Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])(F)[CH2:3][NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([C:15]([OH:17])=[O:16])=[CH:10][CH:11]=2)[N:6]=1.F[CH:21](F)CN>>[F:1][C:2]([F:19])([CH3:21])[CH2:3][NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([C:15]([OH:17])=[O:16])=[CH:10][CH:11]=2)[N:6]=1
Reactant: NCC(F)F
Reactant: O=C(O)c1ccc2ccc(NCC(F)(F)F)nc2c1
Product: CC(F)(F)CNc1ccc2ccc(C(=O)O)cc2n1

Procedure:
The title compound was prepared by a method analogous to that described for Intermediate 44, using 2,2-difluoroethylamine instead of 2,2,2-trifluoroethylamine. +ESI (M+H) 267.2; 1H NMR (400 MHz, DMSO-d6, δ): 1.63 (t, J=19.02 Hz, 3H) 3.89-3.99 (m, 2H) 6.97 (d, J=8.97 Hz, 1H) 7.54 (t, 1H) 7.62-7.68 (m, 1H) 7.71 (d, J=8.19 Hz, 1H) 7.96 (d, J=9.10 Hz, 1H) 8.06-8.09 (m, 1H) 12.95 (bs, 1H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](C=O)=[CH:3][CH:2]=1.C1C[O:16][CH2:15]C1.[BH4-].[Na+].N1C2C(=CC=CC=2)C(CO)=CC=1>CCO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:15][OH:16])[CH:2]=1
Reactant: C1CCOC1
Reactant: O=Cc1ccnc2ccccc12
Agent: OCc1ccnc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To a solution of 4-quinolinecarboxaldehyde (0.47 g, 3.00 mmol) in a mixture of EtOH:THF=1:1 (40 mL) at 0° C. in a 100 mL round-bottomed flask equipped with a magnetic stirrer was added NaBH4 (0.11 g, 3.01 mmol) and the mixture was stirred overnight at RT. The solution was then cooled down to 0° C. before quenching a 6 N aq. HCl solution (2 mL). The reaction mixture was stirred at RT for 15 min then basified with a 2 N aq. NaOH solution (6 mL). EtOH was removed at 40° C. under vacuum and the residue was extracted with CH2Cl2 (2×50 mL). The organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 0:100) gave, after evaporation and drying, quinolin-4-ylmethanol MDE 32014 as an off-white solid (311 mg, 65% yield).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].Cl.[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH:16][O:17][CH3:18])=[O:15])=[CH:9][CH:8]=1.C(N(CC)CC)C.O>O1CCCC1.C(OCC)C>[N:6]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH:16][O:17][CH3:18])=[O:15])=[CH:9][CH:8]=1)=[C:1]=[S:2]
Reactant: S=C(Cl)Cl
Reactant: CONC(=O)Nc1ccc(N)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: O
Product: CONC(=O)Nc1ccc(N=C=S)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62 %

Procedure:
Thiophosgene (0.38 ml, 1.1 eq) is added dropwise to a solution cooled down to 0° C., of N-(4-aminophenyl)-N′-methoxyurea hydrochloride (1 g) and triethylamine (3.2 ml, 5 eq) in tetrahydrofuran (90 ml). The mixture is stirred for 15 min at 0° C. then water and diethyl ether are added. After decantation and extractions, the phases organic are combined, washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification by flash chromatography on silica gel (eluent:heptane/ethyl acetate 7:3 to 3:7) produces the expected compound (630 mg; 62% yield).
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[N:15][C:14]=3[C:24](O)=[O:25])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C([O:29][C:30]([C:32]1([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([NH2:43])[CH:38]=2)[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31])C>>[C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([CH:18]4[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]4)=[N:15][C:14]=3[C:24]([NH:43][C:39]3[CH:38]=[C:37]([C:32]4([C:30]([OH:29])=[O:31])[CH2:33][CH2:34][CH2:35][CH2:36]4)[CH:42]=[CH:41][CH:40]=3)=[O:25])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)c1nc(C2CCCCC2)[nH]c1CCC12CC3CC(CC(C3)C1)C2
Reactant: CCOC(=O)C1(c2cccc(N)c2)CCCC1
Product: O=C(Nc1cccc(C2(C(=O)O)CCCC2)c1)c1nc(C2CCCCC2)[nH]c1CCC12CC3CC(CC(C3)C1)C2

