Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][CH3:4])[CH3:2].CS(O[CH2:10][CH2:11][CH2:12][N:13]([C:15]([O:17][CH:18]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]/[CH:45]=[CH:46]\[CH2:47]/[CH:48]=[CH:49]\[CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:16])[CH3:14])(=O)=O>CCO.C(Cl)Cl>[CH2:1]([N:3]([CH3:4])[CH2:10][CH2:11][CH2:12][N:13]([CH3:14])[C:15](=[O:16])[O:17][CH:18]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]/[CH:45]=[CH:46]\[CH2:47]/[CH:48]=[CH:49]\[CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH3:2]
Reactant: CCNC
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(CCCCCCCC/C=C\C/C=C\CCCCC)OC(=O)N(C)CCCOS(C)(=O)=O
Solvent: ClCCl
Solvent: CCO
Product: CCCCC/C=C\C/C=C\CCCCCCCCC(CCCCCCCC/C=C\C/C=C\CCCCC)OC(=O)N(C)CCCN(C)CC
Reaction time: 50 h
Yield: 64 %

Procedure:
A solution of ethylmethylamine (2 mL) in EtOH (10 mL) was treated with 3-((((6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yloxy)carbonyl)(methyl)amino)propyl methanesulfonate (500 mg, 0.7 mmol) in CH2Cl2 (2.5 mL). The solution was stirred (50 h), concentrated and subjected to chromatography (EtOAc) to yield (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl (3-(ethyl(methyl)amino)propyl)(methyl)carbamate (305 mg, 64%) as a pale yellow oil. Rf 0.41 (10% CH3OH—CH2Cl2), 1H NMR (400 MHz, CDCl3, δH) 5.47-5.34 (m, 8H, C═CH×8), 4.81-4.75 (m, 1H, CHO2CNR2), 3.33 (br. s, 2H, CH2NCH3), 2.94 (br. s, 3H, CO2NCH3), 2.83 (app. t, 4H), 2.45 (q, 2H, N(CH3)CH2CH3), 2.37 (t, 2H, CH2N(CH3)CH2CH3), 2.25 (s, 3H, N(CH3)CH2CH3), 2.14-2.07 (m, 8H, CH2HC═C×4), 1.81-1.70 (m, 4H, CH2×2), 1.62-1.50 (m, 4H, CH2×2), 1.46-1.25 (m, 34H, CH2×17), 1.09 (t, 3H, CH3NCH2CH3), 0.93 (t, 6H, H3×2), FW 685.16, C45H84N2O2.
Reaction SMILES: [CH2:1]([Si:3]([CH2:35][CH3:36])([CH2:33][CH3:34])[O:4][CH:5]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][CH:27]=[CH:26]2)[CH2:6][C:7](N1[C@@H]2CC3C(C)(C)C2(CC3)CS1(=O)=O)=[O:8])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl.CCCCCC>[CH2:35]([Si:3]([CH2:1][CH3:2])([CH2:33][CH3:34])[O:4][C@H:5]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][CH:27]=[CH:26]2)[CH2:6][CH:7]=[O:8])[CH3:36]
Reactant: CC[Si](CC)(CC)OC(CC(=O)N1[C@@H]2CC3CCC2(CS1(=O)=O)C3(C)C)c1ccc2ncccc2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: CCCCCC
Product: CC[Si](CC)(CC)O[C@@H](CC=O)c1ccc2ncccc2c1
Temperature: -78 °C
Reaction time: 6 h

Procedure:
A solution of (2R)-N-[3-(triethylsilyloxy)-3-(6-quinolyl)-propionyl]bornane-10,2-sultam (52.8 gm) in 1000 mL of CH2Cl2 is cooled to −78° C., and a 1.0 M solution of diisobutylaluminum hydride in hexane is added dropwise so as to keep the reaction temperature below −65° C. The mixture is stirred for an additional 6 hours at −78° C., then is quenched by addition of sat. aq. NH4Cl and allowed to warm to ambient temperature. The mixture is washed with brine, and the organic phase is dried over MgSO4, filtered, and evaporated. The product is purified by silica gel chromatography.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][C:10]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=2)([C:13]([F:16])([F:15])[F:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>O1CCCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:17]2[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([Cl:23])[CH:22]=2)([C:13]([F:16])([F:15])[F:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)C=CN(Cc2ccccc2)C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CCN(Cc2ccccc2)C1
Yield: 88.3 %

