Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:16]=[CH:15][CH:14]=[CH:13][C:10]=2[CH:11]=O)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[N:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][C:30](OCC)=[O:31])=[CH:22][CH:21]=1.[Li+].CC([N-]C(C)C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]3[C:10](=[CH:13][CH:14]=[CH:15][N:16]=3)[CH:11]=[C:29]([CH2:28][CH2:27][CH2:26][C:23]3[CH:22]=[CH:21][N:20]=[CH:25][CH:24]=3)[C:30]2=[O:31])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: O=Cc1cccnc1Nc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CCCCc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: O=c1c(CCCc2ccncc2)cc2cccnc2n1-c1ccc(Cl)c([N+](=O)[O-])c1
Yield: 34 %

Procedure:
The procedure of Example 1 was repeated using 2-(4-chloro-3-nitrophenylamino)nicotinaldehyde (1.0 eq.; prepared in Synthetic Example 1d)), ethyl 5-(pyridin-4-yl)pentanoate (1.5 eq.; prepared in Synthetic Example 2) and LDA (1.5 eq.) to obtain 1-(4-chloro-3-nitrophenyl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one (yield 34%). The target product was purified through flash column chromatography and recrystallization, mp 136–137° C./DMF.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH:12]=[C:13]([C:15](=[O:21])[CH:16]=[CH:17][N:18](C)C)[CH:14]=1)=[O:8])[CH3:5].OOS(N)(=O)=O>CO>[CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH:12]=[C:13]([C:15]2[O:21][N:18]=[CH:17][CH:16]=2)[CH:14]=1)=[O:8])[CH3:5]
Reactant: COCC(C)NC(=O)c1cc(C(=O)C=CN(C)C)cc(-c2ccc(C)cc2)c1
Agent: NS(=O)(=O)OO
Solvent: CO
Product: COCC(C)NC(=O)c1cc(-c2ccc(C)cc2)cc(-c2ccno2)c1
Reaction time: 0.67 h
Yield: 50 %

Procedure:
To a 0° C. solution of 5-(3-dimethylamino-acryloyl)-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (180 mg, 0.4737 mmol) in MeOH (3 mL) was added hydroxyl-amine-O-sulfonic acid (3 eq.) in one portion. The reaction mixture was stirred for 40 minutes, during which time the temperature was allowed to rise to room temperature. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was subjected to Preparative HPLC to give 83 mg, (50%) of 5-isoxazol-5-yl-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide, MS (M+H)=351.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.[NH2:25][CH2:26][CH2:27][CH2:28][OH:29]>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([NH:25][CH2:26][CH2:27][CH2:28][OH:29])=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: NCCCO
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(NCCCO)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, and 3-amino-propan-1-ol. 1H NMR (400 MHz, DMSO-d6): δ 8.70 (t, J=5.81 Hz, 1H), 7.59 (d, J=9.12 Hz, 1H), 7.47-7.50 (m, 2H), 7.24 (t, J=5.41 Hz, 1H), 6.82 (d, J=9.21 Hz, 1H), 4.58-4.60 (m, 1H), 3.46-3.51 (m, 2H), 3.39-3.44 (m, 2H), 3.20-3.23 (m, 2H), 2.00-2.03 (m, 2H), 1.82-1.85 (m, 3H), 1.68-1.76 (m, 4H), 1.22-1.31 (m, 2H). m/z: 412.2 [M+H]+
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:36])([F:35])[F:34])[CH:27]=2)[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[N:14]([CH2:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[C:13]([CH3:24])=[N:12][CH:11]=2)[CH2:5][CH2:4]1.B1([O-])O[O:38]1.O.O.O.O.[Na+]>CO.O>[OH:1][CH2:2][C:3]1([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:34])([F:35])[F:36])[CH:27]=2)[CH2:4][CH2:5][N:6]([CH2:9][C:10]2[N:14]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([NH2:21])=[O:38])=[CH:22][CH:23]=3)[C:13]([CH3:24])=[N:12][CH:11]=2)[CH2:7][CH2:8]1
Reactant: [O-]B1OO1
Reactant: Cc1ncc(CN2CCC(CO)(Cc3cccc(OC(F)(F)F)c3)CC2)n1Cc1ccc(C#N)cc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ncc(CN2CCC(CO)(Cc3cccc(OC(F)(F)F)c3)CC2)n1Cc1ccc(C(N)=O)cc1
Temperature: 50 °C

