Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([CH2:9][CH:10]1[O:24][CH:13]2[O:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:16][CH:12]2[CH2:11]1)#[N:8].O.[OH-].[Na+]>C1COCC1>[NH2:8][CH2:7][CH2:9][CH:10]1[O:24][CH:13]2[O:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[CH2:16][CH:12]2[CH2:11]1
Reactant: N#CCC1CC2CC(c3ccc(F)cc3)OC2O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCCC1CC2CC(c3ccc(F)cc3)OC2O1
Reaction time: 8 h

Procedure:
Lithium aluminium hydride (92 mg, 2.5 mmol) was added to a stirred solution of 2-(cyanomethyl)-5-(4-fluorophenyl)hexahydrofuro[2,3-b]furan (300 mg, 1.2 mmol) in dry THF. The reaction mixture was stirred overnight and water (0.9 ml), 15% sodium hydroxide (0.9 ml) and water (2.7 ml) are added in succession. The white percipitate was filtered off and the solvent removed under reduced pressure to give crude 5-(2-aminoethyl)-2-(4-fluorophenyl)hexahydrofuro[2,3-b]furan which is used directly in the next step.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].I[CH2:13][CH2:14][CH2:15][CH3:16].O>CN(C)C=O>[CH2:13]([CH:2]([C:1]#[N:5])[C:3]#[N:4])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCI
Reactant: N#CCC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(C#N)C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
26.4 g of malononitrile was dissolved in 60 ml of N,N-dimethylformamide and 56 g of potassium carbonate was added thereto, followed by stirring for 1 hour at room temperature. To the solution was added 40 g of iodobutane at about 0° C. and stirred for 30 minutes at the same temperature and for additional 4 hours at room temperature. Then, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography to give 17 g of 2-butylmalononitrile.
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.COC(=O)[O-].C([N+](C)(C)C)CCC.[CH:24]#[N:25].OP(O)(O)=O>>[O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.[C:24]([C:4]1([CH3:10])[CH2:5][C:6]([CH3:8])([CH3:7])[CH2:9][C:2](=[O:1])[CH2:3]1)#[N:25]
Reactant: C#N
Agent: CCCC[N+](C)(C)C
Agent: COC(=O)[O-]
Agent: O=P(O)(O)O
Solvent: CC1=CC(=O)CC(C)(C)C1
Product: CC1(C)CC(=O)CC(C)(C#N)C1

Procedure:
To 622 g (4.5 mol) of isophorone in the presence of 4.14 g (0.02mol) of butyltrimethylammonium methylcarbonate there are added 288.3 g of a mixture of 3 mol of HCN and 1.5 mol of isophorone over a period of 120 min and at a temperature of 115° C. Following neutralization with 4 g of H3PO4 the mixture is distilled. There are obtained 424.3 g of isophorone and 478.3 g of 3-cyano-3,5,5-trimethylcyclohexanone. This is equivalent to a yield of 98.8% based on converted isophorone and 96.5% based on HCN used.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[N:18][CH:17]=[C:16]([Cl:20])[C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=1)=[O:5]>C(Cl)Cl.CO.O=[Mn]=O>[Cl:20][C:16]1[CH:17]=[N:18][CH:19]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]=[O:15])=[CH:12][CH:13]=1)=[O:5]
Reactant: O=C(NCc1ccc(CO)cc1)c1c(Cl)cncc1Cl
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: CO
Product: O=Cc1ccc(CNC(=O)c2c(Cl)cncc2Cl)cc1
Temperature: 25 °C
Yield: 66.1 %

