Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11]3[C:14]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])=[CH:15][C:16]4[NH:17][C:18]([CH3:21])=[N:19][C:20]=4[C:10]=3[O:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:30][CH2:31][CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]>CN(C)C=O>[Si:34]([O:33][CH2:32][CH2:31][CH2:30][N:19]1[C:20]2[C:10]3[O:9][CH:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:13][CH2:12][C:11]=3[C:14]([C:22]([N:24]([CH3:25])[CH3:26])=[O:23])=[CH:15][C:16]=2[N:17]=[C:18]1[CH3:21])([C:37]([CH3:38])([CH3:39])[CH3:40])([CH3:36])[CH3:35]
Reactant: Cc1nc2c3c(c(C(=O)N(C)C)cc2[nH]1)CCC(c1ccc(F)cc1)O3
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2cc(C(=O)N(C)C)c3c(c2n1CCCO[Si](C)(C)C(C)(C)C)OC(c1ccc(F)cc1)CC3
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
To a solution of 8-(4-fluorophenyl)-N,N,2-trimethyl-3,6,7,8-tetrahydrochromeno[7,8-d]imidazole-5-carboxamide (52.0 mg, 0.147 mmol, Step 8) in N,N-dimethylformamide (1.5 mL), was added sodium hydride (7.1 mg, 0.18 mmol) at 0° C. and the mixture was stirred at 0° C. for 30 minutes. Then (3-bromopropoxy)(tert-butyl)dimethylsilane (48.4 mg, 0.191 mmol) was added to the mixture at 0° C. The mixture was allowed to warm to room temperature, stirred for 4 hours and left at the same temperature overnight. The reaction was quenched by saturated ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate. The combined organic layers were washed with water and brine. It was dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC eluting with hexane/ethyl acetate (1:1 and then 1:4) to afford the title compound as a brown oil (35.5 mg, 46%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:11])[N:4]([CH3:10])[N:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(CC)CC)C>C(O)C.[Pd]>[CH3:9][O:8][C:7]1[CH:6]=[N:5][N:4]([CH3:10])[C:3](=[O:11])[CH:2]=1
Reactant: COc1cnn(C)c(=O)c1Cl
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cnn(C)c(=O)c1
Yield: 89.1 %

