Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:8](=[O:23])[N:9]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.N#N.C([Sn](CCCC)(CCCC)[C:31]1[O:32][CH:33]=[CH:34][N:35]=1)CCC>C1COCC1.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>[O:32]1[CH:33]=[CH:34][N:35]=[C:31]1[C:2]1[C:3]2[N:4]([C:8](=[O:23])[N:9]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1n(CCc2ccc3ccccc3n2)nc2c(Br)cccn12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: C1CCOC1
Product: O=c1n(CCc2ccc3ccccc3n2)nc2c(-c3ncco3)cccn12
Temperature: 125 °C
Yield: 16.4 %

Procedure:
A solution of bromide 1-6 (43 mg, 0.116 mmol) in THF (2 mL) in a microwave vial was sparged with N2 gas for 5 min, and 2-(tributylstannyl)oxazole (83 mg, 0.233 mmol) and tetrakis(triphenylphosphine)palladium (13 mg, 0.012 mmol) were added. The vial was capped and heated at 125° C. under microwave irradiation for 20 min, then another 30 min at 130° C. An additional portion of 2-(tributylstannyl)oxazole (50 mg, 0.140 mmol) was added, and the vial was heated at 85° C. in an oil bath for 16 h. After cooling, the reaction mixture was directly purified by silica gel flash column chromatography (12 g cartridge), eluting with 40-100% EtOAc/hexanes then 2% EtOH/EtOAc. The fractions containing the desired product (4-1) were pooled, and after solvent removal in vacuo, 6.8 mg (16%) of a yellow solid were obtained. 1H NMR (300 MHz, CHCl3-d): δ 8.07 (d, J=8.4 Hz, 1H), 8.02 (d, J=7.8 Hz, 1H), 7.92 (dd, J=6.9, 1.2 Hz, 1H), 7.88 (dd, 6.9, 1.2 Hz, 1H), 7.80 (d, J=0.6 Hz, 1H), 7.78 (d, J=8.1 Hz, 1H), 7.68 (ddd, J=8.4, 7.2, 1.5 Hz, 1H), 7.50 (ddd, Jr=7.8, 6.6, 1.2 Hz, 1H), 7.35 (s, 1H), 7.33 (s, 1H), 6.64 (t, J=7.2 Hz, 1H), 4.69 (t, J=7.5 Hz, 2H), 3.61 (t, J=7.5 Hz, 2H). HRMS (ES) 358.1299 (M+H) found, 358.1302 required.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:36].[CH3:37][N:38]([CH3:44])[CH2:39][CH2:40][CH2:41][NH:42][CH3:43]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:42]([CH2:41][CH2:40][CH2:39][N:38]([CH3:44])[CH3:37])[CH3:43])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:36]
Reactant: CCCNC(=O)c1ccc(C)c(-c2nc(S(C)(=O)=O)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Reactant: CNCCCN(C)C
Solvent: ClCCl
Product: CCCNC(=O)c1ccc(C)c(-c2nc(N(C)CCCN(C)C)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Temperature: 25 °C

Procedure:
3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide (0.04 g, 0.078 mmol), N,N,N′-trimethyl-1,3-propanediamine (0.134 g, 0.115 mmol), and TEA (0.016 g, 0.156 mmol) were combined in CH2Cl2 (5 mL) and stirred under argon at room temperature. The solvents were pumped off in vacuo. The residue was flash chromatographed on silica gel (10 g) eluted with CH2Cl2 to 6:1:0.1, CH2Cl2:ethanol:NH4OH. The compound had an impurity which was removed by filtering through a silica gel plug with 3% MeOH/CH2Cl2 to give the title compound as an off-white amorphous solid. mp 104-109° C. LC-MS m/z 549 (M+H)+, 1.65 min (ret time).
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:17])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:16].CCN(CC)CC.[CH2:25]([CH:29]1[CH2:35][CH:34]2[NH:36][CH:31]([CH2:32][CH2:33]2)[CH2:30]1)[CH2:26][CH2:27][CH3:28]>C(Cl)Cl.CC(O)C>[CH2:25]([CH:29]1[CH2:30][CH:31]2[N:36]([CH2:2][C@@H:3]([CH3:17])[CH2:4][N:5]3[C:10]4[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=4[O:8][CH2:7][C:6]3=[O:16])[CH:34]([CH2:33][CH2:32]2)[CH2:35]1)[CH2:26][CH2:27][CH3:28]
Reactant: Cc1ccc2c(c1)N(C[C@H](C)CI)C(=O)CO2
Reactant: CCCCC1CC2CCC(C1)N2
Solvent: ClCCl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)COc2ccc(C)cc21
Yield: 62.6 %

