Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[O:17][N:16]=[C:15]([CH:18]=O)[CH:14]=1)=[C:5]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[NH2:26]O.C(OC(=O)C)(=O)C>CO.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[O:17][N:16]=[C:15]([C:18]#[N:26])[CH:14]=1)=[C:5]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NO
Reactant: O=Cc1cc(-c2c(-c3ccccc3)c3cc(Cl)ccc3[nH]c2=O)on1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: N#Cc1cc(-c2c(-c3ccccc3)c3cc(Cl)ccc3[nH]c2=O)on1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of 5-(6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-yl)-isoxazole-3-carboxaldehyde in MeOH (20 mL), aq. NH2OH (1 mmol) was added. The resulting mixture was stirred at RT for 2 hr. The reaction mixture was concentrated and water (20 mL) was added. The precipitate formed was then collected by suction filtration and dried in vacuo. Above oxime (365 mg, 1 mmol) was dissolved in pyridine (10 mL) and acetic anhydride (0.3 mL, 2 mmol) was added. The resulting mixture was stirred overnight and concentrated. The residue obtained was purified with (30% EtOAc:Hexane) to obtain the title compound. Yield 67%.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7]1([CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]1)[C:6]2=[N:19]S(C(C)(C)C)=O.CCOCC>O1CCOCC1>[Br:2][C:3]1[CH:4]=[C:5]2[C:9]([CH2:8][C:7]3([CH2:12][CH2:13][C:14]([F:17])([F:18])[CH2:15][CH2:16]3)[C:6]2=[NH:19])=[CH:10][CH:11]=1
Reactant: CC(C)(C)S(=O)N=C1c2cc(Br)ccc2CC12CCC(F)(F)CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: N=C1c2cc(Br)ccc2CC12CCC(F)(F)CC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.6 %

Procedure:
HCl (4M in 1,4-dioxane, 3.38 mL, 13.51 mmol) was added to a solution of N-(5′-bromo-4,4-difluorospiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide (Example 27 Step 1, 565 mg, 1.35 mmol) in anhydrous 1,4-dioxane (4 mL). The resulting mixture was stirred under a nitrogen atmosphere at r.t. for 90 min. Et2O (2 mL) was added and the precipitate was filtered off and washed with Et2O. The solid was partitioned between DCM (8 mL) and sat. aq. NaHCO3 (8 mL). The phases were separated and the organic layer was dried over MgSO4 and concentrated to give 6′-bromo-4,4-difluorospiro[cyclohexane-1,2′-inden]-1′(3′H)-imine (418 mg, 99% yield), that was used directly in the next step. MS (ES+) m/z 314 [M+H]+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([CH2:13][CH2:14][CH2:15][CH2:16][C:17](O)=[O:18])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.[OH-].[K+]>CCOCC>[C:7]1([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)CCCCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: OCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
Under nitrogen atmosphere, at 0° C., to a stirring mixture of LiAlH4 (0.84 g, 22.44 mmol) in dry Et2O (55 mL), 5-phenylpentanoic acid (1.00 g, 5.61 mmol) in dry Et2O (10 mL) was added dropwise. The mixture was left to react at rt for 4 h, then at 0° C. H2O (0.85 mL), 3M KOH solution (0.85 mL) and H2O (2.85 mL) were very slowly added. The mixture was stirred for 1 h at 0° C., filtered to remove the solid residue, and the organic phase dried over Na2SO4. The organic solution was again filtered and concentrated to dryness affording the title compound (0.881 g, 95%) as a colorless oil. 1H NMR (CDCl3): δ 1.36-1.46 (m, 2H), 1.54-1.72 (m, 5H), 2.58-2.71 (m, 2H), 3.59-3.71 (m, 2H), 7.14-7.33 (m, 5H).
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[C@H:8]([O:9][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:19]=2[N:18]=[C:17]([C:20]2[N:24]4[CH:25]=[CH:26][C:27]([O:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:28][C:23]4=[N:22][CH:21]=2)[CH:16]=[CH:15]3)[CH2:7][N:6]([C:34]([O:36][CH2:37][C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=2)=[O:35])[CH2:5]1.I[CH3:49]>CN(C=O)C>[CH3:49][O:3][C@H:4]1[C@H:8]([O:9][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:19]=2[N:18]=[C:17]([C:20]2[N:24]4[CH:25]=[CH:26][C:27]([O:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:28][C:23]4=[N:22][CH:21]=2)[CH:16]=[CH:15]3)[CH2:7][N:6]([C:34]([O:36][CH2:37][C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=2)=[O:35])[CH2:5]1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(O[C@@H]5CN(C(=O)OCc6ccc7ccccc7c6)C[C@H]5O)c4n3)cnc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1ccn2c(-c3ccc4cccc(O[C@@H]5CN(C(=O)OCc6ccc7ccccc7c6)C[C@H]5OC)c4n3)cnc2c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 45 %