Procedure:
A solution of 3.90 g (22.34 mmol) of 4-chloro-5-methoxy-2-methyl-2H-pyridazin-3-one and 3.74 ml (2.71 g, 26.8 mmol) of triethylamine in 60 ml of ethanol was hydrogenated at atmospheric pressure over 950 mg (0.894 mmol) of 10% palladium on charcoal for 20 h at 55° C. The suspension was filtered hot and the catalyst was washed three times with 10 ml of ethanol. The filtrate was concentrated in vaccuo, and the residue was taken up in 70 ml of methylene chloride, which was washed four times with 20 ml of water, dried over magnesium sulfate and concentrated to yield 2.79 g (19.9 mmol, 89%) of the title compound as a crystalline white solid, MS: 141.2 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[C:15](OC(=O)C)(=[O:17])[CH3:16].C>CO.CO.ClCCl>[C:15]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: NCCCCCO
Agent: C
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCCCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A solution of 5-amino-1-pentanol (0.650 g, 6.31 mmol) in methanol (15 ml) was cooled to 0° C. and treated with triethylamine (1.62 ml, 11.6 mmol) followed by acetic anhydride (0.891 ml, 9.45 mmol). The reaction mixture was stirred at room temperature overnight. TLC analysis (8% methanol/dichloromethane) then revealed some unreacted material, so additional triethylamine (1.6 ml, 11.6 mmol) and acetic anhydride (0.9 ml, 9.5 mmol) were added at room temperature and the solution was stirred 16 h further. Concentration in vacuo and flash chromatography (7% methanol/dichloromethane) afforded III-20 (1 g, 94% yield) as a pale yellow oil: IR (film) 3300 (s), 3100 (m), 2940 (s), 2870 (m), 1650 (s), 1560 (s), 1439 (m), 1372 (m), 1295 (m), 1220 (w), 1180 (w), 1050 (m), 1010 (w) cm−1; 1H NMR (500 MHz, CDCl3) δ 6.21 (s, 1H), 3.62 (t, J=6.4 Hz, 2H), 3.23 (dd, J=12.9, 7.0 Hz, 2H), 2.87 (s, 1H), 1.97 (s, 3H), 1.60-1.50 (m, 4H), 1.43-1.37 (m, 2H); high resolution mass spectrum (Cl, CH4) m/z 146.1164 [(M+H)+; calcd for C7H16NO2: 146.1181].
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12](Br)Br)=[C:8]2[C:3]=1[CH:4]=[N:5][CH:6]=[N:7]2.C(O)(C(F)(F)F)=[O:16].CO.[NH4+].[OH-]>CC(C)=O.O.[N+]([O-])([O-])=O.[Ag+]>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]=[O:16])=[C:8]2[C:3]=1[CH:4]=[N:5][CH:6]=[N:7]2
Reactant: O=C(O)C(F)(F)F
Reactant: Brc1ccc(C(Br)Br)c2ncncc12
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CC(C)=O
Solvent: O
Product: O=Cc1ccc(Br)c2cncnc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 5-Bromo-8-(dibromomethyl) quinazoline (61 g, crude mixture) in Acetone (500 mL) and water (100 mL), was added silver nitrate (61 g) in portions at 0° C. The reaction mixture was stirred at RT for 6 h. The reaction completion was confirmed by TLC. The reaction mixture was filtered off and filtrate was extracted with ethyl acetate (3×500 mL). The organic layer was washed with 10% NaHCO3 solution, water and brine solution. The solvent was dried over Na2SO4 and concentrated under vacuum to afford the crude product with HPLC (56%) (25 g, 65%) was subjected to prep.HPLC condition: COLUMN: Xterra, C18 (19×300 mm), 10 micron, Mobile: 0.1% TFA; B: MeOH to isolate the compound. The resulted solid was basified with NH4OH and extracted with EtOAc. The organic layer was washed water. The solvent was dried over Na2SO4 and concentrated under vacuum to yield (6.2 g) of the titled compound as pale yellow solid. 1H NMR (DMSO-d6, 400 MHz) 11.14 (s, 1H), 9.80 (s, 1H), 9.58 (s, 1H), 8.30-8.27 (d, J=12.3 Hz, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[C:5]([F:11])[CH:4]=1)#[N:2].[NH2:12][CH:13]([CH2:21][CH3:22])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:12][CH:13]([CH2:21][CH3:22])[C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])=[C:5]([F:11])[CH:4]=1)#[N:2]
Reactant: CCC(N)C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(CBr)c(F)c1
Product: CCC(NCc1ccc(C#N)cc1F)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared following the general procedure 10 starting from 4-cyano-2-fluoro-benzylbromide (Fluorochem, 8.2 g, 38 mmol) and tert-butyl 2-aminobutanoate (6.2 g, 38 mmol), obtained in step 1. It was isolated as a colorless liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.79-7.76 (d, J=10.2 Hz, 1H), 7.68-7.67 (t, J=2.1 Hz, 2H), 3.84-3.79 (m, 1H) 3.71-3.66 (m, 1H), 2.95-2.91 (m, 1H), 2.52-2.48 (m, 1H), 1.58-1.53 (m, 2H), 1.49 (s, 9H), 0.87-0.83 (m, 3H).
Reaction SMILES: [O:1]1[CH:3]([CH3:4])[CH:2]1[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:21]([CH3:22])[C:20](=[O:23])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:24][CH3:25])[CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1.[C:26]([NH2:30])([CH3:29])([CH3:28])[CH3:27]>>[OH:1][CH:3]([CH2:4][NH:30][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:2][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:21]([CH3:22])[C:20](=[O:23])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:24][CH3:25])[CH:18]=3)[N:13]=2)=[CH:10][CH:11]=1
Reactant: CC(C)(C)N
Reactant: COc1ccc2nc(-c3ccc(OC4OC4C)cc3)n(C)c(=O)c2c1
Product: COc1ccc2nc(-c3ccc(OCC(O)CNC(C)(C)C)cc3)n(C)c(=O)c2c1