Procedure:
To a partially dissolved solution of 3,5-dichloro-N-(4-hydroxymethyl-benzyl)-isonicotinamide (730 mg, 2.35 mmol) in CH2Cl2 (12 mL) and MeOH (1 mL) was added MnO2 (2.43 g, 23.5 mmol) and the resultant suspension was stirred at 40° C. for 16 hours. The reaction mixture was cooled to room temperature and filtered through Celite. The cake was washed with CH2Cl2/MeOH (100:3) and the filtrate was concentrated under reduced pressure to afford a crude white solid (630 mg). Purification by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 100:1:1) afforded the desired aldehyde (480 mg, 66%) as a white solid. 1H NMR (CDCl3) δ 4.78 (d, 2H, J=6.0 Hz), 6.19 (br s, 1H), 7.58 (d, 2H, J=9.0 Hz), 7.90 (d, 2H, J=9.0 Hz), 8.55 (s, 2H), 10.02 (s, 1H).
Reaction SMILES: I.[CH2:2]([N:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[S:8][C:7]1=[NH:15])[CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([O:33][CH3:34])=[C:28]([CH:32]=1)[C:29](Cl)=[O:30]>C(Cl)Cl>[CH2:2]([N:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[S:8]/[C:7]/1=[N:15]\[C:29](=[O:30])[C:28]1[CH:32]=[C:24]([Cl:23])[CH:25]=[CH:26][C:27]=1[O:33][CH3:34])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCn1cc(C(C)(C)C)sc1=N
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Agent: I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCn1cc(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1OC
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of Example 6A (1.4 g, ˜4 mmol) and triethylamine (1.4 mL, 10 mmol) in CH2Cl2 (35 mL) at 0° C. was added 5-chloro-2-methoxy-benzoyl chloride (820 mg, 4 mmol), the mixture was allowed to warm to room temperature was stirred for 14 hours. The mixture was washed sequentially with water, brine, dried with anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography (6:2:2 Hexane-EtOAc-CH2Cl2) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ: 0.94 (t, J=7 Hz, 3H), 1.30 (m+s, 11H), 1.75 (m, 2H), 3.77 (s, 3H), 4.14 (t, J=7 Hz, 2H), 7.10 (d, J=9 Hz, 1H), 7.31 (s, 1H), 7.43 (d-d, J=9 Hz, 3 Hz, 1H), 7.65 (d, J=3 Hz, 1H); MS (ESI+) m/z 381 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.[O:20]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([CH2:31][C:32]([OH:34])=O)[CH:28]=[CH:29][CH:30]=2)=[CH:21]1.Cl.[Cl:36][C:37]1[CH:38]=[CH:39][C:40]([NH:47][C:48](=[O:54])[C@@H:49]2[CH2:53][CH2:52][CH2:51][NH:50]2)=[C:41]([CH:46]=1)[C:42]([O:44][CH3:45])=[O:43].ON1C2C=CC=CC=2N=N1>C(OCC)(=O)C.O.CC(N(C)C)=O>[Cl:36][C:37]1[CH:38]=[CH:39][C:40]([NH:47][C:48](=[O:54])[C@@H:49]2[CH2:53][CH2:52][CH2:51][N:50]2[C:32](=[O:34])[CH2:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([C:22]3[CH:23]=[CH:24][O:20][CH:21]=3)[CH:26]=2)=[C:41]([CH:46]=1)[C:42]([O:44][CH3:45])=[O:43]
Reactant: O=C(O)Cc1cccc(-c2ccoc2)c1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc(Cl)ccc1NC(=O)[C@@H]1CCCN1C(=O)Cc1cccc(-c2ccoc2)c1
Reaction time: 8 h
Yield: 88.1 %

