Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1.C1C=CC2OC(=O)CCC=2C=1.O1C2C(=CC=CC=2)C=CC1=O.[Cl:35][S:36](O)(=[O:38])=[O:37].P(Cl)(Cl)(Cl)(Cl)Cl>ClCCl.CCCCCC>[CH3:1][C:2]1([CH3:12])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:36]([Cl:35])(=[O:38])=[O:37])[CH:8]=2)[O:3]1
Reactant: CC1(C)C=Cc2ccccc2O1
Reactant: O=S(=O)(O)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C1CCc2ccccc2O1
Agent: O=c1ccc2ccccc2o1
Solvent: ClCCl
Solvent: CCCCCC
Product: CC1(C)CCc2cc(S(=O)(=O)Cl)ccc2O1
Temperature: 5 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
A solution of 2,2-dimethylchroman [obtained by an analogous procedure to that described in Chem. Ber., 1904, 37, 494, for the preparation of 2,2-dimethyl-2H-chromene, but using dihydrocoumarin as starting material in place of coumarin] (50 g, 308 mM) in dichloromethane (250 ml) was added dropwise to a solution of chlorosulphonic acid (40 ml, 602 mM) and phosphorus pentachloride (50 g, 204 mM) in dichloromethane (250 ml), cooled to 5° C. under an atmosphere of argon. The colour of the solution changed from pale yellow to orange. When the addition was complete, the mixture was slowly allowed to attain ambient temperature and stirred for 2 hours. The reaction mixture was poured onto ice-water and the organic phase was separated. The aqueous layer was extracted with dichloromethane (3×20 ml), and the combined organic extracts were washed with water and dried (MgSO4). The solvent was removed by evaporation to give 2,2-dimethylchroman-6-sulphonyl chloride as a pale purple solid (42.6 g, 53% yield), m.p. 89°-92° C. (after recrystallisation from hexane).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:9]=[C:10]1[N:14]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]3(C#N)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:17][CH2:16]2)[C:13]2[CH:29]=[CH:30][CH:31]=[CH:32][C:12]=2[NH:11]1.[NH4+].[Cl-].O>C1COCC1>[C:1]1([C:21]2([N:18]3[CH2:19][CH2:20][CH:15]([N:14]4[C:13]5[CH:29]=[CH:30][CH:31]=[CH:32][C:12]=5[NH:11][C:10]4=[O:9])[CH2:16][CH2:17]3)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: N#CC1(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]c2ccccc2n1C1CCN(C2(c3ccccc3)CCCCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.1 %

Procedure:
To a solution of phenylmagnesium bromide (3M solution in diethyl ether, 0.75 ml, 2.25 mmol) in THF (1 ml) was added a suspension of 1-[4-(2-oxo-2,3-dihydro-1H-1,3-benzimidazol-1-yl)piperidino]-1-cyclohexanecarbonitrile (230 mg, 0.71 mmol) in THF (2 ml) at 0° C. Then the reaction mixture was stirred at room temperature for 18 h. To the reaction mixture was added sat.NH4Cl aq. solution (1 ml) followed by addition of water (5 ml). The white precipitate appeared was collected by filtration, washed faith water and CH2Cl2, and dried to give 75 mg (28.1%) of title compound. The filtrate of CH2Cl2 wash was concentrated to give 171 mg of title compound and the starting material mixture, which was purified by column chromatography (silica gel:30 g, CH2Cl2/MeOH:50/1 to 15/1) to give 60 mg(22.5%) of title compound as white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:23])[CH2:12][C:13]2[CH:18]=[C:17]([Br:19])[C:16]([O:20][CH3:21])=[C:15]([Br:22])[CH:14]=2)=[CH:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:25]([O:24][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:23])[CH2:12][C:13]2[CH:18]=[C:17]([Br:19])[C:16]([O:20][CH3:21])=[C:15]([Br:22])[CH:14]=2)[CH:6]=[CH:7][C:2]=1[NH:1][S:38]([C:35]1[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=1)(=[O:40])=[O:39])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1c(Br)cc(CC(=O)NCCc2ccc(N)c(OCc3ccccc3)c2)cc1Br
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1c(Br)cc(CC(=O)NCCc2ccc(NS(=O)(=O)c3ccc(C)cc3)c(OCc3ccccc3)c2)cc1Br
Temperature: 25 °C
Reaction time: 54 h

