Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[S:21][CH:20]=[CH:19][C:18]=2[CH:22]=1.Cl[Si:24]([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[S:21][C:20]([Si:24]([CH3:27])([CH3:26])[CH3:25])=[CH:19][C:18]=2[CH:22]=1
Reactant: Brc1ccc2sccc2c1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cc2cc(Br)ccc2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
To a solution of diisopropylamine (15.5 mL, 110 mmol) in THF (100 mL) at 0° C. was added n-butyllithium (40 mL of 2.5M in hexanes, 100 mmol). The resultant reaction solution was stirred at 0° C. for 30 minutes and then cooled to −40° C., before it was cannulated to a solution of 5-bromobenzothiophene (10.5 g, 50.0 mmol) and chlorotrimethylsilane (12.7 mL, 100 mmol) in THF (150 mL) at −78° C. The reaction solution was stirred at −78° C. for 1 hour, and then it was quenched with aqueous ammonium chloride at −78° C. and warmed to room temperature. The resultant mixture was extracted with ethyl acetate and the organic extract obtained was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue obtained was purified by flash column chromatography (hexanes to 98:2 hexanes/ethyl acetate) to give the desired 5-bromo-2-trimethylsilylbenzothiophene (14.1 g, 98%) as a clear colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.93 (d, J=2.0 Hz, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.39 (dd, J=8.5, 2.0 Hz, 1H), 7.37 (s, 1H), 0.38 (s, 9H).
Reaction SMILES: [C:1]([CH:4]1[NH:9][CH2:8][C:7]2[S:10][C:11]([CH2:13][CH2:14]Br)=[CH:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:17][C:18]1[CH:32]=[CH:31][C:21]2[C:22]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:23][O:24][C:20]=2[CH:19]=1.C([O-])(=O)C([O-])=O>>[C:1]([CH:4]1[NH:9][CH2:8][C:7]2[S:10][C:11]([CH2:13][CH2:14][N:28]3[CH2:27][CH2:26][CH:25]([C:22]4[C:21]5[CH:31]=[CH:32][C:18]([F:17])=[CH:19][C:20]=5[O:24][N:23]=4)[CH2:30][CH2:29]3)=[CH:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)C1Cc2cc(CCBr)sc2CN1
Agent: Cl
Agent: O=C([O-])C(=O)[O-]
Product: CC(=O)C1Cc2cc(CCN3CCC(c4noc5cc(F)ccc45)CC3)sc2CN1
Yield: 68.9 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 0.7 g of 5-acetyl-2-(2-bromoethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine and 0.61 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.7 g of 5-acetyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno[ 2,3-c]pyridine as an oil, m.p. 170°-172° C. as oxalate thereof.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1.CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]1([S:7]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)CCN2
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 96093.7 %

Procedure:
To a mixture of DMAP (1.5 g), benzenesulfonyl chloride (24.0 g, 136 mmol) and indoline (14.7 g, 0.124 mmol) in CH2Cl2 (200 mL) was added dropwise Et3N (19.0 g, 186 mmol) at 0° C. The mixture was stirred at room temperature overnight. The organic layer washed with water (2×), dried over Na2SO4 and concentrated to dryness under reduced pressure to obtain 1-(phenylsulfonyl)indoline (30.9 g, 96%).
Reaction SMILES: [NH:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[CH2:16]([CH:18]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:19]Br)[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:19][CH:18]([CH2:16][CH3:17])[CH2:21][CH2:22][CH2:23][CH3:24])[CH:13]=2)[CH:8]=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: CCCCC(CC)CBr
Reactant: CC(=O)Nc1cccc2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC(CC)COc1ccc2cccc(NC(C)=O)c2c1
Yield: 81.2 %

