Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:14][N:15]1[CH:19]=[C:18]([CH:20]=O)[CH:17]=[N:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[Cl:1][C:2]1[C:3]([N:8]2[CH2:9][CH2:10][N:11]([CH2:20][C:18]3[CH:17]=[N:16][N:15]([CH3:14])[CH:19]=3)[CH2:12][CH2:13]2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: Clc1nccnc1N1CCNCC1
Reactant: Cn1cc(C=O)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc(CN2CCN(c3nccnc3Cl)CC2)cn1
Reaction time: 6 h
Yield: 102.9 %

Procedure:
Dissolve 3′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (3.43 g, 17.3 mmol) in tetrahydrofuran (100 mL). Add 1-methyl-1H-pyrazole-4-carbaldehyde (2.244 g, 20.38 mmol) in dry tetrahydrofuran (5 mL), stir for 10 min. at room temperature, add sodium triacetoxyborohydride (4.32 g, 20.4 mmol), subject the reaction to ultrasound and stir for 6 hr. at room temperature. Add saturated aq. sodium hydrogen carbonate (100 mL) then 2 N sodium hydroxide (10 mL) to the mixture and extract with DCM (2×200 mL). Pass the combined DCM extracts through an IST Phase Separator Frit®, concentrate and purify (silica gel chromatography, eluting with 0:100 to 8:92 methanol:DCM), to give 3′-chloro-4-(1-methyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl as a crystalline solid (5.21 g, 92%). MS (ES): m/z=293.1 [M+H]+.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[Cl:16][C:17]1[CH:22]=[C:21](O)[CH:20]=[CH:19][C:18]=1[CH:24]([CH3:43])[C:25]([C:31]1[CH:42]=[CH:41][C:34]2[N:35]([CH3:40])[C:36](=[O:39])[CH2:37][O:38][C:33]=2[CH:32]=1)([OH:30])[C:26]([F:29])([F:28])[F:27].C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[C:21]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])[CH:20]=[CH:19][C:18]=1[CH:24]([CH3:43])[C:25]([OH:30])([C:31]1[CH:42]=[CH:41][C:34]2[N:35]([CH3:40])[C:36](=[O:39])[CH2:37][O:38][C:33]=2[CH:32]=1)[C:26]([F:28])([F:29])[F:27]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)OCC(=O)N2C)C(F)(F)F
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(c1ccc(OS(=O)(=O)C(F)(F)F)cc1Cl)C(O)(c1ccc2c(c1)OCC(=O)N2C)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoromethanesulfonic anhydride (0.12 ml) was added to 7-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (150 mg, Example 158 step 2) and triethylamine (0.2 ml) in DCM (5 ml). The mixture was stirred for 2 h at room temperature. 10% aqueous citric acid was added and extracted with DCM. The combined organic layers were dried over Na2SO4 and then concentrated to give the title compound (140 mg) as light yellow foam. MS (m/e, ISP neg. ion)=546.2 [M−H+].