Procedure:
Crude (S)-4-(3-iodo-2-methylpropyl)-6-methyl-4H-benzo[1,4]oxazin-3-one (0.19 g, 0.54 mmol), Et3N (0.5 mL) and 3-butyl-8-azabicyclo[3.2.1]octane (0.10 g, 0.61 mmol) were reacted according to GP17. Flash CC (SiO2; CH2Cl2/i-PrOH 92:8) gave the title compound (0.13 g, 62%). 1H NMR (CD3OD) δ 7.05 (s, 1H), 6.86 (d, J=8.4 Hz, 1H), 6.81 (dm, J=8.4 Hz, 1H), 4.52 (ABq J=14.8, 24.8 Hz, 2H), 4.05 (dd, J=5.6, 14.0 Hz, 1H), 3.94 (dd, J=8.8, 14.0 Hz, 1H), 3.05-3.16 (m, 2H), 2.35-2.14 (m, 2H), 2.31 (s, 3H), 2.05-1.78 (m, 3H), 1.63-1.40 (m, 5H), 1.36-1.12 (m, 5H), 0.99 (d, J=6.4 Hz, 3H), 0.90 (t, J=6.8 Hz, 3H); 13C NMR (CD3OD) δ 167.4, 144.9, 133.7, 129.2, 125.6, 117.7, 117.3, 68.5, 63.2 (br), 62.5 (br), 56.0 (Br), 43.3, 37.8 (br), 31.3, 30.5, 30.0, 28.3, 26.7, 26.4, 23.7, 21.0, 16.8, 14.2.
Reaction SMILES: [C:1]([C:4]1[C:8]([S:9][CH3:10])=[C:7]([NH2:11])[N:6]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[Cl:23])[N:5]=1)(=[O:3])[CH3:2].[CH:24]([O-:27])([O-])[O-].O.[C:29]1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CO>[NH2:11][C:7]1[N:6]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:20])([F:21])[F:22])=[CH:14][C:13]=2[Cl:23])[N:5]=[C:4]([C:1]([O:27][CH3:24])([O:3][CH3:29])[CH3:2])[C:8]=1[S:9][CH3:10]
Reactant: [O-]C([O-])[O-]
Reactant: CSc1c(C(C)=O)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(C)(OC)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1SC
Temperature: 40 °C
Reaction time: 64 h

Procedure:
A mixture of 2.0 g (0.0052 mole) of 3-acetyl-5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylthio-1H-pyrazole, 1.7 ml (0.0156 mole) of trinethyl orthoformate, 0.060 g (0.0003 mole) of para-toluenesulfonic acid monohydrate and 10 ml of methanol was heated at 40° C. for about 8 hours, then left 64 h at 20° C. The mixture was mixed with a saturated solution of NaHCO3, extracted with dichloromethane, and successively dried, filtered, evaporated, chromatographed on silica gel. 0.59 g of the title compound having a melting point of about 149° C. was obtained.
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:7]=1[CH:8]([O:14][CH3:15])[O:9]2.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1>[F:21][CH:2]([F:1])[O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6]1[CH:19]=[CH:18][C:17]([NH:20][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:16][C:7]=1[CH:8]([O:14][CH3:15])[O:9]2
Reactant: COC1Oc2cccc(OC(F)F)c2-c2ccc(N)cc21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COC1Oc2cccc(OC(F)F)c2-c2ccc(NS(C)(=O)=O)cc21
Reaction time: 15 h