Procedure:
To a solution of N-[2-(4-amino-3-benzyloxy-phenyl)-ethyl]-2-(3,5-dibromo-4-methoxy-phenyl)-acetamide (0.836 g, 0.00152 mol) and p-toluenesulfonyl chloride (0.440 g, 0.00231 mol) in 40 mL of methylene chloride qas added 4 mL of pyridine. The reaction mixture was stirred for 54 h at room temperature, washed with 1N HCl, 1N NaOH solutions, dried over Na2SO4 and evaporated. A residue was crystallized from ethyl acetate-hexanes mixture. Yield 0.933 g (87%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]=[CH:9][CH2:8]2)(=[O:3])[CH3:2].ClC1C=C(C=CC=1)C(O)=[O:20].[OH-].[Na+]>ClCCl>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]1[O:20][CH:9]1[CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2c(c1)CC=CC2
Reactant: O=C(O)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)Oc1ccc2c(c1)CC1OC1C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 116.8 %

Procedure:
A solution of 15.12 g of 1,4-dihydro-6-naphthol acetate in 160 ml of dichloromethane is cooled to 0° C while 10.5 g of m-chlorobenzoic acid is added over 10 minutes. The mixture is stirred overnight at room temperature and then poured into a slurry of 100 g of ice and 50 ml of 10% aqueous sodium hydroxide. The layers are separated, the aqueous layer re-extracted with dichloromethane (two 100 ml portions), and the combined extracts are washed with water, dried, and evaporated in vacuo to give 16 g of the title compound as a yellow liquid.
Reaction SMILES: [OH:1][C:2]([C:10]1[N:15]=[C:14]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH:13]=[CH:12][CH:11]=1)([C:5]1[S:6][CH:7]=[CH:8][N:9]=1)[CH2:3][CH3:4].[CH3:25]I>C1COCC1>[CH3:25][O:1][C:2]([C:10]1[N:15]=[C:14]([CH2:16][O:17][Si:18]([C:21]([CH3:23])([CH3:22])[CH3:24])([CH3:19])[CH3:20])[CH:13]=[CH:12][CH:11]=1)([C:5]1[S:6][CH:7]=[CH:8][N:9]=1)[CH2:3][CH3:4]
Reactant: CCC(O)(c1cccc(CO[Si](C)(C)C(C)(C)C)n1)c1nccs1
Reactant: CI
Solvent: C1CCOC1
Product: CCC(OC)(c1cccc(CO[Si](C)(C)C(C)(C)C)n1)c1nccs1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 156.1 %

Procedure:
To a solution of alcohol from Step 1 (740 mg, 2.03 mmol) in 20 mL THF at 0° C. was added KH (466 mg, 4.06 mmol, 35% in oil). After 10 min. MeI (1.44 g, 10.1 mmol) was added dropwise. The solution was stirred for 30 min. at 0° C., then poured into an aqueous saturated NH4C1. The aqueous layer was extracted with EtOAc (3×25 mL) and the combined organic layers were washed with brine and dried over anhydrous MgSO4. Evaporation of the solvent and flash chromatography on silica gel (hexane:EtOAc=9:1) gave the title compound (1.2 g) which was used directly in the next step.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].F[C:11](F)(F)[C:12](O)=O.C1(=O)OC(=O)C[C@@H]1O>C(O)C>[CH2:11]([O:8][C:1](=[O:9])[C@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3])[CH3:12]
Reactant: O=C(O)C[C@H](O)C(=O)O
Reactant: O=C(O)C(F)(F)F
Agent: O=C1C[C@H](O)C(=O)O1
Solvent: CCO
Product: CCOC(=O)[C@@H](O)CC(=O)O
Yield: 98.7 %

