Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:14](=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][CH:18]=2)[NH:13][N:12]=1.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:12]1[C:11]([C:4]2[CH:5]=[CH:6][C:7]([OH:9])=[CH:8][C:3]=2[O:2][CH3:1])=[C:19]2[C:14]([C:15]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:17]=[CH:18]2)=[N:13]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)c(OC)c1
Reactant: BrCc1ccccc1
Product: COc1cc(O)ccc1-c1c2cccc(C(F)(F)F)c2nn1Cc1ccccc1

Procedure:
Prepared according to Example 116 from 3-(2,4-dimethoxyphenyl)-7-(trifluoromethyl)-1H-indazole and benzyl bromide.
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]1[C:13]([NH:19][CH:20]=[O:21])(C(OCC)=O)[CH2:12][C:11]2=[CH:22][CH:23]=[CH:24][C:9]3=[C:10]2[N:5]1[CH2:6][CH2:7][CH2:8]3.Cl>CO>[O:3]=[C:4]1[CH:13]([NH:19][CH:20]=[O:21])[CH2:12][C:11]2=[CH:22][CH:23]=[CH:24][C:9]3=[C:10]2[N:5]1[CH2:6][CH2:7][CH2:8]3
Reactant: CCOC(=O)C1(NC=O)Cc2cccc3c2N(CCC3)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=CNC1Cc2cccc3c2N(CCC3)C1=O
Yield: 104.2 %

Procedure:
Sodium hydroxide solution (5.0 mL of 4.0 N, 20 mmol) was slowly added to ethyl 2,3,6,7 - tetrahydro- 3 -oxo -2- (formyl amino) - 1H,5 H-benzo(ij )quinolizine-2-carboxyl ate (3.134 g, 10.0 mmol) in methanol (25 mL). After stirring at room temperature for 30 rain, hydrochloric acid (5.0 mL of 4.0 N) was added and the precipitate was filtered off, washed with water and air dried to give 2.4 g of N-(2,3,6,7-tetrahydro-3-oxo-1H,5H-benzo(ij)quinolizin-2-yl)formamide, mp 149°-152° C. A portion of the product was recrystallized from ethyl acetate for analysis; mp 140-143° . Anal. Calc'd for C13H14N2O2 : C, 67.81; H, 6.13; N, 12.17. Found: C, 67.67; H, 6.07; N, 11.94.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:39]=[CH:38][CH:37]=[CH:36][C:11]=1[C:12]([NH:14][CH:15]([C:17]1[N:22]=[N:21][C:20]([NH:23][C:24]2[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=2)=[N:19][CH:18]=1)[CH3:16])=O)#[N:2].N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:16][C:15]1[N:14]=[C:12]([C:11]2[CH:36]=[CH:37][CH:38]=[CH:39][C:10]=2[S:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])[N:22]2[C:17]=1[CH:18]=[N:19][C:20]([NH:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=1)=[N:21]2
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3Sc3ccccc3C#N)nn2)cc(OC)c1OC
Agent: c1nc[nH]n1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(Nc2ncc3c(C)nc(-c4ccccc4Sc4ccccc4C#N)n3n2)cc(OC)c1OC
Yield: 37 %

