Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:13][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH2:12])[CH:10]=[C:5]2[CH:4]=1.[Cl:16][C:17]1[C:22]([F:23])=[C:21]([CH2:24][CH3:25])[N:20]=[CH:19][N:18]=1.CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[ClH:16].[CH2:24]([C:21]1[N:20]=[CH:19][N:18]=[C:17]([NH:12][CH2:11][C:9]2[CH:10]=[C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[NH:13][C:6]3=[N:7][CH:8]=2)[C:22]=1[F:23])[CH3:25]
Reactant: CCc1ncnc(Cl)c1F
Reactant: NCc1cnc2[nH]c(C(F)(F)F)cc2c1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCc1ncnc(NCc2cnc3[nH]c(C(F)(F)F)cc3c2)c1F
Product: Cl
Temperature: 25 °C

Procedure:
A solution of 1-[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methanamine (Intermediate 5, 50 mg, 0.232 mmol) in dry NMP (2 mL) was treated with 4-chloro-6-ethyl-5-fluoropyrimidine (Intermediate 27, 74.6 mg, 0.465 mmol) and DIPEA (0.081 mL, 0.465 mmol). The reaction mixture was then stirred at room temperature over the weekend. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL). The organic extract was then washed with water (20 mL×2), dried (MgSO4), filtered and the solvent was removed. The resulting residues were then purified on the MDAP and fractions containing desired product were combined and evaporated to dryness. The resulting residues were then dissolved in methanol (10 mL) and 4M HCl in dioxane (1 mL) was added. The mixture was then evaporated to dryness to give the title compound as an off white solid (45 mg).
Reaction SMILES: Br[C:2]1[CH:29]=[C:5]2[N:6]=[C:7]([CH3:28])[C:8]([C@H:18]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]([O:21]C)=[O:20])=[C:9]([N:10]3[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH2:12][CH2:11]3)[N:4]2[N:3]=1.Br[C:31]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:34]=[CH:33][N:32]=1.C([Sn](CCCC)(CCCC)[Sn](CCCC)(CCCC)CCCC)CCC.O[Li].O>O1CCOCC1.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.CO>[C:24]([O:23][C@@H:18]([C:8]1[C:7]([CH3:28])=[N:6][C:5]2[N:4]([N:3]=[C:2]([C:31]3[CH:36]=[C:35]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH:34]=[CH:33][N:32]=3)[CH:29]=2)[C:9]=1[N:10]1[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH2:12][CH2:11]1)[C:19]([OH:21])=[O:20])([CH3:27])([CH3:25])[CH3:26]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(Br)nn2c1N1CCC(C)(C)CC1
Reactant: Brc1cc(-c2ccccc2)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](CCCC)(CCCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Li]O
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: Cc1nc2cc(-c3cc(-c4ccccc4)ccn3)nn2c(N2CCC(C)(C)CC2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 85 °C
Reaction time: 2 h
Yield: 6.2 %

Procedure:
To a solution of (S)-methyl 2-(2-bromo-7-(4,4-dimethylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.050 g, 0.107 mmol, 1 equiv) in dioxane (1.0 mL) was added 2-bromo-4-phenylpyridine (0.030 g, 0.128 mmol, 1.2 equiv), hexabutyldistannane (0.12 mL, 0.235 mmol, 2.2 equiv), and Pd(PPh3)4 (0.012 g, 0.011 mmol, 0.1 equiv). The reaction was heated at 85° C. for 72 h. The reaction temperature was then lowered to 60° C. Methanol (1 mL), water (0.3 mL), and LiOH.H2O (26 mg, 1.07 mmol, 10 equiv) added and heating was continued for 2 h. Upon completion of the saponification, the reaction was removed from heat and filtered through a syringe filter. The crude reaction mixture was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column. Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 20-mM ammonium acetate; Gradient: 45-85% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min, to provide (S)-2-(tert-butoxy)-2-(7-(4,4-dimethylpiperidin-1-yl)-5-methyl-2-(4-phenylpyridin-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetic acid (3.5 mg, 6%). 1H NMR (500 MHz, DMSO-d6) δ 8.73 (d, J=4.9 Hz, 1H), 8.48 (s, 1H), 7.83 (d, J=7.6 Hz, 2H), 7.75 (d, J=4.0 Hz, 1H), 7.60-7.49 (m, 3H), 7.06 (s, 1H), 5.72 (br. s., 1H), 3.61-3.55 (m, 4H), 2.53 (s, 3H), 1.65 (br. s., 2H), 1.50 (br. s., 2H), 1.18 (s, 9H), 1.11 (br. s., 6H). LCMS (ESI, M+1): 528.3.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][CH:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:30])[CH:28]=[CH2:29])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[C:27]([NH:26][C:23]1[CH:24]=[CH:25][C:20]([S:17]([N:14]2[CH2:15][CH2:16][CH:11]([NH:10][C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:12][CH2:13]2)(=[O:18])=[O:19])=[CH:21][CH:22]=1)(=[O:30])[CH:28]=[CH2:29]
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCC(N)CC2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCC(NC(=O)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.3 %