Reaction SMILES: CO[CH:3]([O:9]C)[CH2:4][C:5]1([OH:8])[CH2:7][CH2:6]1.C(Cl)Cl.O([Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])S(C(F)(F)F)(=O)=O.FC(F)(F)S(O[Si](CC)(CC)CC)(=O)=O>O>[Si:22]([O:8][C:5]1([CH2:4][CH:3]=[O:9])[CH2:6][CH2:7]1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: COC(CC1(O)CC1)OC
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1(CC=O)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a 2.0 L RBF containing 1-(2,2-dimethoxyethyl)cyclopropanol (17.400 g, 119 mmol) was added DCM (550 ml) and the mixture was allowed to stir at 0° C. for 15 min. 2,4,6-Colliding (63.1 ml, 476 mmol) was added and the reaction was allowed to chill for 5 min before the addition of tert-butyldimethylsilyl triflate (27.3 ml, 119 mmol) over 10 min. The reaction was allowed to stir for 20 min and then analyzed by tlc which showed that all of the tertiary alcohol had been protected as its TBS ether. So, triethylsilyl trifluoromethanesulfonate (53.8 ml, 238 mmol) was added via syringe over 10 min. After 20 min, tic showed all of the material was converted to a baseline Rf material (mixed acetal) and then water (300 mL) was added and the reaction was allowed to stir overnight. The layers were separated. The DCM was washed with dilute HCl to remove the 2,4,6-collidine. The aq. layer was back extracted with DCM. The combined organics were washed with sodium bicarbonate, brine, dried with sodium sulfate and filtered though a plug of silica gel. Desired fractions were collected to give the product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:17]O)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(Cl)(=O)=O.S([O-])(=O)(=O)C.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>ClCCl.O>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:17][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(CO)cc2C1
Reactant: C1CCNC1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2ccc(CN3CCCC3)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.25 g 5-hydroxymethyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (5.01 mmol) in 14 ml dichloromethane was slowly added 0.781 ml methanesulfonyl chloride (10.03 mmol) at room temperature. Subsequently the mixture was heated for 4 hours at reflux. LCMS control indicted a near complete formation of the corresponding mesylate, which was not isolated. After cooling to room temperature, 1.244 ml pyrrolidine (15.04 mmol) were added and the mixture was stirred at room temperature overnight. The reaction was complete according to LCMS. Water was added to the reaction mixture, the acidic aqueous phase was extracted two times with dichloromethane, and the water phase was basified and extracted three times with ethyl acetate. The combined ethyl acetate solutions were extracted with brine, dried over Na2SO4, filtered, and the organic solvent was removed under reduced pressure to provide the title compound. The dichloromethane phase was extracted two times with diluted NaOH, once with brine and then dried over Na2SO4. Filtration and removal of the organic solvent under reduced pressure provided additional title compound. Both fractions were combined and used in the next step without further purification. LCMS: m/z 303.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[OH:11].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[O:11][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CBr
Reactant: COc1cccc(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1c(OC)cccc1OC
Temperature: 30 °C
Reaction time: 20 h
Yield: 91.6 %

Procedure:
