Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:20]([O:21][CH3:22])=[CH:19][C:6]([C:7]([C:9]2[NH:13][N:12]=[N:11][C:10]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:8])=[C:5]([N+:23]([O-:25])=[O:24])[CH:4]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:38]([O:40][CH2:41]OCC)[CH3:39]>C(Cl)Cl>[CH2:38]([O:40][CH2:41][N:12]1[N:11]=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([C:7](=[O:8])[C:6]2[CH:19]=[C:20]([O:21][CH3:22])[C:3]([O:2][CH3:1])=[CH:4][C:5]=2[N+:23]([O-:25])=[O:24])=[N:13]1)[CH3:39]
Reactant: CCOCOCC
Reactant: CCOC(=O)c1nn[nH]c1C(=O)c1cc(OC)c(OC)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CCOCn1nc(C(=O)OCC)c(C(=O)c2cc(OC)c(OC)cc2[N+](=O)[O-])n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
Ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (Synthesis Example 2) (210 mg) and p-toluenesulfonic acid monohydrate (62 mg) were suspended in methylene chloride (5 ml) under an argon atmosphere. Diethoxymethane (0.5 ml) was added to the suspension. The mixture was stirred at 80° C. for 2 hr. The mixture was post-treated by a conventional method and subjected to separation and purification to give ethyl 2-(ethoxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (242 mg, 99%) as a yellow powder.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl.C(N(CC)CC)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]([CH:29]([CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)[CH2:30][O:31][C:32]3[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][C:33]=3[F:40])=[C:27]3[C:22]([CH:23]=[CH:24][CH:25]=[CH:26]3)=[N:21]2)=[CH:16][CH:15]=1>CN(C=O)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]([CH:29]([CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)[CH2:30][O:31][C:32]3[CH:39]=[CH:38][C:35]([C:36]4[N:1]=[N:2][NH:3][N:37]=4)=[CH:34][C:33]=3[F:40])=[C:27]3[C:22]([CH:23]=[CH:24][CH:25]=[CH:26]3)=[N:21]2)=[CH:16][CH:15]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(OCC(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(F)c1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Fc1cc(-c2nn[nH]n2)ccc1OCC(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Temperature: 120 °C
Reaction time: 14 h
Yield: 37.2 %

Procedure:
Sodium azide (14 mg, 215 umol) and triethylamine hydrochloride (29 mg, 215 umol) were added to a solution of [rac]-4-{2-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-2-cyclohexyl-ethoxy}-3-fluoro-benzonitrile (20 mg, 43 umol; example 30) in DMF (0.4 ml). The solution was stirred at 120° C. for 14 h, poured onto ice water/1 N aqueous HCl solution 1/1 and extracted two times with iPrOAc. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. The solvent was removed under reduced pressure to give a solid which was crystallized from acetonitrile to obtain the title compound (8 mg, 16 umol; 37%) as off-white solid. MS: m/e=518.0 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].Br[CH2:37][CH2:38][CH2:39][F:40]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:37][CH2:38][CH2:39][F:40])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: FCCCBr
Reactant: COc1cc2c(cc1O)CCN(CC(=O)NCc1ccccc1)C2Cc1ccc(OC)c(OC)c1
Product: COc1ccc(CC2c3cc(OC)c(OCCCF)cc3CCN2CC(=O)NCc2ccccc2)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-6-hydroxy-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with 1-bromo-3-fluoro-propane
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:19]([N:20]([CH3:29])[C@H:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:22])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:30]([O:32]C)=[O:31])[CH:16]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[OH-].[Na+].O>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:19]([N:20]([CH3:29])[C@H:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:22])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:30]([OH:32])=[O:31])[CH:16]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]ncc4c3)c(N(C)[C@@H](C)c3ccccc3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@@H](c1ccccc1)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.2 %

Procedure:
To a solution of (S)-methyl 2-(1H-indazol-5-yl)-3-(methyl(1-phenylethyl)amino)quinoxaline-6-carboxylate (100 mg, 0.23 mmol) in methanol (20 mL) was added NaOH (37 mg, 0.93 mmol) and water (1 mL) with stirring for 1 day at room temperature. The resulting mixture was concentrated under vacuum, diluted with water (20 mL), and adjusted to pH 5 with HCl (3N). The product was precipitated from solution via the addition of water and collected by filtration to give (S)-2-(1H-indazol-5-yl)-3-(methyl(1-phenylethyl)amino)quinoxaline-6-carboxylic acid as a yellow solid (48.9 mg, 51%).
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH2:11](Cl)[C:12]#[CH:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:11]#[C:12][CH2:13][NH:1][C@H:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: NC1CCc2ccccc21
Reactant: C#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCN[C@@H]1CCc2ccccc21