Procedure:
To a solution of Example 96B (3.9 g, 13 mmol) in pyridine (40ml) at 0° C. was added methylsulfonylchloride (1.5 g, 13 mmol). The mixture was stirred for 15 hour, concentrated under reduced pressure. The residue was dissolved in 10% HCl solution (50 mL) and extracted with ethyl acetate (3×30 mL). The combined extract were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate in hexanes to provide the titled compound. MS (ESI(−)Q1MS) m/z 370 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(N(CC)CC)C.[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[CH:20]=[CH2:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH2:24]([O:23][C:19](=[O:22])/[CH:20]=[CH:21]/[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[CH3:25]
Reactant: C=CC(=O)OCC
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(Cl)cc1[N+](=O)[O-]

Procedure:
1-bromo-4-chloro-2-nitrobenzene (5 g), triethylamine (4.42 ml), ethyl acrylate (22.9 ml), palladium (II) acetate (0.048 g) and triphenylphosphine (0.111 g) in DMF (30 ml) was refluxed at 87° C. for 10 h. Toluene was added and the mixture washed with 2M hydrochloric acid and water. The organics were dried and concentrated under reduced pressure to a brown oil which was triturated with isohexane to give a light brown solid. Yield 4.95 g.
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[CH3:44][O:45][C:46]1[N:51]=[CH:50][C:49]([NH2:52])=[CH:48][CH:47]=1>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]2[CH:41]=[C:40]([NH:52][C:49]3[CH:50]=[N:51][C:46]([O:45][CH3:44])=[CH:47][CH:48]=3)[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: COc1ccc(N)cn1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: COc1ccc(Nc2ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c2)cn1

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 6-methoxy-pyridin-3-ylamine according to procedure B followed by deprotection yielded the title compound as an pale brown foam. MS (ESI): m/z=386.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](OS(C(F)(F)F)(=O)=O)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[SH:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1.O.C(O)(=O)C>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1
Reactant: Cc1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Reactant: O=C(O)c1ccc(S)cc1
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(Sc2ccc(C(=O)O)cc2)c([N+](=O)[O-])c1
Yield: 91.6 %

Procedure:
The product from Example 4a (0.94 g, 3.31 mmol) was reacted with 4-mercapto-benzoic acid (0.51 g, 3.31 mmol) in aqueous ethanol at 80° C. under nitrogen. The reaction mixture was poured into water and acidified with glacial acetic acid. The solid product was collected by filtration, water washed and dried in vacuo to give the title compound (0.877 g, 91%) sufficiently pure for use as isolated.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[C:12]([O:20][CH:21]([O:28][C:29]([NH:31][CH2:32][C:33]1([CH2:39][C:40]([O:42]CCC#N)=[O:41])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[C:12]([O:20][CH:21]([O:28][C:29]([NH:31][CH2:32][C:33]1([CH2:39][C:40]([OH:42])=[O:41])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N#CCCOC(=O)CC1(CNC(=O)OC(OC(=O)c2ccccc2)c2ccccc2)CCCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: O=C(O)CC1(CNC(=O)OC(OC(=O)c2ccccc2)c2ccccc2)CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 4.7 %