Procedure:
5-(2-Adamantan-1-yl-ethyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid (Example 252) was reacted with 1-(3-amino-phenyl)-1-cyclopentanecarboxylic acid ethyl ester (prepared from 1-(4-chloro-phenyl)-1-cyclopentanecarboxylic acid using Mutti's procedure (S. Mutti et al. Synth. Comm. 1997, 27, 425)) according to the procedure of Example 20, step d. The ethyl ester was hydrolysed using the same procedure as in Example 247, step b to afford the title compound. 1H NMR (300 MHz, d6-DMSO) 12.00 (1H, br s), 9.29 (1H, br s), 7.63 (2H, m), 7.16 (1H, m), 7.02 (1H, d), 2.85 (2H, m), 2.49 (3H, m), 1.98-1.34 (33H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 62.88; H, 8.79; N, 7.07%. C41H62N4O8.2.5 mols H2O requires: C, 62.81; H, 8.61; N, 7.15%.
Reaction SMILES: [C:1]([N:4]1[C:8]2=[N:9][C:10]3[N:11]([CH3:29])[C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][CH2:20][C@@H:21](OS(C)(=O)=O)[CH3:22])[C:14](=[O:16])[C:15]=3[N:7]2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[N-:30]=[N+:31]=[N-:32].[Na+].O>CS(C)=O>[C:1]([N:4]1[C:8]2=[N:9][C:10]3[N:11]([CH3:29])[C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([N:30]=[N+:31]=[N-:32])[CH3:22])[C:14](=[O:16])[C:15]=3[N:7]2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCn2c1nc1c2c(=O)n(CCCC[C@H](C)OS(C)(=O)=O)c(=O)n1C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)N1CCn2c1nc1c2c(=O)n(CCCC[C@@H](C)N=[N+]=[N-])c(=O)n1C
Temperature: 65 °C
Reaction time: 7 h
Yield: 82.4 %

Procedure:
A mixture of (S)-8-acetyl-7,8-dihydro-3-(5-methanesulfonyloxyhexyl)-1-methyl-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione (560 mg, 1.28 mmol) and sodium azide (416 mg, 6.4 mmol) in dimethylsulfoxide (5 ml) was stirred at 65° C. for 7 hours. After cooling to room temperature, the reaction mixture was treated with water. After stirring for 1 hour, the solid was filtered, washed with water, and dried under vacuum to provide (R)-8-acetyl-3-(5-azidohexyl)-7,8-dihydro-1-methyl-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione (395 mg, 84% yield) as a white powder.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].C(N(CC)CC)C.C(Cl)Cl.[OH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([S:24][CH3:25])[C:19]=1[N+:26]([O-:28])=[O:27]>O>[S:1]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([S:24][CH3:25])[C:19]=1[N+:26]([O-:28])=[O:27])([CH3:4])(=[O:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: CSc1cccc(CO)c1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CSc1cccc(COS(C)(=O)=O)c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
76 mg (0.66 mmol) of mesyl chloride and then 69 mg (0.68 mmol) of triethylamine were added to 5 ml of a methylene chloride solution containing 100 mg (0.50 mmol) of 2-hydroxymethyl-6-methylthio-1-nitro-benzene, in an ice bath. The mixture was stirred at the temperature of the ice bath for 1 hour and 15 minutes. At the end of this time, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic extract was separated and washed with 2N aqueous hydrochloric acid and then with water. The solvent was then removed by distillation under reduced pressure, to obtain the title compound. This product was used for the next step without purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]([N:11]2[C:17]3[CH:18]=[CH:19][C:20]([NH2:22])=[CH:21][C:16]=3[O:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH2:3]1.[CH3:23][NH:24][C:25]([C:27]1[S:28][CH:29]=[CH:30][C:31]=1[NH:32][C:33]1[C:38]([Cl:39])=[CH:37][N:36]=[C:35](Cl)[N:34]=1)=[O:26]>>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]([N:11]2[C:17]3[CH:18]=[CH:19][C:20]([NH:22][C:35]4[N:34]=[C:33]([NH:32][C:31]5[CH:30]=[CH:29][S:28][C:27]=5[C:25](=[O:26])[NH:24][CH3:23])[C:38]([Cl:39])=[CH:37][N:36]=4)=[CH:21][C:16]=3[O:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH2:3]1
Reactant: CN1CCCC(OC(=O)N2CCCOc3cc(N)ccc32)C1
Reactant: CNC(=O)c1sccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1sccc1Nc1nc(Nc2ccc3c(c2)OCCCN3C(=O)OC2CCCN(C)C2)ncc1Cl