Procedure:
1-Benzyl-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-2,3-dihydro-1H-pyrrole (100 mg, 90% purity, 242 μmol) was dissolved in tetrahydrofurane (2 mL) and sodium borohydride (26.0 mg, 677 μmol) was added at room temperature. After 30 minutes at room temperature the reaction mixture was acidified with hydrochloric acid (3.6%) and extracted twice with dichloromethane. The combined organic phases were washed with water, dried over sodium sulfate, filtered and the solvents evaporated. This procedure yielded 1-benzyl-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine (80.0 mg, 79% purity, 70% yield).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][C:10]=1[C:18]([F:21])([F:20])[F:19].Cl.[CH3:23][NH:24][OH:25]>C(Cl)(Cl)Cl>[CH3:23][N:24]([OH:25])[C:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([Cl:8])=[C:10]([C:18]([F:19])([F:20])[F:21])[CH:11]=1)=[O:17]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(O)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 68.9 %

Procedure:
33 ml of triethylamine and then 44.3 g of 4-chloro-3-trifluoromethylphenyl isocyanate in 200 ml of chloroform were added to a mixture of 21 g of N-methyl hydroxylamine hydrochloride and 200 ml of chloroform at 0° C and the mixture was stirred at 20° C for 16 hours. The mixture was washed with water and was reduced to a volume of 100 ml under reduced pressure. The mixture was iced and vacuum filtered. The crystals were washed with water and dried to obtain 37 g of N-methyl-N-hydroxy-N'-(4'-chloro-3'-trifluoromethylphenyl)-urea melting at 114°-115° C.
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[C:4]#[C:5][CH3:6].[CH2:8]([NH:10][NH2:11])[CH3:9]>C(O)CCC.O>[CH2:8]([N:10]1[C:5]([CH3:6])=[CH:4][C:3]([CH2:2][CH3:1])=[N:11]1)[CH3:9]
Reactant: CCNN
Reactant: CC#CC(=O)CC
Solvent: CCCCO
Solvent: O
Product: CCc1cc(C)n(CC)n1
Temperature: 25 °C

Procedure:
A solution of 18.9 g (0.2 mol) of hex-4-yn-3-one (from Step B) in 120 mL of n-butanol was treated with 40 mL (0.227 mol) of ethyl hydrazine, 34% solution in water. The resulting mixture was heated at reflux for 1.5 h, then cooled to rt. The mixture was concentrated to ˜150 μL volume; this was partitioned between 1 L of ether and 250 mL of water. The layers were separated and the organic layer was dried and concentrated to afford the title compound, which was used without further purification. 1H-NMR (400 MHz) δ 1.22 (t, J=7.6, 3H), 1.37 (t, J=7.2, 3H), 2.23 (s, 3H), 2.59 (q, J=7.6, 2H), 4.01 (q, J=7.2, 2H), 5.81 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:12][CH3:13])[C:5](=[CH:9][C:10]=1[CH3:11])[C:6]([OH:8])=O.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(O)(=O)C>[OH:8][C:6]1[C:5]2[C:4](=[CH:3][C:2]([CH3:1])=[C:10]([CH3:11])[CH:9]=2)[N:12]([CH3:13])[C:14](=[O:16])[CH:15]=1
Reactant: CNc1cc(C)c(C)cc1C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1cc2c(O)cc(=O)n(C)c2cc1C

Procedure:
To a solution of 4,5-dimethyl-N-methyl anthranilic acid (30.0g.; 0.168 mole; m.p. 190° - 191° C) in glacial acetic acid (75 ml.) was added acetic anhydride (75 ml.) and the mixture was refluxed for 4 hrs. After cooling the dark solution was poured onto crushed ice, made alkaline (pH 9), and filtered. On bringing the filtrate to pH5 with concentrated hydrochloric acid the title product separated as a white solid, m.p. (EtOH) 300° - 305° C (Found: C, 70.12; H, 6.30; N, 7.12; C12H13NO2 requires; C, 70.92; H, 6.45; N, 6.89%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[S:20][C:21](Br)=[CH:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[S:20][C:21]([C:31]3[CH:30]=[CH:29][CH:28]=[C:27]([C:26]([F:37])([F:36])[F:25])[CH:32]=3)=[CH:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CC(NC(=O)c1ccc(Br)s1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CC(NC(=O)c1ccc(-c2cccc(C(F)(F)F)c2)s1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 69.4 %