Procedure:
1.7 gm (5 mmols) of the epoxide obtained in (a) were heated in a steel cylinder with 17 ml of tert. butylamine at 120° C. for 3 hours. Thereafter, the excess amine was distilled off in vacuo, and the oily residue was recrystallized from acetone/ether.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[CH2:15][C:14](=[O:16])[NH:13][C:12](=[O:17])[CH2:11]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33]Cl)[CH2:27][CH2:26]2)=[CH:21][CH:20]=1.[I-].[Na+].N1C(=O)CNCC1=O>CN(C)C=O>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[CH2:15][C:14](=[O:16])[N:13]([CH2:33][CH2:32][CH2:31][N:28]2[CH2:29][CH2:30][N:25]([C:22]3[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=3)[CH2:26][CH2:27]2)[C:12](=[O:17])[CH2:11]1
Reactant: Fc1ccc(N2CCN(CCCCl)CC2)cc1
Reactant: O=C1CN(Cc2ccccn2)CC(=O)N1
Agent: O=C1CNCC(=O)N1
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: O=C1CN(Cc2ccccn2)CC(=O)N1CCCN1CCN(c2ccc(F)cc2)CC1
Temperature: 60 °C
Yield: 60 %

Procedure:
A suspension of 0.098 mole of sodium hydride in 30 ml of anhydrous dimethylformamide is heated to 60° C. A solution of 0.098 mole of 4-(2-pyridylmethyl)-2,6-piperazinedione in 15 ml of anhydrous dimethylformamide is added dropwise. When the addition is complete, the mixture is maintained at 60° C. for two hours. The reaction medium is then cooled to 25° C. and a solution of 0.126 mole of 4-(4-fluorophenyl)-1-(3-chloropropyl)piperazine in 10 ml of anhydrous dimethylformamide and 0.1 g of sodium iodide are added rapidly. The mixture is heated to 70° C. until the starting 2,6-piperazinedione has completely disappeared. The reaction medium is concentrated under vacuum. The solid residue is recrystallized in a mixture of iospropyl ether and ethanol (90:10). Pure crystals of 4-(2-pyridylmethyl)-1-{3-[1-(4-fluorophenyl)-4-piperazinyl]propyl}-2,6-piperazinedione are obtained.
Reaction SMILES: N[C:2]1[S:3][CH:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[BrH:11].N([O-])=O.[Na+].S([O-])(O)=O.[Na+].[OH-].[Na+]>O>[Br:11][C:2]1[S:3][CH:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1
Reactant: Nc1nc(C(F)(F)F)cs1
Reactant: Br
Agent: O=N[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: FC(F)(F)c1csc(Br)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
2-Amino-4-(trifluoromethyl)thiazole (Wako Pure Chemical Industries, Ltd., 500 mg) was added to 48% aqueous hydrogen bromide (6 ml) and, under ice-cooling, sodium nitrite (266 mg) dissolved in water (1 ml) was added dropwise thereto. The mixture was stirred at 0° C. for 1 hr. A sodium hydrogen sulfite aqueous solution, and then an aqueous sodium hydroxide solution were added, and the mixture was extracted with diethyl ether. The organic layer was dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane (1:9)) to give 2-bromo-4-(trifluoromethyl)thiazole (167 mg, yield 24%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:6][C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[N:10]2[N:27]=[CH:28][C:29]([CH:30]([CH3:32])[CH3:31])=[C:9]2[N:8]=1)[CH2:4][CH3:5].N[C@H](CO)[C@@H](C)[OH:36]>>[OH:1][CH2:2][C@@H:3]([NH:6][C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:19][CH:20]=2)[N:10]2[N:27]=[CH:28][C:29]([CH:30]([CH3:31])[CH3:32])=[C:9]2[N:8]=1)[C@H:4]([OH:36])[CH3:5]
Reactant: CC[C@H](CO)Nc1nc(NCc2ccc(-c3ccccn3)cc2)n2ncc(C(C)C)c2n1
Reactant: C[C@@H](O)[C@H](N)CO
Product: CC(C)c1cnn2c(NCc3ccc(-c4ccccn4)cc3)nc(N[C@H](CO)[C@@H](C)O)nc12
Yield: 43 %

