Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([S:10][C:11]2[N:12]=[C:13]([NH:22][C@H:23]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][OH:25])[C:14]3[S:19][C:18]([O:20]C)=[N:17][C:15]=3[N:16]=2)[CH3:9])=[N:6][CH:7]=1>[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([S:10][C:11]2[N:12]=[C:13]([NH:22][C@@H:23]([CH2:24][OH:25])[CH2:26][CH:27]([CH3:28])[CH3:29])[C:14]3[S:19][C:18](=[O:20])[NH:17][C:15]=3[N:16]=2)[CH3:9])=[N:6][CH:7]=1
Reactant: COc1nc2nc(S[C@@H](C)c3ccc(Cl)cn3)nc(N[C@@H](CO)CC(C)C)c2s1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(C)C[C@H](CO)Nc1nc(S[C@@H](C)c2ccc(Cl)cn2)nc2[nH]c(=O)sc12
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
The title compound was prepared from (2R)-2-[(5-{[(1S)-1-(5-chloropyridin-2-yl)ethyl]thio}-2-methoxy[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol from the previous step using General method D except that the reaction mixture was stirred at 50° C. for 2.5 h and then at room temperature over night. After complete reaction the reaction mixture was diluted with Brine and extracted with DCM (three times). The combined organic extracts were dried over sodium sulphate and concentrated in vacuo.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH:21][C:22](=O)OC(C)(C)C)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CI.C(N1C2C=C(N(C)C(=O)OC(C)(C)C)C3N(C(C)=NN=3)C=2C=C1C)C1C=CC=CC=1.FC(F)(F)C(O)=O>O1CCCC1.C(OCC)(=O)C.O>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH:21][CH3:22])[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2c(cc(NC(=O)OC(C)(C)C)c3nnc(C)n32)n1Cc1ccccc1
Agent: Cc1cc2c(cc(N(C)C(=O)OC(C)(C)C)c3nnc(C)n32)n1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CI
Product: CNc1cc2c(cc(C)n2Cc2ccccc2)n2c(C)nnc12
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (6-benzyl-1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-4-yl)carbamate (9.0 mg, 0.023 mmol, Example 248) in tetrahydrofuran (1 mL) at 0° C. was added NaH (60% in mineral oil, 2.4 mg, 0.060 mmol). After 30 minutes, a solution of methyl iodide (2.9 μL, 0.046 mmol, Aldrich) in THF (95 μL) was added to the reaction mixture, and the reaction mixture was stirred overnight, after which time additional NaH (60% in mineral oil, 8.3 mg, 0.21 mmol) and a solution of methyl iodide (5.8 μL in 0.19 mL THF, 0.092 mmol) were added. After 4 hours, water and ethyl acetate were added. Layers were separated, and the organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude tert-butyl (6-benzyl-1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-4-yl)(methyl)carbamate was treated with Trifluoroacetic Acid (2.0 mL, 26 mmol) for 1 hour. The solvent was removed in vacuo, and the title product was isolated by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (2.5 mg, 36%).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH:16]=[CH:17][O:18]C)=[C:11]([CH:15]=1)[C:12]([OH:14])=O>>[Cl:6][C:7]1[CH:15]=[C:11]2[C:10]([CH:16]=[CH:17][O:18][C:12]2=[O:14])=[CH:9][CH:8]=1
Reactant: COC=Cc1ccc(Cl)cc1C(=O)O
Agent: O=S(=O)(O)O
Product: O=c1occc2ccc(Cl)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
Concentrated sulphuric acid (15 ml) was added to 5-chloro-2(2-methoxyvinyl)-benzoic acid (4.43 g) at 0° C. The mixture was stirred for 2 hours, then diluted with ice/water. The product was extracted with ethyl acetate (3×15 ml) and the combined extracts washed with saturated sodium bicarbonate solution. The solution was dried (magnesium sulfate), filtered and concentrated. The residue was purified by flash chromatography (0-5% ethyl acetate/hexane) to afford the sub-title compound as a white solid (3.04 g, 81%); mp 109.8-110.9° C.; 1H NMR (400 MHz, CDCl3) δ 6.51(1H, d), 7.28-7.32(1H, m), 7.41(1H, d), 7.64-7.70(1H, m), 8.28(1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]([NH:17][C:18]([C:20]3([C:23]4[CH:33]=[CH:32][C:26]5[O:27][C:28]([F:31])([F:30])[O:29][C:25]=5[CH:24]=4)[CH2:22][CH2:21]3)=[O:19])[N:11]=2)[C:5]([O:8]C)=[N:6][CH:7]=1.I[Si](C)(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]=[C:12]([NH:17][C:18]([C:20]3([C:23]4[CH:33]=[CH:32][C:26]5[O:27][C:28]([F:30])([F:31])[O:29][C:25]=5[CH:24]=4)[CH2:22][CH2:21]3)=[O:19])[CH:13]=[CH:14][C:15]=2[CH3:16])[C:5](=[O:8])[NH:6][CH:7]=1