Procedure:
A solution of 4-{5-[4-hydroxymethyl-4-(3-trifluoromethoxy-benzyl)-piperidine-1-ylmethyl]-2-methylimidazol-1-ylmethyl}benzonitrile (71 mg, 0.142 mmol; Example 31) and sodium perborate tetrahydrate (92.8 mg, 0.6 mmol) in a mixture of methanol (2.5 mL) and water (1 mL) was heated at 50° C. for 7 h. The resultant mixture was concentrated under vacuum, and the residue was partitioned between chloroform and dilute hydrochloric acid (0.5M). The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 10% methanol in chloroform. Collection and concentration of appropriate fractions provided the title compound as white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20])[CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:25]=1[CH2:26]Br>C(Cl)Cl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:13]1[C:14]([CH3:20])=[CH:15][CH:16]=[CH:17][C:18]=1[CH3:19])[CH2:11][O:12][CH2:26][C:25]1[C:24]([F:23])=[CH:31][CH:30]=[CH:29][C:28]=1[F:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1cccc(F)c1CBr
Reactant: Cc1cccc(C)c1C(CO)CNC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccc(C)c1C(CNC(=O)OC(C)(C)C)COCc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
19 g (68 mmol) of N-tert.-butoxycarbonyl-3-hydroxy-2-(2,6-dimethylphenyl)-propylamine are dissolved in 150 ml CH2Cl2, mixed with 100 ml of 50% sodium hydroxide solution, 3 g of tetrabutylammonium hydrogen sulphate and 16.5 g (80 mmol) of 2,6-difluorobenzylbromide. The mixture is stirred for 3 h at ambient temperature, the organic phase is separated off and the aqueous phase is extracted once with 100 ml of dichloromethane. The combined organic phases are washed once with 50 ml of 2 N hydrochloric acid, dried and the solvent is eliminated in vacuo. The residue is crystallised from diisopropylether. Yield: 23.5 g (85.1% of theory), melting point: 100° C.
Reaction SMILES: C1COCC1.CO.[Li+].[BH4-].[CH3:10][CH:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][N:12]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>CC(C)=O>[CH2:21]([O:20][C:18]([N:12]1[CH2:13][CH:14]([OH:17])[CH2:15][CH2:16][CH:11]1[CH3:10])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC1CCC(=O)CN1C(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC1CCC(O)CN1C(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of THF (200 mL) and MeOH (11 mL) was added LiBH4 (2 M, 89 mL, 0.18 mol). Some gas evolution and small exotherm were observed. The reaction was aged at room temperature for 30 min before being cooled to −10° C. with an acetone:ice bath. ±benzyl 2-methyl-5-oxopiperidine-1-carboxylate (22.0 g, 0.089 mol) was then added dropwise, keeping the temperature below −5° C. The reaction was then aged at −10° C. for 30 min. The reaction was quenched by adding half-saturated, aqueous NaHCO3, then extracted with EtOAc. The layers were separated and the organics dried with MgSO4. The organics were concentrated to give the titled compound as a crude, colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.[CH3:10][N:11]1[C:15]([CH2:16]O)=[N:14][CH:13]=[N:12]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>O1CCCC1.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH:7]=1)[O:8][CH2:16][C:15]1[N:11]([CH3:10])[N:12]=[CH:13][N:14]=1
Reactant: Cn1ncnc1CO
Reactant: Oc1cc(Br)ccc1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cn1ncnc1COc1cc(Br)ccc1F
Reaction time: 8 h
Yield: 37 %

Procedure:
A cooled (0° C.) solution of 5-bromo-2-fluorophenol, (2-methyl-2H-[1,2,4]triazol-3-yl)methanol and triphenylphosphine in tetrahydrofuran was treated dropwise with diisopropyl azodicarboxylate over 10 min. The resulting mixture was stirred overnight and then acetic acid was added. The reaction mixture was evaporated to dryness and the residue was partitioned between ethyl acetate and 0.01N sodium hydroxide solution. The organic phase was washed with water and brine, dried over anhydrous magnesium sulphate and pre-adsorbed onto silica. Purification by flash column chromatography on silica gel, eluting with isohexane on a gradient of ethyl acetate (10-50%), led to product-containing fractions that were combined. The material was further purified by flash column chromatography on silica gel, eluting with dichloromethane containing 1% ammonia on a gradient of methanol (0.5-3%), to give 5-(5-bromo-2-fluoro-phenoxymethyl)-1-methyl-1H-[1,2,4]triazole as an off-white solid (2.1 g, 37%): δH (360 MHz, CDCl3) 4.01 (3H, s), 5.29 (2H, s), 6.96-6.99 (1H, m), 7.09-7.13 (1H, m), 7.29 (1H, dd, J 5 and 2), 7.88 (1H, s); m/z (ES+) 288 [MH+].
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:33])[CH:21]([O:24][C:25]2[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:32])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:51])[C@@H:15]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si](C(C)(C)C)(C)C)[CH2:37]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:33])[CH:21]([O:24][C:25]2[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:32])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:51])[C@@H:15]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([OH:43])[CH2:37]2)=[CH:10]1
Reactant: CCC(Oc1c(C)cccc1C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(Oc1c(C)cccc1C)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Yield: 59.3 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 1.17 g of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[(2RS)-2-(2,6-dimethylphenoxy)butyryloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 4, above] and 23.7 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 0.48 g of the title compound, melting at between 125° and 127° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br.ClCCl>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)c2cccc(C)c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cccc(C(=O)c2ccc(O)cc2)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 55.9 %