Procedure:
According to the same conditions resulting in the preparation of the compound 2, the compound 12 is prepared from IIa.2 by oxidation reaction of the sulfur atom and then introduction of L-threoninol. Yield=43%. Oil. 1H NMR (300 MHz, CDCl3): δ 8.69 (d, 1H, J=4.7 Hz, Harom), 7.97 (d, 2H, J=8.3 Hz, Harom), 7.78-7.69 (m, 2H, Harom), 7.63 (8, 1H, Harom), 7.45 (d, 2H, J=8.3 Hz, Harom), 7.26-7.21 (m, 1H, Harom), 6.75 (bs, 1H, NH), 5.63 (d, 1H, J=5.8 Hz, NH), 4.77 (d, 2H, J=6.0 Hz, CH2), 4.22-4.15 (m, 1H, CH), 3.97-3.84 (m, 3H, CH+CH2), 3.01 (hept, 1H, J=7.0 Hz, CH), 1.29 (d, 3H, J=6.2 Hz, CH3), 1.28 (d, 6H, J=7.0 Hz, 2 CH3). MS (ESI): m/z 448 (MH+).
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]4.[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[CH2:19]>>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1/[CH:18]=[CH:19]/[C:2]1[C:10]2[NH:9][C:8]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]4
Reactant: C=Cc1ccccn1
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Product: C(=C/c1cccc2c3c([nH]c12)C1CCN(CC1)C3)\c1ccccn1

Procedure:
The product of Example 1B (110 mg, 0.38 mmol; Aldrich) and 2-vinylpyridine (40 mg, 0.38 mmol; Aldrich) were processed as described in Example 1D to provide the title compound: 1H NMR (500 MHz, methanol-d4) δ ppm 2.04-2.17 (m, 4 H), 3.04-3.12 (m, 2 H), 3.13-3.17 (m, 1 H), 3.26 (ddd, J=14.1, 8.5, 5.8 Hz, 2 H), 4.25 (s, 2 H), 7.04 (t, J=7.6 Hz, 1 H), 7.26 (ddd, J=7.4, 5.0, 1.1 Hz, 1 H), 7.28-7.34 (m, 2 H), 7.41 (d, J=7.3 Hz, 1 H), 7.71-7.74 (m, J=7.9 Hz, 1 H), 7.82 (td, J=7.6, 1.8 Hz, 1 H), 7.93-8.01 (m, 1 H), 8.51 (dd, J=5.0, 0.8 Hz, 1 H); MS (APCI) m/z 316 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[C:9]([NH2:12])[S:10][CH:11]=2)=[CH:4][CH:3]=1.[CH2:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)[CH2:14][CH3:15]>>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[C:9]([NH:12][S:22]([C:19]3[CH:20]=[CH:21][C:16]([CH2:13][CH2:14][CH3:15])=[CH:17][CH:18]=3)(=[O:24])=[O:23])[S:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Nc1nc(-c2ccc(Cl)s2)cs1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Product: CCCc1ccc(S(=O)(=O)Nc2nc(-c3ccc(Cl)s3)cs2)cc1

Procedure:
The title compound was prepared from 4-(5-chloro-2-thienyl)-1,3-thiazol-2-amine and 4-n-propylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a brown solid (16.4 mg) with purity >80%. MS (pos) m/z 399.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13]3([OH:19])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][CH:9]=2)=[N:6][CH:7]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[N:31]=[C:32]=[O:33]>O1CCCC1>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[NH:31][C:32]([NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[S:12][C:11]([C:13]3([OH:19])[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[N:10][CH:9]=2)=[CH:4][CH:3]=1)=[O:33]
Reactant: Nc1ccc(-c2cnc(C3(O)CCOCC3)s2)nc1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Solvent: C1CCOC1
Product: O=C(Nc1ccc(-c2cnc(C3(O)CCOCC3)s2)nc1)Nc1cc(C(F)(F)F)ccc1F
Reaction time: 1 h

Procedure:
To a solution of Example 7B (0.042 mg, 0.151 mmol) in tetrahydrofuran (1 mL) was added 2-fluoro-5-trifluoromethylphenyl isocyanate (0.022 mL, 0.151 mmol). After 1 h, the mixture was concentrated under reduced pressure. The residue was purified by RP-HPLC (preparative reversed-phase high pressure liquid chromatography) using a Zorbax SB-C18 7M 21.2×250 mm column with UV detection analyzed at 220 and 254 nM (preparative method: water with 0.1% trifluoroacetic acid and CH3CN with 0.1% trifluoroacetic acid gradient 5-95% CH3CN over 30 minutes at 15 mL/min) to provide the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.68 (br d, J=12.9 Hz, 2 H), 2.07-2.17 (m, 2 H), 3.68-3.80 (m, 4 H), 6.15 (s, 1 H), 7.40-7.45 (m, 1 H), 7.52 (m, 1 H), 7.89 (m, 1 H), 8.08 (m, 1 H), 8.25 (s, 1 H), 8.55-8.60 (m, 2 H), 9.10 (s, 1 H), 9.40 (s, 1 H); MS (ESI) m/z 483 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15](OC)=[O:16])[CH:13]=2)[CH:8]=[N:7]1.[BH4-].[Na+]>CO>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][OH:16])[CH:13]=2)[CH:8]=[N:7]1
Reactant: COCCCn1ncc2ccc(C(=O)OC)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COCCCn1ncc2ccc(CO)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.3 %