Reactant: COc1ncc(Cl)cc1-c1nc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)ccc1C
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cc(Cl)c[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
To N-(5′-chloro-2′-methoxy-3-methyl-2,3′-bipyridin-6-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (55 mg, 0.12 mmol) in chloroform (1 mL) was added iodotrimethylsilane (70 mg, 0.35 mmol). The reaction mixture was stirred at room temperature overnight. At this point the reaction mixture was purified directly by silica gel chromatography (eluting with a gradient of 0-5% methanol in dichloromethane) to yield the product (24 mg, 41%). ESI-MS m/z calc. 459.08. found 459.95 (MW+1)+. Retention time 1.62 minutes.
Reaction SMILES: [CH2:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[N:12]([O-])=O.[Na+].O.O.[Sn](Cl)Cl>Cl.O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:9][NH2:12])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=N[O-]
Reactant: CCCCc1ccc(N)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CCCCc1ccc(NN)cc1
Reaction time: 0.75 h
Yield: 83.9 %

Procedure:
To 300 ml of concentrated hydrochloric acid was added a solution of 4-n-butylaniline (20.0 g, 134.2 mmole) in 200 ml 1 N hydrochloric acid at ice bath temperature. To the resulting slurry was added a solution of sodium nitrite (21.6 g, 313 mmole) in 90 ml of water. The resulting brown solution was stirred at ice bath temperature for 45 minutes and treated dropwise with a solution of tin (II) chloride dihydrate (82.0 g, 363.0 mmole) in 90 ml of concentrated hydrochloric acid. The reaction was stirred for 1 hour at 5° C. and the hydrazine hydrochloride salt was collected by filtration. This was then dissolved in 300 ml of 3N sodium hydroxide solution and the aqueous solution was extracted with diethyl ether (2×200 ml). The combined organic layers were dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to give 18.5 g (84% crude yield) of the titled hydrazine as brown solid which melts around room temperature.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Cl-].[Cl-].[Al+3].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=O)[C:21](=O)[C:22]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]3[CH2:31][CH2:32][NH:33][CH2:34][CH2:35][C:23]=23)=[CH:15][CH:14]=1>C1COCC1>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][CH2:20][CH2:21][C:22]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]3[CH2:31][CH2:32][NH:33][CH2:34][CH2:35][C:23]=23)=[CH:17][CH:18]=1
Reactant: COc1ccc(NC(=O)C(=O)c2c3n(c4ccccc24)CCNCC3)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(NCCc2c3n(c4ccccc24)CCNCC3)cc1
Temperature: 25 °C
Yield: 82.7 %

Procedure:
A solution of 1M lithium aluminum hydride (7 mL, 7 mmol) and THF (14 mL) is cooled to 0° C. and portion-wise treated with aluminum trichloride (317 mg, 2.4 mmol) with gas evolution. The resulting colorless solution with a small amount of precipitate is drop-wise treated with a solution of N-(4-methoxyphenyl)-2-oxo-2-(2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-11-yl)acetamide (433 mg, 1.19 mmol) in THF (10 mL) with additional gas evolution. The resulting yellow suspension is warmed to rt for 20 hr followed by heating to 50° C. for 8 hours. At this time, the reaction is quenched by the successive addition of water (0.27 mL), 5M sodium hydroxide (0.24 mL), and water (0.93 mL). The resulting gelatinous suspension is diluted with dichloromethane, filtered through a pad of celite, with the organics washed once with 1N sodium hydroxide (35 mL), once with brine (35 mL), dried over MgSO4, filtered, and concentrated to give a tan oil. This