Procedure:
4-Methoxyphenyl 3-methylphenyl ketone (603 mg) obtained in Example 131 was dissolved in dichloromethane (3 ml), a 1.0 M boron tribromide-dichloromethane solution (11 ml) was added while cooled in ice, and the admixture was stirred at room temperature for 22 hours, after which the reaction mixture was treated in the same manner as described in Example 121 to obtain 316 mg of the title compound (yield: 56%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[CH2:13]O.S(Cl)([Cl:17])=O>C(Cl)Cl>[Cl:17][CH2:13][C:3]1[CH:4]=[C:5]([O:11][CH3:12])[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[F:1]
Reactant: COc1cc(CO)c(F)cc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cc(CCl)c(F)cc1[N+](=O)[O-]

Procedure:
A solution of (2-fluoro-5-methoxy-4-nitrophenyl)methanol (Compound 130D, 1.45 g, 7.21 mmol) in anhydrous DCM (17.0 mL) was charged with Thionyl chloride (1.055 mL, 14.5 mmol). and stirred while refluxing for 16 h. The reaction mixture was concentrated under reduced pressure to yield a brown solid. This material was used without any further purification. 1H NMR (CDCl3, 400 MHz): δ=3.99 (s, 3H), 4.65 (d, J=1.01 Hz, 2H), 7.19 (d, J=5.81 Hz, 1H), 7.65 (d, J=8.84 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: Fc1cccc2sc(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc5c(F)cccc5s4)cc3CC[C@@H]12
Yield: 58 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-4-fluorobenzothiazole (86 mg, 0.46 mmol and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 48 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 91 mg (58%) of the title compound as an amorphous solid. mp 140°-145°. FDMS: m/e=412. α[D]589 =+70.06 (c=0.52, chloroform).
Reaction SMILES: [CH3:1][C:2]([NH2:20])([CH3:19])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=2)=[CH:7][N:6]=1.C1C=C(Cl)C=C(C(OO)=[O:29])C=1>C(O)(=O)C.C(Cl)Cl.C(Cl)Cl>[CH3:18][S:17]([C:13]1[N:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:4]#[C:3][C:2]([NH2:20])([CH3:1])[CH3:19])=[N:6][CH:7]=2)[CH:16]=[CH:15][N:14]=1)=[O:29]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nccc(-c2ccc(C#CC(C)(C)N)nc2)n1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CS(=O)c1nccc(-c2ccc(C#CC(C)(C)N)nc2)n1

Procedure:
1,1-Dimethyl-3-[5-(2-methylsulfanyl-pyrimidin-4-yl)-pyridin-2-yl]-prop-2-ynylamine (500 mg, 1.76 mmol) in acetic acid/DCM (2.6 ml/8.8 ml) was treated at 0° C. with mCPBA (content 70%, 455 mg, 2.64 mmol) for 10 minutes. The reaction mixture was diluted with DCM and washed with 2N-solution of sodium carbonate. The organic phase was dried over sodium sulfate, filtered, evaporated to give the title compound as brownish crystals. Yield: 500 mg (98%).
Reaction SMILES: [CH2:1]([Si:3]([C:8]#[CH:9])([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].I[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(N(CC)CC)C>CN(C=O)C.[Cu]I>[CH2:8]([Si:3]([C:6]#[C:7][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([CH2:4][CH3:5])[CH2:1][CH3:2])[CH3:9]
Reactant: Oc1ccc(I)cc1
Reactant: C#C[Si](CC)(CC)CC
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[Si](C#Cc1ccc(O)cc1)(CC)CC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Triethylsilylacetylene 108 (3 eq.) was coupled to 4-iodophenol 107 (1 eq.) in the presence of CuI (0.05 eq.), Pd[PPh3]4 (0.05 eq.), and triethylamine (2 eq.) in DMF. The mixture was stirred at ambient temperature for 5 hours after which it was concentrated under vacuum to afford a crude black oil. The oil was purified by flash column chromatography to afford pure p-(triethylsilyl)ethynyl phenol 109.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[O:11]1[CH2:16][CH:15]=[C:14]([C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])[CH2:13][CH2:12]1.C(N(CC)CC)C>ClCCl.O>[O:11]1[CH2:12][CH:13]=[C:14]([C:17]([CH3:21])([CH3:20])[CH:18]=[O:19])[CH2:15][CH2:16]1
Reactant: CC(C)(CO)C1=CCOCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C=O)C1=CCOCC1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 125.2 %

