Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)(O)[CH3:9])=[C:5]([CH3:7])[N:6]=1.C1(P([N:30]=[N+:31]=[N-:32])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1C=CC=CC=1.C(OCC)(=O)C.O>[N:30]([C:8]([C:4]1[S:3][C:2]([CH3:1])=[N:6][C:5]=1[CH3:7])([C:11]1[S:12][CH:13]=[CH:14][N:15]=1)[CH3:9])=[N+:31]=[N-:32]
Reactant: Cc1nc(C)c(C(C)(O)c2nccs2)s1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1nc(C)c(C(C)(N=[N+]=[N-])c2nccs2)s1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1-(2,4-Dimethyl-5-thiazolyl)-1-(2-thiazolyl)ethanol (200 mg) was suspended in benzene (2 ml ) at room temperature. Diphenylphosphoryl azide (212 μl) was added, followed by 1,8-diazabicyclo[5,4,0]undec-7-ene (152 μl). The mixture was stirred at ambient temperature for 72 hours and was then diluted with ethyl acetate and water. Work-up in the usual fashion including flash chromatography then gave the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17]([O:19]CC)=O)=[CH:11][CH:10]=1)#[N:2].[Si:27]([O:34][CH:35]1[CH2:40][CH2:39][CH:38]([NH:41][C:42]2[NH:46][CH:45]=[N:44][N:43]=2)[CH2:37][CH2:36]1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].C(N(CC)C1C=CC=CC=1)C>C(OCC)(=O)C>[Si:27]([O:34][CH:35]1[CH2:40][CH2:39][CH:38]([N:41]2[C:17](=[O:19])[C:16]([CH2:15][C:12]3[CH:11]=[CH:10][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:1]#[N:2])=[N:14][CH:13]=3)=[C:22]([CH2:23][CH2:24][CH3:25])[N:43]3[N:44]=[CH:45][N:46]=[C:42]23)[CH2:37][CH2:36]1)([C:30]([CH3:33])([CH3:31])[CH3:32])([CH3:29])[CH3:28]
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)nc1)C(=O)OCC
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(Nc2nnc[nH]2)CC1
Solvent: CCN(CC)c1ccccc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)nc2)c(=O)n(C2CCC(O[Si](C)(C)C(C)(C)C)CC2)c2ncnn12
Temperature: 180 °C
Reaction time: 8 h
Yield: 15.3 %

Procedure:
A mixture of ethyl 2-{[6-(2-cyanophenyl)pyridin-3-yl]methyl}-3-oxohexanoate (1.8 g), N-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-4H-1,2,4-triazol-3-amine (1.4 g) and N,N-diethylaniline (30 mL) was stirred at 180° C. for 8 hr. The obtained reaction mixture was diluted with ethyl acetate, washed 3 times with 1 N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.42 g, 21%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:15]1[N:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[N:23]=2)[CH:16]=1>CN(C=O)C>[NH2:28][C:24]1[N:23]=[C:22]([NH:21][C:17]2[CH:16]=[C:15]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:20]=[CH:19][N:18]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Nc1cccc(Nc2cc(Cl)ncn2)n1
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cccc(Nc2cc(Nc3ccccc3)ncn2)n1
Temperature: 110 °C
Reaction time: 16 h
Yield: 37.8 %

Procedure:
To a stirring solution of 2 (0.25 g, 1.235 mmol) and K2CO3 (0.512 g, 3.705 mmol) in dry DMF (2.5 mL) was added 1 (0.320 g, 1.235 mmol) at rt, and the reaction was stirred at 110° C. for 16 h under nitrogen atmosphere. The reaction mixture was quenched with water and extracted with ethyl acetate (3×5 mL). The combined extracts were washed with water (2×25 mL), brine (25 mL), dried over Na2SO4 and concentrated under reduced pressure to give 3 (0.130 g, 21%) as a white solid, which was used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C@@H:5]([CH2:7][CH2:8]OS(C)(=O)=O)[CH2:4][O:3]1.[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C)C=O>[N:15]([CH2:8][CH2:7][C@H:5]1[CH2:4][O:3][C:2]([CH3:14])([CH3:1])[O:6]1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)OC[C@H](CCOS(C)(=O)=O)O1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](CCN=[N+]=[N-])O1
Temperature: 25 °C
Reaction time: 70 h
Yield: 88.9 %