Procedure:
Diisopropylethylamine (0.14 ml, 0.8 mmol) was added in one portion to a stirred solution of N-[4-(4-amino-piperidine-1-sulfonyl)-phenyl]-acrylamide (0.1 g, 0.32 mmol) in THF (3 ml) at room temperature. To this mixture was added benzoyl chloride (0.048 ml, 0.42 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time, the mixture was concentrated under vacuum and the resulting residue purified by flash column chromatography (elution: 70% heptane, 30% ethyl acetate to 40% heptane, 60% ethyl acetate) to give the title compound (7 mg, 5% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[N:13]=[C:14]([C:16]([OH:18])=O)[CH:15]=[C:9]2[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH2:19]([N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[N:13]=[C:14]([C:16](=[O:18])[NH:32][CH:29]3[CH2:30][CH2:31][N:26]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:27][CH2:28]3)[CH:15]=[C:9]2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)c1c[nH]c2cc(C(=O)O)nn2c1=O
Product: CCOC(=O)c1c[nH]c2cc(C(=O)NC3CCN(Cc4ccccc4)CC3)nn2c1=O

Procedure:
The expected compound was obtained according to general procedure F using Key Intermediate V and 1-benzyl-piperidin-4-ylamine. The expected compound was isolated as white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([OH:9])=O)([O-:3])=[O:2].O=S(Cl)Cl.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.CCN(CC)CC>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]([N:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)=[O:9])[CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])([O-:3])=[O:2]
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)CC1
Temperature: 5 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
A mixture of 3,4-dinitrobenzoic acid (10.6 g, 50 mmol) and SOCl2 (50 mL) was heated at reflux for 6 hrs. Then the mixture was evaporated to dryness in vacuo. The residue was dissolved in CH2Cl2 (50 mL) and cooled to 5° C. To this solution, N-methylpiperazine (5.5 g, 55 mmol) and Et3N (5.5 g, 55 mmol) were added dropwise as a solution in CH2Cl2 (50 mL). After stirring overnight at rt, the combined organic phase was washed with water (100 mL), dried over Na2SO4, filtered and concentrated, the resulting residue was purified by silica gel chromatography (eluent: 5% MeOH in CH2Cl2) to give a yellow solid (14.0 g, 95.2%). 1H NMR (300 MHz, DMSO-d6) δ: 8.29 (1H, s), 8.25-8.27 (1H, d, J=9.0 Hz), 7.95-7.98 (1H, d, J=9.0 Hz), 3.62 (2H, m), 3.28 (2H, m), 2.38 (2H, m), 2.26 (2H, m), 2.19 (3H, s).
Reaction SMILES: [CH2-:1][C:2]([CH3:4])=[O:3].[NH2:5][CH2:6][C@@H:7]1[C@H:11]([OH:12])[C@H:10]([OH:13])[C@H:9]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][CH:17]=[N:18][C:19]=3[CH:23]2[CH2:27][CH2:26][O:25][CH2:24]2)[O:8]1.C([N:30]([CH2:33]C)[CH2:31][CH3:32])C.[CH2:35]([OH:37])[CH3:36]>>[CH2-:1][C:2]([CH3:4])=[O:3].[O:37]1[C:35]2[CH:36]=[CH:1][CH:2]=[CH:32][C:31]=2[N:30]=[C:33]1[NH:5][CH2:6][C@@H:7]1[C@H:11]([OH:12])[C@H:10]([OH:13])[C@H:9]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][CH:17]=[N:18][C:19]=3[CH:23]2[CH2:27][CH2:26][O:25][CH2:24]2)[O:8]1
Reactant: CCO
Reactant: NC[C@H]1O[C@@H](n2cnc3c(C4CCOC4)ncnc32)[C@@H](O)[C@H]1O
Reactant: CCN(CC)CC
Agent: [CH2-]C(C)=O
Product: O[C@@H]1[C@H](O)[C@H](n2cnc3c(C4CCOC4)ncnc32)O[C@@H]1CNc1nc2ccccc2o1