Procedure:
Step D To a solution of oxalyl chloride (2.84 mL, 33 mmol) (Aldrich) in dichloromethane (150 mL) at −78° C. was added the solution of dimethyl sulfoxide (4.6 mL, 65 mmol) in dichloromethane (25 mL) dropwise. After 5 mins, the solution of 2-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-propan-1-ol (4.6 g, 29 mmol) in dichloromethane (25 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 15 min. Triethylamine (14.8 mL, 110 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HCl, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 2-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-propionaldehyde as a brown oil (Yield: 5.6 g, 89%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:24][C:25]([NH:27][S:28]([C:31]2[S:32][C:33]([Cl:36])=[CH:34][CH:35]=2)(=[O:30])=[O:29])=[O:26])[CH:7]=[CH:8][C:9]=1[N:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][C:14]([F:22])=[C:15]([NH:20][CH3:21])[CH:16]=2)[C:11]1=[O:23])(=[O:3])[CH3:2].[BH4-].[Na+]>C(O)C>[Cl:36][C:33]1[S:32][C:31]([S:28]([NH:27][C:25]([NH:24][C:6]2[CH:7]=[CH:8][C:9]([N:10]3[CH:19]=[CH:18][C:17]4[C:12](=[CH:13][C:14]([F:22])=[C:15]([NH:20][CH3:21])[CH:16]=4)[C:11]3=[O:23])=[C:4]([CH:1]([OH:3])[CH3:2])[CH:5]=2)=[O:26])(=[O:29])=[O:30])=[CH:35][CH:34]=1
Reactant: CNc1cc2ccn(-c3ccc(NC(=O)NS(=O)(=O)c4ccc(Cl)s4)cc3C(C)=O)c(=O)c2cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CNc1cc2ccn(-c3ccc(NC(=O)NS(=O)(=O)c4ccc(Cl)s4)cc3C(C)O)c(=O)c2cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
This analog compound was obtained from reduction of N-[({3-acetyl-4-[7-fluoro-6-(methylamino)-1-oxoisoquinolin-2(1H)-yl]phenyl}amino)carbonyl]-5-chlorothiophene-2-sulfonamide of Example 70. To a solution of N-[({3-acetyl-4-[7-fluoro-6-(methylamino)-1-oxoisoquinolin-2(1H)-yl]phenyl}amino)carbonyl]-5-chlorothiophene-2-sulfonamide (18 mg, 0.033 mmol) in 2 mL ethanol, was added sodium borohydride (20 mg, 0.53 mmol). The mixture was stirred at room temperature for 30 minutes. Workup and purification provided 5-chloro-N-({[4-[7-fluoro-6-(methylamino)-1-oxoisoquinolin-2(1H)-yl]-3-(1-hydroxyethyl)phenyl]amino}carbonyl)thiophene-2-sulfonamide as a mixture of rotamers. ES-MS (M+H)+=551, 553(Cl).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:26]([NH:28][OH:29])=[NH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](Cl)=[O:39])=[CH:33][CH:32]=1.O>C1COCC1>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:26]([NH:28][O:29][C:38](=[O:39])[CH2:37][C:34]1[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=1)=[NH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(NO)c1nc2ccc(N3CCOCC3)cn2c(=O)c1OCc1ccccc1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Solvent: O
Solvent: C1CCOC1
Product: N=C(NOC(=O)Cc1ccc(F)cc1)c1nc2ccc(N3CCOCC3)cn2c(=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
The product of example 20 (200 mg, 0.51 mmol) and 4-fluorophenylacetyl chloride (0.073 mL, 0.53 mmol) were dissolved in THF (5 ml). To this solution was added TEA (0.14 mL, 1.02 mmol) dropwise at 0° C. The mixture was stirred at room temperature overnight and then poured into water (30 ml). The crude product was obtained by filtration. It was recrystallized from CH2Cl2/PE to give the titled product (261 mg, yield 97.0%)