Procedure:
The title compound was prepared from 3-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid 1-methyl-piperidin-3-yl ester and 3-(2,5-dichloro-pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methylamide in an analogous manner to Example 1410. Product isolated as an orange foam (112 mg, 60%). LCMS (m/e) 572 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 11.32 (bs, 1H), 8.47-8.30 (m, 1H), 8.13 (s, 1H), 7.46-7.13 (m, 3H), 7.13-7.04 (m, 1H), 7.01-6.88 (m, 1H), 5.82-5.68 (m, 1H), 4.98-4.71 (m, 1H), 4.25-4.06 (m, 2H), 3.90-3.64 (m, 2H), 3.03 (d, 3H, J=4.8 Hz), 2.91-2.81 (m, 1H), 2.64-2.50 (m, 1H), 2.37-2.21 (m, 3H), 2.16-2.04 (m, 3H), 2.03-1.75 (m, 3H), 1.65-1.45 (m, 1H), 1.32-1.13 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]2[N:9]([C@@H:12]3[O:32][C@H:31]([CH2:33][O:34]CC4C=CC=CC=4)[C@@H:22]([O:23]CC4C=CC=CC=4)[C@@H:13]3[O:14]CC3C=CC=CC=3)[CH:10]=[N:11][C:4]=2[CH:3]=1.C(O)(=O)C.COC(O)C>[Pd].O>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]2[N:9]([C@@H:12]3[O:32][C@H:31]([CH2:33][OH:34])[C@@H:22]([OH:23])[C@@H:13]3[OH:14])[CH:10]=[N:11][C:4]=2[CH:3]=1
Reactant: Nc1cc2ncn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2c(=O)[nH]1
Agent: [Pd]
Agent: COC(C)O
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3O)c2c(=O)[nH]1
Yield: 13.9 %

Procedure:
A mixture of 5.9 g of 6-amino-3-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-3,5-dihydro-4H-imidazo-[4,5-c]pyridin-4-one, one g of 20% palladium on carbon, 5 ml of acetic acid, and 95 ml of methoxyethanol is hydrogenated at 50° C. and ca 3 atmospheres until hydrogen uptake ceases, the mixture is filtered, evaporated in vacuo, and co-evaporated with xylenes to provide a syrup which is dissolved in water and treated with 50 ml of wet IR-45 ion exchange resin. The resin is filtered, washed several times with boiling water and the combined filtrates are evaporated in vacuo to provide 2.5 g of crude product. Recrystallization from ethanol-water provides 0.42 g of 6-amino-3-β-D-arabinofuranosyl-3,5-dihydro-4H-imidazo[4,5-c]pyridin-4-one.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:29])([CH3:28])[O:6][CH:7]1[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:8]1=O)([CH3:4])[CH3:3].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]([Si:5]([CH3:29])([CH3:28])[O:6][CH:7]1[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:8]1=[S:39])([CH3:4])[CH3:3]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(S(=O)(=O)c2ccc(N3CCCCC3)cc2)C1=O
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OC1CCN(S(=O)(=O)c2ccc(N3CCCCC3)cc2)C1=S
Yield: 133.1 %

Procedure:
A mixture of 2.7 g of the product obtained in Stage A above with 1.55 g of Lawesson reagent in 25 cm3 of toluene is taken to reflux for 3 hours 15 minutes. After cooling, the solvent is eliminated and the residue is chromatographed on silica (eluant: ethyl acetate - n-hexane (3-7)). 2.32 g of the desired product is obtained. M.p.=152.5-153° C. after dissolution in ethyl acetate and precipitation with hexane.
Reaction SMILES: [CH:1]1([C:8]2[CH:13]=[C:12]([C:14](OC)=[O:15])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=2[F:26])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[CH:1]1([C:8]2[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=2[F:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2CCCCCC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(CO)cc2C2CCCCCC2)c1
Reaction time: 1 h
Yield: 83.5 %