Procedure:
DBU (79.2 mg, 78 μL, 0.520 mmol) was added to a solution of 2-cyanoethyl 1-{[α-benzoyloxybenzyloxy)carbonyl]aminomethyl}-1-cyclohexane acetate (11) (166 mg, 0.347 mmol) in 10 mL of CH2C1 at −10° C. The reaction mixture was stirred at 0° C. for 1 hour, then allowed to warm to room temperature, stirred for two hours and cooled to 0° C. Another 78 μL of DBU was added, the reaction mixture was stirred for 3 hours at 0° C. and then allowed to warm to room temperature. The reaction mixture was diluted with CH2Cl2, washed with citric acid and brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by reversed phase HPLC to afford 7 mg (4.7%) of the title compound. M.p. 75.5-76.0° C. 1H NMR (CDCl3): δ 8.08 (2H, dd, J=8.8, 1.2 Hz); 7.89 (1H, s); 7.63-7.55 (3H, m); 7.46-7.26 (5H, m); 5.38 (1H, t, J=6.8 Hz); 3.26 (2H, dd, J=6.8, 0.8 Hz); 2.34 (2H, s); 1.58-1.35 (10H, m). MS (ESI) m/z 424 (M−H−).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[N:5][CH:4]=1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(=O)([O-])[O-].[Na+].[Na+]>[Cl:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:10][CH2:11][N:12]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:13][CH2:14]2)[CH:6]=[N:5][CH:4]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Clc1cncc(N2CCNCC2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(c1ccccc1)N1CCN(c2cncc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Using a procedure similar to that of Example 4, 2.35 g (0.010 mole) of 6-chloro-2-(1-piperazinyl)-pyrazine hydrochloride is dissolved in 20 ml saturated aqueous sodium carbonate solution and treated with 2 ml benzoyl chloride. After stirring 10 minutes at room temperature, the crude product is extracted with toluene and recrystallized from n-butyl-chloride-cyclohexane (charcoal treatment) to give colorless crystals of the title compound, mp 104.5°-105° C.
Reaction SMILES: [C:1]1([CH:7]([OH:13])[CH2:8][CH2:9][C:10]#[C:11][CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14](=O)[CH3:15].C[Si]([O:21][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23])(C)C.C([O-])(O)=O.[Na+]>ClCCl.C(OCC)C>[F:26][C:25]([F:28])([F:27])[S:22]([O:24]/[C:11](=[C:10]1/[CH:14]([CH3:15])[O:13][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]/1)/[CH3:12])(=[O:23])=[O:21]
Reactant: CC#CCCC(O)c1ccccc1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: C/C(OS(=O)(=O)C(F)(F)F)=C1/CCC(c2ccccc2)OC1C
Reaction time: 1 h
Yield: 76 %

Procedure:
In dichloromethane (3.0 mL) were dissolved 1-phenylhex-4-yn-1-ol (0.28 mmol) and ethanal (0.34 mmol) and the solution was cooled to −78° C. before the addition of trimethylsilyltriflate (TMSOTf) (0.86 mmol) thereto. At the same temperature, the reaction solution was stirred for 1 hour, followed by slow temperature elevation to room temperature over 3 hours. Stirring was further conducted at room temperature for an additional one to two hours in the reaction solution. After the addition of an aqueous NaHCO3 solution, the reaction solution was diluted with diethylether. The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated. The purification of the concentrate through column chromatography afforded the title compound (Yield 76%).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH:32]([N:37]4[CH2:42][CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39][CH2:38]4)[C:33]([F:36])([F:35])[F:34])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=3)[N:10]=2)=CC=1.FC(F)(F)C(O)=O.F[C:69](F)(F)[S:70](O)(=[O:72])=[O:71]>>[F:29][C:27]1[CH:28]=[C:23]([NH:22][C:21]2[C:16]([C:11]3[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([NH2:8])[N:10]=3)=[CH:17][C:18]([CH:32]([N:37]3[CH2:38][CH2:39][N:40]([S:70]([CH3:69])(=[O:72])=[O:71])[CH2:41][CH2:42]3)[C:33]([F:34])([F:35])[F:36])=[CH:19][N:20]=2)[CH:24]=[N:25][C:26]=1[O:30][CH3:31]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(N4CCN(C(=O)OC(C)(C)C)CC4)C(F)(F)F)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncc(C(N3CCN(S(C)(=O)=O)CC3)C(F)(F)F)cc2-c2nc(C)nc(N)n2)cc1F