Procedure:
EP436492 discloses process for preparation of R-(+)-Rasagiline hydrochloride which involves reaction of racemic 1-aminoindan (2) with propargyl chloride (6) in presence of potassium carbonate in acetonitrile (ACN) at 60° C. for 16 hours to obtain racemic Rasagiline base (4) which is purified using column chromatography. The ethereal solution of purified racemic base is then treated with HCl gas followed by recrystallization using isopropanol (IPA) to obtain racemic Rasagiline hydrochloride (7). R-(+)-Rasagiline is separated from the obtained racemic Rasagiline base (4) by preparative HPLC chromatography and further converted to its hydrochloride salt.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1>>[C:13]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3)c2)cn1
Reactant: Fc1cccc(Br)c1
Product: O=C(c1cccc(F)c1)c1cn(-c2cccc(-c3ccccc3)c2)cn1

Procedure:
This compound was prepared by method C using compound 12a and 1-bromo-3-fluorobenzene. HRMS (ESI+): m/z=343.1231 [M+H]
Reaction SMILES: C[O:2][C:3](=[O:32])[C@@H:4]([O:29][CH2:30][CH3:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([CH3:27])[CH:21]=3)[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[Cl:28].[Li+].[OH-]>>[Cl:28][C:7]1[CH:8]=[C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([CH3:27])[CH:21]=3)[O:17][C:18]=2[CH3:19])[CH:10]=[CH:11][C:6]=1[CH2:5][C@H:4]([O:29][CH2:30][CH3:31])[C:3]([OH:32])=[O:2]
Reactant: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccc(F)c(C)c3)oc2C)cc1Cl)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccc(F)c(C)c3)oc2C)cc1Cl)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], (S)-3-{2-chloro-4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionic acid methyl ester was treated with LiOH to obtain (S)-3-{2-chloro-4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionic acid as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=S)[NH:12][C@H:13]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:17][CH:16]=1>CN(C=O)C.Cl[Hg]Cl>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][CH2:23][CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][C@@H:13]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH:12][C:11]2[NH:10][C:3]3[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=3[N:1]=2)=[CH:16][CH:17]=1)[CH3:29]
Reactant: CCOC(=O)CCCOc1ccc(C[C@H](NC(=S)Nc2ccc(OC)cc2N)C(=O)OC(C)(C)C)cc1
Agent: Cl[Hg]Cl
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(C[C@H](Nc2nc3cc(OC)ccc3[nH]2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
500 mg of HgCl2 is added to the amino thiourea 4-3a (530 mg, 1 mmole) in 30 ml of DMF and 3 ml of TEA, followed by agitating for 2 hours at ambient temperature, evaporating under reduced pressure and taking up in a water/NaHCO3/AcOEt mixture. The organic phase is decanted, dried and evaporated to dryness under reduced pressure. The residue is chromatographed eluting with a gradient of heptane/AcOEt (100/0→50/50). 430 mg of crude product 4-4a is obtained.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[N:11]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[NH:14][CH2:13][CH2:12]2.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.O>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[N:14]1[CH:15]2[CH2:18][CH2:19][N:11]([CH2:17][CH2:16]2)[CH2:12][CH2:13]1
Reactant: Clc1nc2ccccc2s1
Reactant: C1CN2CCC(CC2)N1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: c1ccc2sc(N3CCN4CCC3CC4)nc2c1
Temperature: 100 °C
Yield: 34.3 %

Procedure:
2-Chlorobenzothiazole (Aldrich, 109 μL, 0.841 mmol) was added to a solution of 1,4-diazabicyclo[3.2.2]nonane (57%, 169 mg, 0.765 mmol), Et3N (213 μL, 1.53 mmol) in DMF (2.5 mL). The reaction mixture was heated at 100° C. for 2 h. The mixture was allowed to cool to RT, diluted with EtOAc and H2O and the layers were partitioned. The aqueous layer was extracted with EtOAc (3×) and the combined organic extracts were washed successively with H2O and brine and then dried (Na2SO4), filtered and concentrated. The crude residue was purified by chromatography (Biotage, 12 L) eluting with 5% MeOH in CHCl3 to afford 68 mg (34%) of the title compound as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 7.58 (d, 1H, J=7.9 Hz), 7.57 (d, 1H, J=7.9 Hz), 7.27 (t, 1H, J=8.3 Hz), 7.04 (td, 1H, J=7.9, 1.2 Hz), 4.31 (s, 1H), 3.92 (t, 2H, J=5.8 Hz), 3.19-2.98 (m, 6H), 2.25-2.16 (m, 2H), 1.84-1.77 (m, 2H); MS (Cl) m/z 260.2 (M+1). The hydrochloride salt was prepared by dissolving the title compound in iPrOH and adding 0.1 mL of 6 M hydrochloric acid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]([C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)[CH2:11][CH3:12])(C)(C)C.O1CCOCC1.[ClH:27]>O1CCOCC1>[ClH:27].[ClH:27].[Br:19][C:16]1[CH:15]=[CH:14][C:13]([N:10]([CH2:11][CH3:12])[CH2:9][CH2:8][NH2:7])=[CH:18][CH:17]=1
Reactant: CCN(CCNC(=O)OC(C)(C)C)c1ccc(Br)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCN(CCN)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 126.5 %