Procedure:
81 g of 1-acetamino-7-hydroxy-naphthalene and 85 g of 2-ethylhexyl bromide were reacted with each other in 250 ml of dimethylformamide in the presence of 66.5 g of anhydrous potassium carbonate over a steam bath for 5 hours to obtain 102.4 g of 1-acetamino-7-(2-ethylhexyloxy)naphthalene. This compound was dissolved in a mixed solution of 100 ml of acetic anhydride and 200 ml of glacial acetic acid. 44.2 g of concentrated nitric acid having a specific gravity of 1.42 was dropwise added thereto over about one hour at a temperature of not higher than 10° C., and the components were reacted for about 3 hours at about 10° C. Crystals which precipitated were collected by filtration to obtain 43.5 g of 1-acetamino-4-nitro-7-(2-ethylhexyloxy)naphthalene.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3].[C:14]1([S:24](Cl)(=[O:26])=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.O.Cl>[OH-].[Na+].O1CCOCC1>[C:14]1([S:24]([NH:1][C@H:2]([C:4]([N:6]2[CH2:13][CH2:12][CH2:11][C@H:7]2[C:8]([OH:10])=[O:9])=[O:5])[CH3:3])(=[O:26])=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](NS(=O)(=O)c1cccc2ccccc12)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
L-alanyl-L-proline (1.86 g, 10 mmole) was dissolved in 1N aqueous sodium hydroxide (10 ml)-dioxane (5 ml), and dioxane (5 ml) solution of α-naphthalenesulfonylchloride (2.26 g, 10 mmole) was added dropwise to the solution while cooling with ice and stirring while keeping pH value thereof to between 10 and 11 with 1N aqueous sodium hydroxide. After the addition, the mixture was stirred further for 2 hours at room temperature. Water (20 ml) was added thereto and the mixture thus obtained was washed with diethyl ether (40 ml). The water layer was filtered and the filtrate thus obtained was adjusted to pH 2.0 with 1N aqueous hydrochloric acid while cooling with ice and stirring and extracted with ethyl acetate (100 ml). The ethyl acetate was washed with 1N aqueous hydrochloric acid (50 ml) and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure and crystallized by cooling with ice to give N-α-naphthalenesulfonyl-L-alanyl-L-proline[yield: 1.77 g, 47.0%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1.[CH:21]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)=[CH2:22].C(N(C(C)C)CC)(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[N:26]1[CH:27]=[CH:28][C:23](/[CH:21]=[CH:22]/[C:2]2[C:10]3[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=3)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=2)=[CH:24][CH:25]=1
Reactant: C=Cc1ccncc1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(/C=C/c2ccncc2)c2ccc(C=O)cc21
Temperature: 100 °C
Yield: 49 %

Procedure:
A solution of 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (2.0 g, 4.98 mmol), 4-vinylpyridine (0.69 mL, 6.47 mmol), diisopropylethylamine (1.74 mL, 9.96 mmol) and DMF (50 mL) was purged with Ar gas for 20 min at which time Pd(OAc)2 (112 mg, 0.500 mmol) and P(o-tol)3 (457 mg, 1.50 mmol) were added and the reaction heated to 100° C. for 20 hours. The reaction was cooled to room temperature and partitioned between EtOAc and NH4Cl. The aqueous layer was extracted with EtOAc (3×) and the combined organics washed with water (2×) and brine (2×). The organic layer was dried over MgSO4 and the EtOAc removed in vacuo. The residue was purified by column chromatography (silica gel, 97:3 CH2Cl2/MeOH) to give 927 mg, 49% of the title compound which was used without further purification. MS ESI 380.2 [M+H]+, calcd for [C21H25N3O2Si+H]+ 380.18.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[S:24][C:16]3=[N:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N:15]3[CH2:14][CH2:13]2)(=O)=O)=CC=1.[CH2:26]([NH:29][CH2:30][CH2:31][CH3:32])[CH2:27][CH3:28].O1CCOCC1>O>[CH2:26]([N:29]([CH2:11][CH:12]1[S:24][C:16]2=[N:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:15]2[CH2:14][CH2:13]1)[CH2:30][CH2:31][CH3:32])[CH2:27][CH3:28]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCn3c(nc4ccccc43)S2)cc1
Reactant: CCCNCCC
Solvent: O
Solvent: C1COCCO1
Product: CCCN(CCC)CC1CCn2c(nc3ccccc32)S1
Yield: 14.3 %