Procedure:
In a similar manner as described for Example 9, 2-[(2-cyanophenyl)thio]-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (Intermediate 39) (269 mg, 0.49 mmol), and 1,2,4-triazole (210 mg, 2.94 mmol) in pyridine (3 mL) and phosphorous oxychloride (0.14 mL, 1.5 mmol) gave 2-[(2-{5-methyl-2-[(3,4,5-trimethoxyphenyl)amino]imidazo[5,1-f][1,2,4]triazin-7-yl}phenyl)thio]benzonitrile (95 mg, 37%) as a yellow solid. 1H NMR (CDCl3): δ8.77 (s, 1H), 7.70 (m, 1H), 7.57 (m, 1H), 7.42-7.47 (m, 3H), 7.10-7.23 (m, 3H), 6.85 (s, 1H), 6.79 (s, 2H), 3.80 (s, 3H), 3.63 (s, 6H), 2.57 (s, 3H). MS m/z 524 (M+1).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N+:12]([C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>N1C=CC=CC=1.[Cu].O>[C:5]([C:4]1[CH:3]=[C:2]([O:21][C:17]2[CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:20]=[CH:19][CH:18]=2)[CH:11]=[CH:10][CH:9]=1)([O:7][CH3:8])=[O:6]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: COC(=O)c1cccc(I)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1cccc(Oc2cccc([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of methyl 3-iodobenzoate (2.54 g), 3-nitrophenol (1.48 g), and K2CO3 (3.97 g) in 60 mL of pyridine was warmed to 100° C. under nitrogen atmosphere. Copper powder (1.84 g) was added, and the reaction mixture was heated to reflux. After 22 h, The reaction was cooled to room temperature and poured into ethyl acetate and water. The organic layer was washed twice with 10% aq. HCl solution, then with sat. aq. NaHCO3 solution, then with brine. The solution was dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product. Purification by silica gel chromatography (CH2Cl2) provided the product as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:23][O:24][CH2:25][CH2:26][OH:27]>>[CH3:23][O:24][CH2:25][CH2:26][O:27][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][C:13]=2[Cl:22])[CH:9]=[CH:10][C:2]=1[Cl:1]
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Cl
Reactant: COCCO
Product: COCCOC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Cl
Yield: 87 %

Procedure:
In 20 ml methyl cellosolve was heated 2.0 g (0.0054 mol) of 2-chloro-5-(2-chloro-4-trifluoromethylphenoxy)benzoyl chloride to temperatures of 80°-120° C. for 3 hours with stirring. After methyl cellosolve was distilled off, the residue was extracted with benzene. The extract was washed with a dilute aqueous solution of caustic soda and with water, and then dehydrated by adding sodium sulfate. By vacuum concentration thereof 2.2 g (0.0047 mol) of the intended product was obtained as a viscous oily substance; yield 87.0%, nD25 1.5321.
Reaction SMILES: CC([C:5]1(C(C)(C)C)[CH:10]([C:11]2[C:20]3[CH2:19][O:18][CH2:17][NH:16][C:15]=3[N:14]=[C:13]([C:21]3[C:26]([O:27]CC4C=CC(OC)=CC=4)=[CH:25][CH:24]=[CH:23][C:22]=3[O:37][CH2:38][CH:39]3[CH2:41][CH2:40]3)[CH:12]=2)[CH2:9][CH2:8][CH2:7][N:6]1C([O-])=O)(C)C.[ClH:49]>O1CCOCC1>[ClH:49].[CH:39]1([CH2:38][O:37][C:22]2[C:21]([C:13]3[CH:12]=[C:11]([CH:10]4[CH2:9][CH2:8][CH2:7][NH:6][CH2:5]4)[C:20]4[CH2:19][O:18][CH2:17][NH:16][C:15]=4[N:14]=3)=[C:26]([OH:27])[CH:25]=[CH:24][CH:23]=2)[CH2:40][CH2:41]1
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCCN(C(=O)[O-])C3(C(C)(C)C)C(C)(C)C)c3c(n2)NCOC3)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Oc1cccc(OCC2CC2)c1-c1cc(C2CCCNC2)c2c(n1)NCOC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 95 %

Procedure:
To a stirred solution of 1,1-dimethylethyl(tert-butyl)-3-{7-[2-[(cyclopropylmethyl)oxy]-6-({[4-(methyloxy)phenyl]methyl}oxy)phenyl]-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl}-1-piperidinecarboxylate (0.050 g, 0.083 mmol) in 1,4-Dioxane was added 4N HCl in 1,4-dioxane (2.000 mL). The mixture was stirred at room temperature for 6 hrs. The reaction mixture was concentrated under reduced pressure. The resulting residue was washed with acetonitrile to give 3-(cyclopropylmethoxy)-2-[5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-7-yl]-phenol hydrochloride as a colorless solid (0.033 g, yield; 95%).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3I)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:34]([C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1)([CH3:36])[CH3:35].COCCOC.C([O-])([O-])=O.[Na+].[Na+]>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.CCO>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:41]3[CH:40]=[CH:39][CH:38]=[C:37]([CH:34]([CH3:36])[CH3:35])[CH:42]=3)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I
Reactant: CC(C)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CC(C)c1cccc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Temperature: 100 °C