Procedure:
To a solution of (4S,2R,3R,5R)-2-aminomethyl-5-[6-(tetrahydrofuran-3-yl)-purin-9-yl]-tetrahydrofuran-3,4-diol acetonide, a compound of formula (11) (100 mg), in ethanol (5 mL) was added triethylamine and 2-chlorobenoxazole, and the mixture was refluxed for 16 hours. The solvent was evaporated and the residue purified by preparative TLC (5% MeOH/DCM) to give (4S,2R,3R,5R)-2-(benzoxazol-2-ylaminomethyl)-5-[6-(tetrahydrofuran-3-yl)-purin-9-yl]-tetrahydrofuran-3,4-diol acetonide, a compound of formula (12).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:10]=2)[CH:8]=1.CCN(C(C)C)C(C)C.[F:35][C:36]1[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38](Cl)=[O:39]>C1COCC1>[Cl:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:38](=[O:39])[C:37]2[CH:41]=[CH:42][CH:43]=[CH:44][C:36]=2[F:35])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[N:10]=1
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Reactant: O=C(Cl)c1ccccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1)c1ccccc1F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 37.7 %

Procedure:
To a solution of 3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-63, 0.060 g, 0.162 mmol) in dry THF (5 mL) was added DIPEA (3 mL) and stirred for 20 minutes. The reaction mixture was cooled to 0° C. and 2-fluorobenzoyl chloride (0.038 g, 0.243 mmol) was added and stirred for 3 h at room temperature. The reaction mass was quenched in water, extracted with DCM:MeOH and concentrated to afford crude product which was purified by column chromatography eluting with MeOH:DCM to afford 0.030 g of pure product. 1H NMR (400 MHz, DMSO d6): δ 4.50-4.52 (d, J=8 Hz, 2H), 7.25-7.33 (m, 2H), 7.52-7.55 (m, 2H), 7.63-7.65 (m, 2H), 7.72-7.86 (d, J=2.4 Hz, 1H), 7.83-7.86 (d, J=11.6 Hz, 2H), 8.17-8.20 (d, J=11.6 Hz, 2H), 8.95-8.99 (t, 1H), 12.69 (br s, 1H); MS (m/z): 491.17 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=CC=C(F)[C:3]=1[C:9]1[C:13](C(OC)=O)=[C:12](C(C(=O)C(F)(F)F)=CN(C)C)[O:11][N:10]=1.ClC1C=C([NH:36][NH2:37])C=CC=1.C(N(CC)C(C)C)(C)C>C(O)C>[NH:36]1[CH:7]=[CH:2][C:3]([C:9]2[CH:13]=[CH:12][O:11][N:10]=2)=[N:37]1
Reactant: NNc1cccc(Cl)c1
Reactant: COC(=O)c1c(-c2c(F)cccc2Cl)noc1C(=CN(C)C)C(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: c1cc(-c2ccon2)n[nH]1
Yield: 225.8 %