Procedure:
5-Bromo-thiophene-2-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.12 mmol) was reacted with 3-trifluoromethyl phenyl boronic acid (42 mg, 0.23 mmol) as described in example 60 to give the title compound (42 mg, 77%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[CH:25]=O.[BH4-].[Na+].O>C(O)C>[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[CH2:25][NH:14][CH2:13][CH2:12][CH2:11][N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:25][C:16]2[CH:17]=[CH:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]=2)[CH2:10][CH2:9]1
Reactant: NCCCN1CCN(CCCN)CC1
Reactant: O=Cc1ccc2ccccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1ccc2cc(CNCCCN3CCN(CCCNCc4ccc5ccccc5c4)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1,4-bis(3-aminopropyl)piperazine (0.513 mL, 2.49 mmol) and 2-naphtaldehyde (818 mg, 5.24 mmol) in absolute ethanol (20 mL) was added 3 Å molecular sieves (5 g). After stirring the mixture for 12 h at room temperature, sodium borohydride (1.9 g, 49.9 mmol) was added and the mixture was stirred for 12 h at room temperature. Then the reaction mixture was quentched by dropwise addition of water (20 mL) and ethanol was removed under reduced pressure. The aqueous residue was extracted with CH2Cl2 (3×30 mL) and the combined organic layers were extracted with HCl 1N (2×50 mL). The combined aqueous layers were neutralized with NaOH 1N (50 mL) and extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried over MgSO4, evaporated to dryness and the oily residue purified by flash chromatography (neutral aluminium oxide, CH2Cl2/MeOH: 90/10).
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7](C)[C:8](C)(C)[NH:9][C:10](=[O:11])[C:5]=2[S:4][C:3]=1[C:15]1[CH:16]=[N:17][NH:18][CH:19]=1.[ClH:20]>CO>[ClH:20].[ClH:20].[Br:1][C:2]1[C:6]([NH:7][CH3:8])=[C:5]([C:10]([NH2:9])=[O:11])[S:4][C:3]=1[C:15]1[CH:16]=[N:17][NH:18][CH:19]=1
Reactant: CN1c2c(sc(-c3cn[nH]c3)c2Br)C(=O)NC1(C)C
Agent: Cl
Solvent: CO
Product: CNc1c(C(N)=O)sc(-c2cn[nH]c2)c1Br
Temperature: 50 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
A mixture of 7-bromo-1,2,2-trimethyl-6-(1H-pyrazol-4-yl)-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (171 mg, 0.50 mmol), 1 M HCl (2.5 mL, 2.50 mmol) and MeOH (5 mL) was stirred at 50° C. for 1 h. The mixture was concentrated under reduced pressure to afford the title compound (182 mg, 97%) as a pale yellow solid. This material was used for the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[K+].[CH2:11](Cl)[C:12]#[CH:13].O>CN(C=O)C.CCOCC>[Cl:1][C:2]1[C:7]([O:8][CH2:13][C:12]#[CH:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C#CCCl
Reactant: Oc1cccnc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: C#CCOc1cccnc1Cl
Temperature: 15 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
To a solution of 15.6 g (0.12 mole) 2-chloro-3-pyridinol in 200 ml DMF were added 6.7 g (0.12 mole) powdered potassium hydroxide. After cooling to 15° C., 9.0 g (0.12 mole) propargyl chloride was added dropwise. This mixture was stirred at room temperature for 2 hrs., then 200 ml water and 400 ml ether were added. After agitating, the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated to leave 16.0 g crude product. Recrystallization from hexane gave 10.5 g pure 2-chloro-3-(2-propynyloxy)pyridine, mp 78°-79°.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][NH:13][C:12](=O)[C@@H:11]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:10]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1.C(=O)(O)[O-].[Na+].O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][NH:13][C:12](=[S:33])[C@@H:11]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2cccc(F)c2F)CNC1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2cccc(F)c2F)CNC1=S
Temperature: 40 °C
Reaction time: 16 h
Yield: 140.4 %

Procedure:
To a solution of tert-butyl [(3S,5S)-5-(2,3-difluorophenyl)-2-oxopiperidin-3-yl]carbamate (300 mg, 0.92 mmol) in toluene (9.2 mL) was added Lawesson's Reagent (190 mg, 0.47 mmol). The mixture was stirred at 40° C. After 16 h, the mixture was cooled to ambient temperature and saturated aqueous sodium bicarbonate was added. Water was added, and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase chromatography (C-18, 90% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (226 mg). MS 365.3 (M+Na).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:14]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:14]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:11]2[CH2:12][CH2:13][N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH2:9][CH2:10]2)[CH:15]=1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Reactant: Fc1cccc(N2CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: Fc1cccc(N2CCN(Cc3cccc(-c4ccccc4)c3)CC2)c1