Procedure:
Sodium hydride (0.017 g, 0.43 mmol) was added to a solution of (trans)-naphthalen-2-ylmethyl 3-hydroxy-4-(2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-yloxy)pyrrolidine-1-carboxylate (0.117 g, 0.194 mmol) in DMF (1 mL). The reaction was cooled to 0° C. and stirred for 20 minutes. Iodomethane (0.012 ml, 0.194 mmol) was added, and the ice bath was removed. The reaction was stirred for 1 hour. Water was added, and the reaction mixture was extracted with CHCl3. The combined organic layers were washed with brine, dried and condensed. The residue was purified by silica gel chromatography to provide 54 mg of the desired product. MS APCI (+) m/z 619.1 (M+1) detected.
Reaction SMILES: [I-].[Li+].[C:3]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([N:24]2[CH2:29][CH2:28][S:27][C:26]([CH3:31])([CH3:30])[C@@H:25]2[C:32]([O:34]C(C)(C)C)=[O:33])(=[O:23])=[O:22])=[CH:17][CH:16]=1)(=[O:5])[CH3:4]>>[C:3]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([S:21]([N:24]2[CH2:29][CH2:28][S:27][C:26]([CH3:30])([CH3:31])[C@@H:25]2[C:32]([OH:34])=[O:33])(=[O:22])=[O:23])=[CH:19][CH:20]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)OCCCCC#CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)[C@@H]2C(=O)OC(C)(C)C)cc1
Agent: [I-]
Agent: [Li+]
Product: CC(=O)OCCCCC#CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)[C@@H]2C(=O)O)cc1
Yield: 100.1 %

Procedure:
According to the procedure of Example 251, lithium iodide mediated ester cleavage of 0.456 g (0.845 mmol) of tert-butyl (3S)-4-[(4-{[7-(acetyloxy)-2-heptynyl]-oxy}phenyl)sulfonyl]-2,2-dimethyl-3-thiomorpholinecarboxylate provided 0.409 g (100%) of (3S)-4-[(4-{[7-(acetyloxy)-2-heptynyl]oxy}phenyl)sulfonyl]-2,2-dimethyl-3-thiomorpholinecarboxylic acid as a colorless oil. Electrospray Mass Spec: 446.0 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:5]=[C:4]([Cl:19])[C:3]=1[NH2:20].[C:21]([C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=1[N+:32]([O-:34])=[O:33])#[N:22].N1C=CC=CC=1.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1>ClCCl>[C:21]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:20][C:3]2[C:4]([Cl:19])=[CH:5][C:6]([C:9]([F:18])([C:10]([F:12])([F:13])[F:11])[C:14]([F:15])([F:16])[F:17])=[C:7]([F:8])[C:2]=2[Cl:1])=[O:28])=[CH:25][C:24]=1[N+:32]([O-:34])=[O:33])#[N:22]
Reactant: Nc1c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)c(F)c1Cl
Reactant: N#Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ccc(C(=O)Nc2c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)c(F)c2Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 91.2 %