Procedure:
To a solution of 0.5047 g (1.1994 mmol) methyl 3-(2-chloro-6-fluorophenyl)-5-(1-(dimethylamino)-4,4,4-trifluoro-3-oxobut-1-en-2-yl)isoxazole-4-carboxylate in dry ethanol, 0.1790 g (0.9995 mmol) 3-Chlorophenylhydrazine and 0.17 mL (0.9995 mmol) N,N-Diisopropylethylamine (DIPEA) were added. The reaction mixture was heated under reflux for 2 h. The product was isolated by using column chromatography (Petroleum ether:Diethyl ether 80:20), and 0.305 g (yield of theory: 61%) of the pyrazolyl-isoxazole derivative were obtained. Result of LC/MS [M+H]+: 499.9; 1H NMR (DMSO-d6; CCl4): 3.66 (3H, s, CH3), 7.45-7.50 (1H, dd, CH-arom.), 7.55-7.58 (1H, d, CH-arom.), 7.65-7.77 (1H, d, CH-arom.), 7.65-7.77 (1H, dd, CH-arom. phenylhydrazine), 7.65-7.77 (1H, d, CH-arom. phenylhydrazine), 7.85 (1H, s, CH-arom phenylhydrazine), 8.56 (1H, s, 1-pyrazole)
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[C:10]([N+:15]([O-:17])=[O:16])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:19]1CCN2C(=NCCC2)CC1.CI>CN(C=O)C>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([N:7]([CH3:19])[C:6](=[O:18])[OH:5])=[N:9][C:10]=1[N+:15]([O-:17])=[O:16].[C:1]([O:5][C:6](=[O:18])[N:7]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[C:10]([N+:15]([O-:17])=[O:16])[N:9]=1)[CH3:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)c([N+](=O)[O-])n1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: CI
Product: CN(C(=O)O)c1ccc(Br)c([N+](=O)[O-])n1
Product: CN(C(=O)OC(C)(C)C)c1ccc(Br)c([N+](=O)[O-])n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 70.7 %

Procedure:
To a solution of (5-bromo-6-nitro-pyridin-2-yl)-carbamic acid tert-butyl ester (11) (4.2 g, 13.2 mmol) in dry DMF (21 mL), DBU (5.02 g, 33.0 mmol)! was added at 0° C. Methyl iodide (3.75 g, 26.4 mmol) was added slowly at 0° C. After stirring for 3 hours at 0° C. the reaction mixture was quenched and the product was precipitated upon addition of aqueous NaHSO4(1M). The crude product was isolated by filtration and purified by recrystallisation from a mixture of MeCN and water to afford (5-bromo-6-nitro-pyridin-2-yl)-methyl-carbamic acid ten-butyl ester 12 (1.55 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH3:10].[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][Br:11]
Reactant: COc1ccc(C)c(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(CBr)c(Cl)c1
Yield: 90.1 %

Procedure:
186 g of 2-chloro-4-methoxytoluene are dissolved in 1000 ml of carbon tetrachloride and, together with 212 g of N-bromosuccinimide, heated at reflux for 2 h while 2.4 g of AIBN are added. The solid is filtered off and washed with a small amount of carbon tetrachloride, the filtrate is concentrated, and the residue which remains is fractionated. 252 g of orange oil are obtained (Purity 82%).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH:20]([C:23]([OH:25])=O)[CH2:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[CH3:27][NH:28][O:29][CH3:30].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(Cl)(Cl)Cl.O>[CH3:30][O:29][N:28]([CH3:27])[C:23]([CH:20]1[CH2:21][CH2:22][N:18]([C:16]([O:15][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:17])[CH2:19]1)=[O:25]
Reactant: CNOC
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.7 %

Procedure:
Triethylamine (1.68 mL, 12.0 mmol) was added dropwise to 1-[(benzyloxy)carbonyl]pyrrolidine-3-carboxylic acid (1.00 g, 4.01 mmol), N,O-dimethylhydroxylamine hydrochloride (782 mg, 8.02 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.54 g, 8.02 mmol) and 1-hydroxybenzotriazole (1.08 g, 8.02 mmol) in chloroform (20 mL), and the reaction mixture was stirred at room temperature for 16 hours. After addition of water, the reaction mixture was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1→3/7 (v/v)) to give the title compound as a yellow oil (1.11 g, yield 95%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])=[N:4][C:5]([N:30]([CH2:36][CH2:37][O:38][CH3:39])[CH2:31][C@@H:32]2[CH2:34][C@H:33]2[CH3:35])=[CH:6][C:7]=1[C:8]1[O:12][C:11]([C@@:13]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:21])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][N:9]=1.O[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([N:40]([S:41]([CH3:44])(=[O:42])=[O:43])[CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=2)=[N:4][C:5]([N:30]([CH2:36][CH2:37][O:38][CH3:39])[CH2:31][C@@H:32]2[CH2:34][C@H:33]2[CH3:35])=[CH:6][C:7]=1[C:8]1[O:12][C:11]([C@@:13]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:21])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][N:9]=1
Reactant: COCCN(C[C@@H]1C[C@H]1C)c1cc(-c2nnc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)c(Cl)c(NS(C)(=O)=O)n1
Reactant: OCc1ccccn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COCCN(C[C@@H]1C[C@H]1C)c1cc(-c2nnc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)c(Cl)c(N(Cc2ccccn2)S(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.1 %