material is purified by LC (230-400 silica gel) eluting with 5:0.75:94.25 methanol/NH4OH/dichloromethane to afford 330 mg of 4-methoxy-N-[2-(2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-11-yl)ethyl]aniline as a light golden oil. This material is dissolved in ethyl acetate and treated with 2M hydrochloric acid in methanol (1.1 mL) with immediate formation of a white solid that is collected by filtration and recrystallized from methanol/ethyl acetate to afford 343 mg of 4-methoxy-N-[2-(2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-11-yl)ethyl]aniline dihydrochloride as a white solid. IR (drift) 2818, 2803, 2746, 2726, 2694, 2669, 2642, 2585, 2552, 2449, 1514, 1471, 1255, 1244, 757 cm−1; OAMS supporting ions at: ESI+ 336.2.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([N:18]1[C:23](=[O:24])[C:22]2[N:25]=[CH:26][S:27][C:21]=2[N:20]=[C:19]1[CH:28]([NH:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[CH2:29][CH3:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH2:11]([N:18]1[C:23](=[O:24])[C:22]2[N:25]=[CH:26][S:27][C:21]=2[N:20]=[C:19]1[CH:28]([N:31]([CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:29][CH3:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CCC(NCCN(C)C)c1nc2scnc2c(=O)n1Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(c1nc2scnc2c(=O)n1Cc1ccccc1)N(CCN(C)C)C(=O)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
A solution of 4-bromobenzoyl chloride (1 equiv) in dichloromethane is added to a solution of 6-benzyl-5-(1-{[2-(dimethylamino)ethyl]amino}-propyl)[1,3]thiazolo[5,4-d]pyrimidin-7(6H)-one (1-4, 1 equiv) and N,N-diisopropylethylamine (1 equiv) in dichloromethane, and the resulting mixture is stirred under ambient conditions for 1 h. The reaction mixture is washed with saturated aqueous NaHCO3 solution, and brine, then dried (MgSO4) and concentrated. The residue is purified by flash chromatography. Elution with CH2Cl2 to 5% NH3—EtOH/CH2Cl2 gives N-[1-(6-benzyl-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-5-yl)propyl]4-bromo-N-[2-(dimethylamino)ethyl]benzamide (1-5).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[N:15][N:16]4[C:21]=3[CH:20]=[CH:19][N:18]=[C:17]4SC)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=O.[NH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1>ClCCl>[CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[N:15][N:16]4[C:21]=3[CH:20]=[CH:19][N:18]=[C:17]4[N:42]3[CH2:46][CH2:45][CH2:44][CH2:43]3)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSc1nccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn12
Reactant: C1CCNC1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Fc1ccc(-c2nn3c(N4CCCC4)nccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Reaction time: 1 h
Yield: 59 %

Procedure:
To a solution of N-cyclopentyl-4-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]pyrimidin-2-amine (24 mg, 0.057 mmol) in dichloromethane (3 mL) was added 3-chloroperoxybenzoic acid (15mg, 0.086 mmol) and the reaction mixture stirred for 1 hour. Pyrrolidine (3 mL) was added and the reaction mixture stirred for 2 hours before being diluted with dichloromethane. The organic phase was washed with saturated sodium bicarbonate, washed with brine, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 5% acetone in dichloromethane to yield N-cyclopentyl-4-[2-(4-fluorophenyl)-7-pyrrolidin-1-ylpyrazolo[1,5-c]pyrimidin-3-yl]pyrimidin-2-amine (15 mg, 59%). 1H NMR (CDCl3): δ 8.05 (d, 1H), 7.65 (d, 1H), 7.60 (dd, 2H), 7.43 (d,1H), 7.10 (t, 2H), 6.27 (d, 1H), 5.05 (d, 1H), 4.29 (m, 1H), 4.09 (t, 4H), 1.99 (m, 6H), 1.45–1.78 (m, 6H). MS m/z 444 (M+1).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[CH:11]=[CH:10][CH:9]=1)(=O)=O.[K].CCSC(N(CC(C)C)CC(C)C)=O>O1CCCC1.O>[CH3:19][O:18][C:15]1[CH:16]=[C:17]2[C:12]([CH:11]=[CH:10][CH:9]=[C:8]2[CH:7]=[CH2:6])=[CH:13][CH:14]=1
Reactant: COc1ccc2cccc(CCOS(C)(=O)=O)c2c1
Agent: CCSC(=O)N(CC(C)C)CC(C)C