Procedure:
Under ice-cooling, 0.096 mL (0.690 mmol) of triethylamine and 144 mg (0.752 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added while stirring to a DMAc (5 mL) solution comprising 127 mg (0.627 mmol) of [3-(furan-3-yl)phenyl]acetic acid, 200 mg (0.627 mmol) of methyl 5-chloro-2-(L-prolylamino)benzoate hydrochloride, and 102 mg (0.752 mmol) of 1-hydroxybenzotriazole; and the mixture was stirred overnight. After water and ethyl acetate were added to the reaction mixture and the mixture was stirred, the organic layer was separated and washed with saturated sodium bicarbonate water, 0.1% hydrochloric acid, and saturated saline, followed by drying over sodium sulfate, filtration, and condensation. The crude product was purified by silica gel chromatography (n-hexane/ethyl acetate=4/1→2/1→1/1), thereby giving 258 mg of methyl 5-chloro-2-[(1-{[3-(furan-3-yl)phenyl]acetyl}-L-prolyl)amino]benzoate (yield: 88%).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.CCOCC.[CH2:14]([NH:16][C:17](=[O:26])[C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[Cl:25])[CH3:15].[CH3:27][Si:28](Cl)([CH3:30])[CH3:29]>C1COCC1>[Cl:24][C:22]1[C:23]([Si:28]([CH3:30])([CH3:29])[CH3:27])=[C:18]([C:19]([Cl:25])=[CH:20][CH:21]=1)[C:17]([NH:16][CH2:14][CH3:15])=[O:26]
Reactant: C[Si](C)(C)Cl
Reactant: CCNC(=O)c1cc(Cl)ccc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCNC(=O)c1c(Cl)ccc(Cl)c1[Si](C)(C)C
Temperature: -100 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
A solution of 1.5M LDA in THF (13 mL, 19.5 mmol) was added dropwise to an ether/liquid N2 cooled solution of N-ethyl 2,5-dichlorobenzamide (2.0 g, 9.2 mmol) and TMSCl (1.5 mL, 11.5 mmol) in THF (50 mL), maintaining the internal reaction temperature ≦−80° C. The resulting reaction mixture was stirred at −100° C. for 30 min, then was partitioned between ether and sat aq NaHCO3. The ether solution was dried (MgSO4), concentrated, and crystallized from EtOAc/hexanes to afford 1.15 g of the title compound as a white solid. m.p. 150-153° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCCOC)[C:19](=[O:27])[C:18]3[C:13](=[CH:14][C:15](I)=[CH:16][CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.O=C1C2C(=CC(C3C=CC=CC=3)=CC=2)N=C(N2C=C(C(O)=O)C=N2)N1.[Cl:54][C:55]1[CH:56]=[C:57](B(O)O)[CH:58]=[CH:59][CH:60]=1>>[Cl:54][C:55]1[CH:60]=[C:59]([C:15]2[CH:14]=[C:13]3[C:18]([C:19](=[O:27])[NH:20][C:11]([N:9]4[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]4)=[N:12]3)=[CH:17][CH:16]=2)[CH:58]=[CH:57][CH:56]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(I)ccc3c(=O)n2COCCOC)c1
Reactant: OB(O)c1cccc(Cl)c1
Agent: O=C(O)c1cnn(-c2nc3cc(-c4ccccc4)ccc3c(=O)[nH]2)c1
Product: O=C(O)c1cnn(-c2nc3cc(-c4cccc(Cl)c4)ccc3c(=O)[nH]2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 184, steps C-E using 1-[7-iodo-3-(2-methoxy-ethoxymethyl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Intermediate from Example 184, product from step B) and 3-chlorophenylboronic acid in step C. MS (ESI): mass calcd. for C18H11ClN4O3, 366.1; m/z found, 367.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 13.04 (br s, 1H), 12.94 (br s, 1H), 8.97 (s, 1H), 8.28 (s, 1H), 8.21 (d, J=8.0 Hz, 1H), 8.00 (s, 1H), 7.91 (s, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.82 (d, J=6.7 Hz, 1H), 7.60-7.52 (m, 2H).
Reaction SMILES: [Cl:1]/[C:2](=[CH:7]\[C@@H:8]1[C@H:10]([C:11](Cl)=[O:12])[C:9]1([CH3:15])[CH3:14])/[C:3]([F:6])([F:5])[F:4].[CH3:16][C:17]1[C:24]([F:25])=[C:23]([F:26])[C:20]([CH2:21][OH:22])=[C:19]([F:27])[C:18]=1[F:28]>>[Cl:1]/[C:2](/[C:3]([F:6])([F:5])[F:4])=[CH:7]\[C@@H:8]1[C@H:10]([C:11]([O:22][CH2:21][C:20]2[C:19]([F:27])=[C:18]([F:28])[C:17]([CH3:16])=[C:24]([F:25])[C:23]=2[F:26])=[O:12])[C:9]1([CH3:15])[CH3:14]
Reactant: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Reactant: Cc1c(F)c(F)c(CO)c(F)c1F
Product: Cc1c(F)c(F)c(COC(=O)[C@H]2[C@@H](/C=C(\Cl)C(F)(F)F)C2(C)C)c(F)c1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 104.3 %

