Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([Si:4]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[O:5][CH2:6][CH2:7][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:19]2[CH:20]=[C:21]([S:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH2:31]O)[CH:22]=[CH:23][C:18]2=[N:17][N:16]=1)([CH3:3])[CH3:2].CS(OS(C)(=O)=O)(=O)=O.C([N:50](CC)CC)C.N.CO>C1(C)C=CC=CC=1.O>[CH:36]([Si:4]([CH:1]([CH3:2])[CH3:3])([CH:33]([CH3:34])[CH3:35])[O:5][CH2:6][CH2:7][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:19]2[CH:20]=[C:21]([S:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH2:31][NH2:50])[CH:22]=[CH:23][C:18]2=[N:17][N:16]=1)([CH3:37])[CH3:38].[C:10]1([CH3:15])[CH:11]=[CH:12][CH:13]=[CH:14][CH:9]=1
Reactant: CCN(CC)CC
Reactant: CC(C)[Si](OCCSc1ccccc1-c1nnc2ccc(Sc3ccccc3CO)cn12)(C(C)C)C(C)C
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: N
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: CC(C)[Si](OCCSc1ccccc1-c1nnc2ccc(Sc3ccccc3CN)cn12)(C(C)C)C(C)C
Temperature: 5 °C
Reaction time: 3 h

Procedure:
To a slurry of benzyl alcohol of Example 8 (25.0 g, 0.044 moles) in toluene (250 ml), was added methanesulfonic anhydride (10.77 g, 0.062 moles) then cooled to 5° C. Triethylamine (6.93 g, 0.068 moles) was added over 30 minutes and stirred at this temperature for 3 hours. The resultant solution was added to 7M ammonia in methanol solution (316 ml, 2.21 moles) and stirred for 16 hours. Water (250 ml) was added and the organic phase washed with water (250 ml). The aqueous phases were extracted with toluene (125 ml) and the combined organics were dried by azeotropic distillation under reduced pressure to leave the title compound as a clear brown solution in toluene (125 ml) (assumed quantitative yield).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].C[N:33]1CCO[CH2:35][CH2:34]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:34]([NH:33][C:3](=[O:4])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:29])[F:30])[O:14][N:13]=2)=[CH:10][CH:11]=1)[CH3:35]
Reactant: CN1CCOCC1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 56.5 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.041 mL, 0.371 mmol), ethanamine, HCl (4.92 mg, 0.060 mmol), and HATU (31.7 mg, 0.083 mmol). This was stirred overnight and was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention time=12.0 min) to give (R/S)-N-ethyl-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (14.5 mg, 0.026 mmol, 56.5% yield): LCMS=459.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.17 (2 H, d, J=8.35 Hz), 7.66-7.74 (4 H, m), 7.53-7.64 (3 H, m), 5.10 (1 H, s), 3.21-3.30 (2 H, m), 1.14 (3 H, t, J=7.25 Hz). HPLC Peak RT=10.60 min (Analytical Method C).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([C:18]([OH:20])=O)[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.P([N:44]=[N+:45]=[N-:46])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O>C1COCC1>[C:1]([O:5][C:6]([C:8]1([C:18]([N:44]=[N+:45]=[N-:46])=[O:20])[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)C1(C(=O)O)CCc2ccccc2C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C1(C(=O)N=[N+]=[N-])CCc2ccccc2C1
Yield: 58 %

Procedure:
3,4-Dihydro-1H-naphthalene-2,2-dicarboxylic acid tert-butyl ester from Example 43A was dissolved in THF (50 mL) followed by addition of Et3N (5.05 g, 50 mmol) and (PhO)2PON3 (11 g, 40 mmol) at 0° C. After 3 hours the volatiles were removed under reduced pressure and the residue purified by column chromatography to provide the titled compound (13.1 g, 58% over three steps).
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][N:14]=1.[CH2:20]1[O:30][C:23]2([CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]2)[O:22][CH2:21]1>C1(C)C=CC=CC=1.ClCCl>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C:26]2([OH:29])[CH2:27][CH2:28][C:23]3([O:30][CH2:20][CH2:21][O:22]3)[CH2:24][CH2:25]2)=[N:14][CH:15]=1
Reactant: Brc1ccc(Br)nc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: ClCCl
Product: OC1(c2ccc(Br)cn2)CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 53.7 %