Agent: [K]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1cccc2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound obtained in Step A (21.4 mmol) is dissolved in 120 ml of tetrahydrofuran, and potassium tent-butylate (64.2 mmol) is added in small portions. After stirring for 30 minutes at ambient temperature, the reaction mixture is evaporated to dryness. The residue obtained is taken up in 150 ml of water and the aqueous phase is extracted twice with 60 ml of diethyl ether. The organic phase is washed with water, dried over magnesium sulphate, decolourised on vegetable carbon and evaporated. The residue obtained is purified on silica gel (eluant: petroleum ether) to yield the title product in the form of a yellow oil.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:37]1[S:41][N:40]=[CH:39][N:38]=1)[S:7]([C:10]1[CH:18]=[C:17]2[C:13]([C:14]([C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:29]=3[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)=[CH:15][N:16]2[CH3:19])=[CH:12][CH:11]=1)(=[O:9])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:19][N:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]([S:7]([NH:6][C:37]3[S:41][N:40]=[CH:39][N:38]=3)(=[O:8])=[O:9])[CH:18]=2)[C:14]([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:29]=2[CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:15]1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4cccc5c4CN(C(=O)OC(C)(C)C)CC5)cn(C)c3c2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(-c2cccc3c2CNCC3)c2ccc(S(=O)(=O)Nc3ncns3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tert-butyl 8-(6-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-1-methyl-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.223 g, 0.330 mmol) was dissolved in 0.5 mL of DCM and TFA (0.1 ml, 1.298 mmol) was added. The reaction was stirred overnight at room temperature. The reaction was concentrated, dissolved in acetonitrile, and passed through a Biotage Isolute® PE-AX ion exchange column (Biotage AB, Uppsala, SE). The column was flushed several times with acetonitrile, then the product was liberated by flushing several times with an HCl solution in 15% MeOH/EtOAc. The resulting solution was concentrated. The material was redissolved in DCM and ethyl acetate and dried over magnesium sulfate. The solution was filtered and concentrated to afford 1-methyl-3-(1,2,3,4-tetrahydroisoquinolin-8-yl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide as a light pink solid. m/z (ESI) 427.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm=7.89 (s, 1 H), 7.79 (s, 1 H), 7.57 (br. s., 1 H), 7.48 (d, J=8.2 Hz, 1 H), 7.39 (d, J=8.7 Hz, 1 H), 7.29 (d, J=7.9 Hz, 1 H), 7.25-7.13 (m, 2 H), 3.99 (br. s., 1 H), 3.89 (s, 3 H), 2.99 (br. s., 2 H)
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:13]([CH:14]=[O:15])=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]1.[CH3:16]I.O>CN(C)C=O>[CH3:16][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[C:13]([CH:14]=[O:15])[C:4]1=[O:3]
Reactant: CI
Reactant: O=Cc1cc2ccccc2[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c(C=O)cc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
Sodium hydride (555 w/w suspension in oil; 0.268 g) was added portionwise to a stirred suspension of 1,2-dihydro-2-oxoquinoline-3-carbaldehyde (1 g) in dimethylformamide (10 ml) which had been cooled in an ice bath. The mixture was allowed to warm to ambient temperature and was then heated to 60° C. for 1 hour. The mixture was recooled in an ice bath and methyl iodide (0.41 ml) was added. Dimethylformamide (50 ml) was added and the mixture was stirred at ambient temperature for 16 hours. The mixture was poured into water (50 ml) and extracted with methylene chloride (3×50 ml). The combined extracts were washed with water (50 ml) and evaporated. The residue was triturated under diethyl ether to give 1,2-dihydro-1-methyl-2-oxoquinoline-3-carbaldehyde as a pale yellow solid (0.81 g, 74%).