To a solution of 2,6-dimethoxyphenol (1.54 g, 10 mmol) and ethyl bromoacetate (2.00 g, 12 mmol) in 15 mL of anhydrous DMF, was added 2.76 g (20 mmol) of K2CO3. The reaction mixture was stirred at 30° C. for 20 hours. The mixture was concentrated in vacuo to remove volatiles. The resulting residue was extracted with EtOAc, washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacou to give 2.2 g (91.6%) of ethyl 2-(2,6-dimethoxyphenoxy)acetate. The obtained ester (1.2 g, 5 mmol) was dissolved in a suspension of Silica Gel (2.0 g) in 20 mL of DCM. To this was dropwise added of a solution of concentrated HNO3 (20 mL) in 20 mL of DCM at rt. After being stirred at room temperature for 1 hour, it was transferred into a separatory funnel and then brown bottom layer was discarded into 100 g of ice. The remaining top organic layer was washed with brine, dried over anhydrous sodium sulfate, and then concentrated in vacou to give 1.4 g (98%) of ethyl 2-(2,6-dimethoxy-4-nitrophenoxy)acetate as a brown solid. The obtained nitrophenoxy ester (1.34 g, 4.7 mmol) was dissolved in anhydrous THF (20 mL). To this, was slowly added of 1M DIBAL solution (10.3 mL, 10.3 mmol) in toluene with ice bath cooling. After 1 hour at rt, the reaction was quenched by addition of 1N-NaOH solution, and then extracted with EtOAc. The obtained organic layer was dried over anhydrous sodium sulfate, and passed through Silica Gel pad. The resulting filtrate was concentrated in vacuo to afford 2-(2,6-dimethoxy-4-nitrophenoxy)ethanol (1.01 g, 88%) as a pale yellow solid; MS (ESI) m/z 326 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH:15]2[CH2:17][CH2:16]2)[N:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH:15]1([NH:14][C:4]2[N:3]=[C:2]([N:28]3[CH2:29][CH2:30][CH:25]([C:22]4[CH:21]=[CH:20][C:19]([F:18])=[CH:24][CH:23]=4)[CH2:26][CH2:27]3)[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=2)[CH2:17][CH2:16]1
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NC2CC2)nc1NCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(NCCO)nc(NC2CC2)nc1N1CCC(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 47b, 4-chloro-2-cyclopropylamino-6-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile (example 47a) was treated with the 4-(4-fluorophenyl)-piperidine in dioxane in the presence of N-ethyl-diisopropylamine at 100° C. to yield the 2-cyclopropylamino-4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-6-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=397.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:18][C:19]2[NH:20][C:21](=[O:29])[CH:22]3[CH2:28][O:27][CH2:26][CH2:25][CH:23]3[N:24]=2)[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]2)=[O:7])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[C:39]1([SH:45])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:39]1([S:45][C:15]([CH:12]2[CH2:11][CH2:10][N:9]([CH2:8][C:6](=[O:7])[N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[CH2:18][C:19]3[NH:20][C:21](=[O:29])[CH:22]4[CH2:28][O:27][CH2:26][CH2:25][CH:23]4[N:24]=3)[CH2:14][CH2:13]2)=[O:17])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(O)C1CCN(CC(=O)N(CC2=NC3CCOCC3C(=O)N2)CC2CC2)CC1
Reactant: Sc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Sc1ccccc1)C1CCN(CC(=O)N(CC2=NC3CCOCC3C(=O)N2)CC2CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
To a solution of 1-{[cyclopropylmethyl-(4-oxo-3,4a,5,7,8,8a-hexahydro-4H-pyrano[4,3-d]pyrimidin-2-ylmethyl)-carbamoyl]-methyl}-piperidine-4-carboxylic acid (0.5 g, 1.24 mmol, 1 eq.) in 5 mL of DMF was added DIEA (0.432 mL, 2.47 mmol, 2 eq.), thiophenol (0.14 mL, 1.36 mmol, 1.1 eq.), followed by HATU (0.517 g, 1.36 mmol, 1.1 eq.) at 0° C. The resulting mixture was allowed to warm to room temperature and stirred overnight. After 18 h, the reaction mixture was concentrated in vacuo to give an oil. This oil was purified by silica gel column chromatography (98/1/1 to 95/4/1 dichloromethane/MeOH/NH4OH) to give the title compound as an orange sticky oil (0.4 g). 