Procedure:
1.6M n-Hexane solution of n-butyl lithium (66 ml) was added dropwise to a solution of 2,5-dibromopyridine (23.9 g) in toluene (420 ml) at −78° C., and stirred at the same temperature for an hour. Next, a solution of 1,4-cyclohexanedione monoethyleneketal (15 g) in dichloromethane (60 ml) was added dropwise, and the reaction solution was warmed up to room temperature over 7 hours. After completion of the reaction, a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate three times. The organic solution was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) and recrystallized from n-hexane/diethyl ether to give 8-(5-bromopyridin-2-yl)-1,4-dioxaspiro[4,5]decan-8-ol (16.2 g) as a white solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][C:8]2=O.[CH3:14][CH2:15][O:16][C:17]([CH3:19])=[O:18]>C1COCC1.[Rh]>[CH2:15]([O:16][C:17](=[O:18])[CH2:19][CH:8]1[C:9]2[C:5](=[C:4]([Cl:3])[CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:7]1)[CH3:14]
Reactant: CCOC(C)=O
Reactant: O=C1CCc2c(Cl)cccc21
Agent: [Rh]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCc2c(Cl)cccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Use of 2-chlorocinnamic acid (Intermediate TWENTYTHREE-1) (commercially available from Aldrich) in the applicable process steps described in Method TWENTY produced 4-chloro-indan-1-one (Intermediate TWENTYFOUR-1). Triethylphosphonoacetate (3.5 mL, 17.2 mmol) was added to a mixture of NaH (0.69 g, 12.2 mmol) in THF (25 mL). After 30 m, a solution of 4-chloro-indan-1-one (Intermediate TWENTYFOUR-1) (1.46 g, 8.8 mmol) in THF (20 mL) was added to the mixture. The reaction mixture was allowed to stir for 16 h at rt. The solution was quenched with water and diluted with EtOAc. The layers were separated and the organic phase was dried over MgSO4, filtered and evaporated under reduced pressure. The residue was subjected to chromatography on silica gel with 3% EtOAc:hexane. The fractions that contained the unsaturated esters were collected and evaporated to give the product, 1.67 g. The mixture of esters (1.67 g, 7.06 mmol) in EtOAc was hydrogenated in the presence of 5% Rh on Alumina (0.14 g) at 40-50 psi H2 at rt for 2 d. The mixture was filtered through a plug of Celite® and concentrated in vacuo to produce (4-chloro-indan-1-yl)-acetic acid ethyl ester (Intermediate TWENTYFOUR-2). Use of (4-chloro-indan-1-yl)-acetic acid ethyl ester (Intermediate TWENTYFOUR-2) in the applicable process steps described in Method SEVENTEEN and Method A produced 4-(4-chloro-indan-1-ylmethyl)-1,3-dihydro-imidazole-2-thione (Compound 166).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:5][NH:6][CH:7]=1.CCN(C1C=CC=CC=1)CC.P(Cl)(Cl)([Cl:25])=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C.O>[Cl:25][C:5]1[C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:3][C:2]([I:1])=[CH:7][N:6]=1
Reactant: COC(=O)C1=CC(I)=CNC1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)c1ccccc1
Product: COC(=O)c1cc(I)cnc1Cl
Temperature: 25 °C
Yield: 52 %

Procedure:
To a mixture containing 2.0 g of methyl 5-iodo-1,2-dihydro-3-pyridinecarboxylate, 1.6 g of diethylaniline, 1.64 g of benzyltriethylammonium chloride and 3.6 ml of distilled phosphorus oxychloride in 100 ml of dry acetonitrile are added 15 drops of water. The mixture is heated under reflux for 18 hours. After cooling the reaction mixture to room temperature, the solvent is removed under reduced pressure and the residue taken up in methylene chloride and extracted with water. The organic solution is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on a column of flash silica gel using methylene chloride as the eluent. Evaporation of the eluent yields a pale yellowish solid which is recrystallized from aqueous ethanol to give 1.1 g (52%) of methyl 2-chloro-5-iodo-3-pyridinecarboxylate as a white solid: m.p. 73°-73.5° C.; NMR (80 MHz, CDCl3) delta 3.96 (s, 3H), 8.43 (d, 1H, J= 2.3 Hz), 8.71 (d, 1H, J=2.3 Hz).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[CH:4]=O.[SH:11][CH2:12][C:13](=[O:15])[CH3:14].CCN(CC)CC.O>CS(C)=O>[C:13]([C:12]1[S:11][C:2]2[CH:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=2[CH:4]=1)(=[O:15])[CH3:14]
Reactant: O=Cc1c(F)cccc1I
Reactant: CC(=O)CS
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)c1cc2c(I)cccc2s1
Temperature: 80 °C
Yield: 60.6 %