Procedure:
The title compound was prepared from tert-butyl 4-(1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-2,2,2-trifluoroethyl)piperazine-1-carboxylate via the similar deprotection step as previously described in Example 178, Step 4 using trifluoroacetic acid and trifluoromethanesulfonic acid and isolated (quantitative) as a yellow solid. m/z (ESI, +ve ion) 572 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.96 (s, 1H) 8.84 (d, J=2.15 Hz, 1H) 8.40 (d, J=2.35 Hz, 1H) 8.29-8.39 (m, 2H) 8.03 (br. s., 1H) 7.88 (br. s., 1H) 4.86 (q, J=9.45 Hz, 1H) 3.95 (s, 3H) 3.13 (t, J=4.60 Hz, 4H) 2.86 (s, 3H) 2.69-2.78 (m, 2H) 2.58-2.69 (m, 2H) 2.45 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([N:14]([CH3:16])[CH3:15])/[CH:3]=[CH:4]/[CH:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][CH:7]=[C:6]1[CH3:13].[CH2:17]([Br:19])[CH3:18]>>[Br-:19].[CH3:1][CH:2]([N+:14]([CH3:16])([CH3:15])[CH2:17][CH3:18])/[CH:3]=[CH:4]/[CH:5]1[C:10]([CH3:11])([CH3:12])[CH2:9][CH2:8][CH:7]=[C:6]1[CH3:13]
Reactant: CC1=CCCC(C)(C)C1/C=C/C(C)N(C)C
Reactant: CCBr
Product: CC[N+](C)(C)C(C)/C=C/C1C(C)=CCCC1(C)C
Product: [Br-]
Yield: 26.2 %

Procedure:
A mixture of [1-methyl-3-(2,6,6-trimethyl-2-cyclohexenyl)-2(trans)-propenyl]dimethylamine (2.3 g) and ethylbromide (6.0 g) was refluxed for 3 hours, and then the excess ethylbromide was distilled off. The residue was recrystallized from a mixed solvent of benzene and ether to give colorless crystals (0.9 g) of [1-methyl-3-(2,6,6-trimethyl-2-cyclohexenyl)-2(trans)-propenyl]dimethylethylammonium bromide.
Reaction SMILES: [CH2:1]([C:5]1[CH:6](O)[C:7]2[C:12]([CH:13]=1)=[C:11]([C:14]1[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=1)[CH:10]=[CH:9][CH:8]=2)[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.CS(Cl)(=O)=O.O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([C:5]1[CH2:6][C:7]2[C:12]([CH:13]=1)=[C:11]([C:14]1[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=1)[CH:10]=[CH:9][CH:8]=2)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CC1=Cc2c(-c3cccc4ccccc34)cccc2C1O
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)CC1=Cc2c(cccc2-c2cccc3ccccc23)C1
Reaction time: 3 h
Yield: 92.6 %

