Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][C:6]1[CH:7]=[C:8]([SH:13])[CH:9]=[C:10]([CH3:12])[CH:11]=1.[C:14](Cl)(=[O:18])[C:15](Cl)=[O:16]>C(Cl)Cl>[CH3:12][C:10]1[C:9]2[C:15](=[O:16])[C:14](=[O:18])[S:13][C:8]=2[CH:7]=[C:6]([CH3:5])[CH:11]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(C)cc(S)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(C)c2c(c1)SC(=O)C2=O
Temperature: 25 °C
Yield: 36.1 %

Procedure:
To a solution of AlCl3(0.4 g, 3.6 mmol) in CH2Cl2 (4 mL) at −20° C. under nitrogen are added 3,5-dimethylbenzenethiol (1 g, 7.2 mmol) and oxalyl chloride (0.6 mL, 7.2 mmol) respectively. The solution is warmed to room temperature for 1 hour and is heated to 120° C. in a microwave reactor for 15 minutes. The solution is cooled and is poured into crushed ice. The solution is extracted with CH2Cl2 and the organic layer is collected. The solution is dried with MgSO4 and is filtered. The filtrate is concentrated and the residue is purified by flash chromatography with 5% EtOAc in Hexane as the eluent to afford 4,6-dimethyl-benzo[b]thiophene-2,3-dione (500 mg, 35%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]3[N:14]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[F:33])[C:15](=[O:24])[C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][C:17]=4[Cl:23])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:34]([F:37])([F:36])[F:35].[CH:38](=O)[CH3:39]>C1(C)C=CC=CC=1.C(O)(=O)C>[Cl:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[C:15](=[O:24])[N:14]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33])[C:13]([C:11]1[S:12][C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][CH2:38][CH3:39])=[C:3]([C:34]([F:37])([F:36])[F:35])[CH:4]=3)=[CH:9][CH:10]=1)=[CH:22]2
Reactant: Nc1ccc(-c2ccc(-c3cc4cccc(Cl)c4c(=O)n3Cc3ccc(F)cc3F)s2)cc1C(F)(F)F
Reactant: CC=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCNc1ccc(-c2ccc(-c3cc4cccc(Cl)c4c(=O)n3Cc3ccc(F)cc3F)s2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 34 %

Procedure:
To a solution of 3-[5-(4-amino-3-trifluoromethylphenyl)thiophen-2-yl]-8-chloro-2-(2,4-difluorobenzyl)-2H-isoquinolin-1-one (28 mg, 51 μmol) in toluene (1 mL) was added one drop of acetic acid, and a molar excess of acetaldehyde. The mixture was stirred for 20 minutes at ambient temperature and then concentrated under reduced pressure. The residue was taken up in 25% HOAc/MeOH (1 mL), and a molar excess of NaCNBH3 was added. After stirring for 16 hours at ambient temperature there was still starting material present. Additional acetaldehyde was added. After 30 minutes a yellow solid appeared in the reaction. This solid was collected by filtration and was purified by silica gel column chromatography eluting with a gradient from 0% to 20% ethyl acetate/hexane on silica. The product peak was collected to afford 8-chloro-2-(2,4-difluorobenzyl)-3-[5-(4-ethylamino-3-trifluoromethylphenyl)thiophen-2-yl]-2H-isoquinolin-1-one (10 mg, 34% yield) as a yellow solid. 1H-NMR (400 MHz, CDCl3): δ 7.62-7.60 (1H, m), 7.55-7.51 (3H, m), 7.44-7.40 (1H, m), 7.05-6.98 (2H, m), 6.85 (1H, d, J=3.8 Hz), 6.82-6.72 (3H, m), 6.67 (1H, s), 5.36 (2H, s), 4.40 (1H, s), 3.29-3.22 (2H, m), 1.32 (3H, t, J=7.1 Hz) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([OH:13])=[O:12].[CH3:14][C:15]([CH3:17])=O>C(O)(C(F)(F)F)=O.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>[CH3:14][C:15]1([CH3:17])[O:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[C:11](=[O:13])[O:12]1
Reactant: O=C(O)c1ccc(O)c(C(=O)O)c1
Reactant: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC1(C)OC(=O)c2cc(C(=O)O)ccc2O1
Temperature: 100 °C
Yield: 77 %