Procedure:
A mixture of 2.53 g (10.1 mmol) of 2-fluoro-6-iodo benzaldehyde, 1.0 g (11.1 mmol) of mercapto-2-propanone and 3.5 mL (2.5 g, 25 mmol) of Et3N in 15 mL of DMSO was heated to 80° C. overnight. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water (2 times), brine and dried over MgSO4. After evaporation of the solvents, the crude product was purified over silica gel column chromatography to afford 1.85 g (6.12 mmol, yield: 61%) of 2-acetyl-4-iodo benzo[b]thiophene as an orange powder. 1H-NMR (CDCl3), δ: 7.97 (s, 1H), 7.83 (d, J=7.9 Hz, 2H), 7.16 (t, J=7.9 Hz, 1H), 2.70 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][C:17]([OH:19])=[O:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:21](O)[CH3:22]>>[C:1]([C:5]1[CH:6]=[C:7]([CH2:16][C:17]([O:19][CH2:21][CH3:22])=[O:18])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:15])[CH3:14])[C:10]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCO
Reactant: CC(C)(C)c1cc(CC(=O)O)cc(C(C)(C)C)c1O
Agent: Cl
Product: CCOC(=O)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
In ethanol (60 mL) was dissolved 3,5-di-t-butyl-4-hydroxyphenyl-acetic acid (8.0 g, 30.3 mmol). The solution was saturated with HCl gas and stirred at room temperature for 18 hours. The mixture was evaporated in vacuo and the residue was dissolved in ethyl acetate (100 mL). The organic phase was washed with water (100 mL) and then brine (100 mL). The organic phase was dried over magnesium sulfate and evaporated in vacuo to give 7.95 g (90%) of the product as an oil.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([Si:19]([CH3:22])([CH3:21])[CH3:20])=[C:15]([F:23])[C:14]=2[F:24])=[C:9]([F:25])[CH:8]=1.[I:26]CCI.O>C1COCC1.C(OC)(C)(C)C>[CH3:20][Si:19]([CH3:22])([CH3:21])[C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([I:26])=[CH:8][C:9]=2[F:25])=[C:14]([F:24])[C:15]=1[F:23]
Reactant: C[Si](C)(C)c1ccc(-c2ccc(Br)cc2F)c(F)c1F
Reactant: ICCI
Agent: [Li]CCCC
Solvent: O
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)c1ccc(-c2ccc(I)cc2F)c(F)c1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
30 ml (48 mmol) of 1.6 M BuLi are added dropwise at −78° C. to a solution of 15.8 g (44 mmol) of 7 in 132 ml of dry THF. After 15 minutes, 16 g (57.2 mmol) of 1,2-diiodoethane are added as solid, and the mixture is allowed to warm to room temperature over the course of 1 hour. Water and methyl tert-butyl ether are subsequently added. The organic phase is washed with water, sat. Na2S2O5 and sat. NaCl, dried over MgSO4 and filtered through SiO2. The solvent is removed under reduced pressure, petroleum ether is added to the oily residue, and the product is recrystallised at −25° C. (yield: 84%, m.p. 76.0° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][O:19][CH2:20][O:21][CH3:22])=[CH:13][CH:12]=2)=[C:7]([OH:9])[CH:8]=1.[C:23]([O:26][C@@H:27]1[C@@H:39]([O:40][C:41](=[O:43])[CH3:42])[C@H:38]([O:44][C:45](=[O:47])[CH3:46])[C@@H:37]([CH2:48][O:49][C:50](=[O:52])[CH3:51])[O:36][C@@H:28]1OC(=N)C(Cl)(Cl)Cl)(=[O:25])[CH3:24].C(=O)([O-])O.[Na+]>ClCCl>[C:23]([O:26][C@@H:27]1[C@@H:39]([O:40][C:41](=[O:43])[CH3:42])[C@H:38]([O:44][C:45](=[O:47])[CH3:46])[C@@H:37]([CH2:48][O:49][C:50](=[O:52])[CH3:51])[O:36][C@H:28]1[O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][O:19][CH2:20][O:21][CH3:22])=[CH:13][CH:12]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: COCOCCc1ccc(Cc2ccc(OC)cc2O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCOCCc1ccc(Cc2ccc(OC)cc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Reaction time: 0.33 h
Yield: 83 %