Procedure:
113.2 mg of the target compound (0.33 mmol, 59.4%) was obtained using 1-(3-fluorophenyl)piperazine (198 mg, 1.10 mmol), biphenyl-3-carbaldehyde (100 mg, 0.55 mmol) and NaBH(OAc)3 (355 mg, 1.65 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:7]([C:9]1[C:10](=[O:27])[N:11]([CH3:26])[C:12]2[C:17]([C:18]=1[O:19][P:20]([CH2:24][CH3:25])([CH2:22][CH3:23])=[O:21])=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8].[N+]([O-])([O-])=O.[NH4+].[Ce].CC#N>>[C:28]1([NH:6][C:7]([C:9]2[C:10](=[O:27])[N:11]([CH3:26])[C:12]3[C:17]([C:18]=2[O:19][P:20]([CH2:24][CH3:25])([CH2:22][CH3:23])=[O:21])=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:8])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCP(=O)(CC)Oc1c(C(=O)N(Cc2ccc(OC)cc2OC)c2ccccc2)c(=O)n(C)c2ccccc12
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Product: CCP(=O)(CC)Oc1c(C(=O)Nc2ccccc2)c(=O)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
N-(2,4-dimethoxybenzyl)-N-phenyl-4-diethylphosphoryloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide (125 mg, 0.22 mmol) was added to a solution of cerium ammonium nitrate in 95% aq. MeCN (0.50 mmol, 0.1 M, 5.0 mL). The reaction mixture was stirred at room temperature for 1 h, concentrated at reduced pressure, and then partitioned between EtOAc and water. The organic phase was washed with water and brine, dried (Na2SO4), and concentrated at reduced pressure. The residue was purified by silica column chromatography (EtOAc) to give the title compound (45 mg, 49%).
Reaction SMILES: [CH3:1][C:2]([NH:13][CH2:14][C@@H:15]([C:17]1[CH:18]=[CH:19][C:20]2[N:21](N=N[N:25]=2)[CH:22]=1)[OH:16])([CH3:12])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.[ClH:26]>CO>[ClH:26].[ClH:26].[NH2:25][C:20]1[N:21]=[CH:22][C:17]([C@H:15]([CH2:14][NH:13][C:2]([CH3:12])([CH3:1])[CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=2)[OH:16])=[CH:18][CH:19]=1
Reactant: CC(C)(CCc1cccc(O)c1)NC[C@H](O)c1ccc2nnnn2c1
Agent: Cl
Solvent: CO
Product: CC(C)(CCc1cccc(O)c1)NC[C@H](O)c1ccc(N)nc1

Procedure:
A solution of 137 mg (0.40 mmol) of (R)-a-[[(1,1-dimethyl-3-(3-hydroxyphenyl)propyl)amino]methyl]tetrazolo[1,5-a]pyridine-6-methanol and 182 mg (0.81 mmol) of SnCl2 ·H2O in 20 ml of methanol was heated at reflux for 21 hours. The reaction mixture was cooled in an ice bath and H2S was bubbled through the solution. The precipitate was removed by filtration and the filtrate concentrated. The residue was chromatographed on silica gel (94:6:2 CH2Cl2 :MeOH:NH4OH) to give pure product which was converted into its hydrochoride salt with ethanolic HCl, 97.3 mg, [a]D =-17.3° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[O:26][CH2:27][C:28]([O:30]CC)=[O:29].O.[OH-].[Li+]>O1CCCC1.O>[O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[O:26][CH2:27][C:28]([OH:30])=[O:29]
Reactant: CCOC(=O)COc1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.3 %