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][Zn+].[CH:11]1([C:17](Cl)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][C:17]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:18]
Reactant: O=C(Cl)C1CCCCC1
Reactant: Fc1ccccc1C[Zn+]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Product: O=C(Cc1ccccc1F)C1CCCCC1
Temperature: 0 °C

Procedure:
To a mixture of 36 ml of 2-fluorobenzylzinc chloride (0.5 M sol. in tetrahydrofuran) and 0.008 g of dichlorobis(triphenylphosphine)palladium(II) stirred at 0° C. was added dropwise via a syringe 2.14 ml of cyclohexanecarbonyl chloride. Afterwards, the reaction mixture was stirred at r.t. for 4 h, quenched with an aqueous saturated solution of ammonium chloride (25 ml), extracted with 20 ml of EtOAc, which was dried (Na2SO4) and evaporated to dryness in vacuo affording 3.52 g of the title compound as a crude, which could be used in the following step without further purification.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1([C:11]2[N:12]=[N:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([N:25]4[CH2:30][CH2:29][C:28]([CH2:37][C:38]([OH:41])([CH3:40])[CH3:39])([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[O:27][C:26]4=[O:42])[CH3:24])=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])C.Cl>CO>[OH:41][C:38]([CH3:39])([CH3:40])[CH2:37][C@@:28]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:27][C:26](=[O:42])[N:25]([C@H:23]([C:20]2[CH:19]=[CH:18][C:17]([C:14]3[N:13]=[N:12][C:11]([C:8]4([C:6]([OH:7])=[O:5])[CH2:10][CH2:9]4)=[CH:16][CH:15]=3)=[CH:22][CH:21]=2)[CH3:24])[CH2:30][CH2:29]1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(C(C)N4CCC(CC(C)(C)O)(c5ccccc5)OC4=O)cc3)nn2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H](c1ccc(-c2ccc(C3(C(=O)O)CC3)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4 M aqueous NaOH solution (1.5 mL) was added to a solution of 1-[6-(4-{1-[6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridazin-3-yl]-cyclopropane-carboxylic acid ethyl ester (0.81 g) in methanol (5 mL) at room temperature. The solution was stirred at room temperature for 2 h and was then neutralized with 1 M aqueous hydrochloric acid. Most of the methanol was evaporated, the residue was diluted with water, and the resulting mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4), and concentrated to give the title compound as a solid. Yield: 0.72 g (93% of theory); LC (method 1): tR=1.44 min; Mass spectrum (ESI+): m/z=516 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:11]3[CH:12]=[CH:13][C:14]([N+:16]([O-])=O)=[CH:15][C:10]=3[S:9](=O)[C:8]=2[CH:20]=1)([O-])=O>C(O)C.[Pd]>[CH:12]1[C:11]2[C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:20][C:8]=3[S:9][C:10]=2[CH:15]=[C:14]([NH2:16])[CH:13]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)S(=O)c1cc([N+](=O)[O-])ccc1-2
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)sc1cc(N)ccc12

Procedure:
Two batches of the above solid 3,7-dinitro-dibenzothiophene 5-oxide was hydrogenated at 45 psi in ethanol (250 mL for each batch) with 10% Pd on carbon (0.46 g each batch) for 2 hours. Two batches were combined and filtered through CELITE to give an orange solution. Hydrogen chloride gas was bubbled into the solution to form precipitate (at pH 1). The precipitate was filtered and washed with small amount of ethanol and dried on vacuum to give an orange solid Dibenzothiophene-3,7-diamine (2.46 g). LCMS-ESI−: calc'd for C12H10N2S: 214.29. Found: 215.0 (M+H+).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1)[CH3:11]>>[CH2:10]([O:12][C:13](=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:7]([C:5]2[S:6][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:9])[CH:16]=1)[CH3:11]
Reactant: O=C(O)c1ccc(Br)s1
Reactant: CCOC(=O)Cc1cccc(N)c1
Product: CCOC(=O)Cc1cccc(NC(=O)c2ccc(Br)s2)c1

Procedure:
5-Bromothiophene-2-carboxylic acid (232 mg, 1.1 mmol) was coupled with ethyl ester (6) (201 mg, 1.1 mmol) following Method C to give the title compound.