Procedure:
Cis-Z 3-(2-chloro-1,1,1-trifluoro-2-propenyl)-2,2-dimethylcyclopropane carbonyl chloride (257 g) was charged to a reactor fitted with an agitator, thermometer, sub-surface nitrogen inlet and jacketed dropping funnel. Nitrogen sparging was applied to the acid chloride and maintained throughout subsequent processing. Molten 4-methyl-2,3,5,6-tetrafluorobenzyl alcohol (188.1 g) was charged to the dropping funnel. The temperature in the funnel was maintained at 80° C. The alcohol was charged to the acid chloride mixture over three hours. The maximum reaction temperature allowed during the addition was 45° C. On completion of the addition the temperature of the reaction mass was raised to 95° C. and held for 2 hours. GC analysis was used to determine if full conversion of acid chloride had occurred and that no excess reactants were remaining. The mixture was cooled to 60° C. and the molten reaction mass discharged, weighed and analysed. The reaction yielded 423.3 g of molten 4-methyl-2,3,5,6-tetrafluorobenzyl cis-3-((Z)-2-chloro-3,3.3-trifluoroprop-1-enyl)-2,2-dimethylcyclopropane carboxylate, analysis against a known standard showed this material to be 92.5 wt % giving an overall reaction yield of 96.5%.
Reaction SMILES: [CH:1]1(/[CH:6]=[C:7](\[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:21]([CH3:22])=[N:20][N:19]=[N:18]3)=[C:13]([F:23])[CH:12]=2)/[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH3:30][NH:31][C:32]([NH2:34])=[O:33].N1C=CC=CC=1.Cl>FC1C=CC=CC=1.CN(C)C=O.C(OCC)(=O)C>[CH:1]1(/[CH:6]=[C:7](\[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:21]([CH3:22])=[N:20][N:19]=[N:18]3)=[C:13]([F:23])[CH:12]=2)/[C:8]([NH:34][C:32]([NH:31][CH3:30])=[O:33])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nnnn1-c1ccc(/C(=C\C2CCCC2)C(=O)O)cc1F
Reactant: CNC(N)=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: Fc1ccccc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CNC(=O)NC(=O)/C(=C/C1CCCC1)c1ccc(-n2nnnc2C)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
A solution of (E)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylic acid (158 mg, 0.5 mmol) in fluorobenzene (1 mL) and N,N-dimethylformamide (2 μL) at 25° C. was treated dropwise with oxalyl chloride (54 μL, 0.6 mmol) over 2-3 min. The clear solution was stirred for 1 h at 25° C. and then treated with methyl urea (11 mg, 1.5 mmol). The resulting suspension was heated at 70° C. (bath temperature) for 10 min and then treated with pyridine (81 μL, 1 mmol). The reaction mixture was then stirred at 70° C. for 20 h. The reaction mixture was then cooled to 25° C. and diluted with ethyl acetate (30 mL) and a 3N aqueous hydrochloric acid solution (30 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×20 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 1/1 hexanes/ethyl acetate) afforded the (E)-1-{3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acryloyl}-3-methyl-urea (41 mg, 22%) as a white solid: mp 186-192° C.; EI-HRMS m/e calcd for C18H21FN6O2 (M+) 372.1710, found 372.1708.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[Cl:10][C:11]1[C:12](Cl)=[N:13][CH:14]=[C:15]([CH:18]=1)[C:16]#[N:17]>>[Cl:10][C:11]1[C:12]([NH:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9])=[N:13][CH:14]=[C:15]([C:16]#[N:17])[CH:18]=1
Reactant: N#Cc1cnc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)CN
Product: CC(C)(C)OC(=O)CNc1ncc(C#N)cc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of glycine tert-butyl ester (5.3 g, 40.4 mmol), TEA (5.6 mL, 40.4 mmol) and 5,6-dichloronicotinonitrile (Bionet GC-0755, 7.0 g, 40.4 mmol) was prepared and stirred at RT for 24 hours. The reaction mixture was filtered to remove inorganic solids and filtrate was concentrated under reduced pressure. The residue taken up with EtOAc (100 mL) and washed with water (2×100 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. After purification by flash chromatography (silica, pet ether/EtOAc), the title compound was obtained as a white powder. 1H NMR (DMSO-d6, 400 MHz) δ 8.41 (1H, d), 8.15 (1H, d), 7.84 (1H, t), 4.00 (2H, m), 1.38 (9H, s).
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Mg].[F:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[S:18][C:19]1[CH:26]=[CH:25][C:24]([S:27][C:28]([F:31])([F:30])[F:29])=[CH:23][C:20]=1[CH:21]=[O:22].[Cl-].[NH4+]>O1CCCC1>[CH3:8][N:5]1[CH2:6][CH2:7][CH:2]([CH:21]([OH:22])[C:20]2[CH:23]=[C:24]([S:27][C:28]([F:31])([F:29])[F:30])[CH:25]=[CH:26][C:19]=2[S:18][C:12]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=2[F:10])[CH2:3][CH2:4]1
Reactant: CN1CCC(Cl)CC1
Reactant: O=Cc1cc(SC(F)(F)F)ccc1Sc1cc(F)ccc1F
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1CCC(C(O)c2cc(SC(F)(F)F)ccc2Sc2cc(F)ccc2F)CC1
Yield: 98.9 %