Procedure:
Step B To a solution of methanesulfonic acid 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl ester (31.7 g, 0.14 mol) in N,N-dimethylformamide (200 mL) was added NaN3 (46 g, 0.71 mol). The reaction mixture was stirred at room temperature for 70 h. Then the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine several times, dried over MgSO4, concentrated to give (S)-4-(2-azido-ethyl)-2,2-dimethyl-[1,3]dioxolane as a yellow oil (21.3 g, 88%).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:10]1[N:14]([CH3:15])[N:13]=[N:12][N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:22][C:23]1[S:24][C:25]([Cl:30])=[C:26]([CH2:28]Cl)[N:27]=1>CC#N>[Cl:22][C:23]1[S:24][C:25]([Cl:30])=[C:26]([CH2:28][O:1][N:2]=[C:3]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:27]=1
Reactant: ClCc1nc(Cl)sc1Cl
Reactant: Cn1nnnc1C(=NO)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cn1nnnc1C(=NOCc1nc(Cl)sc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.2 %

Procedure:
To a stirred solution of N-hydroxy-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (2.15 g, 10.58 mmol, 1.0 eq.) in 20 ml of MeCN was added Cs2CO3 (4.12 g, 12.69 mmol, 1.2 eq.) followed by KI (0.17 g, 1.05 mmol, 0.1 eq.) in one portion. The resulting suspension was stirred for 5 mins before addition of 2,5-dichloro-4-(chloromethyl)-1,3-thiazole (2.35 g, 11.63 mmol, 1.1 eq.) in one portion. The reaction was stirred for 24 hrs at room temperature. The solvent was evaporated and the residue was dissolved in EtOAc and washed with H2O. The organic layer was separated, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel to give N-[(2,5-dichloro-1,3-thiazol-4-yl)methoxy]-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (1.65 g, 42% yield, 86:14 mixture of stereoisomers) as a yellow viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[C:21]([F:23])[CH:22]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:19]3[CH:18]=[C:17]([F:16])[CH:22]=[C:21]([F:23])[CH:20]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: OB(O)c1cc(F)cc(F)c1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1cc(F)cc(F)c1