Procedure:
A suspension of 4-hydroxyisophtalic acid (Aldrich, 5.0 g, 27.5 mmol) in acetone (10 mL), TFA (30 mL) and TFAA (10 mL) was heated at 100° C. for 24 hrs. The reaction mixture was concentrated under reduced pressure. The residue was taken up with an aqueous solution of HCl (100 mL, 1N) and extracted with EtOAc (3×200 L); The combined organic layers were dried over MgSO4 and the solvents were removed under reduced: pressure. The crude compound was recrystallized in Et2O (50 mL) to give 4.67 g (77%) of the title compound as a beige powder. 1H NMR (DMSO-d6) δ: 8.37 (d J=1.9 Hz, 1H), 8.19 (dd, J=2.2 and 8.7 Hz, 1H), 7.23 (d, J=8.3 Hz, 1H), 1.72 (s, 6H). HPLC, Rt: 2.40 min (purity: 95.7%).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[Br:15][C:16]1[CH:17]=[CH:18][C:19]([S:22](Cl)(=[O:24])=[O:23])=[N:20][CH:21]=1>ClCCl.[NH4+].[Cl-]>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([S:22]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:24])=[O:23])=[N:20][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cn1
Reactant: CCOC(=O)CN
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNS(=O)(=O)c1ccc(Br)cn1
Temperature: 25 °C

Procedure:
Triethylamine (543 μL, 3.90 mmol) followed by ethyl glycinate (161 mg, 1.56 mmol) were added to a solution of 5-bromopyridine-2-sulfonyl chloride (200 mg, 0.780 mmol) in dichloromethane (2.6 mL) was added. The reaction mixture was stirred at room temperature and was monitored by LCMS. Upon completion, the reaction was diluted with saturated aqueous NH4Cl and the organic layer was dried over sodium sulfate and was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% MeOH in DCM:hexanes) to yield ethyl N-[(5-bromopyridin-2-yl)sulfonyl]glycinate. MS APCI calc'd for C9H12BrN2O4S [M+H]+ 323 and 325. found 323 and 325.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8](OS(C(F)(F)F)(=O)=O)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2.[O:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH:31]=[C:30]1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH:31]=[C:30]1[C:8]1[C:7]([N:3]2[CH2:4][CH2:5][CH2:6][C@@H:2]2[CH3:1])=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=2)[N:9]=1
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCC[C@@H]3C)nc2c1
Reactant: OB(O)c1cc2ccccc2o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3cc4ccccc4o3)c(N3CCC[C@@H]3C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
To a solution of (S)-methyl 3-(2-methylpyrrolidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (200 mg, crude) in dioxane (6 mL) was added benzofuran-2-ylboronic acid (113.0 mg, 0.70 mmol), K3PO4 (220.0 mg, 1.04 mmol), Pd(PPh3)4 (20.1 mg, 0.02 mmol) and water (3 drops). The resulting solution was stirred for 1 h at 90° C. and then concentrated under vacuum to give a residue, which was purified by a silica gel column with 1%-5% ethyl acetate in petroleum ether to afford (S)-methyl 2-(benzofuran-2-yl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate as a red oil (100.0 mg).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:19][OH:20])=[C:4]([CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH:5]=[N:6][C:7]=1[CH3:8].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=1>>[C:29]([C:26]1[CH:27]=[CH:28][C:23]([CH2:22][O:1][C:2]2[C:3]([CH2:19][OH:20])=[C:4]([CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)[CH:5]=[N:6][C:7]=2[CH3:8])=[CH:24][CH:25]=1)#[N:30]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Cc1ncc(COc2ccc(C#N)cc2)c(CO)c1O
Product: Cc1ncc(COc2ccc(C#N)cc2)c(CO)c1OCc1ccc(C#N)cc1
Yield: 49 %