Procedure:
To a solution of 5-methoxy-2-{4-[2-(methoxymethyl-oxy)ethyl]benzyl}phenol (0.19 g) and 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetoimidoyl-α-D-glucopyranose (0.40 g) in dichloromethane (15 mL) was added boron trifluoride-diethyl ether complex (0.088 mL) at 0° C., and the mixture was stirred 20 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/1) to give 5-methoxy-2-{4-[2-(methoxymethyloxy)ethyl]benzyl}phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.33 g).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH2:38])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26].[C:48]([O:51][C:52]1[CH:60]=[CH:59][CH:58]=[CH:57][C:53]=1[C:54](O)=[O:55])(=[O:50])[CH3:49].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH:38][C:54](=[O:55])[C:53]3[CH:57]=[CH:58][CH:59]=[CH:60][C:52]=3[O:51][C:48](=[O:50])[CH3:49])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: CC(=O)Oc1ccccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Oc1ccccc1C(=O)Nc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O

Procedure:
HATU condensation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 2-acetyloxybenzoic acid (6.0 mg) and N,N-diisopropylethylamine (22 l) in tetrahydrofuran (1 ml) was performed according to the method described in example 11.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][C:6](=[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])[C:5]2=O.O.[NH2:22][NH2:23].[C:24](Cl)([CH3:26])=[O:25].CCOC(C)=O>N1C=CC=CC=1.[Cl-].[Na+].O>[C:24]([N:22]1[C:12]([CH3:13])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]2[CH2:7][O:8][C:9]3[CH:10]=[CH:11][C:2]([F:1])=[CH:3][C:4]=3[C:5]2=[N:23]1)(=[O:25])[CH3:26]
Reactant: CC(=O)Cl
Reactant: NN
Reactant: CC(=C1COc2ccc(F)cc2C1=O)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)N1N=C2c3cc(F)ccc3OCC2C1(C)c1ccccc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 165 mg (0.62 mmol) 2-1 in 4 mL of pyridine was added 45 μL (0.93 mmol) hydrazine hydrate and the reaction was heated at 90° C. for 30 min. After cooling to room temperature, and then to 0° C., 250 μL (3.15 mmol) of AcCl was added dropwise, the mixture was warmed to room temperature and allowed to stir overnight. The reaction was dumped into a separatory funnel with EtOAc and brine, the layers were separated, the organic was washed twice with 1M HCl, then with brine, and finally dried over Na2SO4. After concentration, the crude material was purified by silica gel chromatography with EtOAc/hexanes to provide 2-2 as a white solid (2:1 mixture of diastereomers).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[N:13]1[NH:14][C:15]([CH2:22][CH2:23][C:24](O)=O)=[C:16]2[C:21]=1[CH2:20][CH2:19][CH2:18][CH2:17]2.Cl[C:28]1C=CC(C2CCNCC2)=CC=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:28][CH2:24][CH2:23][CH2:22][C:15]2[NH:14][N:13]=[C:21]3[C:16]=2[CH2:17][CH2:18][CH2:19][CH2:20]3)[CH2:11][CH2:12]1
Reactant: O=C(O)CCc1[nH]nc2c1CCCC2
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: Clc1ccc(C2CCNCC2)cc1
Product: c1ccc(N2CCN(CCCCc3[nH]nc4c3CCCC4)CC2)nc1

Procedure:
In the same manner as in Example 102 except that 4-(4,5,6,7-tetrahydro-2H-indazol-3-yl)-n-butyric acid obtained in Starting Material Synthesis Example 3 and 1-(2-pyridyl)piperazine were used instead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 1 and 4-(4chlorophenyl)piperidine, 3-(4-(4-(2-pyridyl)piperazin-1-yl)butyl)-4,5,6,7-tetrahydro-2H-indazole was obtained.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH3:34][O:35][CH2:36][C:37]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)=[O:38]
Reactant: COCC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)cc1F
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A166) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CCCC)CCCC)CCC.[C]=O>CO.C1(P([Pd-](Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:5][C:6]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Br)ccc21
Agent: Cl[Pd-]([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [C]=O
Solvent: CO
Solvent: CCCCN(CCCC)CCCC
Product: COC(=O)c1ccc2c(c1)CCN2C(=O)OC(C)(C)C
Temperature: 100 °C