1H NMR (400 MHz, chloroform-d) δ ppm 7.48-7.58 (m, 2H), 7.33-7.48 (m, 3H), 4.54-4.64 (m, 2H), 4.48-4.54 (m, 1H), 4.34-4.46 (m, 1H), 3.91-4.06 (m, 2H), 3.23-3.42 (m, 3H), 2.92-3.08 (m, 1H), 2.80-2.89 (m, 1H), 2.54-2.76 (m, 2H), 2.18-2.37 (m, 2H), 1.60-1.84 (m, 6H), 0.92-1.01 (m, 1H), 0.41-0.63 (m, 2H), 0.19-0.35 (m, 2H). Exact mass calculated for C26H33N4O4S1 497.2. MS (ESI) m/z 497.2 (M+H)+ (5-95% CH3CN/H2O over 2 min with 0.1% formic acid, Inertsil 3×3 mm C-8-3 column with flow rate of 2 mL/min).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:14]2[CH2:13][CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
A solution of 1-fluoro-4-nitrobenzene (500 mg, 3.54 mmol) and tert-butyl piperazine-1-carboxylate (726 mg, 3.9 mmol) in dimethylformamide was treated with potassium carbonate (735 mg, 5.32 mmol) and the suspension was heated at 55° C. for 4 hours and then stirred overnight at room temperature. The reaction was poured into water and the suspension was filtered with water washes to provide the title compound after vacuum drying.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9](Cl)(=[O:11])=[O:10].[NH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]1>N1C=CC=CC=1>[CH3:13][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][O:22][S:9]([C:2]2[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=2[CH3:13])(=[O:11])=[O:10])[CH2:16][CH2:15]1)(=[O:11])=[O:10]
Reactant: OCCC1CCNCC1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: c1ccncc1
Product: Cc1cc(C)c(S(=O)(=O)OCCC2CCN(S(=O)(=O)c3c(C)cc(C)cc3C)CC2)c(C)c1
Temperature: 0 °C
Reaction time: 44 h

Procedure:
2-Mesitylenesulfonyl chloride (24.78 g, 0.113 mol) in pyridine (60 ml) was added all at once to 4-piperidineethanol (5.58 g, 43.2 mmol) in pyridine (25 ml) at -16° C.; the temperature rose to -11° C. The flask was stored in the refrigerator at 5.5° C. for 44 hours under argon. The reaction mixture was poured into ice (1 kg) and after 3 hours, 16.00 g (75%) of (2) as a yellow solid was filtered off: mp 93.5°-94° C.; NMR (CDCl3 /TMS) δ 1.4-2.1 (m, 7H), 2.27 (s, 6H), 2.44-2.96 (m+s, 14H), 3.37-3.69 (m, 2H), 3.97 (t, 2H, J=5), 6.90 and 6.93 (2s, 4H). Anal. calcd. for C25H35NO5S5 : C-60.82, H-7.15, N-2.84. Found: C-60.90, H-7.13, N2.85.
Reaction SMILES: [N:1]1([CH2:6][C:7]23[CH2:16][CH:11]4[CH2:12][CH:13]([CH2:15][C:9]([O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26])([CH2:10]4)[CH2:8]2)[CH2:14]3)[CH:5]=[CH:4][CH:3]=[N:2]1.[Li][CH2:28]CCC.IC>O1CCCC1>[CH3:28][C:5]1[N:1]([CH2:6][C:7]23[CH2:14][CH:13]4[CH2:12][CH:11]([CH2:10][C:9]([O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26])([CH2:15]4)[CH2:8]2)[CH2:16]3)[N:2]=[CH:3][CH:4]=1
Reactant: [Li]CCCC
Reactant: OCCOCCOCCOC12CC3CC(CC(Cn4cccn4)(C3)C1)C2
Solvent: CI
Solvent: C1CCOC1
Product: Cc1ccnn1CC12CC3CC(C1)CC(OCCOCCOCCO)(C3)C2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a cold (−78° C.) solution of EXAMPLE 83A (1.0 g) in tetrahydrofuran (10 mL) was added n-BuLi (5 mL, 2.5 M in hexane). The reaction mixture was stirred for 90 minutes, and iodomethane (1 mL) was added. The reaction mixture was stirred at −78° C. for 90 minutes and quenched by the addition of 1 drop of trifluoroacetic acid. The reaction mixture was warmed to room temperature and concentrated to dryness. The residue was used in the subsequent step without further purification.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH:9]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[CH2:8]2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH:9]2[O:10][CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:19]=[CH:20][C:2]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[Cl:21])=[CH:3][CH:4]=3)[CH2:8]2)[CH:14]=1