Procedure:
To a solution of 2,6-dichloro-3-fluoro-4-(1,2,2,2-tetrafluoro-1-trifluoromethylethyl)-phenylamine (Example 3.2) (3.48 g, 10 mmol) and 4-cyano-3-nitrobenzoic acid (made as in WO 2008/074427) (3.84 g, 20 mmol) in dichloromethane (40 ml) was added pyridine (4.17 ml, 30 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (“BOP-Cl”) (5.09 g, 20 mmol). The reaction mixture was heated to reflux for 6 hours. The reaction mixture was cooled to ambient temperature and quenched by addition of aqueous hydrochloric acid (1N) (50 ml). The mixture was then extracted three times with dichloromethane. The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent:cyclohexane/ethyl acetate 7:3) to give 4-cyano-N-[2,6-dichloro-3-fluoro-4-(1,2,2,2-tetrafluoro-1-trifluoromethylethyl)phenyl]-3-nitrobenzamide (4.76 g, 91% yield). LC-MS (Method 2): RT=2.08, [M−H]−=520.
Reaction SMILES: [C:1]([N:4]([CH:6]1[CH2:10][CH2:9][NH:8][CH2:7]1)[CH3:5])(=[O:3])[CH3:2].[CH3:11][O:12][C:13]1[N:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][CH:17]=[C:16]2OS(C(F)(F)F)(=O)=O.C(N(CC)CC)C>O1CCOCC1>[CH3:11][O:12][C:13]1[N:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][CH:17]=[C:16]2[N:8]1[CH2:9][CH2:10][CH:6]([N:4]([CH3:5])[C:1](=[O:3])[CH3:2])[CH2:7]1
Reactant: COc1ccc2nccc(OS(=O)(=O)C(F)(F)F)c2n1
Reactant: CC(=O)N(C)C1CCNC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc2nccc(N3CCC(N(C)C(C)=O)C3)c2n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 106 %