Procedure:
In a tube were placed (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (52.5 mg, 0.0879 mmol), 3-isopropylbenzeneboronic acid (17.3 mg, 0.106 mmol), DME (370 μL), EtOH (120 μL), and 1M aqueous Na2CO3 (264 μL, 0.264 mmol). The mixture was degassed with N2. Next, Pd(PPh3)4 (10.2 mg, 8.8×10−3 mmol) was added and the mixture was degassed again with N2. The tube was sealed and heated at 100° C. for two hours. The reaction was then cooled to room temperature, diluted with EtOAc (50 mL), and washed with water and brine (15 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (0 to 15% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[3′-isopropyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. Rf=0.29 (15% EtOAc/hexanes). LCMS=590.1 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.85 (s, 1H), 7.72 (s, 1H), 7.68 (s, 2H), 7.64 (d, J=8.0 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.29 (d, J=7.8 Hz, 1H), 7.15 (bs, 1H), 7.11 (bd, J=7.5 Hz, 1H), 5.46 (d, J=8.0 Hz, 1H), 4.91 (d, J=15.7 Hz, 1H), 4.21 (d, J=15.8 Hz, 1H), 3.69 (m, 1H), 2.96 (m, 1H), 1.26-1.28 (m, 6H), 0.38 (d, J=6.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH3:12])[CH3:11])=[CH:4][CH:3]=1.CC(C)=[O:15].S([O-])([O-])(=O)=O.[Mg+2].[Mn]([O-])(=O)(=O)=O.[K+]>O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[C:6](=[O:15])[CH2:7][C:8]2([CH3:12])[CH3:11]
Reactant: CC(C)=O
Reactant: CC1(C)CCc2ccc(Cl)cc21
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC1(C)CC(=O)c2ccc(Cl)cc21
Reaction time: 8 h
Yield: 67 %

Procedure:
To a solution of 6-chloro-1,1-dimethylindane (6.00 g, 0.0332 mol) in acetone (100 mL, 2 mol) was added 1.5 M of magnesium sulfate in water (30 mL) and potassium permanganate (12.3 g, 0.0780 mol). The reaction was stirred overnight, the resulting deposit was filtered, and the solution was concentrated to a reduced volume. The solution was extracted with EtOAc (3×100 ml) and the organic layer was concentrated. Purification by flash chromatography (10% EtOAc/hexanes) afforded the title compound (4.33 g, 67%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH2:18])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-].[Na+:20].[O:21]1CCOCC1>O>[NH2:3][C:4]1[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:2]([O-:21])=[O:1].[Na+:20]
Reactant: C1COCCO1
Reactant: Nc1ccccc1Oc1cccc2c1NC(=O)C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccccc1Oc1cccc(CC(=O)[O-])c1N

Procedure:
A mixture of 2-oxo-7-(2-aminophenoxy)indoline (3.5 g.), sodium hydroxide (1.2 g.), dioxane (10 ml.) and water (50 ml.) was refluxed under heating for 48 hours with stirring. After cooling, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol under warming and filtered. The filtrate was concentrated under reduced pressure, and the residue was crystallized with a mixture of ethanol and ethyl acetate to give the captioned compound (3 g.). mp 103° to 110° C.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Na].[CH:19]([OH:22])([CH3:21])[CH3:20]>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:22][CH:19]([CH3:21])[CH3:20])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Reactant: CC(C)O
Agent: [Na]
Product: CC(C)OC(=N)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and sodium isopropylate in isopropanol there is obtained isopropyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and therefrom with hydrochloric acid in alcohol there is obtained the hydrochloride, m.p. 158° C. (with decomposition);
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH:13]([CH3:15])[CH3:14])[CH:6]=[C:5]2[C:16]([F:19])([F:18])[F:17].[C:20]([O:23]CC)(=[O:22])C.O>>[CH:13]([O:12][C:7]1[CH:6]=[C:5]([C:16]([F:19])([F:18])[F:17])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:20]([OH:23])=[O:22])[CH:3]=2)[N:8]=1)([CH3:15])[CH3:14]
Reactant: CC(C)Oc1cc(C(F)(F)F)c2cc(Br)ccc2n1
Reactant: CCOC(C)=O
Solvent: O
Product: CC(C)Oc1cc(C(F)(F)F)c2cc(C(=O)O)ccc2n1