Procedure:
tert-Butyl{2-[(4-bromophenyl)(ethyl)amino]ethyl}carbamate (896 mg) synthesized in Production Example 83, step 3 was dissolved in dioxane (5 ml), and 4M-hydrogen chloride dioxane solution (5 ml, 20 mmol) was added dropwise at 0° C. After stirring at room temperature for 2 hrs, the mixture was concentrated under reduced pressure. Dichloromethane was added to the residue, and the mixture was concentrated under reduced pressure, which operation was performed 3 times to remove volatile components such as hydrogen chloride and the like. The residue was dried under reduced pressure to give N-(4-bromophenyl)-N-ethylethane-1,2-diamine dihydrochloride (1.044 g) as a yellow gum-like solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH2:15]Br)=[C:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2].[OH-].[NH4+:26]>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH2:15][NH2:26])=[C:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2]
Reactant: [NH4+]
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(n2ccccc2=O)=C1CBr
Agent: [OH-]
Solvent: CCO
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(n2ccccc2=O)=C1CN
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 6-nitro-2,2-dimethyl-3-bromomethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran (0.1 g, 0.255 mmol) in ethanol (2 ml) containing concentrated aqueous ammonium hydroxide solution (2 ml) was stirred at room temperature for four hours. The solvent was evaporated and the residue treated with ethanolic hydrochloric acid (2 ml) with heating. Crystallization was induced by addition of diethyl ether, giving 0.07 g of 6-nitro-2,2-dimethyl-3-aminomethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran as a hydrochloride salt, m.p. 231° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Si]([O:37]CC=O)(C(C)(C)C)(C)C>O1CCCC1.CCCCCC.CCOCC.C(OCC)(=O)C.C(O)(=O)C>[CH2:13]([O:20][CH2:21][CH2:22][CH2:23][CH:24]1[CH:29]([OH:37])[CH2:28][O:27][C:25]1=[O:26])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: CCOC(=O)CCCCOCc1ccccc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C1OCC(O)C1CCCOCc1ccccc1
Temperature: 0 °C