Procedure:
To a stirred solution of ethyl {3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]phenoxy}acetate (0.46 g, 0.98 mmol) in a mixture of tetrahydrofuran (30 mL) and water (15 mL) was added lithium hydroxide monohydrate (0.32 g, 2.3 mmol) at ambient temperature. The mixture was stirred at ambient temperature for 16 h. The mixture was concentrated in vacuo to a small volume, diluted with water (15 mL), washed with diethyl ether (60 mL), and acidified with 37% hydrochloric acid to pH 1. A white precipitate was formed. The mixture was extracted with ethyl acetate (3×60 mL). The combined organic solution was washed with water (30 mL), brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford {3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]phenoxy}acetic acid (0.41 g, 95%): mp 95-96° C.; 1H NMR (300 MHz, CDCl3) 7.33-7.14 (m, 3H), 7.07-6.97 (m, 2H), 6.92 (br s, 1H), 6.88-6.77 (m, 2H), 6.48 (s, 1H), 6.42 (s, 1H), 5.08-4.95 (m, 2H), 4.88-4.79 (m, 1H), 4.74-4.67 (m, 1H), 4.63 (s, 2H), 4.57-4.48 (m, 2H), 3.09-2.89 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 178.2, 172.6, 161.8, 161.3, 157.9, 141.9, 137.6, 132.6, 130.1, 128.8, 123.9, 123.6, 120.9, 120.0, 118.9, 113.9, 113.7, 113.7, 109.3, 93.2, 80.5, 72.4, 64.7, 57.8, 44.0, 29.0; MS (ES+) m/z 444.0 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[CH3:30][O:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:35]4[CH2:36][CH2:37][CH:32]([O:31][CH3:30])[CH2:33][CH2:34]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: COC1CCNCC1
Product: COC1CCN(CCOc2n[nH]c3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)CC1
Yield: 35 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 13) and 4-methoxypiperidine (prepared as described in Example 118, starting material) to give the title compound in 35% yield; NMR Spectrum: 1.35-1.42 (m, 2H), 1.78-1.80 (m, 2H), 2.18-2.22 (m, 2H), 2.77-2.79 (m, 4H), 3.11-3.16 (m, 1H), 3.20 (s, 3H), 4.40 (t, 2H), 5.29 (s, 2H), 7.24 (d, 1H), 7.36-7.38 (m, 1H), 7.55-7.58 (m, 2H), 7.86-7.90 (m, 2H), 8.29 (s, 1H), 8.50 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 510 (MH+).
Reaction SMILES: [NH:1]([CH3:21])[C@H:2]([C:18]([NH2:20])=[O:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[N:22]([C:31]([O:33][CH2:34][CH:35]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]2[C:36]1=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:32])([CH3:30])[C@H:23]([C:27](O)=[O:28])[CH:24]([CH3:26])[CH3:25].O>C1COCC1>[N:22]([C:31]([O:33][CH2:34][CH:35]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]2[C:36]1=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:32])([CH3:30])[C@H:23]([C:27]([N:1]([CH3:21])[C@H:2]([C:18]([NH2:20])=[O:19])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:9]=1)=[O:28])[CH:24]([CH3:26])[CH3:25]
Reactant: CN[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(N)=O
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(N)=O)N(C)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.6 %

Procedure:
To a solution of N-Me-Tyr(Bzl)—NH2 (329 mg, 1.16 mmol) in THF (15 ml), Fmoc-N-Me-Val-OH (533 mg, 1.51 mmol), CMPI (415 mg, 1.62 mmol) and TEA (0.323 ml, 2.32 mmol) were added under cooling with ice, followed by stirring for 4 hours at room temperature. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and evaporated to remove the solvent under-reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=2:1) to give the titled compound (680 mg, 95%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([CH:13]([F:15])[F:14])=[CH:11][CH:12]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18]([CH3:20])=O)[N:3]=1.SC[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([CH:13]([F:15])[F:14])=[CH:11][CH:12]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:20][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[N:3]=1
Reactant: SCCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(-c2ccc(C(F)F)o2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(SCCc2ccccn2)nc(N)nc1-c1ccc(C(F)F)o1

Procedure:
From 2-amino-4-(5-difluoromethyl-furan-2-yl)-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%): 374 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([O:30][CH3:31])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH:5]=[C:4]([Cl:32])[N:3]=1.[CH3:33][O-:34].[Na+]>C1COCC1.C(Cl)Cl>[Cl:32][C:4]1[N:3]=[C:2]([O:34][CH3:33])[C:7]2[C:8]([O:30][CH3:31])=[N:9][N:10]([C:11]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:5]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(Cl)c12
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1nc(Cl)cc2c1c(OC)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
4,6-dichloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine (Intermediate 37B, 100 mg, 0.217 mmol) in THF (1086 μl) was treated with sodium methoxide (4.6 N in MeOH) (51.9 μl, 0.239 mmol) and stirred @ 40° C. for 1 h. Reaction was diluted in with DCM and concentrated in vacuo on silica. Material was purified by normal phase column chromotography eluting with Hex/EtOAc (0-10%) affording 6-chloro-3,4-dimethoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine (56B, 86 mg, 0.189 mmol, 87% yield) as a white foam. MS: [M+H]+ m/z 456.