Procedure:
To a solution of tert-butyl (1R)-1-(5-{3-chloro-6-((2-methoxyethyl){[trans-2-methylcyclopropyl]methyl}amino)-2-[(methylsulfonyl)amino]pyridin-4-yl}-1,3,4-oxadiazol-2-yl)-1-methyl-2-phenylethylcarbamate (intermediate 8.4.2, 0.028 g, 0.043 mmol) in toluene (1 ml) at 0 oC was added 2-(hydroxymethyl)pyridine (0.004 ml, 0.043 mmol) and triphenylphosphine (0.011 g, 0.043 mmol) followed by diisopropyl azodicarboxylate (0.008 ml, 0.043 mmol). The ice bath was removed and the solution stirred at room temperature overnight. The next day the solution was concentrated in vacuo, taken up in DMF and filtered. The product was purified by reverse phase HPLC affording 0.015 g of tert-butyl (1R)-1-(5-{3-chloro-6-((2-methoxyethyl){[trans-2-methylcyclopropyl]methyl}amino)-2[(methylsulfonyl)(pyridin-2-ylmethyl)amino]pyridin-4-yl}-1,3,4-oxadiazol-2-yl)-1-methyl-2-phenylethylcarbamate LCMS [M+H]740.2.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[C:8]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([Cl:25])[CH:19]=4)[CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].C(OC)(OC)OC.C(O)(=O)C.[CH2:41]1[CH2:45][O:44][CH2:43][CH2:42]1>CO>[Cl:25][C:20]1[CH:19]=[C:18]([C:8]2[CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]3[NH:12][C:13]4[C:5]([C:6]=3[CH:7]=2)=[CH:4][CH:3]=[C:2]([N:1]2[CH2:41][CH2:45][O:44][CH2:43][CH2:42]2)[CH:14]=4)[CH:23]=[CH:22][C:21]=1[OH:24]
Reactant: NC(=O)c1cc(-c2ccc(O)c(Cl)c2)cc2c1[nH]c1cc(N)ccc12
Reactant: C1CCOC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Solvent: CC(=O)O
Product: NC(=O)c1cc(-c2ccc(O)c(Cl)c2)cc2c1[nH]c1cc(N3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
7-Amino-3-(3-chloro-4-hydroxyphenyl)-9H-carbazole-1-carboxamide (700 mg, 1.094 mmol, Example 406A) and sodium cyanoborohydride (400 mg, 6.37 mmol) were dissolved in methanol (20 mL)+THF (20.00 ml). Trimethyl orthoformate (10 ml, 90 mmol) and acetic acid (100 μl, 1.747 mmol) were added, followed by 28 ml of the crude reaction mixture from Example 406B (contained ˜4 mmol of 2,2′-oxydiacetaldehyde in CH2Cl2). The reaction mixture was stirred at room temperature for 90 minutes, then filtered through a Waters MCX cartridge (18 g adsorbent). The cartridge was washed with water, methanol and dichloromethane, then the product was eluted with 2M NH3 in MeOH. Evaporation of volatiles and purification by prep HPLC gave 149.0 mg 3-(3-chloro-4-hydroxyphenyl)-7-morpholino-9H-carbazole-1-carboxamide. MS (ESI) m/e+=422/424, m/e−=420/422 [1 Cl isotope pattern]. HPLC retention time 7.34 min. (Sunfire C18 3.5 μm, 3.0×150 mm column, 15 min gradient, 10-100% B, 0.5 mL/min. Solvent A: 5% CH3CN—95% H2O—0.1% TFA; Solvent B: 95% CH3CN—5% H2O—0.1% TFA). 1H NMR (DMSO-d6) δ ppm 11.13 (s, 1H), 10.22 (b, 1H), 8.45 (d, 1H, J=1.5), 8.32 (b, 1H), 8.11 (d, 1H, J=1.7), 8.07 (d, 1H, J=8.8), 7.89 (d, 1H, J=2.3), 7.67 (dd, 1H, J=8.5, 2.3), 7.50 (b, 1H), 7.27 (d, 1H, J=1.0), 7.09 (d, 1H, J=8.5), 6.97 (dd, 1H, J=8.7, 1.7), 3.86-3.79 (m, 4H), 3.25-3.19 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:15]=2)[CH:10]=[CH:9][C:8]=1[OH:24])[CH3:2].[Br:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:15]=2)[CH:10]=[CH:9][C:8]=1[O:24][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][Br:26])[CH3:2]
Reactant: BrCCCCCBr
Reactant: CCOC(=O)CCc1c(O)ccc2ccc(OCC(=O)OCC)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCc1c(OCCCCCBr)ccc2ccc(OCC(=O)OCC)cc12
Temperature: 65 °C
Reaction time: 17.5 h
Yield: 74.4 %