Procedure:
To a solution of methyl 1-(3-methoxypropyl)-1H-indazole-6-carboxylate (1.26 g, 5 mmol) in MeOH (15 mL), NaBH4 (1.52 g, 40 mmol) was added in portions such that the temperature remained below 40° C. The mixture was stirred at rt for 12 h. TLC showed the starting material had been consumed. The solvent was removed in vacuo and the residue was partitioned between water and EtOAc. The organic layers were washed with H2O and brine, dried over Na2SO4, and evaporated to produce (1-(3-methoxypropyl)-1H-indazol-6-yl)methanol (1.05 g, 95%), which was used in the next step without purification.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[Br:11][C:12]1[CH:13]=[C:14]2[CH2:23][CH2:22][N:21]3[C:15]2=[C:16]([CH:34]=1)[CH:17]([CH2:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[NH:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=13.[OH-].[Na+]>C(Cl)(Cl)Cl.O.ClCCl>[Br:11][C:12]1[CH:13]=[C:14]2[CH2:23][CH2:22][N:21]3[C:15]2=[C:16]([CH:34]=1)[CH:17]([CH2:28][CH2:29][CH2:30][N:31]([CH3:32])[CH3:33])[N:18]([CH:5]=[O:7])[C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=13
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)CCCC1Nc2ccccc2N2CCc3cc(Br)cc1c32
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN(C)CCCC1c2cc(Br)cc3c2N(CC3)c2ccccc2N1C=O
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Acetic anhydride (7.8 ml) and formic acid (12.5 ml) were mixed together and stirred at -10° C. for 1 hour. This solution now containing formic-acetic mixed anhydride was added to a solution of 4-bromo-N,N-dimethyl-1,2,6,7-tetrahydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine-6-propanamine (21.3 g) in chloroform (250 ml) at room temperature in one portion. The resulting solution was shaken for 30 minutes The reagent and solvent were removed on a rotary evaporator to give a foam-oil mixture. This was dissolved into dichloromethane and water and the mixture was basified with 10% sodium hydroxide. The organic phase was separated, washed with water and brine (2×250 ml) and dried over anhydrous magnesium sulfate. Removal of the solvent gave an oily crude product. Purification was conducted by flash chromatography on silica gel (140 g) eluted with 2 liters of dichloromethane, 2 liters of 1% methanol/dichloromethane and 2 liters of 2% methanol/dichloromethane. Fractions containing the pure product were combined and concentrated to afford 14.7 g of solid. Recrystallization from ethanol (40 ml) at 0° C. gave 10.6 g of crystals, m.p. 126°-127° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH:19]=O)[CH:8]=[CH:9][CH:10]=1.[CH2:22]([NH2:24])[CH3:23]>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:19][NH:24][CH2:22][CH3:23])[CH:8]=[CH:9][CH:10]=1
Reactant: CCN
Reactant: COC(=O)Cc1cccc(-c2c(C=O)cccc2OC)c1
Product: CCNCc1cccc(OC)c1-c1cccc(CC(=O)OC)c1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using the following starting materials: (2′-formyl-6′-methoxy-biphenyl-3-yl)-acetic acid methyl ester and ethylamine (2M in THF).
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[C:3]([C:5]1[C:13]2[NH:12][C:11](=[O:14])[CH:10]=[N:9][C:8]=2[N:7]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:6]=1)=[O:4].[CH:25]1(O)[CH2:29][CH2:28][CH2:27][CH2:26]1.C(P(CCCC)CCCC)CCC.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH:25]1([O:14][C:11]2[N:12]=[C:13]3[C:5]([C:3](=[O:4])[C:2]([CH3:24])([CH3:23])[CH3:1])=[CH:6][N:7]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:20])([CH3:22])[CH3:21])[C:8]3=[N:9][CH:10]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(=O)[nH]c12
Reactant: OC1CCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(OC3CCCC3)nc12
Temperature: 65 °C
Reaction time: 2.5 h
Yield: 49.6 %