Procedure:
A 200-ml three-necked round flask equipped with a stirring bar, a Dimroth condenser, a dropping funnel and a thermometer was charged with 4.54 g (14.4 mmol) of 2-i-butyl-1-hydroxy-4-(1-naphthyl)indene, 5.13 g (50.8 mmol) of triethylamine, 0.10 g (0.82 mmol) of 4-dimethylaminopyridine and 57.7 ml of methylene chloride. To the mixture was added dropwise a solution containing 3.87 ml (33.8 mmol) of methanesulfonyl chloride dissolved in 7.7 ml of methylene chloride under a nitrogen atmosphere while cooling with ice bath. After the addition was completed, the temperature was elevated to room temperature and the mixture was further stirred for 3 hours. The reaction mixture was poured onto 100 ml of water. Thereafter, the organic phase was separated, and the aqueous phase was extracted with 50 ml of methylene chloride. The extracted organic phases were combined and washed with a saturated NaCl aq., followed by dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure. The residue was separated and purified with silica gel chromatography (eluting with hexane/ethyl acetate (20/1 parts by volume)) to obtain 3.98 g of the desired product (mixture of two isomers) as a pale yellow pasty liquid (yield: 93%).
Reaction SMILES: [H-].[Na+].O[CH2:4][CH:5]([CH2:8][OH:9])[CH2:6][OH:7].IC.[C:12](OCC)(=O)C.CN([CH:21]=[O:22])C>>[CH3:12][O:9][CH2:8][CH:5]([CH2:4][O:22][CH3:21])[CH2:6][OH:7]
Reactant: OCC(CO)CO
Reactant: CCOC(C)=O
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COCC(CO)COC
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Sodium hydride (60% dispersion in oil) (2.93 g, 73.2 mmol) was added to an ice-cooled solution of 2-hydroxymethyl-propane-1,3-diol (M. R. Harnden et al. J. Med. Chem. 1990, 33, 187) (3.53 g, 33.3 mmol) in DMF (100 ml) and the mixture was stirred at room temperature for 40 min. The reaction mixture was cooled with ice and iodomethane (4.56 ml, 73.2 mmol) was added, the stirring was continued allowing the mixture to reach room temperature over 24 h. The mixture was poured into ethyl acetate (300 ml) and washed with brine (150 ml). The organic phase was dried (MgSO4), and the solvent was evaporated. The crude product was purified by flash column chromatography (silica, ethyl acetate) to afford colourless oil. 1H NMR (300 MHz, CDCl3) 3.72 (2H, d), 3.47 (2H, d), 3.45 (2H, d), 3.32 (6H, s), 2.07(1H, m).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[CH3:14][O:15][C:16]1[CH:30]=[CH:29][CH:28]=[CH:27][C:17]=1[O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH2:23].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[I:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:23]([CH2:22][C:21]1[CH:24]=[CH:25][CH:26]=[C:19]([O:18][C:17]3[CH:27]=[CH:28][CH:29]=[CH:30][C:16]=3[O:15][CH3:14])[CH:20]=1)[CH2:11]2
Reactant: COC(=O)c1c(I)cccc1CBr
Reactant: COc1ccccc1Oc1cccc(CN)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccccc1Oc1cccc(CN2Cc3cccc(I)c3C2=O)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 23.8 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.178 g, 0.5 mmol), 3-(2-methoxy-phenoxy)-benzylamine (0.160 g, 0.6 mmol), and K2CO3 (0.138 g, 1.0 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-iodo-2-[3-(2-methoxy-phenoxy)-benzyl]-2,3-dihydro-isoindol-1-one (0.056 g, 24%). 1H NMR (300 MHz, CDCl3): δ (ppm) 3.82 (s, 3H), 4.16 (s, 2H), 4.74 (s, 2H), 6.84-7.40 (m, 10H), 7.92 (d, 1H). GC-MS: m/z 471 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:13]([CH2:22][CH2:23][CH2:24][OH:25])=[N:12][C:11]=2[CH:26]([CH3:28])[CH3:27])[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClC(Cl)(Cl)[C:31]([N:33]=C=O)=[O:32].C(N(CC)CC)C>O1CCCC1.O>[C:31]([O:25][CH2:24][CH2:23][CH2:22][C:13]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:26]([CH3:28])[CH3:27])[N:12]=1)(=[O:32])[NH2:33]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CC(C)c1nc(CCCO)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)c1nc(CCCOC(N)=O)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
In 7 ml of dry tetrahydrofuran was dissolved 700 mg (1.6 mmol) of the alcohol (137c), and after the solution was cooled to -40° C., 450 mg (2.4 mmol) of trichloroacetyl isocyanate was added and the temperature was elevated gradually to room temperature. After stirring for 30 minutes, 2 ml of water and 1 ml of triethylamine were added and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% methanol-ethyl acetate) and recrystallized from ethyl acetate-n-hexane to provide 610 mg (yield 79%) of Compound I-150 as crystals. mp 114-115° C.