Reactant: Brc1ccc(CN2CCOC(c3cccnc3)C2)cc1
Reactant: OB(O)c1ccccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Clc1ccccc1-c1ccc(CN2CCOC(c3cccnc3)C2)cc1
Temperature: 120 °C
Yield: 97 %

Procedure:
105 mg of 4-(4-Bromo-benzyl)-2-pyridin-3-yl-morpholine was combined with 74 mg of 2-Chlorophenyl boronic acid, 36 mg of tetrakis(triphenylphosphine)palladium(0), 1.055 mL of 2M sodium carbonate solution, 2.8 mL toluene and 1.4 mL ethanol. The reaction mixture was heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was purified by reverse phase HPLC. ES MS (+) m/z 365, 97% yield.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Br[C:20]1[CH:21]=[C:22]([S:27]([CH2:30][CH2:31][OH:32])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:20]2[CH:21]=[C:22]([S:27]([CH2:30][CH2:31][OH:32])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=2[CH3:26])[CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)CCO)cc1Br
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: Cc1ccc(S(=O)(=O)CCO)cc1C#Cc1cc(Cl)ccc1OCC(=O)O

Procedure:
Following the general method as outlined in Example 37, starting from tert-butyl(4-chloro-2-ethynyl phenoxy)acetate (Intermediate 3) and 2-[(3-bromo-4-methylphenyl)sulfonyl]ethanol (Intermediate 67), the title compound was obtained as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]1[C:12](=[O:13])[NH:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[C:8]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:7]1)[CH3:2].Cl[CH2:26][C:27]([CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:28].[I-]>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]1[C:12](=[O:13])[N:11]([CH2:26][C:27]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:28])[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[C:8]([CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)=[N:7]1)[CH3:2]
Reactant: O=C(CCl)C1CCCC1
Reactant: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2NC1=O
Agent: [I-]
Product: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCC2)C1=O

Procedure:
reacting the (5-cyclohexyl-2-oxo-1,2-dihydro-benzo[e][1,2,4]triazepin-3-yl)-acetic acid ethyl ester with 2-chloro-1-cyclopentyl-ethanone; in the presence of an organic or inorganic base; in an organic solvent; in the presence of a source of iodide; to yield [5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-benzo[e][1,2,4]triazepin-3-yl]-acetic acid ethyl ester;
Reaction SMILES: [CH2:1]([SiH:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[Cl:6])[CH:2]([CH3:4])[CH3:3].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:15][C:16](=[C:18]([CH3:20])[CH3:19])[CH3:17].C1(OC)C=CC=CC=1>>[C:16]([Si:5]([CH2:7][CH:8]([CH3:10])[CH3:9])([CH2:1][CH:2]([CH3:4])[CH3:3])[Cl:6])([CH:18]([CH3:20])[CH3:19])([CH3:17])[CH3:15]
Reactant: CC(C)C[SiH](Cl)CC(C)C
Reactant: CC(C)=C(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Product: CC(C)C[Si](Cl)(CC(C)C)C(C)(C)C(C)C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 35.8 g (0.2 mol) of diisobutylchlorosilane and 2.7 g (0.02 mol) of aluminum chloride and heated at 50° C. Once the internal temperature became constant, 16.8 g (0.2 mol) of 2,3-dimethyl-2-butene was added dropwise over one hour. After the completion of dropwise addition, the reaction solution was stirred for one hour at 50° C. The aluminum chloride was deactivated by adding 4.3 g (0.04 mol) of anisole. The reaction solution was distilled, collecting 32.5 g of a boiling point 83° C./133 Pa fraction.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[C:11]([CH:12]=[CH:13][C:4]2=[N:3][C:2]=1[C:14]([OH:16])=O)=[CH:10][CH:9]=[CH:8][CH:7]=3.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:29][C:30]1[NH:34][N:33]=[N:32][N:31]=1>C(OCC)(=O)C>[NH:31]1[C:30]([NH:29][C:14]([C:2]2[N:3]=[C:4]3[CH:13]=[CH:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]3[CH:1]=2)=[O:16])=[N:34][N:33]=[N:32]1