Procedure:
The coupling of 4-(5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethoxy)-benzonitrile (13) (1.08 g, 4.0 mmol) and α-bromo-p-tolunitrile (0.9 g, 4.8 mmol), as described in Example, gave 4-(5-(4-cyano-benzyloxy)-4-hydroxymethyl-6-methyl-pyridin-3-ylmethoxy)-benzonitrile (14) (755 mg, 49% yield) as a colorless solid.
Reaction SMILES: [Br-].[F:2][CH:3]([F:34])[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH:10]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[O:9][C:8]2=[O:33].[Cl:35][C:36]1[CH:37]=[N:38][CH:39]=[C:40]([Cl:44])[C:41]=1[CH:42]=O.C(N(CC)CC)C.Cl>C(Cl)Cl>[Cl:35][C:36]1[CH:37]=[N:38][CH:39]=[C:40]([Cl:44])[C:41]=1[CH:42]=[C:10]1[C:11]2[C:7](=[CH:6][C:5]([O:4][CH:3]([F:2])[F:34])=[CH:13][CH:12]=2)[C:8](=[O:33])[O:9]1
Reactant: O=C1OC([P+](c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(OC(F)F)cc21
Reactant: O=Cc1c(Cl)cncc1Cl
Agent: Cl
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1OC(=Cc2c(Cl)cncc2Cl)c2ccc(OC(F)F)cc21
Temperature: 4 °C
Reaction time: 3 h
Yield: 191.5 %

Procedure:
A solution of (5-difluoromethoxy-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-triphenyl-phosphonium bromide (11.4 g, 21 mmoles), prepared as described in example 96, in dry CH2Cl2 (110 ml), under N2, was added with 3,5-dichloro-4-formyl-pyridine (4.06 g, 23.1 mmoles). The mixture was cooled to 4° C. and added with triethylamine (3.8 ml, 27.3 mmoles) while keeping the temperature below 10° C. At the end of the addition the mixture was stirred at room temperature for 3 hours, then cooled and added with 5% HCl. The organic phase was washed with an aqueous NaCl solution, discoloured with charcoal, filtered over celite and dried to give 14.4 g of the title compound (stoichiometric yield; containing 1 equivalent of triphenylphosphine oxide).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=3[N:7]([CH3:22])[C:6]=2[N:23]=1.[Cl:24][C:25]1[CH:39]=[CH:38][C:28]([CH2:29][O:30][C:31]2[CH:36]=[CH:35][NH:34][C:33](=[O:37])[CH:32]=2)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:39]=[CH:38][C:28]([CH2:29][O:30][C:31]2[CH:36]=[CH:35][N:34]([C:2]3[CH:3]=[CH:4][C:5]4[C:14]5[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=5[N:7]([CH3:22])[C:6]=4[N:23]=3)[C:33](=[O:37])[CH:32]=2)=[CH:27][CH:26]=1
Reactant: Cn1c2c(c3ccc(Br)nc31)CCN(C(=O)OC(C)(C)C)CC2
Reactant: O=c1cc(OCc2ccc(Cl)cc2)cc[nH]1
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cc5)cc4=O)nc31)CCN(C(=O)OC(C)(C)C)CC2
Yield: 69.9 %

Procedure:
tert-Butyl 2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (125 mg, 0.329 mmol) and 4-(4-chlorobenzyloxy)pyridin-2(1H)-one (85 mg, 0.36 mmol) were reacted following the procedure for Example 2 (step d) to provide the title compound (123 mg, 70%) as a white solid: ESI MS m/z 535 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[C:14]2[CH:13]=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[C:8](=[O:16])[C:7]2[N:17]([CH3:20])[N:18]=[CH:19][C:6]1=2)[CH3:4].[CH3:21][S:22]CCl>CN(C)C=O.[Cl-].[Na+].O>[CH3:20][N:17]1[C:7]2[C:8](=[O:16])[C:9]3[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][C:14]=3[N:5]([CH2:3][CH2:4][S:22][CH3:21])[C:6]=2[CH:19]=[N:18]1
Reactant: CCn1c2ccc(C)cc2c(=O)c2c1cnn2C
Reactant: CSCCl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCCn1c2ccc(C)cc2c(=O)c2c1cnn2C
Temperature: 0 °C
Reaction time: 2 h
Yield: 42.7 %