Procedure:
The title compound, MS: m/e=330.3 (M+H+), was prepared in accordance with the general method of example 7 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 3,5-difluorobenzene boronic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16]2[C:17]([CH3:27])=[C:18]([CH:23]=[C:24]([Cl:26])[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:28](=O)[CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(O)(=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([CH2:28][CH3:29])[C:16]2[C:17]([CH3:27])=[C:18]([CH:23]=[C:24]([Cl:26])[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(Cl)cc(N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c1C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCN(c1cc(Cl)cc(C(=O)OC)c1C)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-(((trans)-4-((tert -butoxycarbonyl)amino)cyclohexyl)amino)-5-chloro-2-methylbenzoate (330 mg, 0.831 mmol) and acetaldehyde (200 μL, 3.56 mmol) in 1,2-dichloroethane (DCE) (5 mL) was added acetic acid (400 μL) and the mixture was stirred at room temperature for 1 h. The mixture was cooled to 0° C. in an ice bath and sodium triacetoxyborohydride (700 mg, 3.30 mmol) was added (very thick suspension that slowly dissolved). The reaction was allowed to warm to room temperature and stirred overnight. LCMS showed the reaction was mostly complete. The reaction was neutralized with sat. NaHCO3, extracted with CH2Cl2, dried (Na2SO4), filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Analogix, 5 to 20% EtOAc in hexanes) and the pure fractions were combined and evaporated to dryness to give the product methyl 3-(((trans)-4-((tert -butoxycarbonyl)amino)cyclohexyl)(ethyl)amino)-5-chloro-2-methylbenzoate (250 mg, 0.588 mmol, 70.8% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) 6=7.44 (d, J =2.3 Hz, 1 H), 7.38 (d, J=2.3 Hz, 1 H), 6.68 (d, J=7.8 Hz, 1 H), 3.83 (s, 3 H), 3.16 (br. s., 1 H), 3.05 (q, J=6.9 Hz, 2 H), 2.59 (t, J=11.1Hz, 1 H), 2.34 (s, 3 H), 1.82-1.64 (m, 4 H), 1.47-1.38 (m, 2 H), 1.36 (s, 9 H), 1.16-1.04 (m, 2 H), 0.78 (t, J=6.9 Hz, 3 H). MS(ES) [M+H]+ 425.2.
Reaction SMILES: [P:1]([O-])([O:11][CH2:12][C:13]1C=CC=CC=1)([O:3][CH2:4][C:5]1C=CC=CC=1)=[O:2].C(Cl)(=O)C(Cl)=O.[CH2:26]1[N:31]([CH2:32][CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:42]=[CH:41][C:40]3[CH:43]=[CH:44][C:45]([NH:47][C:39]=3[CH:38]=2)=[O:46])[CH2:30][CH2:29][N:28]([C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[C:49]=2[Cl:55])[CH2:27]1.CC(C)([O-])C.[K+]>ClCCl.CN(C)C=O.CC1CCCO1>[P:1]([O:11][CH2:12][CH3:13])([O:3][CH2:4][CH3:5])([O:46][C:45]1[CH:44]=[CH:43][C:40]2[C:39](=[CH:38][C:37]([O:36][CH2:35][CH2:34][CH2:33][CH2:32][N:31]3[CH2:30][CH2:29][N:28]([C:48]4[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[C:49]=4[Cl:55])[CH2:27][CH2:26]3)=[CH:42][CH:41]=2)[N:47]=1)=[O:2]
Reactant: O=c1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2[nH]1
Reactant: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: CC1CCCO1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOP(=O)(OCC)Oc1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of dibenzyl phosphate (2.48 g, 8.91 mmol) in dichloromethane (25 ml) was added N,N-dimethyl formamide (1 drop) followed by oxalyl chloride (0.75 mL, 8.91 mmol). After 2 hours the reaction mixture was concentrated in vacuo. The residue was dissolved in 2-methyltetrahydrofuran (5 mL) and added to a suspension of dehydro-aripiprazole (1.66 g, 3.71 mmol) and potassium t-butoxide (0.92 g, 8.17 mmol) in 2-methyltetrahydrofuran (35 mL) at 0° C. under argon gas, then allowed to gradually warm to room temperature. After stirring overnight the reaction was quenched with water (25 mL) and 28% aq NH3 (15 mL) and stirred for 10 minutes. The reaction mixture was then extracted with ethyl acetate (2×40 mL). The combined organics were washed with water (50 mL) and brine (50 mL) then dried (MgSO4) and concentrated in vacuo. The crude mixture was purified by column chromatography eluting with 5% methanol (1:1 ethyl acetate/dichloromethane) to give the product. The 1H-NMR showed minor impurities still present (impurities not observed by LCMS). Various further purifications were attempted but failed to remove these impurities.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C:12]([O:14][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(C)CC(CNC(=O)OC(C)(C)C)CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)CC(CNC(=O)OC(C)(C)C)CC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 108.2 %

Procedure:
To a stirred suspension of (37) (1.24 g, 4.78 mmol) and Cs2CO3 (1.56 g, 4.78 mmol) in DMF (20 mL) was added benzyl bromide (0.56 mL, 4.68 mmol). The resulting mixture was stirred at ambient temperature until the reaction was complete (˜2 h, as monitored by LC/MS). The mixture was poured into ice water and extracted with dichloromethane. The combined organic phase was washed with water and brine, then dried over anhydrous Na2SO4. Filtration and removal of the solvent in vacuo afforded the title compound (38) (1.77 g, 100%), which was used without further purification in the following example. 1H-NMR (CDCl3, 400 MHz): δ 0.86 (2 d, 6H), 1.13 (m, 2H), 1.42 (s, 9H), 1.62 (m, 1H), 2.31 (m, 2H), 3.00 (m, 1H), 3.18 (m, 1H), 4.75 (br.s, 1H), 5.10 (s, 2H), 7.33 (m, 5H). MS (ESI) m/z 372.30 (M+Na+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[CH:12](=[N:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: O=Cc1ccccc1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(O)c(N=Cc2ccccc2)c1