Procedure:
3-(N-acetyl-N-methylamino)pyrrolidine (1.00 g, 7.0 mmol) was dissolved in dioxane (15 mL) and treated with 1,1,1-Trifluoro-methanesulfonic acid 6-methoxy-[1,5]naphthyridin-4-yl ester (1.67 g, 5.4 mmol) and triethylamine (0.98 mL, 7.0 mmol). After stirring at 50° C. overnight the reaction mixture was cooled, concentrated to dryness and purified via column chromatography (silica, 2% MeOH in chloroform) to afford the title compound as an off-white solid (1.72 g, quantitive): LC-MS m/z 301 (M+H)+
Reaction SMILES: O1CCCC1.O1CCCC1.C([N-]C(C)C)(C)C.[Li+].[C:19]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[CH3:20].[O:27]1[CH2:31][CH:30]=[CH:29][C:28]1=[O:32]>O>[C:23]([O:22][C:19](=[O:21])[CH2:20][CH:30]1[CH2:29][C:28](=[O:32])[O:27][CH2:31]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C1C=CCO1
Reactant: CC(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC1COC(=O)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
Tetrahydrofuran (50 mL) and Lithium diisopropylamide mono tetrahydrofuran complex (20 mL of 1.5 M in cyclohexane) was cooled in a dry ice/Isopropanol bath for 10 min. Tert-butyl acetate (3.5 mL 26 mmoles) was added via syringe and stirred at −78° C. for 30 min. 2(5H)-Furanone (1.59 g, 19 mmoles) was added dropwise and the reaction was stirred for 1 h at −78° C. The reaction was poured into water and extracted with ether 2×150 mL The ether extracts were combined and washed with water 100 mL then brine 3×100 mL, dried and the ether removed under reduced pressure to give 2.74 g of product (72%). MS (ESI+) for C10H16O4 m/z 223 (M+Na)+.
Reaction SMILES: [O:1]=[C:2]1[N:14]2[C:5](=[N:6][C:7]3[C:12]([CH2:13]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:4][C:3]1=[CH:15][C:16]([OH:18])=O.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(P(C#N)(CC)=O)C.C(N(CC)CC)C>CN(C)C=O.C1C=CC=CC=1.C(OCC)(=O)C>[CH2:19]([NH:26][C:16](=[O:18])[CH:15]=[C:3]1[S:4][C:5]2=[N:6][C:7]3[C:12]([CH2:13][N:14]2[C:2]1=[O:1])=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)C=c1sc2n(c1=O)Cc1ccccc1N=2
Agent: CCP(=O)(C#N)CC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: O=C(C=c1sc2n(c1=O)Cc1ccccc1N=2)NCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of (3-oxo-5H-thiazolo[2,3-b]quinazolin-2(3H)-ylidene)acetic acid (10.5 g, 1.9 mmols) and benzylamine (0.23 g, 2.1 mmols) in 25 ml dimethylformamide at 0° C., was added diethylphosphoryl cyanide (0.28 g, 2.1 mmols) (in dimethylformamide solution), followed by triethylamine (0.41 g, 4.0 mmols). The reaction mixture was stirred for 4 hours at 0° C. and then, at room temperature overnight. The reaction mixture was diluted with benzene-ethyl acetate and washed sequentially with 5% hydrochloric acid, water, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic solution was dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure to give N-Benzyl-(3-oxo-5H-thiazolo[2,3-b]quinazolin-2(3H)-ylidene)acetamide which was recrystallized from ethyl acetate. Yield--0.09 g. Mp 258°-259° C.
Reaction SMILES: C(N)(=O)C(C)=C.[Na].C(OC)(=O)C(C)=C.[C:15]([O:20][CH2:21][CH:22]1O[CH2:23]1)(=[O:19])[C:16]([CH3:18])=[CH2:17].C(OCCOC(=O)C(C)=C)(=O)C(C)=C>O>[C:15]([O:20][CH2:21][CH:22]=[CH2:23])(=[O:19])[C:16]([CH3:18])=[CH2:17]
Reactant: C=C(C)C(=O)OCC1CO1
Agent: C=C(C)C(=O)OC
Agent: C=C(C)C(=O)OCCOC(=O)C(=C)C
Agent: C=C(C)C(N)=O
Solvent: O
Product: C=CCOC(=O)C(=C)C
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
Subsequently, over a period of 90 minutes, the following are added simultaneously: a solution of 20 g of methacrylamide and 0.6 g of the sodium salt of 4,4'-azobis-(4-cyanovalerianic acid) in 300 g of water, as well as a monomer mixture comprising 35 g of methyl methacrylate, 40 g of glycidyl methacrylate, and 4 g of ethylene glycol dimethacrylate. The mixture is then stirred for a further 60 minutes at 80° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[CH3:30][O:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]([CH2:38][CH2:39][C:40]2[NH:49][C:43]3=[N:44][CH:45]=[C:46](I)[CH:47]=[C:42]3[N:41]=2)[CH:33]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:24][C:19]1[CH:18]=[C:17]([N:14]2[CH2:15][CH2:16][N:11]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:46]4[CH:47]=[C:42]5[N:41]=[C:40]([CH2:39][CH2:38][C:34]6[CH:33]=[C:32]([O:31][CH3:30])[CH:37]=[CH:36][N:35]=6)[NH:49][C:43]5=[N:44][CH:45]=4)=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH2:12][CH2:13]2)[CH:22]=[C:21]([Cl:23])[CH:20]=1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCN(c2cc(Cl)cc(Cl)c2)CC1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccnc(CCc2nc3cc(-c4ccc(S(=O)(=O)N5CCN(c6cc(Cl)cc(Cl)c6)CC5)cc4)cnc3[nH]2)c1
Temperature: 85 °C
Yield: 8.4 %