Procedure:
To a suspension of sodium hydride (60-72% in mineral oil, 225 mg, 5.6 mmol), which was washed with hexane and dried in vacuo, in N,N-dimethylformamide (40 ml) was added a solution of 1,7-dimethyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one (EXAMPLE 47, step 2, 0.80 g, 3.75 mmol) in N,N-dimethylformamide at 0° C. The mixture was stirred at 0° C. for 10 min and at room temperature for 2 h. Chloromethyl methyl sulfide (0.87 ml, 7.5 mmol) was added at 0° C. and the mixture was stirred at room temperature for 10.5 h. Further more, sodium hydride (60-72% in mineral oil, 68 mg, 2.8 mmol) and chloromethyl methyl sulfide (0.87 ml, 7.5 mmol) were added. After 2 h, the mixture was heated at 50° C. for 15.5 h. The mixture was poured into brine (50 ml) and extracted with ethyl acetate (50 ml×2). The organic extracts were dried over magnesium sulfate and concentrated. Purification by column chromatography on silica gel eluting with ethyl acetate/hexane (1:1) gave 0.46 g (43%) of the title compound as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8]C(=O)OC(C)(C)C)[N:5]2[N:16]=[CH:17][C:18]([CH:19]=[O:20])=[C:4]2[N:3]=1.O1CCOCC1.[Cl:27][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=1)[NH2:31]>O>[NH2:8][C:6]1[N:5]2[N:16]=[CH:17][C:18]([CH:19]=[O:20])=[C:4]2[N:3]=[C:2]([NH:31][C:30]2[CH:32]=[CH:33][CH:34]=[C:28]([Cl:27])[CH:29]=2)[CH:7]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)nc2c(C=O)cnn12
Solvent: O
Solvent: C1COCCO1
Product: Nc1cc(Nc2cccc(Cl)c2)nc2c(C=O)cnn12
Temperature: 95 °C
Yield: 38 %

Procedure:
Tert-butyl 5-chloro-3-formylpyrazolo[1,5-a]pyrimidin-7-ylcarbamate (1.1 g, 3.8 mmol) was added to 1,4-dioxane (15 mL) along with 3-chloroaniline (2.4 mL, 22.6 mmol) and p-toluenes sulfonic acid monohydrate (73 mg, 0.4 mmol). The reaction was heated at 95° C. for 12 hours then cooled to room temperature, diluted with water and filtered. Analysis of the recovered solid by LCMS showed product mass (M+1=288), as well as, product with chloro aniline imine mass (M+1=397). To completely convert this mixture to the desired product, the solid was dissolved in 6 mL of MeOH/conc. HCl solution (1:1) and heated at 60° C. for 1.5 hours. The reaction was quenched by slow addition to ice cold 6N NaOH. The mixture was diluted with water then the solid was collected by filtration. The solid was washed several more times with water then dried under vacuum overnight. The product, 7-amino-5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde, was collected as orange-red solid in 38% yield. LCMS (M+1=288)
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][OH:13])[CH:9]=[CH:10][CH:11]=1.[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([N:22]2[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]2)[N:16]=1>CC(O)C.CS(C)=O>[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([N:22]2[CH2:23][CH2:24][CH:25]([NH:28][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][OH:13])[CH:7]=3)[CH2:26][CH2:27]2)[N:16]=1
Reactant: OCc1cccc(OCC2CO2)c1
Reactant: Cc1cc(C)nc(N2CCC(N)CC2)n1
Solvent: CS(C)=O
Solvent: CC(C)O
Product: Cc1cc(C)nc(N2CCC(NCC(O)COc3cccc(CO)c3)CC2)n1
Yield: 9 %