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([O:12][CH3:13])[CH:7]=1)([CH3:3])[CH3:2].CN(CCN(C)C)C.C([Li])CCC.CCCCCC.CN([CH:37]=[O:38])C>CC(OC)(C)C>[OH:38][CH:37]1[C:7]2[C:8]([O:12][CH3:13])=[N:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:14])[N:4]1[CH:1]([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: COc1cc(C(=O)NC(C)C)ccn1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Solvent: CCCCCC
Product: COc1nccc2c1C(O)N(C(C)C)C2=O
Reaction time: 3 h
Yield: 169.8 %

Procedure:
To a stirred suspension of 10.00 g N-isopropyl-2-methoxy-isonicotinamide (51.40 mmol), as obtainable from example 13, in 300 mL TBME were added at room temperature 17.2 mL TMEDA (113.3 mmol, 2.2 eq) resulting in the formation of a clear solution, which was then cooled to −780 C. Subsequently 102.8 mL n-butyllithium in hexane (1.5 M, 154.4 mmol, 3.0 eq) were then added over 35 min and stirring was continued at the same temperature for additional 3 h min and subsequently at −22° C. for another 3 h. To the slightly brown suspension, 13.9 mL DMF (180.0 mmol, 3.5 eq) were added at −28° C. The resulting suspension was quenched after 16 h 45 min by addition of 200 mL saturated aqueous NH4Cl. The mixture was extracted three times with 150 mL, in total 450 mL dichloromethane. The combined organic phases were dried over 20 g Na2SO4 (30 min) and filtered. The filter cake was washed with 40 mL dichloromethane. After evaporation of solvent in a rotary evaporator (40° C./20 mbar), the crude product (19.400 g, 170% w/w, regioselectivity: 11.68:1, as determined by 1H-NMR) was obtained as a brown oil (HPLC purity 77.6%).
Reaction SMILES: Cl[CH2:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[C:5]#[CH:6].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[C:5]#[CH:6])=[CH:13][CH:12]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: C#CC(C)(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CC(C)(C)C(=O)COc1ccc(Cl)cc1
Yield: 94 %

Procedure:
A solution of 98 g (0.67 mole) of 1-chloro-3,3-dimethyl-pent-4-in-2-one is added dropwise, with stirring, to a boiling mixture of 86.1 g (0.67 mole) of 4-chlorophenol and 92.5 g (o.67 mole) of potassium carbonate powder in 500 ml of acetone. After five hours the mixture is filtered, the filtrate is evaporated, the residue is taken up in 250 ml of methylene chloride and this solution is washed with 200 ml of 1N sodium hydroxide solution and 200 ml of water. After the solvent has been distilled off, 149 g (that is to say 94% of theory) of 1-(4-chlorophenoxy)-3,3-dimethyl-pent-4-in-2-one are obtained as a colorless viscous oil, which upon standing solidifies to crystals.