6-(ethyl-methyl-amino)-nicotinic acid isopropyl ester (5.18 g) as a yellow oil; LC-MS: tR=1.38 min, [M+1]+=257.02; 1H NMR (D6-DMSO): δ 1.19 (t, J=6.8 Hz, 3H), 1.30 (d, J=6.0 Hz, 6H), 3.08 (s, 3H), 3.55 (q, J=7.0 Hz, 2H), 5.10 (hept, J=6.3 Hz, 1H), 7.98 (s, 1H), 8.58 (s, 1H).
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[NH:2]1.Cl[C:13]([O:15][CH2:16][CH3:17])=[O:14]>CCN(CC)CC>[O:11]=[C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[N:2]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 56 %

Procedure:
To a solution of isoindoline-1,3-dione (2 g, 13.6 mmol) in Et3N (60 mL) was added ClCOOEt (2.55 g, 16.33 mmol) at 0° C. The mixture was warmed to room temperature and stirred at room temperature for 4 h. The mixture was filtered and the solid was partitioned between water (150 mL) and EtOAc (50 mL) and adjusted pH value to 6 with 1 N HCl. The organic layer was washed with brine and dried over Na2SO4, filtered and concentrated in vacuo to give ethyl 1,3-dioxoisoindoline-2-carboxylate (1.67 g, 53.08%) as a white solid.
Reaction SMILES: [C:1]([O:4][C@H:5]1[O:22][C@H:21]([CH2:23][O:24]C(=O)C)[C@@H:16]([O:17]C(=O)C)[C@H:11]([O:12]C(=O)C)[C@@H:6]1[O:7]C(=O)C)(=O)[CH3:2].OC1C=[CH:31][C:32]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([O:47][CH3:48])=[O:46])[CH:40]=2)=[C:33]([CH:38]=1)[C:34]([O:36][CH3:37])=[O:35]>>[CH3:48][O:47][C:45]([C:41]1[CH:40]=[C:39]([C:32]2[CH:31]=[CH:2][C:1]([O:4][C@@H:5]3[C@@H:6]([OH:7])[C@@H:11]([OH:12])[C@H:16]([OH:17])[C@@H:21]([CH2:23][OH:24])[O:22]3)=[CH:38][C:33]=2[C:34]([O:36][CH3:37])=[O:35])[CH:44]=[CH:43][CH:42]=1)=[O:46]
Reactant: COC(=O)c1cccc(-c2ccc(O)cc2C(=O)OC)c1
Reactant: CC(=O)OC[C@H]1O[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: COC(=O)c1cccc(-c2ccc(O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)cc2C(=O)OC)c1
Yield: 73 %

Procedure:
6 was prepared via glycosidation between α-D-mannose pentaacetate and methyl 5-hydroxy-2-(3-methoxycarbonylphenyl)benzoate following the procedure previously described.25 Yield: 73%. 1H NMR (300 MHz, METHANOL-d4) δ ppm 3.56-3.68 (m, 4H) 3.68-3.84 (m, 3H) 3.86-3.98 (m, 4H) 4.06 (dd, J=3.30, 1.92 Hz, 1H) 5.60 (d, J=1.92 Hz, 1H) 7.29-7.43 (m, 2H) 7.45-7.53 (m, 2H) 7.56 (d, J=2.47 Hz, 1H) 7.84-7.92 (m, 1H) 7.93-8.04 (m, 1H). MS (ESI): found [M+H]+, 449.0.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[CH3:9][O-:10].[Na+]>>[CH3:9][O:10][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: C[O-]
Reactant: ClCc1ccccn1
Agent: [Na+]
Product: COCc1ccccn1

Procedure:
Alternatively, 0.1 mole of 2-(chloromethyl)pyridine and 0.11 mole of sodium methoxide are used in the above procedure to give 2-(methoxymethyl)pyridine.
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]([N:9]1[CH2:12][CH:11]([C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:14]#[N:15])[CH2:10]1)([CH3:8])[CH3:7].[OH-:28].[Na+]>>[CH:6]([N:9]1[CH2:12][CH:11]([C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:14]([NH2:15])=[O:28])[CH2:10]1)([CH3:8])[CH3:7]
Reactant: [OH-]
Reactant: CC(C)N1CC(C(C#N)(c2ccccc2)c2ccccn2)C1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)N1CC(C(C(N)=O)(c2ccccc2)c2ccccn2)C1
Temperature: 70 °C

Procedure:
To 80 ml. of concentrated sulfuric acid preheated to 70° C. was added 15 g. (0.052 mole) of α-(1-isopropyl-3-azetidinyl)-α-phenyl-α-(2-pyridyl)acetonitrile at a rate to maintain 65°-70° C. The solution was heated to 70° C. for 18 hrs. and poured on ice. The mixture was made basic with 50% sodium hydroxide (with ice cooling and extracted with chloroform. The chloroform was dried (sodium sulfate) and concentrated. The residue was crystallized twice from ethyl acetate-isopropyl ether. Yield 6 g. (37%), m.p. 140°-141° C.
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:14]=[CH:15][C:3]=12.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:14]=[CH:15][C:3]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2c(cnn2-c2ccccc2)c1O
Product: CCOC(=O)c1cnc2c(cnn2-c2ccccc2)c1Cl
Yield: 97.8 %

Procedure:
A mixture of 5.76 g (20.33 mmol) of ethyl 4-hydroxy-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate and 15.58 g of phosphorus oxychloride was refluxed 1.5 hr, chilled and poured slowly onto crushed ice. The mixture was filtered and the solid washed with ice-water and dried to give 6.0 g of solid, m.p. 89-91° C.