Procedure:
Synthesis followed SP6 (iPrOH:DMSO 1:1, 120° C., 24 h), using 200 μmol (3-(oxiran-2-ylmethoxy)phenyl)methanol and 1-(4,6-dimethylpyrimidin-2-yl)piperidin-4-amine to give the title compound with 9% yield upon purification by prep. HPLC (reversed phase) and subsequent by prep. TLC (1 mm silica gel, PE/CH2Cl2/MeOH 4:6:1) (LCMS: detected [M+1]=387.2).
Reaction SMILES: [Br-].[CH3:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.[Li]CCCC.[CH3:35][CH:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:37]=O.O>C1COCC1>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]=[CH:35][CH:36]([CH3:37])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:28][CH:29]=1
Reactant: Cc1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCCCCCCC(C)C=O
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCC(C)C=CCc1ccc(C)cc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
p-Methylphenethyltriphenylphosphonium bromide (2.90 g, 6.29 mmol, 1.0 equiv.) in THF (12 mL), was cooled to 0° C. After adding n-BuLi (1.6 M in hexanes, 3.9 mL, 6.29 mmol, 1.0 equiv.) at 0° C., the red solution was stirred at 65° C. for 1 h. The mixture was re-cooled to 0° C., 2-methylundecanal (1.74 g, 9.43 mmol, 1.5 equiv.) in THF (5 mL) was added, and the mixture was stirred at 65° C. for 16 h. After addition of H2O, the aqueous layer was extracted with cyclohexane (2×), the combined organic phases were washed with brine, dried (MgSO4), filtered and the filtrate was concentrated. The residue was purified by flash chromatography on SiO2 (cyclohexane/EtOAc 997:3) to yield 1.24 g (69%) of the title compound as a colorless oil.
Reaction SMILES: [OH:1][C:2]([C@@:5]1([C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=3)[CH2:22][CH2:21]2)=[O:19])[CH2:9][CH2:8][CH:7]([NH:10]C(=O)OC(C)(C)C)[CH2:6]1)([CH3:4])[CH3:3].[ClH:36]>CCOCC.C1COCC1>[ClH:36].[ClH:36].[NH2:10][C@H:7]1[CH2:8][CH2:9][C@@:5]([C:2]([OH:1])([CH3:3])[CH3:4])([C:18]([N:20]2[CH2:21][CH2:22][N:23]([C:26]3[CH:31]=[C:30]([C:32]([F:34])([F:35])[F:33])[CH:29]=[CH:28][N:27]=3)[CH2:24][CH2:25]2)=[O:19])[CH2:6]1
Reactant: CC(C)(C)OC(=O)NC1CC[C@](C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)(C(C)(C)O)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)[C@@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@H](N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
tert-Butyl [(3R)-3 -(1 -hydroxy- 1 -methylethyl)-3-(4- [4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentyl]carbamate (75 mg, 0.15 mmol) was mixed with a 2.00 M solution of hydrogen chloride in ether (2 mL) and THF (1 mL). After being stirred for 1 h at room temperature, the reaction solution was concentrated to provide the desired product (70 mg, 98.7%). LCMS calculated for C17H28F3N4O2: (M+H) 473.2; found 473.2.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[CH2:10](O)[CH3:11]>>[Br:8][C:6]1[N:7]=[C:2]([Br:1])[C:3]2[N:4]([CH:10]=[CH:11][N:9]=2)[CH:5]=1
Reactant: CCO
Reactant: Nc1ncc(Br)nc1Br
Product: Brc1cn2ccnc2c(Br)n1

Procedure:
A solution of 1.00 equivalents (eq.) of 3,5-dibromo-2-aminopyrazine 1 in ethanol is treated with 2.00 eq. of α-bromoaldehyde 2 at room temperature (RT) and heated for 48 hours (hr). The solvent is removed under reduced pressure and the residue is triturated with diethyl ether and filtered to give the HBr salt 3.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([CH3:17])=[C:14]([OH:16])[CH:15]=1.[H-].[Na+].Br[CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].CCOC(C)=O>CN(C=O)C>[Si:24]([O:23][CH2:22][CH2:21][O:16][C:14]1[CH:15]=[C:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH:11]=[CH:12][C:13]=1[CH3:17])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: Cc1ccc(-c2nc3ccccc3o2)cc1O
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc3ccccc3o2)cc1OCCO[Si](C)(C)C(C)(C)C
Reaction time: 0.25 h