Procedure:
To a stirred solution of 78.7D (0.260 g, 0.7 mmol) in THF (7 mL) at 0° C. was added LAH (1 mL, 1 mmol, 1.0M). The reaction was stirred for one hour and then 1N NaOH was added to quench the reaction. The resulting solution was extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was purified on silica gel (0-20% EtOAc in hexanes) to yield 78.7E as a colorless oil (0.192 g, 80% yield). MS ESI (pos.) m/e: 311.2 (M−OH)+.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].CO.Br[CH2:9][CH2:10][CH2:11][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>O>[OH:3][NH:2][CH2:9][CH2:10][CH2:11][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]
Reactant: NO
Reactant: CCOP(=O)(CCCBr)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOP(=O)(CCCNO)OCC
Yield: 62.8 %

Procedure:
To a solution of hydroxylamine hydrochloride (55.6 g.) in water (100 ml.) were added solution of sodium hydroxide (32.0 g.) in water (75 ml.) under ice-cooling and then methanol (75 ml.). To this solution was added dropwise diethyl 3-bromopropylphosphonate (25.5 g.), whereafter the mixture was warmed at 40°-45° C. for 3 hours with stirring. The methanol was distilled off under reduced pressure. The resultant aqueous solution was adjusted to pH 8 with sodium bicarbonate, washed three times with benzene which were discarded (once with 150 ml. and twice with 100 ml. portions) and then extracted with three 150 ml. portions of chloroform. The chloroform extracts were combined, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give oily diethyl 3-(N-hydroxyamino)propylphosphonate (13.05 g.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([Si](C(C)C)(C(C)C)C(C)C)[CH:10]=[C:11]([C:19]3(O)[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([C:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH:20]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C2(O)CCN(C)CC2)c(-c2ccncc2)c1-c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CC[SiH](CC)CC
Agent: [F-]
Solvent: O=C(O)C(F)(F)F
Product: CN1CC=C(c2c[nH]c(-c3ccc(F)cc3)c2-c2ccncc2)CC1
Yield: 91 %

Procedure:
In a similar manner to that described in Example 9(iii) above, using 2-(4-fluorophenyl)- 4-(4-hydroxy-1-methylpiperidin-4-yl)-3-(pyridin-4-yl)-1-triisopropylsilyl- 1H-pyrrole [prepared as described in step 32(i) above], dehydration with triethylsilane/trifluoroacetic acid and desilylation with tetrabutylammonium fluoride were carried out to give the title compound (yield 91%) as a pale yellow powder.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20](OC)=[O:21])=[C:14]([C:24]([F:27])([F:26])[F:25])[CH:13]=1.Cl>C(Cl)Cl>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][OH:21])=[C:14]([C:24]([F:25])([F:26])[F:27])[CH:13]=1
Reactant: COC(=O)CCc1ccc(Cl)cc1C(F)(F)F
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Product: OCCCc1ccc(Cl)cc1C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Diisobutylaluminum hydride (20% in toluene, 34 ml) was added dropwise to a solution of methyl 3-(4-chloro-2-(trifluoromethyl)phenyl)propanoate (5 g) in DCM (150 ml) at −78° C. under nitrogen during 10 minutes. The mixture was then stirred at −78° C. for 1 hour before warming up to room temperature. The mixture was then carefully poured to crushed ice (500 g). After adding 5M HCl to pH 2, the mixture was extracted with DCM (200 ml×3), combined DCM layer was then dried over sodium sulphate, solvent was then removed under reduced pressure. The residue was clean enough for next step (4.5 g).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH2:9])[C:3]=1[NH2:10].CN(C=O)C.Br[CH:17]([CH3:23])[C:18](OCC)=[O:19].C([O-])(O)=O.[Na+]>[Cl-].[Na+].O>[Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:10][C:18](=[O:19])[CH:17]([CH3:23])[NH:9]2
Reactant: CCOC(=O)C(C)Br
Reactant: Nc1ccc(F)c(Br)c1N
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1Nc2ccc(F)c(Br)c2NC1=O
Temperature: 90 °C
Reaction time: 15 h
Yield: 95.5 %