Procedure:
By using the reagents, procedures and conditions described by Example 3A L-malic acid was converted to L-malic anhydride trifluoroacetate and the latter was allowed to react with ethyl alcohol to provide in 98.7% yield L-malic acid monoethyl ester melting at about 48° to about 49.5° C.
Reaction SMILES: [CH2:1]([N:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:7][C:6]1=[O:23])[CH2:2][CH2:3][CH3:4].[Cl:24]N1C(=O)CCC1=O>C(Cl)Cl>[CH2:1]([N:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:12][CH2:13][CH:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:15][CH2:16]2)=[C:7]([Cl:24])[C:6]1=[O:23])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1ccc(N2CCC(c3ccccc3)CC2)cc1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CCCCn1ccc(N2CCC(c3ccccc3)CC2)c(Cl)c1=O
Yield: 80.8 %

Procedure:
A solution of intermediate D19 (0.43 g, 1.40 mmol) and N-chlorosuccinimide (0.19 g, 1.40 mmol) in DCM (10 ml) was stirred at room temperature for 1 hour. The solvent was evaporated in vacuo and the crude product was purified by column chromatography (silica gel; 0-3% methanol/DCM as eluent). The desired fractions were collected and evaporated in vacuo and the resulting solid was recrystallized from diethyl ether to yield compound E2 (0.39 g, 82%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=1[C:12]1[N:13]=[C:14]([NH:17][C:18]([C:20]2[N:21]([CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])[C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[S:15][CH:16]=1.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C1(OC)C=CC=CC=1>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[CH3:11][O:10][C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[C:12]1[N:13]=[C:14]([NH:17][C:18]([C:20]2[N:21]([CH2:29][C:30]([OH:32])=[O:31])[C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[S:15][CH:16]=1
Reactant: COc1cc(C)cc(OC)c1-c1csc(NC(=O)c2cc3ccccc3n2CC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COc1cc(C)cc(OC)c1-c1csc(NC(=O)c2cc3ccccc3n2CC(=O)O)n1

Procedure:
1.07 g of N-[4-(2,6-dimethoxy-4-methylphenyl)-2-thiazolyl]-1-(tert-butoxycarbonylmethyl)indole-2-carboxamide (prepared according to EP-A-0,432,040) are dissolved in a mixture of 2 ml of anisole and 20 ml of TFA. The reaction mixture is left for 3/4 hour at r.t. and then concentrated under vacuum. The residue is taken up in ether, and the precipitate is then filtered off and dried in an oven to obtain 1.13 g of the expected compound; m.p.=223°-224° C.
Reaction SMILES: Cl[CH:2]([C:7](=O)[C:8]([O:12]C)(OC)[CH3:9])[C:3]([O:5][CH3:6])=[O:4].[NH2:15][C:16]([NH2:18])=[S:17]>CCO>[C:8]([C:7]1[N:15]=[C:16]([NH2:18])[S:17][C:2]=1[C:3]([O:5][CH3:6])=[O:4])(=[O:12])[CH3:9]
Reactant: COC(=O)C(Cl)C(=O)C(C)(OC)OC
Reactant: NC(N)=S
Solvent: CCO
Product: COC(=O)c1sc(N)nc1C(C)=O

Procedure:
A solution of 4.37 g (19 mmol) methyl 2-chloro-4,4-dimethoxy-3-oxopentanoate (Intermediate 221) and 1.8 g (24 mmol) thiourea in 50 ml EtOH was heated at reflux for 3 h. Solvent was removed and the residue was dissolved in 1:1 acetone-5N HCl and the solution was heated at reflux for 4 h. Acetone was removed and the aqueous residue was neutralized with 50% NaOH and then basified with aqueous Na2CO3. Precipitated solids were filtered, washed with water and dried in vacuo. NMR (d6-DMSO): 2.4 (s, 3H), 3.7 (s, 3H), 8.0 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[CH:13]1[C:18]([NH:19][NH2:20])=[CH:17][CH:16]=[C:15]([S:21]([NH2:24])(=[O:23])=[O:22])[CH:14]=1.Cl>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:20][NH:19][C:18]1[CH:17]=[CH:16][C:15]([S:21]([NH2:24])(=[O:22])=[O:23])=[CH:14][CH:13]=1
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: Cc1ccc2c(c1)C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2
Yield: 86 %