Procedure:
A mixture of 0.675 g of 1-(4-bromo-benzene-sulfonyl)-4-(3,5-dichlorphenyl)-piperazine, 0.42 g of bis-(pinacolato)-diboron, 0.025 g of 1,1′-bis-(diphenylphosphino)-ferrocene, 0.033 g of [1,1′-bis(diphenyl-phosphino)ferrocene]palladium-dichloride (complex with CH2Cl2), 0.442 g of potassium acetate in 8 ml of degassed dioxane are heated to 85° C. in a sealed tube under N2 for 6 hours. To the resulting mixture 4 ml of degassed dioxane, 0.342 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (starting material A1), 0.104 g of tetrakis(triphenylphosphine)-palladium(0) and a solution of 0.25 g of potassium carbonate and 0.076 g of lithium chloride in 4 ml of degassed water are added under N2. The tube is sealed again, the mixture is heated to 110° under N2 for 17 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with ethylacetate. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 28-24:1). Concentration of the chromatographically pure fractions and crystallization of the residue from ethylacetate gives 0.047 g of the title compound as a solid of m.p. 220-222° C. The mass spectrum shows the molecular peak MH+ at 623.5 Da.
Reaction SMILES: C=O.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]#[C:17][C:18]3[CH:19]=[CH:20][C:21]4[S:30][C:29]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24][C:23]=5[C:22]=4[CH:31]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.[BH3-][C:33]#N.[Na+].C(O)(=O)C.[OH-].[Na+]>O.C(#N)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]#[C:17][C:18]3[CH:19]=[CH:20][C:21]4[S:30][C:29]5[CH2:28][CH2:27][N:26]([CH3:33])[CH2:25][CH2:24][C:23]=5[C:22]=4[CH:31]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: Clc1ccc(-c2ccc(C#Cc3ccc4sc5c(c4c3)CCNCC5)nc2)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: CC(=O)O
Product: CN1CCc2sc3ccc(C#Cc4ccc(-c5ccc(Cl)cc5)cn4)cc3c2CC1
Reaction time: 8 h

Procedure:
0.18 mL (2.41 mmol) 37% formalin solution in water are added to a solution of 100 mg (0.24 mmol) 3-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-6,7,8,9-tetrahydro-5H-10-thia-7-aza-benzo[a]azulene (see 3.60f) in 5 mL acetonitrile. Then 60 mg (0.96 mmol) NaBH3CN and 56 μL (0.96 mmol) acetic acid are added and the reaction mixture is stirred overnight. The solution is combined with 2 M NaOH and extracted with EtOAc. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. The purification is carried out by column chromatography by HPLC-MS.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[O:15])=[CH:4][CH:3]=1.[CH:16]([Mg]Br)=[CH2:17]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:15])[CH:16]=[CH2:17])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: C=C[Mg]Br
Product: C=CC(O)c1c(C)noc1-c1ccc(Br)cc1

Procedure:
Prepared according to the procedure described in Example 35, Step 3, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and vinylmagnesium bromide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([O:11][CH3:12])=[N:9][N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:5]2=[N:6][CH:7]=1.[C:22](=[O:29])([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[NH2:23].C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:12][O:11][C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([NH:23][C:22](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:3]=2)[N:8]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:9]=1
Reactant: COc1ccc(Cn2nc(OC)c3cc(Br)cnc32)cc1
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(OC)c3cc(NC(=O)OC(C)(C)C)cnc32)cc1
Yield: 24.8 %

Procedure:
5-Bromo-3-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine (0.109 g, 0.313 mmol), tert-butyl carbamate (0.110 g, 0.939 mmol), Cs2CO3 (0.153 g, 0.470 mmol), Pd2 dba3*CHCl3 (0.0324 g, 0.0313 mmol) and 4,5-bis(diphenylphosphino)-9,9 dimethylxanthene (0.0362 g, 0.0626 mmol) were taken up in THF, degassed with argon for 15 minutes, and heated to reflux overnight. The solution was partitioned between water and EtOAc. The organic portion was washed with water (3×), brine, dried over Na2SO4 and concentrated to an oil which was purified by column chromatography (4:1 hexane/EtOAc) to give tert-butyl 3-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-ylcarbamate (0.0298 g, 24.8%) as an oil.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]=[C:16]([CH:26]([CH3:28])[CH3:27])[C:15]=2[C:29](OCC)=[O:30])=[CH:10][CH:9]=1>CCOCC>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]=[C:16]([CH:26]([CH3:28])[CH3:27])[C:15]=2[CH2:29][OH:30])=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)cc(-c2ccccc2)nc1C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)c1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1CO
Reaction time: 2.5 h
Yield: 77.8 %