Procedure:
A mixture of 1.08 g (3.12 mmol) of 7-(2-ethoxy-2-oxoethoxy)-2-hydroxy-1-naphthalenepropanoic acid ethyl ester from the preceding example, 4.31 g (18.7 mmol) of 1,5-dibromopentane, 2.59 g (18.7 mmol) of anhydrous granular potassium carbonate, and 70 mL of 2-butanone was heated at 65° C. for 24 hr. After being cooled to room temperature, the mixture was filtered through anhydrous magnesium sulfate. The solids were washed thoroughly with ethyl acetate and the filtrate and the washes were combined and concentrated in vacuo. To the residue was added 60 mL of ethanol and 1 mL of concentrated sulfuric acid and the resulting solution was stirred at room temperature for 17.5 hr. Most of the ethanol was removed under reduced pressure and the residue was flash chromatographed on 110 g of silica gel, eluting with hexane-ethyl acetate (6:1) to give 1.15 g (74.4%) of the title compound as an off-white, waxy solid, mp 29.5°-32° C.
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[CH2:7]([OH:19])[CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18].C(I)C=C>C1COCC1>[CH2:1]=[CH:2][CH2:3][O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][OH:19]
Reactant: CC(C)(C)[O-]
Reactant: OCCOCCOCCOCCO
Agent: C=CCI
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCOCCOCCOCCOCCO
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
2.3 g (19.5 mmol) Potassium tert-butoxide is dissolved in 500 mL dry THF, and 7.18 g (37 mmol) tetraethylene glycol is added dropwise. After stirring for 30 min, a solution of 3.31 g (19.7 mmol) allyl iodide in 60 mL dry THF is added over 1 h, and stirring is continued for 24 h. The crude mixture is filtered over silica gel and the solvent removed in vacuo. The product is purified by silica gel chromatography (gradient: petrol ether/ethyl acetate 10:1→ethyl acetate), yielding 2.41 g 22 (10.3 mmol, 27%) as a colorless liquid.
Reaction SMILES: [N+:1](=[C:3]([C:17]([CH3:19])=[O:18])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-:2].C(N(CC)CC)C.[CH3:27][Si:28](Cl)([CH3:30])[CH3:29].[I-].[Na+]>C(#N)C>[N+:1](=[C:3]([C:17]([O:18][Si:28]([CH3:30])([CH3:29])[CH3:27])=[CH2:19])[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)=[O:5])=[N-:2]
Reactant: C[Si](C)(C)Cl
Reactant: CC(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=C(O[Si](C)(C)C)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 90.2 %

Procedure:
To 1.5 ml of dry acetonitrile were added 100 mg (0.380 millimole) of p-nitrobenzyl 2-diazoacetoacetate, 64.8 μl (0.465 millimole) of triethylamine and 59 μl (0.465 millimole) of trimethylsilyl chloride. A solution obtained by dissolving 70 mg (0.467 millimole) of sodium iodide in 0.5 ml of dry acetonitrile was added dropwise thereto at a room temperature. After agitation for an hour, the reaction mixture was concentrated under a reduced pressure. After addition of 5 ml of hexane, insoluble materials were filtered off and the hexane was distilled off under a reduced pressure to give 115 mg (yield 90.1 %) of the desired compound in a yellow solid.