Procedure:
A solution of 5-bromo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (4.0 g, 13.5 mmol), tributylamine and bis-triphenylphosphinopalladium(II) chloride (0.65 g, 0.926 mmol) in methanol was sealed in a Parr pressure apparatus and pressurized with 600 psi of carbon monoxide. The solution was heated at 100° C. for one week. The vessel was cooled to room temperature and the gas vented. The solution was filtered, and the solvent was evaporated in vacuo. The residue was purified by flash chromatography, on silica gel eluted with 10-40% ethyl acetate in hexane to give the product mixed with tributylamine, 2.5 g (67%). The product was used without further purification in the subsequent step.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13](I)[C:12]=3[N:11]=[C:10]([CH3:20])[C:9]=2[CH:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2].[C:21]1([CH3:33])[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:22]=1OB(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].COCCOC>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>[CH2:1]([CH:3]([N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([C:22]4[C:23]([CH3:28])=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=4[CH3:33])[C:12]=3[N:11]=[C:10]([CH3:20])[C:9]=2[CH:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: Cc1cc(C)c(OB(O)O)c(C)c1
Reactant: CCC(CC)n1ccc2c(C)nc3c(I)cccc3c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: CCC(CC)n1ccc2c(C)nc3c(-c4c(C)cc(C)cc4C)cccc3c21
Temperature: 80 °C
Reaction time: 8 h
Yield: 6.7 %

Procedure:
1-(1-Ethylpropyl)-6-iodo-4-methyl-1H-pyrrolo[3,2-c]quinoline (170 mg, 0.45 mmol), mesitylboric acid (82 mg, 0.50 mmol), barium hydroxide octahydrate (213 mg, 0.68 mmol) and tetrakistriphenylphosphinepalladium (26 mg, 0.02 mmol) were suspended into a mixture of 1,2-dimethoxyethane (6 mL) and water (1 mL), followed by stirring at 80° C. overnight in nitrogen atmosphere. Water was added to the reaction mixture, followed by extracting with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and then evaporated. The residue was purified by silica gel column chromatography (5% ethyl acetate/hexane), to give the title compound (11 mg, 0.03 mmol) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:23])[C:10]([C:16]1[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:24][O:25][C:26](=[O:29])[CH2:27]Br>C1(C)C=CC=CC=1>[CH3:24][O:25][C:26](=[O:29])[CH2:27][O:22][C:18]1[CH:17]=[C:16]([C:10]([OH:15])([C:11]([F:14])([F:13])[F:12])[CH:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH3:23])[CH:21]=[CH:20][N:19]=1
Reactant: COC(=O)CBr
Reactant: CC(c1ccc(Cl)cc1Cl)C(O)(c1cc[nH]c(=O)c1)C(F)(F)F
Solvent: Cc1ccccc1
Product: COC(=O)COc1cc(C(O)(C(C)c2ccc(Cl)cc2Cl)C(F)(F)F)ccn1
Temperature: 145 °C
Reaction time: 3.5 h
Yield: 45.1 %

Procedure:
To a solution of 4-[2-(2,4-dichloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1H-pyridin-2-one (100 mg) in toluene (5 mL) was added bromoacetic acid methyl ester (50 mg, 0.03 mL) and Ag2CO3 (53 mg) and the mixture was allowed to stir for 3.5 hours at 145° C. The mixture was cooled to room temperature, filtered and the residue was purified by flash chromatography (10 silica gel cartridge, using ethyl acetate/heptane 1:9 as an eluent) to provide the title compound as a colorless oil (54 mg). MS (m/e): 438.1 (MH+).
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](N)=[N:4][C:2]1=[O:3].[CH3:9][Si:10]([CH3:17])([CH3:16])[NH:11][Si:12]([CH3:15])([CH3:14])[CH3:13].S([O-])([O-])(=O)=O.[NH4+].[NH4+]>ClCCl>[CH3:9][Si:10]([N:11]([Si:12]([CH3:15])([CH3:14])[CH3:13])[C:8]1[CH:7]=[CH:5][NH:4][C:2](=[O:3])[N:1]=1)([CH3:17])[CH3:16]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: Nc1cc[nH]c(=O)n1
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: ClCCl
Product: C[Si](C)(C)N(c1cc[nH]c(=O)n1)[Si](C)(C)C
Temperature: 23 °C

Procedure:
To 5.78 g of cytosine were added 112 ml of hexamethyldisilazane and 50 mg of ammonium sulfate. This solution was heated to 115° C.-120° C. for 2 hours with stirring and the excess hexamethyldisilazane was subsequently removed. The resulting oil was cooled to 23° C. to form a solid residue which was reconstituted in 35 ml of dichloromethane to form a homogenous bis-trimethylsilylcytosine solution and cooled to 0° C.