Procedure:
The title compound was synthesized by carbonylation of 6-bromo-2-isopropoxy-4-trifluoromethyl-quinoline (CAS [328955-63-1]) in ethyl acetate/water using 50 bar CO, PdCl2 dppf CH2Cl2, 80° C. for 20 h. Light grey solid. MS (m/e, ISP neg. ion)=298.3 [M−H+].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:11][C:12]1[N:17]=[CH:16][C:15]([C:18]2([CH2:24][NH2:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:14][N:13]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:25][CH2:24][C:18]1([C:15]2[CH:16]=[N:17][C:12]([CH3:11])=[N:13][CH:14]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: Cc1ncc(C2(CN)CCOCC2)cn1
Product: Cc1ncc(C2(CNC(=O)c3ccccc3Cl)CCOCC2)cn1

Procedure:
From 2-chlorobenzoic acid and (4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methanamine. LCMS (MH+): m/z=346.1, tR (minutes, Method F)=1.55
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9](=[O:11])[CH3:10])=[C:6]([CH:12]=[O:13])[C:5]([CH2:14][O:15][C:16](=[O:18])[CH3:17])=[CH:4][N:3]=1.[BH4-].[Na+]>C(OCC)C>[CH3:1][C:2]1[C:7]([O:8][C:9](=[O:11])[CH3:10])=[C:6]([CH2:12][OH:13])[C:5]([CH2:14][O:15][C:16](=[O:18])[CH3:17])=[CH:4][N:3]=1
Reactant: CC(=O)OCc1cnc(C)c(OC(C)=O)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(=O)OCc1cnc(C)c(OC(C)=O)c1CO

Procedure:
One equivalent of 2-methyl-3-acetoxy-4-formyl-5-acetoxymethylpyridine in 1 liter of anhydrous diethyl ether is treated with 1.5 equivalents of sodium borohydride and aged 3 hours at room temperature. The reaction mixture is quenched on excess aqueous ammonium chloride solution and the ether layer is separated. After magnesium sulfate drying, concentration in vacuo gives the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][C:14]#[N:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]CC.[Na+].[C:22](=O)([O:26]CC)[O:23][CH2:24][CH3:25].Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:13]([C:14]#[N:15])[C:22]([O:23][CH2:24][CH3:25])=[O:26])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)OCC
Reactant: N#CCc1ccc(OCc2ccccc2)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C#N)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 99.2 %

Procedure:
The 4-benzyloxybenzyl cyanide from step (450a)(3.2 g, 14.33 mmol), sodium ethoxide (1.07 g, 15.7 mmol), and diethyl carbonate (2.23 g, 18.9 mmol) were combined in toluene (100 mL), heated to reflux for 3 h, cooled to rt, and partioned between ethyl acetate and 1 N HCl. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The crude was purified by chromatography on silica gel eluting hexane:ethyl acetate (80:20, v:v) to give ethyl 2-(4-benzyloxyphenyl)cyanoacetate (4.2 g, 99%) as an oil. MS (M+NH4)+=313.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([C:14]2[CH:34]=[CH:33][C:17]3[N:18]=[C:19]([NH:21][CH2:22][CH2:23][N:24](C)[C:25](=O)OC(C)(C)C)[S:20][C:16]=3[CH:15]=2)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([C:14]2[CH:34]=[CH:33][C:17]3[N:18]=[C:19]([NH:21][CH2:22][CH2:23][NH:24][CH3:25])[S:20][C:16]=3[CH:15]=2)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(NC(=O)c2ccc3nc(NCCN(C)C(=O)OC(C)(C)C)sc3c2)cc1OC
Agent: Cl
Solvent: C1COCCO1
Product: CNCCNc1nc2ccc(C(=O)Nc3ccc(OC)c(OC)c3)cc2s1
Reaction time: 2 h