Procedure:
A 500 mL round-bottomed flask charged with 3-bromo-4-fluorobenzene-1,2-diamine (600c) (18 g, 88 mmol), DMF (100 mL), ethyl 2-bromopropionate (Sigma Aldrich, 11.54 mL, 89 mmol) and NaHCO3 (7.60 g powder, 90 mmol) was heated to 90° C. with a reflux condenser for 30 min, then at 120° C. for 15 h. The reaction mixture was cooled to RT, treated with brine and extracted with EtOAc (2×200 mL), washed with brine (3×) and dried over Na2SO4, filtered and concentrated affording crude 8-bromo-7-fluoro-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (21.75 g, 84 mmol, 96% yield) as an orange-brown viscous oil. The material was used in the subsequent step without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.67 (s, 1H) 6.78-6.89 (m, 1H) 6.48-6.78 (m, 1H) 6.07-6.35 (m, 1H) 1.25 (d, J=6.46 Hz, 3H). 19F NMR (377 MHz, DMSO-d6) δ ppm −120.49 (1F, s). m/z (ESI, +ve ion) 259.0/261.0 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:9]([O:11]C)=[O:10].[OH-].[Na+].Cl>CO>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1ccc(OC)c(OCCCCl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)O)cc1OCCCCl
Temperature: 40 °C
Yield: 42.2 %

Procedure:
In a 300 mL volume glass flask equipped with a stirrer, a thermometer and a dropping funnel were placed 18.2 g (69.7 mmol) of methyl 3-(3-chloropropoxy)-4-methoxybenzoate, 69.7 mL of aqueous sodium hydroxide solution (2 mol/L), and 69.7 mL of methanol. The resulting mixture was heated to 40° C. for 4 hours in an argon gas atmosphere. After the reaction was complete, the reaction mixture was cooled to 10° C., and neutralized by 69.7 mL of hydrochloric acid (2 mol/L), to precipitate a crystalline product. The crystalline product was collected and dried under reduced pressure, to give 7.2 g (isolated yield: 95.8%, purity: 99% in terms of area percentage by high performance liquid chromatography) of 3-(3-chloropropoxy)-4-methoxybenzoic acid as a white crystalline product.
Reaction SMILES: Br[C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([CH:11]([CH3:13])[CH3:12])=[CH:4][C:3]=1[CH:14]([CH3:16])[CH3:15].[C:17](=[O:19])=[O:18].Cl>>[CH:14]([C:3]1[CH:4]=[C:5]([CH:11]([CH3:13])[CH3:12])[CH:6]=[C:7]([CH:8]([CH3:10])[CH3:9])[C:2]=1[C:17]([OH:19])=[O:18])([CH3:16])[CH3:15]
Reactant: O=C=O
Reactant: CC(C)c1cc(C(C)C)c(Br)c(C(C)C)c1
Agent: Cl
Product: CC(C)c1cc(C(C)C)c(C(=O)O)c(C(C)C)c1
Yield: 80 %

Procedure:
A Grignard reagent was prepared from 56.7 g of 1-bromo-2,4,6-triisopropylbenzene and poured to 300 g of dry ice, whereupon dry ice sublimated. Hydrochloric acid was added to the reaction mixture for quenching, followed by extraction with 200 g of toluene. The organic layer was taken out, washed with water, and combined with 10 wt % sodium hydroxide aqueous solution. The aqueous layer was taken out, combined with 50 g of 35 wt % hydrochloric acid, and extracted with 200 g of toluene. The organic layer was washed with water again, and concentrated under reduced pressure. The concentrate was crystallized from 150 g of hexane. The crystal precipitate was filtered and dried, obtaining the target compound, 2,4,6-triisopropylbenzoic acid. Amount 39.7 g, yield 80%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:17].[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26](=[NH:30])OCC>C(O)C>[ClH:17].[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:7]2[C:2]([NH:1][C:26](=[NH:30])[CH2:25][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH3:18])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: Nc1ncccc1OCc1ccc(F)cc1
Reactant: CCOC(=N)Cc1ccccc1C
Agent: Cl
Solvent: CCO
Product: Cc1ccccc1CC(=N)Nc1ncccc1OCc1ccc(F)cc1
Yield: 15.5 %