Procedure:
To a solution of 20.4 g (0.201 mole) of diisopropylamine in 250 ml of tetrahydrofurane is added dropwise 100.2 ml (0.201 mole) of 2.01M solution of n-butyllithium in hexane with stirring at 0° C. The solution is cooled to -78° C. and a solution of 40.56 g (0.182 mole) of ethyl 5-benzyloxypentanoate in 30 ml of tetrahydrofurane is added dropwise over a period of 1/2 h. The mixture is stirred at -78° C. for another 1/2 h and a solution of 33.5 g (0.192 mole) of t-butyldimethylsilyloxyacetaldehyde in 20 ml of tetrahydrofurane is added dropwise. The mixture is stirred at -78° C. for 1 h and 12.1 ml of acetic acid is added dropwise. The mixture is warmed to 0° C., diluted with 250 ml of ether and 250 ml of ethyl acetate and washed with water. The organic layer is evaporated, the residue is diluted with 322 ml of methanol and the solution is treated with 43.1 ml of concentrated hydrochloric acid with stirring for 20 h. The mixture is evaporated and the residue is extracted with ethyl acetate. The extracts are washed with water and brine, dried (MgSO4) and evaporated to give an oil which is then purified by flash chromatography using methylene chloride-ethyl acetate (4:1) as the eluent to obtain 2-(3-benzyloxy-propyl)-3-hydroxy-γ-butyrolactone as an oil.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:13]([C:15]2[CH:16]=[C:17]([CH:20]=[C:21]([CH3:23])[CH:22]=2)[CH:18]=O)=[O:14])=[N:5][C:6]([O:11][CH3:12])=[N:7][C:8]=1[O:9][CH3:10])[CH3:2].[C:24]([CH2:26]P(=O)(OCC)OCC)#[N:25].CC(C)([O-])C.[K+]>C1COCC1>[CH2:1]([C:3]1[C:4]([C:13]([C:15]2[CH:16]=[C:17]([CH:18]=[CH:26][C:24]#[N:25])[CH:20]=[C:21]([CH3:23])[CH:22]=2)=[O:14])=[N:5][C:6]([O:11][CH3:12])=[N:7][C:8]=1[O:9][CH3:10])[CH3:2]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CCc1c(OC)nc(OC)nc1C(=O)c1cc(C)cc(C=O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCc1c(OC)nc(OC)nc1C(=O)c1cc(C)cc(C=CC#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
To a stirred mixture of 3-(5-ethyl-2,6-dimethoxy-pyrimidine-4-carbonyl)-5-methyl-benzaldehyde (3.11 g, 9.9 mmol) and diethyl cyanomethyl-phosphonate (1.6 ml, 10 mmol) in anhydrous THF (20 ml) at 0° C. (ice bath) under nitrogen atmosphere, was added potassium t-butoxide (1.26 g, 11.2 mmol). After 1 hr., the mixture was stirred at room temperature for 5 hr. The mixture was then partitioned between ether and water. The ether layer was taken, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a pale yellow syrup. The crude product was purified by silica gel column chromatography (eluent, EA:hexanes (1:4)) to afford 2.39 g (72%) of a white solid. m.p. 165-166° C.; 1H NMR (200 MHz, CDCl3) δ 1.09 (3H, t, J=7.8 Hz), 2.42-2.53 (5H, m), 3.96 (3H, s), 4.09 (3H, s), 5.93 (1H, d, J=16.8 Hz), 7.40 (1H, s, J=16.8 Hz), 7.50 (1H, s), 7.73 (1H, s), 7.79 (1H, s).
Reaction SMILES: [H-].[Na+].[CH3:3]S(C)=O.[NH2:7][C:8]1[CH:13]=[C:12](OC)[C:11](OC)=[CH:10][C:9]=1[C:18](=[O:23])[CH2:19][S:20]([CH3:22])=[O:21]>C1C=CC=CC=1>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:3])=[CH:10][C:9]=1[C:18](=[O:23])[CH2:19][S:20]([CH3:22])=[O:21]
Reactant: COc1cc(N)c(C(=O)CS(C)=O)cc1OC
Reactant: CS(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Cc1ccc(N)c(C(=O)CS(C)=O)c1

Procedure:
This compound was prepared by reacting a solution of 44 g of NaH (57%) in a mixture of 600 ml. of DMSO and 1200 ml. of benzene with 50 g of methyl 5-methyl anthranilate (J. Med. Chem. 11 500) in analogous fashion to 2'-amino-4',5'-dimethoxy-2-(methylsulfinyl)acetophenone. The material was recrystallized from ethyl acetate with the aid of charcoal, m.p. 145°-47°; yield 30 g (47%).
Reaction SMILES: [Cs].[C:2]1([CH2:8][CH:9]2[NH:13][S:12](=[O:15])(=[O:14])[NH:11][C:10]2=[O:16])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:23]1([S:29][CH2:30]Cl)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO>[C:23]1([S:29][CH2:30][N:11]2[C:10](=[O:16])[CH:9]([CH2:8][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[NH:13][S:12]2(=[O:15])=[O:14])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1NS(=O)(=O)NC1Cc1ccccc1
Reactant: ClCSc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Cs]
Solvent: CO
Product: O=C1C(Cc2ccccc2)NS(=O)(=O)N1CSc1ccccc1
Temperature: 0 °C
Yield: 95.9 %

Procedure:
To a mixture of 4-phenylmethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide cesium salt (prepared by reacting 11.43 g (50.52 mmol) of the dioxide in methanol with 8.23 g (25.26 mmol) of Cs2CO3 followed by removal of the solvent) in 150 ml of DMF was added in one portion phenylthiomethyl chloride (8.82 g, 55.57 mmol) and the mixture was heated at 80°-90° C. under nitrogen for 17 hours. The mixture was cooled and poured into 600 ml of ice/water. The reaction mixture was extracted with ethyl acetate (3x), the organic layer was dried over sodium sulfate, and concentrated in vacuo. The residual yellow oil was purified by silica column chromatography (5%-10% ethyl acetate in hexane) to afford 16.88 g (95.9%) of 2-phenylthiomethyl-4-phenylmethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula VI: R1 =H; R2 =CH2Ph; R3 =H) as an yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:24]=1[CH2:25]Br>>[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:24]=1[CH2:25][O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Reactant: Clc1cccc(Cl)c1CBr
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(OCc2c(Cl)cccc2Cl)c1