Procedure:
tert-Butyl 2-(6-(3,4-dimethoxyphenylcarbamoyl)benzo[d]thiazol-2-ylamino)ethyl(methyl)carbamate (327.1 mg, 0.672 mmol) was dissolved in 1,4-dioxane (4 mL) and then treated with 4N HCl in 1,4-dioxane (4 mL, 16.0 mmol). The resulting mixture was stirred for 2 h and a solid separated from the solution. The solid was collected by filtration, washed with 1,4-dioxane, then dried in vacuum oven for 2 d at room temperature to yield the hydrochloride salt of N-(3,4-dimethoxyphenyl)-2-(2-(methylamino)ethylamino)benzo[d]thiazole-6-carboxamide as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:36])[NH:4][C:5](=[O:35])[N:6]([CH:34]=1)[C@@H:7]1[O:33][C@H:11]([CH2:12][O:13]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C@@H:9]([OH:10])[CH2:8]1.[OH-].[K+].[Br:39][C:40]1[S:41][C:42]([CH2:47]Cl)=[C:43]([Br:46])[C:44]=1[Br:45]>O1CCOCC1>[F:1][C:2]1[C:3](=[O:36])[NH:4][C:5](=[O:35])[N:6]([CH:34]=1)[C@@H:7]1[O:33][C@H:11]([CH2:12][OH:13])[C@@H:9]([O:10][CH2:47][C:42]2[S:41][C:40]([Br:39])=[C:44]([Br:45])[C:43]=2[Br:46])[CH2:8]1
Reactant: ClCc1sc(Br)c(Br)c1Br
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3sc(Br)c(Br)c3Br)[C@@H](CO)O2)cc1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 18.1 %

Procedure:
To a solution of 5.00 g of 2'-deoxy-5-fluoro-5'-O-trityluridine in 100 ml of dioxane were added 5.74 g of fine powder of potassium hydroxide and 5.65 g of 2,3,4- tribromo-5-chloromethylthiophene, and the mixture was stirred at a temperature of 80° C. for 2 hours. The reaction mixture was concentrated and the residue was dissolved in 100 ml of ethyl acetate. The solution was washed with aqueous solution of acetic acid, dried and concentrated. To the residue was added 100 ml of 80% acetic acid and the mixture was left to stand at a temperature of 80° C. for one hour. The solvent was distilled off and the residue was placed on silica gel column and eluted with 2% methanol-chloroform for purification, giving 1.07 g (18%) of the desired 2'-deoxy 5-fluoro-3'-O-(3,4,5-tribromo-2-thenyl)uridine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=[CH:9][N:10]=1)=[O:5])[CH3:2].C1C(=O)N([Br:26])C(=O)C1>CC#N>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:16])[CH3:18])[CH:8]=[C:9]([Br:26])[N:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nccn1COCC[Si](C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CCOC(=O)c1nc(Br)cn1COCC[Si](C)(C)C
Temperature: 60 °C
Yield: 38.7 %

Procedure:
To a solution of 1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid ethyl ester (0.20 g, 0.74 mmol)(prepared in the previous step) in 2 mL of CH3CN was added NBS (0.13 g, 0.74 mmol) and the mixture heated to 60° C. for 2 h. The mixture was concentrated and the title compound purified by elution from a 20-g SPE column with 20% EtOAc/hexanes to give 0.10 g (39%) of a colorless oil. Mass spectrum (ESI, m/z): Calcd. for C12H21BrN2O3Si, 349.0 (M+H). found 348.7.
Reaction SMILES: C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:2].C12CC(C=C1)C(=O)N2.C(=O)=O.[OH-].[Na+].[O:29]=[C:30]1[CH:35]2[CH2:36][CH:32]([CH:33]=[CH:34]2)[N:31]1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>O1CCCC1.CN(C)C1C=CN=CC=1.O>[CH3:41][C:40]([CH3:43])([O:39][C:37]([NH:31][C@@H:32]1[CH2:36][C@H:35]([C:30]([OH:2])=[O:29])[CH:34]=[CH:33]1)=[O:38])[CH3:42]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1C(=O)C2C=CC1C2
Agent: CN(C)c1ccncc1
Agent: O=C1NC2C=CC1C2
Agent: O=C=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1C=C[C@@H](C(=O)O)C1
Temperature: 40 °C