Procedure:
A solution of 5-(1,3-benzoxazol-2-yl)-2-methylphenol (355 mg, 1.6 mmol) in DMF (10 mL) was cooled to 0° C. and NaH (70 mg, 1.7 mmol) was added slowly. After 15 min, (2-bromoethoxy)(tert-butyl)dimethylsilane (370 μL, 1.7 mmol) was added. The reaction was then elevated to 90° C. for 1 h and EtOAc (100 mL) was added. The EtOAc solution was washed with brine (3×20 mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash column (silica gel, hexanes:EtOAc 1:5) to afford 2-[3-(2-{[tert-butyl(dimethyl)silyl]oxy}-ethoxy)-4-methylphenyl]-1,3-benzoxazole.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].Cl[C:12]1[CH:13]=[C:14]2[N:21](C(OC(C)(C)C)=O)[C@@H:20]([CH3:29])[CH2:19][N:15]2[C:16](=[O:18])[N:17]=1>>[CH3:29][C@H:20]1[CH2:19][N:15]2[C:16](=[O:18])[N:17]=[C:12]([O:1][CH2:2][C:3]3[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=3)[C:6]#[N:7])[CH:13]=[C:14]2[NH:21]1
Reactant: N#Cc1cccc(CO)c1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C(=O)OC(C)(C)C
Product: C[C@H]1Cn2c(cc(OCc3cccc(C#N)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 3-(hydroxymethyl)benzonitrile and (S)-tert-butyl 7-chloro-2-methyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][O:22][C:23]([C:25]3[S:26][C:27]([CH3:30])=[CH:28][CH:29]=3)=[O:24])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:31][CH3:32])[CH:3]=1.[F:33][C:34]([F:42])([F:41])[CH2:35][CH2:36][S:37](Cl)(=[O:39])=[O:38].C(N(CC)CC)C>C(Cl)Cl>[CH3:32][O:31][C:4]1[CH:3]=[C:2]([O:1][S:37]([CH2:36][CH2:35][C:34]([F:42])([F:41])[F:33])(=[O:39])=[O:38])[CH:7]=[CH:6][C:5]=1[C:8]1[C:9]([CH2:21][O:22][C:23]([C:25]2[S:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[O:24])=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH3:18])([CH3:19])[CH:12]=[C:11]2[CH3:20]
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COC(=O)c1ccc(C)s1)C(C)=CC(C)(C)N2
Reactant: O=S(=O)(Cl)CCC(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(OS(=O)(=O)CCC(F)(F)F)ccc1-c1ccc2c(c1COC(=O)c1ccc(C)s1)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
6-(4-Hydroxy-2-methoxyphenyl)-5-(5-methylthiophen-2-ylcarbonyloxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 3-2, 21.3 mg, 0.0474 mmol) was dissolved in methylene dichloride (1 mL), 3,3,3-trifluoropropane-1-sulfonyl chloride (11.6 mg, 0.0590 mmol) and triethylamine (18 μL, 0.13 mmol) were added thereto, and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (21.5 mg) as a colorless amorphous product. (Yield 80%)
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][CH:4]=1.CN(C=O)C.S(Cl)([Cl:18])=O>>[CH3:1][O:2][C:3]1[S:7][C:6]([C:8]([Cl:18])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)O)s1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Cl)s1

Procedure:
15.0 g (94.8 mmol) 5-methoxy-2-thiophenecarboxylic acid were heated in 100 ml thionyl chloride and 1 ml abs. DMF for 30 minutes under reflux. The excess thionyl chloride was then distilled off under vacuum. The crude product (ca. 18 g brownish oil) was quickly distilled.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]3)[N:12]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:24][CH:23]=3)[N:10]=1)[CH2:2]2.C(O)(C(F)(F)F)=O.[CH2:45]([CH2:47][NH2:48])[OH:46]>>[CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][CH:18]([NH:48][CH2:47][CH2:45][OH:46])[CH2:17][CH2:16]3)[N:12]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:24][CH:23]=3)[N:10]=1)[CH2:2]2
Reactant: NCCO
Reactant: O=C1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccncc1)Nc1ccc(-c2nc(N3CCC(NCCO)CC3)nc(N3CC4CCC(C3)O4)n2)cc1

Procedure:
Starting from 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-TFA (50 mg) and ethanolamine (0.020 mL) and following the procedure as outlined in example 118, the title compound was isolated as its di-TFA salt after HPLC purification. MS (ES+) 546.7 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[N:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:3]=1[C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:26](OCC)(=[O:28])[CH3:27]>>[C:26]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[N:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:3]=1[C:18](=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)(=[O:28])[CH3:27]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2ccc(C#N)cc21
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(C)=O)c2ccc(C#N)cc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 2 (Method A) from 3-amino-2-benzoyl-6-cyano-1-(ethoxycarbonyl)indole (step 2). tlc: Rf=0.1 (33% ethyl acetate in hexanes)