Procedure:
A solution of 6.16 g of 2-amino-4-nitrophenol and 4.77 g of benzaldehyde in ethanol is refluxed. The reaction solution is condensed and cooled. The crystalline precipitates are collected by filtration to give 2-benzylideneamino-4-nitrophenol. 15.5 g of lead tetraacetate are added to a benzene suspension of the product obtained above, and the mixture is stirred. After the reaction, insoluble materials are filtered off. The filtrate is washed, and condensed. The residue is purified by silica gel column chromatography and recrystallized from ethanol, whereby 5.08 g of 5-nitro-2-phenylbenzoxazole are obtained.
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].C(O[C:9]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]=1)C.Cl>>[CH:1]([C:9]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)[Mg]Cl
Reactant: CCOC1=CC(=O)CC1
Agent: Cl
Product: CC(C)C1=CC(=O)CC1
Temperature: 0 °C
Reaction time: 23 h
Yield: 19.7 %

Procedure:
Isopropylmagnesium chloride (5 mL, 10 mmol, 2 M in diethyl ether) was placed in a dry flask and cooled to 0° C. 3-Ethoxycyclopentenone (0.88 g, 7 mmol) was added dropwise to the solution of the Grignard reagent, and the resulting mixture was stirred at room temperature for 23 h. At this point, 1 M HCl (15 mL) was added gradually, the aqueous phase was separated and extracted 3×with diethyl ether. The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo. The product was purified first by Kugelrohr distillation (0.1 torr, 120° C.), then by flash chromatography (1:1 pentane:ether) to afford the product as a colorless liquid (0.171 g, 20%). Spectroscopic data were consistent with previously reported data for this compound.7
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.Cl.[CH3:17][O:18][C:19](=[O:28])[C@H:20]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[NH2:21].C(N(CC)CC)C>CN(C)C=O.CN(C)C1C=CN=CC=1.C(Cl)Cl.C1C=CC=CC=1>[F:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:21][C@H:20]([C:19]([O:18][CH3:17])=[O:28])[CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[O:6]
Reactant: O=C(O)c1ccc(I)cc1F
Reactant: COC(=O)CC[C@H](N)C(=O)OC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CC[C@H](NC(=O)c1ccc(I)cc1F)C(=O)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.5 %

Procedure:
To 20 mL of benzene are added 2.0 g (0.00752 mol) of 2-fluoro4-iodobenzoic acid, followed by 2.3 mL (320 mmol) of thionyl chloride and several drops of dimethylformamide. The mixture is heated at reflux of 3.5 hours. The solvent is then removed in vacuo and the residue pumped dry. The resulting acid chloride is redissolved in 10 ml of methylene chloride, and added dropwise to cooled mixture of 1.67 g (7.89 mmol) of L-glutamic acid dimethyl ester hydrochloride, 5 mg of 4-dimethylaminopyridine, and 2.2 mL (15.8 mmol) of triethylamine in 30 mL of methylene chloride. After the addition, the reaction stirred at room temperature for 18 hours. The reaction mixture is then diluted with additional methylene chloride, washed with 1N hydrochloric acid, water and 5% sodium bicarbonate and dried over sodium sulfate. The solvent is removed in vacuo to give 2.34 g (74%) of dimethyl N-(2-fluoro-4-iodobenzoyl)-L-glutamate as a white solid m.p. 94°-96° C.; IR (KBr, cm-1)=1159, 1177, 1194, 1208, 1229, 1398, 1437, 1477, 1537, 1601, 1642, 1728, 1739, 1756, 3326.
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[N:7]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>C(Cl)Cl>[CH3:11][O:10][C:8]([C:6]1[N:7]=[C:3]([NH:2][S:13]([CH3:12])(=[O:15])=[O:14])[S:4][CH:5]=1)=[O:9]
Reactant: COC(=O)c1csc(N)n1
Reactant: CS(=O)(=O)Cl
Agent: Br
Solvent: ClCCl
Product: COC(=O)c1csc(NS(C)(=O)=O)n1
Reaction time: 1 h
Yield: 45.6 %