Procedure:
A solution of a Grignard reagent is prepared by a reaction of 12.0 g of 4-chloro-1-methylpiperidine with 2.4 g of magnesium in 70 ml of tetrahydrofuran and is treated dropwise for 10 minutes with a solution of 21.2 g of 2-(2,5-difluorophenylthio)-5(trifluoromethylthio)benzaldehyde in 40 ml of tetrahydrofuran. The mixture is refluxed for 5 hours and, after cooling, decomposed with a 20% ammonium chloride solution and extracted with benzene. The extract is washed with water, dried with potassium carbonate and evaporated. There are obtained 26.9 g of crude oily α-(1-methyl-4-piperidyl)-2-(2,5-difluorophenylthio)-5-(trifluoromethylthio)benzyl alcohol which is used in this state for further reaction.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].I[CH3:14]>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:14]
Reactant: Fc1cccc2[nH]ccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2c(F)cccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 61.2 %

Procedure:
In an oven dried, nitrogen purged, 3 neck, 50 mL round bottom flask, 1.00 g (7.40 mmol) of 4-fluoroindole in 10 mL of dry dimethylformamide is reacted with 0.335 g (8.88 mmol) of 60% sodium hydride dispersed in mineral oil at room temperature for 4 h. 0.553 mL (8.88 mmol) of iodomethane is added and the reaction is allowed to stir at room temperature overnight, 15 h. The reaction is quenched with 50 mL of water, extracted 3×50 mL of ethyl acetate, dried (MgSO4), and concentrated. The crude product is purified by chromatography using hexanes:ethyl acetate as a solvent system to obtain 0.675 g of the title compound, 61% yield. MS, ES+=150.1; 1H NMR (DMSO-d6) δ 7.358-7.350 (d, J=3.083, 1H); 7.279-7.258 (d, J=8.368, 1H); 7.126-7.073 (m, 1H); 6.806-6.760 (m, 1H); 6.459-6.452 (d, J=3.083, 1H); 3.787 (s, 1H) ppm.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]([OH:17])=[O:16].[OH:18][CH:19]1[CH:24]([OH:25])[CH:23]([OH:26])[CH:22]([CH2:27][OH:28])[O:21][C:20]1=[O:29]>CO>[OH:21][CH:22]([CH:23]([OH:26])[CH:24]([OH:25])[CH:19]([OH:18])[CH2:20][OH:29])[C:27]([NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]([OH:17])=[O:16])=[O:28]
Reactant: NCCOCCOCC(=O)O
Reactant: O=C1OC(CO)C(O)C(O)C1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)COCCOCCNC(=O)C(O)C(O)C(O)C(O)CO
Temperature: 25 °C

Procedure:
172 mg of sodium carbonate are added to a solution of 450 mg of [2-(2-aminoethoxy)ethoxy]acetic acid and 318 mg of 3,4,5-trihydroxy-6-hydroxymethyltetrahydropyran-2-one in 10 ml of methanol, and the mixture is stirred at room temperature until the reaction has gone to completion. The reaction solution is filtered and concentrated. The residue is taken up in water and acetonitrile (1/1), resulting in the formation of 2 phases. The aqueous phase is concentrated and contains 20:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])[CH:15]=[C:16]([O:19]C)[CH:17]=2)[CH2:12][CH2:11][C:10]1=[O:29].B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])[CH:15]=[C:16]([OH:19])[CH:17]=2)[CH2:12][CH2:11][C:10]1=[O:29]
Reactant: COc1cc(-c2ccc(F)cc2F)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1CCc2c(-c3ccc(F)cc3F)cc(O)cc2N1c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 18 mg of 1-(2,6-dichlorophenyl)-5-(2,4-difluorophenyl)-3,4-dihydro-7-methoxy-2(1H)-quinolinone (INTERMEDIATE 2) in 1 mL of CH2Cl2 was added 0.1 mL of BBr3. The resulting mixture was stirred 30 min at 0° C., then warmed to room temperature and stirred at this temperature for 1 h. The mixture was concentrated and the resulting residue was purified preparative thin layer chromatography, eluting with 98:2 CH2Cl2-MeOH, to yield 1-(2,6-Dichlorophenyl)-5-(2,4-difluorophenyl)-3,4-dihydro-7-hydroxy-2(1H)-quinolinone. Mass spectrum (ESI) 421.0 (M+1). 1H NMR (500 MHz, CDCl3): δ 7.47 (d, J=8.0 Hz, 2H); 7.33 (t, J=8.0 Hz, 1H); 7.27 (m, 1H); 6.95, (m, 2H); 5.82 (s, 1H); 5.23 (s, 1H); 2.56-3.00 (m, 5H).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][NH:5][C:4]2[O:13][C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[C:16](=[O:17])[C:3]1=2>Cl>[O:1]=[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][NH:5][C:4]2[O:13][C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[C:16](=[O:17])[C:3]1=2
Reactant: CCOC(=O)c1c[nH]c2oc3ccccc3c(=O)c2c1=O
Agent: Cl
Product: O=C(O)c1c[nH]c2oc3ccccc3c(=O)c2c1=O
Yield: 88.7 %