Reactant: O=C(O)c1cn2c(ccc3ccccc32)n1
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Product: O=C(Nc1nnn[nH]1)c1cn2c(ccc3ccccc32)n1
Temperature: 160 °C
Reaction time: 0.67 h
Yield: 100.3 %

Procedure:
0.85 g (4 mmol) of imidazo-[1,2-a]-quinoline-2-carboxylic acid [prepared as in published French application No. 2,378,301] was heated at 160° C. in vacuo for one hour to remove water of crystallization and was then dissolved in 25 ml of dimethylformamide. The solution was stirred at 90° to 100° C. with 0.72 g (4.4 mmol) of carbonyldiimidazole and the mixture was stirred at 100° C. for 40 minutes to obtain a slight suspension. 0.375 g of anhydrous 5-amino-tetrazole were added to the mixture which was then stirred at 100° C. for 45 minutes and was then cooled to room temperature. 20 ml of ethyl acetate were added to the mixture and the mixture was cooled in ice and was filtered to obtain 1.12 g of N-(1H-tetrazol-5-yl)-imidazo-[1,2-a]-quinoline-2-carboxamide in the form of colorless crystals melting at 266°-268° C. after crystallization from dimethylformamide.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[N:11]=[C:12](Br)[S:13][CH:14]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1.[NH2:32][CH2:33][C@H:34]([OH:37])[CH2:35][OH:36]>CC(C)=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[N:11]=[C:12]([NH:32][CH2:33][C@H:34]([OH:37])[CH2:35][OH:36])[S:13][CH:14]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1
Reactant: NC[C@H](O)CO
Reactant: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1csc(Br)n1
Solvent: CC(C)=O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1csc(NC[C@H](O)CO)n1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
100 mg (0.183 mmol) of 2-amino-4-(2-bromo-1,3-thiazol-4-yl)-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)pyridine-3,5-dicarbonitrile were initially charged in 2 ml of acetone, 834 mg (9.159 mmol) of (2S)-3-aminopropane-1,2-diol were added and the mixture was stirred at 80° C. for 12 h. A further 834 mg (9.159 mmol) of (2S)-3-aminopropane-1,2-diol were then added, and the mixture was stirred at 80° C. for a further 12 h. The reaction mixture was concentrated and the product was isolated by preparative HPLC. This gave 19 mg (19% of theory) of the target compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:9][CH3:10])[CH:4]1[CH2:8][CH2:7][NH:6][CH2:5]1)[CH3:2].Cl[C:12]1[N:13]=[CH:14][C:15]([C:18]([NH:20][C:21]2[NH:22][N:23]=[C:24]([CH2:26][CH2:27][C:28]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[CH:29]=3)[CH:25]=2)=[O:19])=[N:16][CH:17]=1>CS(C)=O.CO>[CH2:1]([N:3]([CH2:9][CH3:10])[CH:4]1[CH2:8][CH2:7][N:6]([C:12]2[N:13]=[CH:14][C:15]([C:18]([NH:20][C:21]3[NH:22][N:23]=[C:24]([CH2:26][CH2:27][C:28]4[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[CH:29]=4)[CH:25]=3)=[O:19])=[N:16][CH:17]=2)[CH2:5]1)[CH3:2]
Reactant: CCN(CC)C1CCNC1
Reactant: COc1cc(CCc2cc(NC(=O)c3cnc(Cl)cn3)[nH]n2)cc(OC)c1
Solvent: CS(C)=O
Solvent: CO
Product: CCN(CC)C1CCN(c2cnc(C(=O)Nc3cc(CCc4cc(OC)cc(OC)c4)n[nH]3)cn2)C1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 81.6 %

Procedure:
N,N-diethylpyrrolidin-3-amine (142 mg, 1.00 mmol) was added to 5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (136 mg, 0.35 mmol) in anhydrous dimethylsulfoxide (1.75 ml) at 25° C. The resulting solution was stirred at room temperature for 50 mins. The reaction mixture was diluted with methanol (5.00 ml) and the crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford impure product as a brown dry film. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (141 mg, 82%) as a white solid.