Procedure:
A slurry of LiAlH4 (775 mg, 20.4 mmol) in dry Et2O (70 ml) at 0° C. was treated with a solution of 4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinecarboxylic acid, ethyl ester (4.80 gm, 13.2 mmol) in Et2O (5 ml). After 2.5 hours, the reaction was quenched and diluted with H2O and the aqueous layer was extracted twice with Et2O and once with EtOAc. The combined organic layers were washed with H2O and brine, then dried (Na2SO4), filtered and stripped. The resulting solid was dissolved in hot EtOAc and directly chromatographed (flash, Merck SiO2, 20% EtOAc in hexane) to give crude 4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinemethanol. Recrystallization from hot hexane/EtOAc gave 4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinemethanol (3.30 gm) as a white solid. The mother liquor was stripped and recrystallized again to give an additional 230 mg of product (total 3.53 gm, 84%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:4]=1)=O.[C:18]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:20])[CH3:19].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[C:18]([N:21]1[CH2:26][CH2:25][N:24]([CH2:1][C:3]2[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:4]=2)[CH2:23][CH2:22]1)(=[O:20])[CH3:19]
Reactant: Cc1cc(C=O)cc(NC(=O)OC(C)(C)C)n1
Reactant: CC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(=O)N1CCN(Cc2cc(C)nc(NC(=O)OC(C)(C)C)c2)CC1

Procedure:
2-Chloro-6-methyl-pyridine-4-carbaldehyde (13-2, 0.609 g, 3.91 mmol), tert-butylcarbamate (0.550 g, 4.70 mmol), cesium carbonate (1.91 g, 5.87 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.036 g, 0.040 mmol) and Xantphos (0.068 g, 0.030 mmol) were stirred in 10 mL of anhydrous dioxane under N2. The reaction was heated to 80° C. and after 18 hours the reaction was cooled to room temperature. The mixture was diluted with water and extracted 3× with EtOAc. The extracts were dried over Na2SO4, filtered and concentrated. Purification by flash column chromatography afforded impure tert-butyl 4-formyl-6-methylpyridin-2-ylcarbamate. This aldehyde was dissolved in 2 mL of 1,2-dichloroethane. N-Acetylpiperazine (0.074 g, 0.58 mmol) was added followed by addition of 0.05 mL HOAc and NaBH(OAc)3 (0.122 g, 0.58 mmol). After 3 hours the reaction was quenched by the addition of half-saturated NaHCO3 (aq). The mixture was extracted 3× with DCM (dichloromethane) and the extracts were dried over Na2SO4, filtered and concentrated to afford the titled compound, 13-3. 1H NMR (CDCl3) δ 7.67 (s, 1H), 7.47 (s, 1H), 6.84 (s, 1H), 3.64 (t, 2H, J=4.9 Hz), 3.47 (m, 4H), 2.44 (m, 7H), 2.09 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].[CH3:16][O:17][C:18]([C:20]1[CH:29]=[CH:28][C:23]2[S:24][C:25]([CH3:27])=[CH:26][C:22]=2[CH:21]=1)=[O:19].C(OCC)(=O)C>C(Cl)Cl>[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8]([C:26]1[C:22]2[CH:21]=[C:20]([C:18]([O:17][CH3:16])=[O:19])[CH:29]=[CH:28][C:23]=2[S:24][C:25]=1[CH3:27])=[O:9]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc2sc(C)cc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc2sc(C)c(C(=O)c3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Aluminum chloride (1.24 g, 9.3 mmol) was dispersed in methylene chloride (10 ml), and 2,4-dichlorobenzoyl chloride (0.97 g, 4.7 mmol) and then 5-(methoxycarbonyl)-2-methylbenzo[b]thiophene (0.8 g, 3.9 ml) were added thereto. The mixture was stirred at room temperature for 4 hr. The reaction mixture was poured into ice water and ethyl acetate was added. The mixture was extracted. The organic layer was washed twice with a saturated aqueous solution of sodium hydrogencarbonate and once with brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to give the objective compound (1.5 g, quantitative) as pale yellow crystals.