Procedure:
Alkylation reaction of phenol 58 with 2,6-dichlorobenzylbromide gave 2-(3-(3-(2,6-dichlorobenzyloxy)phenyl)propyl)isoindoline-1,3-dione as yellow oil. Yield (0.780 g, 51%): 1H NMR (400 MHz, CDCl3) δ 7.82-7.85 (m, 2H), 7.69-7.72 (m, 2H), 7.35-7.38 (m, 1H), 6.86-6.79 (m, 2H), 6.81 (s, 1H), 6.80 (dd, J=8.2, 2.4 Hz, 1H), 5.25 (s, 2H), 3.76 (t, J=6.2 Hz, 2H), 2.68 (t, J=7.6 Hz, 2H), 2.00-2.09 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[N:9]2[CH2:12][CH:11]([CH:13]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)[C:14]([CH3:17])(O)[CH3:15])[CH2:10]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[FH:39].[OH-].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[N:9]2[CH2:12][CH:11]([C@@H:13]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)[C:14]([F:39])([CH3:17])[CH3:15])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: F
Reactant: CC(C)(O)C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(F)[C@H](c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 42 °C
Reaction time: 9 h

Procedure:
To a solution of 175 mg (0.368 mmol) of 1-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-1-(3,5-difluorophenyl)-2-methylpropan-2-ol in 3 mL of CH2Cl2. 1 mL of hydrogen fluoride-pyridine was added and the reaction was stirred for 9 h at 42° C. Then the reaction mixture was poured to 7 mL of 5N NaOH, 7 mL of ag NaHCO3 and 30 mL of CH2Cl2. Adjusted pH to 8-9 with 2N NaOH. The water layer was extracted with CH2Cl2 (3×30 mL). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with 10% methyl tert-butyl ether-hexane to afford the title compound as a white solid. 1H NMR (CDCl3) δ 1.25 (t, J=22 Hz, 6H), 2.33 (t, J=6.5 Hz, 1H), 2.83-2.89 (m, 2H), 3.09-3.11 (m, 2H), 3.60 (m, 1H), 4.20 (s, 1H), 6.68-6.71 (m, 3H), 7.21-7.33 (m, 8H)
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:12]([Cl:44])=[C:13]([NH:19][C:20]4[N:25]=[C:24]([N:26]([CH:36]5[CH2:38][CH2:37]5)[CH2:27][C:28]5[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=5)[C:23]5=[N:39][CH:40]=[C:41]([C:42]#[N:43])[N:22]5[N:21]=4)[CH:14]=[C:15]([C:17]#[N:18])[CH:16]=3)[CH2:7][CH2:6]2)[CH2:2]1.[C:45](Cl)(=[O:47])[CH3:46].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:45]([N:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:12]([Cl:44])=[C:13]([NH:19][C:20]4[N:25]=[C:24]([N:26]([CH:36]5[CH2:37][CH2:38]5)[CH2:27][C:28]5[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=5)[C:23]5=[N:39][CH:40]=[C:41]([C:42]#[N:43])[N:22]5[N:21]=4)[CH:14]=[C:15]([C:17]#[N:18])[CH:16]=3)[CH2:7][CH2:6]2)[CH2:2]1)(=[O:47])[CH3:46]
Reactant: CC(=O)Cl
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCN(C5CNC5)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCN(C5CN(C(C)=O)C5)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.8 %

Procedure:
To a solution of 2-((3-(4-(azetidin-3-yl)piperazin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (100 mg, 0.164 mmol) in DCM (1.0 mL) was added TEA (0.069 mL, 0.492 mmol) followed by acetyl chloride (0.014 mL, 0.197 mmol) in a drop wise manner. The reaction mixture was allowed to warm to room temperature and stirred for overnight. The reaction mixture was diluted with dichloromethane (50 mL) and poured into a separating funnel containing saturated aqueous sodium bicarbonate (10 mL). The aqueous layer was extracted with dichloromethane (2×50 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude material was precipitated from DCM/Hexane (Dissolved in minimum amount of DCM, precipitated by adding Hexane), filtered and dried to get the 2-((3-(4-(1-acetylazetidin-3-yl)piperazin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (110 mg) as a off white solid.