Procedure:
The title compound was prepared from 5-methyl-1H-indole-2,3-dione (Gassman, et al., Journal of Organic Chemistry 1977, 42, 1344–8) and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G in 86% yield: 1H NMR (DMSO-d6): δ 2.3 (s, 3H), 6.76 (d, J=7.9 Hz, 1H), 7.11 (d, J=7.9 Hz, 1H), 7.20 (s, 2H), 7.57 (d, J=8.8 Hz, 2H), 7.77 (d, J=8.8 Hz, 2H), 8.02 (s, 1H), 10.51 (s, 1H), 10.62 (s, 1H); APCI-MS m/z 329 (M−1)−. Anal. Calcd for C15H14N4O3S: C, 54.54, H, 4.27; N, 16.96; S, 9.71. Found C, 54.54, H, 4.32; N, 16.87; S, 9.62.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C@@H:14]([OH:17])[C@H:13]([F:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH2:25]([C:29]1[N:30]=[N:31][C:32](Cl)=[CH:33][C:34]=1[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:37][CH:36]=1)[CH2:26][CH2:27][CH3:28]>C1COCC1.CCOC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C@@H:14]([O:17][C:32]2[N:31]=[N:30][C:29]([CH2:25][CH2:26][CH2:27][CH3:28])=[C:34]([C:35]3[CH:36]=[CH:37][C:38]([O:41][CH:42]4[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]4)=[CH:39][CH:40]=3)[CH:33]=2)[C@H:13]([F:18])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](O)[C@H](F)C1
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OC2CCCCC2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nnc(O[C@@H]2CCN(C(=O)OCc3ccccc3)C[C@H]2F)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
To a stirred solution of (±)-trans-3-fluoro-4-hydroxy-piperidine-1-carboxylic acid benzyl ester (100 mg, 0.4 mmol) at 0° C. in THF (2 mL) was added potassium tert-butoxide (1.0 M in THF, 0.5 mmol, 0.5 mL). After 15 min 3-butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine (120 mg, 0.34 mmol) in THF (2 mL) was added. The solution was stirred overnight at 40° C., diluted with EtOAc and washed with water. The organics were dried over sodium sulfate, filtered, concentrated, and purified by column chromatography using 20-40% EtOAc in hexanes to provide (±)-trans-4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-3-fluoro-piperidine-1-carboxylic acid benzyl ester (65 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C@@H:29]([C:37]([CH3:40])([CH3:39])[CH3:38])/[CH:30]=[CH:31]/[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:9]=2)=[N:6][CH:7]=1.CCOC(C)=O.[H][H]>CO.[Pd]>[F:1][C:2]1[C:3]([NH:28][C@@H:29]([C:37]([CH3:38])([CH3:40])[CH3:39])[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=3)(=[O:20])=[O:19])[CH:9]=2)=[N:6][CH:7]=1
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/[C@@H](Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F)C(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)CC[C@@H](Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F)C(C)(C)C

Procedure:
To a nitrogen purged flask charged with 10% Pd/C (0.033 g, 0.310 mmol) was added enough methanol to cover the catalyst. To this mixture was added a solution of (R,E)-ethyl 4-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5,5-dimethylhex-2-enoate, 38a, (0.330 g, 0.579 mmol) in MeOH. Note, a small amount of EtOAc was added to fully solubilize the starting material. The reaction mixture was then stirred under 1 atmosphere of hydrogen for 3 hours. LCMS shows presence of significant amounts of starting material. The contents of the reaction mixture were transferred to a pressure vessel containing a fresh source of palladium (0.033 g, 0.310 mmol). The reaction mixture was stirred in a Parr hydrogenation flask under 46 psi of hydrogen overnight. The mixture was diluted with methanol and filtered through celite. The filtrate was concentrated in vacuo to afford 331 mg of the desired product that was used without further purification: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=3.75 minutes (M+H) 572.35.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([CH2:13][O:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[CH:12]=1.[CH3:25][C:26]([CH3:28])=[O:27]>C1(C)C=CC=CC=1>[CH:16]([Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[O:14][CH2:13][C:11]1[CH:12]=[C:7]([C:26]([OH:27])([CH3:28])[CH3:25])[CH:8]=[N:9][CH:10]=1)([CH3:18])[CH3:17]
Reactant: CC(C)=O
Reactant: CC(C)[Si](OCc1cncc(Br)c1)(C(C)C)C(C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC(C)[Si](OCc1cncc(C(C)(C)O)c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.38 h
Yield: 94.7 %