Procedure:
A suspension of ethyl 4,5-dihydro-4,5-dioxo-1H-1-benzopyrano[2,3-b]-pyridine-3-carboxylate (3.0 g, 0.011 mole) in 5N hydrochloric acid (100 ml) is refluxed under nitrogen for 16 hrs., cooled, filtered, washed with acetone and sucked dry. Recrystallization from DMF gives white crystals (2.51 g, 93%), mp 335°-340° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[BH4-].[Na+].C(O)(=O)C>C(O)C.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([OH:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(=O)c1ccco1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(O)c1ccco1
Yield: 70.5 %

Procedure:
Ethyl 2-(furan-2-yl)-2-oxoacetate (15.5 g, 92.1 mmol) in ethanol (500 mL) and water (25 mL) at 0° C. was treated with sodium borohydride (1.74 g, 46.05 mmol). The mixture was stirred for 15 minutes, at which point acetic acid (10 mL) was slowly added. After the cessation of gas evolution, water (100 mL) was carefully added, and the reaction mixture was concentrated. The residue was dissolved in methylene chloride and washed with brine. The crude product was dried and concentrated to give ethyl 2-(furan-2-yl)-2-hydroxyacetate as a pale brown viscous oil (11.05 g, 71%) which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[NH2:12].O=[CH:16][C:17]([OH:19])=[O:18].[BH3-]C#N.[Na+]>CO>[F:14][C:2]([F:1])([F:13])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[NH:12][CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=CC(=O)O
Reactant: Nc1n[nH]c2ccc(C(F)(F)F)cc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNc1n[nH]c2ccc(C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 5-(trifluoromethyl)-1H-indazol-3-amine (as prepared in the previous step, 50 mg, 0.25 mmol, 1.00 equiv) in MeOH (10 mL), 2-oxoacetic acid (80% in water) (27.6 mg, 0.37 mmol, 1.20 equiv) and NaBH3CN (105 mg, 0.50 mmol, 2.00 equiv). The reaction mixture was stirred for 2 h at room temperature, then concentrated under vacuum to give 2-(5-(trifluoromethyl)-1H-indazol-3-ylamino)acetic acid as a yellow solid. LC-MS-(ES, m/z) 261[M+H]+
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7](F)=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:24][C:23]3[CH2:22][CH2:21][NH:20][C:19](=[O:25])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].Cl.CN.C[CH2:31][N:32](C(C)C)C(C)C>CS(C)=O.C(Cl)Cl>[C:1]([NH:5][C:6]1[C:7]([NH:32][CH3:31])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:24][C:23]3[CH2:22][CH2:21][NH:20][C:19](=[O:25])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1F
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: CNc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)C
Yield: 27.4 %

Procedure:
A solution of 2-(3-(tert-butylamino)-2-fluoroquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (343) (16 mg, 0.04 mmol), methanamine hydrochloride (15 mg, 0.22 mmol, Sigma-Aldrich), and DIEA (47.4 μL, 0.27 mmol) in DMSO (0.45 mL) was stirred at RT for 2 h. The reaction mixture was diluted with DCM (100 mL), added to a separatory funnel, and washed with saturated aq. NaHCO3 (2×75 mL) before the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 1-4% of 2 M NH3 in MeOH/DCM to give 2-(3-(tert-butylamino)-2-(methylamino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4 (5H)-one (344) (4 mg, 24% yield) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55 (s, 9H) 2.85 (t, J=6.85 Hz, 2H) 2.95 (d, J=4.30 Hz, 3H) 3.42 (td, J=6.80, 2.45 Hz, 2H) 6.32 (s, 1H) 6.89 (d, J=2.15 Hz, 1H) 6.90 (br. s., 1H) 7.17 (t, J=7.63 Hz, 1H) 7.28 (dd, J=8.02, 1.37 Hz, 1H) 7.30-7.33 (m, 1H) 7.51 (dd, J=7.63, 1.37 Hz, 1H) 12.10 (br. s., 1H). MS (ESI, pos. ion) m/z: 365.3 (M+1).