Procedure:
A solution of 7-(2,2-dimethyl-propionyl)-5-(2-trimethylsilanyl-ethoxymethyl)-1,5-dihydro-pyrrolo[2,3-b]pyrazin-2-one (0.029 g, 0.082 mmol), 1 mL of tetrahydrofuran, cyclopentanol (0.010 mL, 0.11 mmol), tributylphosphine (0.025 mL, 0.1 mmol), and diisopropyl azodicarboxylate (0.020 mL, 0.10 mmol) under nitrogen was stirred at 65° C. for 17.5 h then allowed to cool. Additional cyclopentanol (0.020 mL, 0.22 mmol), tributylphosphine (0.050 mL, 0.20 mmol), and diisopropyl azodicarboxylate (0.040 mL, 0.21 mmol) were added, and the solution stirred at 65° C. for 2.5 h. The yellow solution was partitioned between 5 mL of water and 5 mL of ethyl acetate. The organic layer was washed with 5 mL of a sat. aq. NaCl solution, dried over MgSO4, filtered and concentrated to a yellow oil. Silica gel chromatography (10% EtOAc/hexanes) afforded 0.017 g (51%) of 1-[2-cyclopentyloxy-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:41]1([C:45]2[O:49][N:48]=[C:47]([C:50]3[C:55]([Cl:56])=[CH:54][N:53]=[CH:52][C:51]=3[Cl:57])[C:46]=2[CH2:58]O)[CH2:44][CH2:43][CH2:42]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH:41]1([C:45]2[O:49][N:48]=[C:47]([C:50]3[C:51]([Cl:57])=[CH:52][N:53]=[CH:54][C:55]=3[Cl:56])[C:46]=2[CH2:58][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[C:10]4[C:15](=[CH:16][CH:17]=3)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]4)=[CH:4][CH:3]=2)[CH2:42][CH2:43][CH2:44]1
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)cc3)ccc2n1
Reactant: OCc1c(-c2c(Cl)cncc2Cl)noc1C1CCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cncc5Cl)noc4C4CCC4)cc3)ccc2n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 26.3 %

Procedure:
To a solution of methyl 6-(4-hydroxyphenyl)-2-quinolinecarboxylate (0.10 mg, 0.36 mmol), triphenylphosphine (94 mg, 0.36 mmol) and [5-cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolyl]methanol (Example 9e) (0.11 mg, 0.36 mmol) in dichloromethane (2.5 mL) was added diisopropyl azodicarboxylate (0.064 mL, 0.36 mmol). The mixture was heated to 90° C. for 10 minutes and then allowed to stand overnight. The mixture was adsorbed onto silica gel and purified by chromatography (silica gel, 0-40% ethyl acetate in hexanes gradient elution followed by further purification (silica gel, 0-30% ethyl acetate in hexanes gradient elution) to afford methyl 6-[4-({[5-cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (53 mg, 26%). 1H-NMR (400 MHz, DMSO-d6) δ 8.81 (s, 2H), 8.55 (d, J=9 Hz, 1H), 8.28 (s, 1H), 8.18-8.10 (m, 3H), 7.73 (d, J=9 Hz, 2H), 6.88 (d, J=9 Hz, 2H), 4.93 (s, 2H), 4.08-3.99 (m, 1H), 3.94 (s, 3H), 2.45-2.34 (m, 4H), 2.15-2.02 (m, 1H), 1.99-1.89 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[CH2:10][CH2:11][Si:12](Cl)([Cl:14])[Cl:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:17]([CH3:20])([O-:19])=[O:18].C(N(CC)CC)C>>[CH2:1]([O:8][C:9](=[O:16])[CH2:10][CH2:11][Si:12]([Cl:14])([Cl:13])[CH2:20][N+:17]([O-:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CC[Si](Cl)(Cl)Cl)OCc1ccccc1
Reactant: C[N+](=O)[O-]
Solvent: CCN(CC)CC
Product: O=C(CC[Si](Cl)(Cl)C[N+](=O)[O-])OCc1ccccc1
Temperature: 0 °C

Procedure:
298 g (1 mole) of 3-(trichlorosilyl) propionic acid benzyl ester (I) is dissolved in 540 ml (10 mol) of nitromethane and cooled to 0° C. Added dropwise 139 ml (1 mol) of triethylamine over a period of 2 hours. The mixture is then distilled through a 22 mm×4 ft. Podbielniak column packed with Heli-pak to give 3-(dichloronitromethylsilyl) propionic acid benzyl ester (II).