Procedure:
Toluene (30 mL) in a 3-necked flask was cooled down to −78° C. n-BuLi (1.6 M in hexane, 8.35 mL, 0.13.35 mmol) was slowly added to the toluene. After 10 minutes a solution of the 3-bromo-5-((triisopropylsilyloxy)methyl)pyridine (4.0 g, 11.62 mmol) in toluene (30 mL) was added dropwise. A yellow solid precipitated. The resulting slurry was aged for 15-30 min, then THF (20 mL) was added slowly, keeping the internal temperature at <−50° C. The mixture was aged for 15 min, then acetone (1.7 mL, 23.24 mmol) was added over 2 min. The solids dissolved and a brown homogeneous solution was obtained. The reaction solution was warmed to rt and quenched with saturated aqueous NH4Cl and diluted with EtOAc. The phases were separated and aqueous layer was extracted with EtOAc twice. The organic layers were combined and concentrated to dryness. Purification by flash chromatography (silica gel, hexanes/EtOAc) gave 2-(5-((triisopropylsilyloxy)methyl)pyridin-3-yl)propan-2-ol as a light yellow solid (3.56 g, 96%). 1H NMR (CDCl3): d: 1.250-1.055 (m, 21H), 1.606 (s, 6H), 4.865 (s, 2H), 7.830 (s, 1H), 8.458 (s, 1H), 8.621 (s, 1H).
Reaction SMILES: [C:1]12([C:9]3[CH:10]=[C:11]([N:19]4[C:23]([NH2:24])=[N:22][C:21]([NH:25][C:26]5[CH:27]=[CH:28][C:29]6[CH2:35][CH2:34][C@H:33]([NH:36]C(OC(C)(C)C)=O)[CH2:32][CH2:31][C:30]=6[CH:44]=5)=[N:20]4)[N:12]=[C:13]4[C:18]=3[NH:17][CH2:16][CH2:15][CH2:14]4)[CH2:8][CH2:7][C:4]([CH:5]=[CH:6]1)=[CH:3][CH2:2]2.Cl.CO.[OH-].[Na+]>O1CCOCC1>[C:1]12([C:9]3[CH:10]=[C:11]([N:19]4[C:23]([NH2:24])=[N:22][C:21]([NH:25][C:26]5[CH:27]=[CH:28][C:29]6[CH2:35][CH2:34][C@H:33]([NH2:36])[CH2:32][CH2:31][C:30]=6[CH:44]=5)=[N:20]4)[N:12]=[C:13]4[C:18]=3[NH:17][CH2:16][CH2:15][CH2:14]4)[CH2:8][CH2:7][C:4]([CH:3]=[CH:2]1)=[CH:5][CH2:6]2
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2ccc(Nc3nc(N)n(-c4cc(C56C=CC(=CC5)CC6)c5c(n4)CCCN5)n3)cc2CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: Nc1nc(Nc2ccc3c(c2)CC[C@@H](N)CC3)nn1-c1cc(C23C=CC(=CC2)CC3)c2c(n1)CCCN2
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.8 %