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[C:12](=[O:13])[NH:11][C:10]([C:14]([OH:16])=O)=[CH:9][CH:8]=2)[CH:6]=1.[F:17][C:18]1[CH:30]=[CH:29][C:21]([O:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27]O)=[C:20]([C:31]([F:34])([F:33])[F:32])[CH:19]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>O.ClCCl>[F:17][C:18]1[CH:30]=[CH:29][C:21]([O:22][CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][N:11]3[C:12](=[O:13])[C:7]([N:5]4[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]4)=[CH:8][CH:9]=[C:10]3[C:14]2=[O:16])=[C:20]([C:31]([F:32])([F:33])[F:34])[CH:19]=1
Reactant: OCCNCCOc1ccc(F)cc1C(F)(F)F
Reactant: Cc1cn(-c2ccc(C(=O)O)[nH]c2=O)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cn(-c2ccc3n(c2=O)CCN(CCOc2ccc(F)cc2C(F)(F)F)C3=O)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
5-(4-Methyl-1H-imidazol-1-yl)-6-oxo-1,6-dihydropyridine-2-carboxylic acid, 0.7 hydrobromide salt (P1) (201 mg, 0.729 mmol) and 2-({2-[4-fluoro-2-(trifluoromethyl)phenoxy]ethyl}amino)ethanol (C36) (214 mg, 0.801 mmol) were combined with dichloromethane (15 mL) and N,N-diisopropylethylamine (0.508 mL, 2.92 mmol), and the mixture was stirred for 5 minutes at room temperature. O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 97%, 857 mg, 2.19 mmol) was added in one portion, and the reaction was stirred for an additional 16 hours. Water (50 mL) was added, and the mixture was extracted with dichloromethane (3×50 mL). The combined organic layers were washed sequentially with saturated aqueous sodium bicarbonate solution (50 mL), water (50 mL) and saturated aqueous sodium chloride solution (50 mL), then dried over magnesium sulfate and concentrated in vacuo. Purification was carried out twice using silica gel chromatography (Gradient #1: 0% to 20% methanol in dichloromethane; Gradient #2: 0% to 70% [10% 2 N ammonia in methanol/90% ethyl acetate] in ethyl acetate) to afford the title compound as a white solid. Yield: 268 mg, 0.595 mmol, 82%. LCMS m/z 451.0 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.24 (d, J=0.9 Hz, 3H), 3.90-3.95 (m, 2H), 4.01 (dd, J=5.1, 5.1 Hz, 2H), 4.32-4.37 (m, 4H), 7.21-7.26 (m, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.30-7.32 (m, 1H), 7.32-7.39 (m, 2H), 7.76 (d, J=7.8 Hz, 1H), 8.30 (d, J=1.3 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13]I)[CH:6]=[C:5]2[CH:15]=[O:16].N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1.C([SnH](CCCC)CCCC)CCC.[F-].[K+]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH2:13][C:6]3=[C:5]([CH:15]=[O:16])[C:4]=2[CH:3]=1
Reactant: O=Cc1cn(CCCI)c2ccc(Cl)cc12
Agent: CCCC[SnH](CCCC)CCCC
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1c2n(c3ccc(Cl)cc13)CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.8 %

Procedure:
To a stirred solution of 5-chloro-1-(3-iodopropyl)indole-3-carboxaldehyde (5.0 g, 14 mmol) in toluene (75 mL) at reflux under argon was added dropwise over 2 h a solution of 1,1′-azobis(cyclohexanecarbonitrile) (3.5 g, 14 mmol) and tri-n-butyltin hydride (7.8 mL, 29 mmol) in toluene (75 mL). The mixture was stirred for 3 h, cooled to room temperature, and potassiurn fluoride (3.5 g, 60 mmol) and water (15 mL) were added. The mixture was stirred for 18 h and filtered through a pad of kieselguhr. The filter-cake was washed (ethyl acetate) and the filtrate was concentrated in vacuo, purified by colurnn chromatography [SiO2; ethyl acetate-hexane (9:1)] and recrystallised (methanol) to give the product as a white solid (1.1 g, 36%): mp 179-180° C.; Found: C, 65.54; H, 4.61; N, 6.38%. C12H10ClNO requires: C, 65.61; H, 4.59; N, 6.37%.