Procedure:
To a well stirred solution of methyl 2-amino-thiazole-4-carboxylate hydrobromide (Justus Liebigs Ann. Chem. 1951, 571, 44, Heterocycles 1997, 45, 1299) (13 g, 51 mmol) and TEA (40 mL, 290 mmol) in DCM (130 mL) at rt was added methanesulfonyl chloride (11 mL, 140 mmol) dropwise. After stirring for 1 h, the reaction mixture was filtered and the filtrate concentrated. The residue was re-suspended in ethyl acetate, filtered and chromatographed on silica gel (ethyl acetate/ethanol, 97:3) to provide 2-methanesulfonylamino-thiazole-4-carboxylic acid methyl ester (5.5 g). MS (ESI−) for C6H8N2O4S2 m/z 234.9 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[N:13][C:14]([NH2:18])=[N:15][CH:16]=3)[N:11]([CH3:19])[N:10]=2)=[CH:5][C:4]=1[C:20]([F:23])([F:22])[F:21].[Cl:24]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>S(=O)(=O)(O)O>[Cl:24][C:8]1[CH:7]=[C:6]([C:9]2[C:17]3[C:12](=[N:13][C:14]([NH2:18])=[N:15][CH:16]=3)[N:11]([CH3:19])[N:10]=2)[CH:5]=[C:4]([C:20]([F:21])([F:23])[F:22])[C:3]=1[O:2][CH3:1]
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: COc1ccc(-c2nn(C)c3nc(N)ncc23)cc1C(F)(F)F
Agent: O=S(=O)(O)O
Product: COc1c(Cl)cc(-c2nn(C)c3nc(N)ncc23)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(4-Methoxy-3-trifluoromethyl-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (Example 111, step 1) (182 mg, 0.56 mmol) is dissolved in concentrated sulfuric acid (11 ml) to give a red solution. Trichloroisocyanuric acid (44 mg, 0.188 mmol) is added and the reaction mixture is stirred at room temperature overnight then poured onto ice-water. After stirring for 30 minutes, the resulting precipitate is collected by filtration, washed with water and dried under vacuum (45°) to afford the title compound as the sulfate salt.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][NH:9][CH2:8][C:7](=[O:11])[N:6]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([N:21]=[C:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:14]=1)=[O:4].CCN(C(C)C)C(C)C.[Cl:44][C:45]1[CH:46]=[CH:47][C:48]2[CH:52]=[C:51]([S:53](Cl)(=[O:55])=[O:54])[S:50][C:49]=2[CH:57]=1>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9]([S:53]([C:51]2[S:50][C:49]3[CH:57]=[C:45]([Cl:44])[CH:46]=[CH:47][C:48]=3[CH:52]=2)(=[O:55])=[O:54])[CH2:8][C:7](=[O:11])[N:6]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([N:21]=[C:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:14]=1)=[O:4]
Reactant: COC(=O)C1CNCC(=O)N1Cc1ccc(C#N)c(N=C(c2ccccc2)c2ccccc2)c1
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC(=O)N1Cc1ccc(C#N)c(N=C(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 73.2 %