Procedure:
To 1.12 g of 3,4-dihydro-2-p-toluenesulfonyloxymethyl-2H-(1,3)-thiazino[3,2-a]benzimidazole were added 4 ml of di-n-propylamine and 20 ml of dioxane. The mixture was reacted in a sealed tube, at 120° C. and for 67 hours. After cooling down the temperature of the reaction mixture, it was condensed under reduced pressure. Water was added to the condensed reaction mixture, followed by an extraction with chloroform and dried over anhydrous magnesium sulfate. Chloroform was evaporated under reduced pressure and the residue was chromatographed on silica gel and eluted with chloroform to obtain 0.13 g (yield: 14.3%) of the intended product, m.p. 82°-84° C.;
Reaction SMILES: O1CCCC1.Cl.[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[C:10]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:9]=1.[CH3:28][C:29](=[CH2:33])[C:30](Cl)=[O:31]>C(N(CC)CC)C>[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[C:10]([N:22]2[CH2:27][CH2:26][N:25]([C:30](=[O:31])[C:29]([CH3:33])=[CH2:28])[CH2:24][CH2:23]2)[N:9]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: C=C(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)C(=O)N1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Reaction time: 0.5 h
Yield: 39 %

Procedure:
To 20 ml of tetrahydrofuran were added 2.4 g of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline hydrochloride and 2.6 g of triethylamine, after which the mixture was stirred for 30 minutes. There was then added 0.6 g of 2-methylacryloyl chloride, after which the mixture was stirred at room temperature for 8 hours. The crystals which were produced were collected by filtration, washed with water and recrystallized from ethanol to give 0.8 g of the desired Compound No. 2 in the form of colourless needles melting at 262°-263° C. (with decomposition).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2.CN(C=O)C.[Br:19][C:20]1[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=1>CCOC(C)=O>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([N:6]2[CH:5]=[C:4]3[C:8]([C:9]([C:11]([NH2:13])=[O:12])=[CH:10][C:2]([F:1])=[CH:3]3)=[N:7]2)=[CH:22][CH:21]=1
Reactant: NC(=O)c1cc(F)cc2cn[nH]c12
Reactant: Fc1ccc(Br)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1cc(F)cc2cn(-c3ccc(Br)cc3)nc12
Temperature: 180 °C

Procedure:
To a solution of D2 (1.0 eq) in DMF (0.2 M) K2CO3 (1.3 eq) and 4-bromofluorobenzene (10.0 eq) were added and the reaction mixture was heated under MW conditions at 180° C. for 20 min. The reaction mixture was cooled to RT and diluted with EtOAc. The organic phase was washed with brine; dried (Na2SO4). Evaporation of the solvent gave (D3) which was purified by chromatography on silica gel eluting with 50-70% EtOAc/Petroleum ether to obtain the title compound as a yellow powder. 1H NMR (400 MHz, DMSO-d6, 300K) δ 9.34 (1H, s), 8.50 (1H, br. s), 8.17 (2H, d, J=9.0 Hz), 8.03 (1H, br. s), 7.90-7.80 (4H, m). MS (ES+) C14H9BrFN3O requires: 334/336. Found: 335/337 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:21](I)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[F:23][C:24]1[CH:25]=[N:26][CH:27]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:29]=1>>[Cl:1][C:2]1[C:21]([C:28]2[CH:27]=[N:26][CH:25]=[C:24]([F:23])[CH:29]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(I)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 56 using 6-chloro-5-iodo-N-(4-(trifluoromethoxy)phenyl)nicotinamide and 3-fluoropyridine-5-boronic acid pinacol ester to afford the title product as a beige solid. UPLC-MS (Condition 2) tR=1.13 min, m/z=412 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.39 (d, J=8.99 Hz, 2H) 7.85 (d, J=8.99 Hz, 2H) 8.02-8.12 (m, 1H) 8.49 (d, J=2.35 Hz, 1H) 8.64-8.76 (m, 2H) 8.99 (dd, J=2.35, 0.78 Hz, 1H) 10.65 (s, 1H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](Cl)=[O:7])(=[O:3])[CH3:2].[Br:9][C:10]1[CH:11]=[C:12]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:13]([O:22][CH3:23])=[C:14]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:4][CH2:5][C:6]([N:19]1[CH2:18][CH2:17][N:16]([C:14]2[CH:15]=[C:10]([Br:9])[CH:11]=[C:12]([C:24]([CH3:25])([CH3:27])[CH3:26])[C:13]=2[O:22][CH3:23])[CH2:21][CH2:20]1)=[O:7])(=[O:3])[CH3:2]
Reactant: COc1c(N2CCNCC2)cc(Br)cc1C(C)(C)C
Reactant: CC(=O)OCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(N2CCN(C(=O)COC(C)=O)CC2)cc(Br)cc1C(C)(C)C
Reaction time: 1 h