Procedure:
(7S)-1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N3-(7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine (23 mg, 0.038 mmol) was added to a 4M solution of HCl in dioxane. In order to improve solubility, 2 mL of MeOH were added which resulted in a clear solution. The reaction mixture was stirred for 6 h at ambient temperature and then neutralized with 2M NaOH which caused the precipitation of the free amine. The product was filtered off, washed with water and dried over night in HV to yield the amino compound, (7S)-1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N3-(7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine (18 mg, 96%). The product was then dissolved in dry DCM. Subsequently, acetaldehyde (˜5 mg, 0.1 mmol) and NaBH(OAc)3 (21 mg, 0.1 mmol) were added. After the mixture was stirred for 2 d at ambient temperature, the solvents were evaporated and the desired product, (7S)-1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N3-(7-(diethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine, compound #35, was isolated via reverse phase HPLC (10.8 mg, 52% two steps); 1H NMR (DMSO-d6, 300 MHz): 9.04 (s, 1H), 8.69 (s br, 1H), 7.75 (s br, 2H), 7.54-7.66 (m, 5H), 7.41 (d, 1H), 7.26 (s, 1H), 7.01 (d, 1H), 2.87-3.18 (m, 8H), 2.60-2.81 (m, 4H), 2.51-2.55 (m, 2H), 2.00-2.28 (m, 4H), 1.66-1.87 (m, 2H), 1.30-1.56 (m, 2H), 1.12-1.28 (m, 6H) ppm; MS (ES) 549.22 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=1[O:26][CH2:27][CH2:28][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2].[C:40](Cl)(=[O:42])[CH3:41].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:39])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:40](=[O:42])[CH3:41])=[CH:21][C:20]=1[O:26][CH2:27][CH2:28][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(N)cc1OCCc1cccc2ccccc12
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(C)=O)cc1OCCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
To a solution of 3-[4-amino-2-(2-naphthalen-1-yl-ethoxy)-benzenesulfonylamino]-N-methoxy-N-methyl-succinamic acid tert-butyl ester (300 mg, 0.54 mmol) and acetyl chloride (45 mg, 0.57 mg) in methylene chloride (10 mL) was added triethylamine (58 mg, 0.57 mmol) and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was taken up in ethyl acetate (50 mL). The resulting solution was extracted with 0.1N HCl (50 mL) and brine (50 mL), dried (MgSO4), and evaporated to give 3-(4-acetylamino-2-(2-naphthalen-1-yl-ethoxy)-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester (300 mg) as an amorphous solid.
Reaction SMILES: [NH:1]1[C:7]2=[C:8]3[C:13](=[N:14][C:15]4=[CH:16][CH:17]=[CH:18][C:5](=[C:6]24)[O:4][CH2:3][C:2]1=[O:19])[CH2:12][CH2:11][CH2:10][CH2:9]3.[CH3:20][C:21](C)([O-])[CH3:22].[K+].BrCCC>O1CCCC1>[CH2:20]([N:1]1[C:7]2=[C:8]3[C:13](=[N:14][C:15]4=[CH:16][CH:17]=[CH:18][C:5](=[C:6]24)[O:4][CH2:3][C:2]1=[O:19])[CH2:12][CH2:11][CH2:10][CH2:9]3)[CH2:21][CH3:22]
Reactant: CC(C)(C)[O-]
Reactant: O=C1COc2cccc3nc4c(c(c23)N1)CCCC4
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCBr
Product: CCCN1C(=O)COc2cccc3nc4c(c1c23)CCCC4
Reaction time: 0.25 h
Yield: 76.2 %

Procedure:
To a suspension of 1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (4.94 g) in dry tetrahydrofuran (150 ml) was added potassium tert-butoxide (2.62 g). The mixture was stirred for 15 mins, 1-bromopropane (7.07 ml) was added, and the reaction mixture was refluxed overnight. The reaction mixture was concentrated, diluted with saturated potassium carbonate solution, and extracted with ethyl acetate. The organic extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was to adhered to adhered to silica, and flash chromatographed (30% ethyl acetate/hexane). The appropriate fractions were evaporated and the residue was triturated with diethyl ether to yield 4.39 g (76%) of 1,3,9,10,11,12-hexahydro-1-propyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N+:6]([O-])=[CH:7][CH:8]=1.P([C:24]#[N:25])(=O)(OCC)OCC.C(N(CC)CC)C>C(#N)C>[CH3:1][S:2][C:3]1[CH:8]=[C:7]([C:24]#[N:25])[N:6]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:4]=1
Reactant: CSc1cc[n+]([O-])c(-c2ccccn2)c1
Reactant: CCOP(=O)(C#N)OCC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CSc1cc(C#N)nc(-c2ccccn2)c1
Yield: 72 %

Procedure:
4-Methylsulfanyl-[2,2′]bipyridinyl 1-oxide (480 mg, 2.20 mmol) was treated under nitrogen with diethyl phosphorocyanidate and triethylamine in dry acetonitrile following a described procedure (I. Antonioni; G. Cristalli; P. Franchetti; M. Grifantini; S. Martelli, Il Farmaco, 1986, 41, 346-354). Crystallization in ethyl acetate afforded 4-methylsulfanyl-[2,2′]bipyridinyl-6-carbonitrile as a white solid (360 mg, 72% yield)