Procedure:
A solution containing (±)-1-[3-(benzhydrylidene-amino)-4-cyano-benzyl]-6-oxo-piperazine-2-carboxylic acid methyl ester (55 mg, 0.12 mmol) in CH2Cl2 (1 mL) is cooled to 0° C. DIPEA (24 mg, 0.18 mmol) is then added followed by the addition of 6-chloro-benzo[b]thiophene-2-sulfonyl chloride (32 mg, 0.12 mmol), EXAMPLE 1. The reaction mixture is warmed to ambient temperature. After 16 h, the reaction mixture is absorbed directly onto silica gel and chromatographed (CH2Cl2 to 2% MeOH/CH2Cl2) to provide 60 mg (73%) of the title compound. 1H NMR (300 MHz, CDCl3) δ2.77 (dd, J=12.3, 3.4 Hz, 1H), 3.50-3.72 (m, 3H), 3.79 (s, 3H), 4.15 (dd, J=12.3, 1.4 Hz, 1H), 4.24 (d, J=16.9 Hz, 1H), 5.41 (d, J=15.3 Hz, 1H), 6.50 (s, 1H), 6.76 (dd, J=7.9, 1.4 Hz, 1H), 7.11-7.86 (m, 15H) ppm; MS (ISP loop): m/z 683 (M+H).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:24])[C:5]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19]CC)=[O:18])=[CH:15][CH:14]=2)=[C:6]([NH2:8])[N:7]=1.[OH-].[Na+].Cl>C(O)C>[NH2:1][C:2]1[NH:3][C:4](=[O:24])[C:5]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:23]=[CH:22][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)=[C:6]([NH2:8])[N:7]=1
Reactant: CCOC(=O)c1ccc(OCCCc2c(N)nc(N)[nH]c2=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc(N)c(CCCOc2ccc(C(=O)O)cc2)c(=O)[nH]1
Temperature: 40 °C
Yield: 57.8 %

Procedure:
Compound 1B (6.76 g, 20.3 mmoles) was treated with 300 mL of 1:1 ethanol/1.0N sodium hydroxide (V/V) and heated to 40° C. for 5 hours. The solution was treated with concentrated hydrochloric acid to pH 3.5, and the resulting solid was filtered and washed with 3 volumes (30 mL) of water. The solid was dissolved in 0.1N sodium hydroxide (355 mL) and treated dropwise with concentrated hydrochloric acid to pH 6.4 and filtered. The filtrate was further acidified to pH 3.5, refiltered, and the resulting solid was washed with 3 volumes (20 mL) of water and was dried at 50° C. in vacuo to yield 3.57 g (58%) of the title compound, 1C, as a white solid. Anal: Calcd for C14H16N4O4C, 55.26; H 5.29, N 18.41. Found: C 55.34; H, 5.31; N, 18.31. NMR (DMSO-d6) δ 1.8 (m, 2H, CH2 --CH2 --CH2), 2.3 (t, 2H, CH2 --CH2CH2 --O), 4.0 (t, 2H, CH2 --O), 5.7 (s, 2H, NH2), 5.9 (s, 2H, NH2), 9.8 (br s, ring NH), 12.6 (br, 1H, CO2H), 7.0 (d, 2H, benzoic H's ortho to oxygen), 7.85 (d, 2H, benzoic H's ortho to carbonyl). MS: (CI) 305 (M+1), 167 (M-OPhCO2H), 139 (H2OPhCO2H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:40]([F:43])([F:42])[F:41])=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([OH:12])[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][O:21][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:15][CH:14]=3)[C:6]=2[CH:39]=1.[H-].[Na+].[CH3:46]I.O>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:40]([F:43])([F:41])[F:42])=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([O:12][CH3:46])[CH3:11])[N:7]([C:13]3[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][O:21][Si:22]([C:35]([CH3:36])([CH3:38])[CH3:37])([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:17][CH:18]=3)[C:6]=2[CH:39]=1
Reactant: CC(O)c1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(C)c1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
A solution of 1-[6-chloro-1-[4-(2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}ethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazol-2-yl]ethanol (step 4, 590 mg, 0.95 mmol) in DMF (10 ml) was added NaH (45 mg, 1.13 mmol). Then the mixture was added MeI (0.08 ml, 1.23 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was added water (30 ml) and extracted with ethyl acetate (100 ml). The organic layer was washed with water (50 ml), brine (50 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (3:1) to afford 550 mg (91%) of the title compound as colorless oil.