Procedure:
Acetoxyacetyl chloride (0.14 ml) was added to a solution of 1-[5-bromo-3-(tert-butyl)-2-methoxyphenyl]piperazine (360 mg) and triethylamine (0.31 ml) in CH2Cl2 (5 ml) while cooling on ice and the mixture was brought to room temperature and stirred for 1 hour. After quenching the reaction with brine, extraction was performed with ethyl acetate to yield a crude product of 2-{4-[5-bromo-3-(tert-butyl)-2-methoxyphenyl]piperazino}-2-oxoethyl acetate as a red oil. This crude product was dissolved in methanol (2.5 ml) and potassium carbonate (167 mg) was added. After 15 minutes, brine was added, extraction was performed with ethyl acetate, the extract was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (285 mg) as light orange crystals (67%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][Cl:15])=[CH:10][N:9]=1.C1OCCOCCOCCOCCOCCOC1.[CH2:34]([O:36][C:37]([C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([OH:48])[CH:46]=2)[N:41]([C:49]2[CH:54]=[CH:53][C:52]([O:55][C:56]([F:59])([F:58])[F:57])=[CH:51][CH:50]=2)[C:40]=1[CH2:60][C:61]([O:63][CH2:64][CH3:65])=[O:62])=[O:38])[CH3:35]>CCOC(C)=O.CN(C=O)C>[CH2:34]([O:36][C:37]([C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([O:48][C:8]3[CH:13]=[CH:12][C:11]([CH2:14][Cl:15])=[CH:10][N:9]=3)[CH:46]=2)[N:41]([C:49]2[CH:50]=[CH:51][C:52]([O:55][C:56]([F:59])([F:57])[F:58])=[CH:53][CH:54]=2)[C:40]=1[CH2:60][C:61]([O:63][CH2:64][CH3:65])=[O:62])=[O:38])[CH3:35]
Reactant: ClCc1ccc(Cl)nc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(OC(F)(F)F)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(CCl)cn3)ccc2n1-c1ccc(OC(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
K2CO3 (138 mg, 1.0 mmol), 2-chloro-5-chloromethylpyridine (32 mg, 0.2 mmol) and 18-crown-6 (5 mg) were added to a mixture of 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-trifluoromethoxyphenyl)indole-3-carboxylic acid ethyl ester (90 mg, 0.2 mmol, see step (b) Example 9) and DMF (5 mL). The mixture was stirred for 48 h at 70° C., cooled, diluted with EtOAc, filtered through Celite®, concentrated and purified by chromatography. Yield 60 mg (520%).
Reaction SMILES: [C:1]([S@@:5](/[N:7]=[CH:8]/[CH2:9][CH2:10][C@@:11]1([C:26]([O:28][CH3:29])=[O:27])[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:6])([CH3:4])([CH3:3])[CH3:2].[F:30][C:31]1[CH:32]=[C:33]([Mg]Br)[CH:34]=[C:35]([F:37])[CH:36]=1>C1(C)C=CC=CC=1.C1COCC1>[C:1]([S@@:5]([NH:7][C@H:8]([C:33]1[CH:32]=[C:31]([F:30])[CH:36]=[C:35]([F:37])[CH:34]=1)[CH2:9][CH2:10][C@@:11]1([C:26]([O:28][CH3:29])=[O:27])[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])=[O:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1cc(F)cc([Mg]Br)c1
Reactant: COC(=O)[C@]1(CC/C=N/[S@@](=O)C(C)(C)C)CCCN1C(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)[C@]1(CC[C@H](N[S@@](=O)C(C)(C)C)c2cc(F)cc(F)c2)CCCN1C(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of 1-benzyl 2-methyl (2R)-2-((3E)-3-{[(S)-tert-butylsulfinyl]imino}propyl)pyrrolidine-1,2-dicarboxylate from Step B (1.56 g, 3.70 mmol) in toluene (30 mL) at −78° C. was added 3,5-difluorophenylmagnesium bromide (14.8 mL of a 0.5 M solution in THF, 7.41 mmol) dropwise. The reaction mixture was stirred for 30 min at −78° C., 3.5 h at −10° C., and then at ambient temperature for 1.5 h. The mixture was quenched with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—95:5 to 0:100, to give the title compound. MS: m/z=537 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([CH:14]=[O:15])[N:11]([CH3:16])[N:10]=2)=[CH:5][CH:4]=1.[CH3:17][C:18]1[C:22](B(O)O)=[C:21]([CH3:26])[O:20][N:19]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O>[CH3:17][C:18]1[C:22]([C:13]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[N:10][N:11]([CH3:16])[C:12]=2[CH:14]=[O:15])=[C:21]([CH3:26])[O:20][N:19]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: COc1ccc(-c2cc(C=O)n(C)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2nn(C)c(C=O)c2-c2c(C)noc2C)cc1
Yield: 32 %