Procedure:
A mixture of 2-amino-3-(4-fluorobenzyloxy)pyridine (4.36 g, 20 mmol) and ethyl 2methylphenylacetimidate hydrochloride (4.69 g, 22 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil, which was purified by flash chromatography (chloroform/methanol) to obtain the product (1.2 g), m.p. 199°-200° C.
Reaction SMILES: [N+](=C[Si](C)(C)C)=[N-].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[C:11]([F:19])[CH:10]=1.[N+](=[CH2:22])=[N-]>C1(C)C=CC=CC=1.CO>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH3:22])=[O:17])=[C:11]([F:19])[CH:10]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)Cc1ccc(Br)cc1F
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccc(Br)cc1F
Yield: 91 %

Procedure:
Diazomethyl-trimethyl-silane (11.6 mL of 2.0 M, 23.2 mmol) was added dropwise to a solution of 2-(4-bromo-2-fluoro-phenyl)acetic acid (4.50 g, 19.3 mmol) in toluene (7.7 mL) and MeOH (7.7 mL) under a nitrogen atmosphere at room temperature. A persistent yellow color remained after complete addition of diazomethane. The reaction was then quenched with a few drops of acetic acid and the solvents were removed under reduced pressure. The residue was purified by silica gel flash column chromatography using 0-10% EtOAc in hexanes to yield methyl 2-(4-bromo-2-fluoro-phenyl)acetate (4.32 g, 91%). 1H NMR (400 MHz, CDCl3) δ 7.28-7.22 (m, 2H), 7.15 (t, J=8.0 Hz, 1H), 3.71 (s, 3H), 3.63 (d, J=1.0 Hz, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1(O)[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1.S(Cl)(Cl)=O.O.CCOC(C)=O>N1C=CC=CC=1>[O:10]1[C:9]2([CH2:14][CH2:15][C:6]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[CH:7][CH2:8]2)[O:13][CH2:12][CH2:11]1
Reactant: OC1(c2nccs2)CCC2(CC1)OCCO2
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C1=C(c2nccs2)CCC2(C1)OCCO2
Temperature: 0 °C
Reaction time: 2 h
Yield: 36.4 %

Procedure:
To a mixture of 8-(1,3-thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol (0.8 g, 3.32 mmol) in pyridine (10 mL) at 0° C. was added thionyl chloride (2.5 mL, 34.3 mmol) under N2. After being stirred for 2 h at 0° C. under N2, water and EtOAc were added. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with saturated NaCl, dried (MgSO4), concentrated and flash chromatographed using 10% EtOAc/hexane to give 0.27 g of the title compound in 36% yield. MS (EI) calcd: (M+1)+=224.1; found: 224.2.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12](=O)[C:13]([O:15]C)=O)=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25](C3CNCC3)[CH:26]=2)[C:21]([CH2:33][C:34]([NH2:36])=[O:35])=[CH:20]1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[C:13](=[O:15])[NH:36][C:34](=[O:35])[C:33]=3[C:21]3[C:22]4[C:27](=[CH:26][C:25]([N:8]5[CH2:9][CH2:5][CH2:6][CH2:7]5)=[CH:24][CH:23]=4)[N:19]([CH3:18])[CH:20]=3)=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: COC(=O)C(=O)c1cn(C)c2cc(Br)ccc12
Reactant: Cn1cc(CC(N)=O)c2ccc(C3CCNC3)cc21
Product: Cn1cc(C2=C(c3cn(C)c4cc(N5CCCC5)ccc34)C(=O)NC2=O)c2ccc(Br)cc21
Yield: 84.6 %

Procedure:
3-(6-Bromo-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)pyrrole-2,5-dione (49 mg, 46%) was prepared from methyl (6-bromo-1-methyl-1H-indol-3-yl)-glyoxylate (68 mg, 0.23 mmol) and (1-methyl-6-pyrrolidin-4-yl-1H-indol-3-yl)acetamide (54 mg, 0.21 mmol).