Procedure:
Di-tert-butyl dicarbonate (968 g) was added to a stirred solution of racemic 2-aza bicyclo[2.2.1]hept-5-ene-3-one (1)(440 g) in tetrahydrofuran (THF)(1800 ml). A catalytic amount of 4-dimethylaminopyridine (DMAP)(4.9 g) was added as a single bolus and the solution stirred at ca 25-30° C. until the evolution of carbon dioxide had ceased. A solution of sodium hydroxide (177.4 g) in water (4400 ml) was added to the thus formed 3-oxo-2-azabicyclo[2.2.1]hept-5-ene-2-carboxylic acid, 1,1-dimethylethyl ester (2) and the reaction heated to 40° C. for 15 hours. The reaction mixture was cooled and partitioned with toluene (3500 ml). The phases were separated and the aqueous layer extracted with more toluene (1700 ml). The aqueous layer was treated with activated charcoal (44 g) at ambient temperature, filtered and then acidified to pH3.6 with concentrated hydrochloric acid (400 ml). The precipitated product was filtered off, washed with water (400 ml) then dried in vacuo at 50° C. The yield of 4-[[(1,1-dimethylethoxy)carbonyl]amino]-2-cyclopentene-1-carboxylic acid was 882 g, 96% of theory. Mp 125-28° C.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:22])[C@@H:5]([NH:14]C(OC(C)(C)C)=O)[CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>>[ClH:1].[ClH:1].[CH3:2][O:3][C:4](=[O:22])[C@@H:5]([NH2:14])[CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COC(=O)[C@H](CCN1CCCCC1)NC(=O)OC(C)(C)C
Agent: Cl
Product: COC(=O)[C@@H](N)CCN1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
HCl (0.45 mL of 4M in dioxane) was added to (S)-2-tert-Butoxycarbonylamino-4-piperidin-1-yl-butyric acid methyl ester and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and dried under high vacuum for 16 hours to provide the product (46% yield).
Reaction SMILES: C([Li])(C)(C)C.CC[O:8][CH2:9][CH3:10].Br[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1C)[NH:17][CH:16]=[C:15]2[CH3:22]>CN(C=O)C>[CH3:22][C:15]1[C:14]2[C:18](=[CH:19][C:20]([CH3:12])=[C:10]([CH:9]=[O:8])[CH:13]=2)[NH:17][CH:16]=1
Reactant: CCOCC
Reactant: Cc1cc2[nH]cc(C)c2cc1Br
Agent: [Li]C(C)(C)C
Solvent: CN(C)C=O
Product: Cc1cc2[nH]cc(C)c2cc1C=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
tert-Butyl lithium (16.7 mL, 28.3 mmol, 1.7 M in pentanes) was added to a dry ether (20 mL) solution of 5-bromo-3,6-dimethyl-1H-indole (1.27 g, 5.67 mmol) at −78° C. under Argon. The mixture was stirred at 0° C. for 30 min then cooled to −78° C. DMF (18 mL) was added and the mixture was stirred at 0° C. for 1 h. The reaction was quenched with cold, saturated NH4Cl solution at −78° C. The mixture was diluted with ether and hexane, washed with brine, dried and evaporated. Crystallization from a CH2Cl2/hexane mixture afforded the title compound (810 mg 82%). 1H NMR (300 MHz, CDCl3) 10.29 (s, 1H), 8.06 (s, 1H), 8.00 (s, br, 1H), 7.15 (1s, 1H), 6.97 (s, 1H), 2.76 (s, 3H), 2.36 (s, 3H).