Procedure:
A mixture of 4-bromo-3-(4-methoxyphenyl-1-methyl-1H-pyrazole-5-carbaldehyde (74.5 mg, 0.25 mmol), 3,5-dimethylisoxazol-4-ylboronic acid (53.4 mg, 0.38 mmol), K2CO3 (140 mg, 1.01 mmol) and Pd(PPh3)4 (14.6 mg, 0.01 mmol) in 1 DME/water (1 mL/1 mL) was flushed with argon and irradiated in the microwave at 140° C. for 30 min, extracted with EtOAc (3×4 mL) after 3 mL water were added. The mixture was concentrated and purified on silica gel to give 4-(3,5-dimethylisoxazol-4-yl)-3-(4-methoxyphenyl)-1-methyl-1H-pyrazole-5-carbaldehyde (25.6 mg, 0.08 mmol, 33%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH2:12]([NH2:15])[CH2:13][NH2:14].Cl>O>[ClH:1].[NH2:14][CH2:13][CH2:12][NH:15][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1Cl
Reactant: NCCN
Agent: Cl
Solvent: O
Product: NCCNc1cc(O)ccc1[N+](=O)[O-]
Temperature: -10 °C

Procedure:
0.432 mol (75 g) of 3-chloro-4-nitrophenol is introduced into 282 ml of ethylenediamine and the reaction medium is then heated in a boiling water-bath for 13 hours. The cooled solution is then poured into 2.6 liters of iced water to which 1.09 liters of hydrochloric acid (d=1.18) has been added. After cooling at -10° C. for a few hours, the 3-β-aminoethylamino-4-nitrophenol hydrochloride crystallises. It is filtered off and washed with an ice-cold 2N solution of hydrochloric acid and then with ethanol. After recrystallisation from water, the dried product melts with decomposition at a temperature above 260° C.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][N:7]([C:9]3[CH:10]=[C:11]([CH2:19][C:20]([NH2:22])=[O:21])[C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:6][CH2:5][NH:4]2)[CH2:2]1.C[O:24][C:25](=O)[C:26]([C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]([CH3:37])[CH:29]=1)=O.CC([O-])(C)C.[K+]>C1COCC1>[CH2:2]1[C:3]2([CH2:8][N:7]([C:9]3[CH:10]=[C:11]([C:19]4[C:20](=[O:21])[NH:22][C:25](=[O:24])[C:26]=4[C:28]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]([CH3:37])[CH:29]=4)[C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:6][CH2:5][NH:4]2)[CH2:1]1
Reactant: COC(=O)C(=O)c1cn(C)c2ccccc12
Reactant: NC(=O)Cc1cc(N2CCNC3(CC3)C2)cc2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1cc(C2=C(c3cc(N4CCNC5(CC5)C4)cc4ccccc34)C(=O)NC2=O)c2ccccc21
Reaction time: 0.08 h

Procedure:
2-[3-(4,7-Diaza-spiro[2.5]oct-7-yl)-naphthalen-1-yl]-acetamide (100 mg, 0.30 mmol) and (1-methyl-1H-indol-3-yl)-oxo-acetic acid methyl ester (97 mg, 0.44 mmol) are azeotroped three times with dry THF and then dissolved in dry THF (3 ml). A solution of 1.0 M KOtBu In THF (1.2 ml) is added dropwise over 20 minutes at RT. After 5 minutes, TLC analysis indicates complete conversion of starting materials. The reaction is quenched by the addition of water (5 ml). The mixture is diluted with EtOAc and washed twice with saturated aq. NH4Cl. The aqueous layers are back extracted twice with EtOAc. The combined organic layers are dried over Na2SO4 and the solvent is evaporated. The residue is purified by FCC (EtOAc/AcOH/H2O 800:55:45) to afford the title compound as its acetate salt. The compound is dissolved in MeOH/TFA and the solvent is removed to yield the title compound as its trifluoroacetate salt. 1H NMR (DMSO, 400 MHz) δ 0.95 (M, 4H), 3.39 (br, 4H), 3.49 (br, 2H), 3.86 (s, 3H), 6.16 (d, J=7.9 Hz, 1H), 6.46 (dd, J=6.6/7.9 Hz, 1H), 7.00 (dd, J=6.6/7.9 Hz, 1H), 7.13 (dd, J=7.6/7.6 Hz, 1H), 7.40 (m, 4H), 7.55 (d, J=8.5 Hz, 1H), 7.78 (d, J=7.6 Hz, 1H), 8.14 (s, 1H), 9.10 (br, 2H), 11.17 (s, 1H); ES-MS: 463 [M+H]+.
Reaction SMILES: C1C(C(O)CCCN2CC3C4C=C(F)C=CC=4N(C4C=CC(F)=CC=4)C=3CC2)=CC=C(F)C=1.[F:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41]N)=[CH:37][CH:36]=1.[C:43]([N:48]1[CH2:53][CH2:52][C:51](=O)[CH2:50][CH2:49]1)([O:45][CH2:46][CH3:47])=[O:44]>>[F:34][C:35]1[CH:40]=[CH:39][C:38]2[NH:41][C:51]3[CH2:52][CH2:53][N:48]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:49][C:50]=3[C:37]=2[CH:36]=1
Reactant: NNc1ccc(F)cc1
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: OC(CCCN1CCc2c(c3cc(F)ccc3n2-c2ccc(F)cc2)C1)c1ccc(F)cc1
Product: CCOC(=O)N1CCc2[nH]c3ccc(F)cc3c2C1

Procedure:
Plattner et al. and Harbert et al. also describe the earliest synthesis of flutroline: p-fluorophenylhydrazine is condensed with N-carbethoxy-4-piperidone to form 8-fluoro-2-carbethoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. By the Ullman reaction the latter is arylated to form the 5-(p-fluorophenyl) derivative and then hydrolyzed under vigorous basic conditions to yield 8-fluoro-5-(p-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (an intermediate common to the present processes). The earlier synthesis of flutroline is completed by 2-alkylation with 3-(p-fluorobenzoyl)propyl chloride and reduction of the ketone to an alcohol group with sodium borohydride.