Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17]COC)=[CH:14][CH:15]=2)[C:10]([CH2:21][NH:22][CH2:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=2)=[C:9]1[CH:32]([CH3:34])[CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)(C)C.C1COCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([CH2:21][NH:22][CH2:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=2)=[C:9]1[CH:32]([CH3:34])[CH3:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1ccc2c(c1)c(CNCc1cc(F)cc(F)c1)c(C(C)C)n2Cc1ccccc1
Agent: Cl
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(C)c1c(CNCc2cc(F)cc(F)c2)c2cc(O)ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(1-benzyl-2-isopropyl-5-(methoxymethoxy)-1H-indol-3-yl)-N-(3,5-difluorobenzyl)methanamine (Compound 5, 117 mg, 0.25 mmol) in isopropanol (2.0 ml) and THF (2.0 ml) was added 6 M HCl (0.4 ml). The mixture was stirred at room temperature for 16 h, and concentrated under vacuum. The mixture was diluted with EtOAc, and washed with phosphate buffer (pH=7.2), and brine, and dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with 20-60% EtOAc-hexanes to yield 1-benzyl-3-((3,5-difluorobenzylamino)methyl)-2-isopropyl-1H-indol-5-ol (Compound 6) as a yellow solid.
Reaction SMILES: C(N1CCNCC1)=O.[C:9]12([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2.[IH:25].CS[C:28](=[NH:30])[NH2:29]>>[IH:25].[C:9]12([N:19]3[CH2:24][CH2:23][N:22]([C:28](=[NH:29])[NH2:30])[CH2:21][CH2:20]3)[CH2:16][CH:15]3[CH2:14][CH:13]([CH2:12][CH:11]([CH2:17]3)[CH2:10]1)[CH2:18]2
Reactant: C1CN(C23CC4CC(CC(C4)C2)C3)CCN1
Reactant: CSC(=N)N
Agent: I
Agent: O=CN1CCNCC1
Product: N=C(N)N1CCN(C23CC4CC(CC(C4)C2)C3)CC1
Yield: 72.3 %

Procedure:
The title compound was prepared as described for 1-formylpiperazine in Example 1 of the published European patent application No. 39,190, starting with 1-(1-adamantyl)piperazine and S-methyl-isothiourea hydroiodide, mp. 278°-280° C., yield: 72.3 %.
Reaction SMILES: [F:1][CH:2]1[C:7]([F:9])(O)[CH:6]=[CH:5][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:3]1.[CH2:16]([C@H:19]1[CH2:24][CH2:23][C@H:22]([C:25](Cl)=[O:26])[CH2:21][CH2:20]1)[CH2:17][CH3:18].[OH2:28]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:16]([C@H:19]1[CH2:24][CH2:23][C@H:22]([C:25]([O:26][C:13]2[CH:14]=[CH:15][C:10]([C:4]3[CH:5]=[CH:6][C:7]([F:9])=[C:2]([F:1])[CH:3]=3)=[CH:11][CH:12]=2)=[O:28])[CH2:21][CH2:20]1)[CH2:17][CH3:18]
Reactant: O
Reactant: CCC[C@H]1CC[C@H](C(=O)Cl)CC1
Reactant: OC1(F)C=CC(c2ccccc2)=CC1F
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCC[C@H]1CC[C@H](C(=O)Oc2ccc(-c3ccc(F)c(F)c3)cc2)CC1
Temperature: 60 °C

Procedure:
3,4-Difluoro-4-hydroxybiphenyl (2.0 g, 10 mmols) was dissolved in dried pyridine (5 cc), followed by adding to the solution, a solution obtained by dissolving trans-4-propylcyclohexanecarboxylic acid chloride (2 g, 11 mmols) in dry toluene (10 cc), heating the mixture at 60° C. for 3 hours with stirring, then adding the resulting material to water (100 cc), then washing the separated toluene layer with 6N hydrochloric acid, 2N aqueous solution of NaOH and further with water, distilling off toluene from the toluene layer, and recrystallizing the residual crystals from ethyl acetate (10 cc) to obtain the objective 3,4-difluoro-4'-biphenylyl trans-4-propylcyclohexanecarboxylate (2.5 g, 70%).
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]2[CH2:15][O:14][CH2:13][CH2:12][C:10]=2[N:11]=1)([CH3:3])[CH3:2].[F:17][C:18]1[CH:35]=[CH:34][C:21]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([CH2:30][C:31](O)=[O:32])[CH2:26][CH2:25]2)=[O:23])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([CH:24]2[CH2:25][CH2:26][N:27]([CH2:30][C:31]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][C:6]3[NH:7][C:8](=[O:16])[C:9]4[CH2:15][O:14][CH2:13][CH2:12][C:10]=4[N:11]=3)=[O:32])[CH2:28][CH2:29]2)=[O:23])=[CH:34][CH:35]=1
Reactant: CC(C)NCc1nc2c(c(=O)[nH]1)COCC2
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Product: CC(C)N(Cc1nc2c(c(=O)[nH]1)COCC2)C(=O)CN1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
Following general procedure of Example 4, the title compound was prepared (26.4 mg) from 2-((isopropylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. Exact mass calculated for C25H31FN4O4 470.5. found 471.6 (ESI, M+H); 1H NMR (400 MHz, dichloromethane-d2) δ ppm 7.91-8.18 (m, 2H) 7.19 (t, J=8.59 Hz, 2H) 4.53-4.69 (m, 2H) 4.50 (s, 1H) 4.24-4.43 (m, 1H) 4.19 (br. s., 1H) 3.86-4.08 (m, 3H) 3.80 (d, J=7.58 Hz, 1H) 3.58 (br. s., 2H) 3.33-3.50 (m, 1H) 3.28 (br. s., 1H) 2.74 (t, J=5.31 Hz, 2H) 2.19 (d, J=10.61 Hz, 2H) 2.13 (s, 1H) 1.11-1.33 (m, 5H) 1.07 (d, J=6.06 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH:5](O)[CH2:6][NH:7][C:8]1[NH:9][CH2:10][CH2:11][N:12]=1.S(=O)(=O)(O)O.[OH-].[Na+]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]2[N:12]3[CH2:11][CH2:10][NH:9][C:8]3=[N:7][CH2:6]2)[CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: OC(CNC1=NCCN1)c1ccc(Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cl
Product: Clc1ccc(C2CN=C3NCCN32)cc1Cl

Procedure:
4.3 parts of 3,4-dichloro-α-(2-imidazolin-2-ylaminomethyl)benzyl alcohol are added portionwise to 16.2 parts of sulfuric acid solution 80% while stirring and cooling. Upon completion, the mixture is stirred for 2 hr. 30 min. at room temperature. The reaction mixture is poured onto ice-water, alkalized with concentrated sodium hydroxide solution and the product in base form is extracted with methylene chloride. The organic layer is dried, filtered and evaporated. The residue is converted into the hydrochloride salt in 2-propanol, yielding 5-(3,4-dichlorophenyl)-2,3,5,6-tetrahydro-1H-imidazo[1,2-a]imidazole hydrochloride; m.p. 298.4°C (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([F:10])[C:3]=1N.F[B-](F)(F)F.N#[O+].[C-:18]#[N:19].[K+]>C(Cl)Cl>[Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([F:10])[C:3]=1[C:18]#[N:19]
Reactant: [C-]#N
Reactant: Nc1c(F)cc(Cl)cc1Br
Agent: F[B-](F)(F)F
Agent: N#[O+]
Agent: [K+]
Solvent: ClCCl
Product: N#Cc1c(F)cc(Cl)cc1Br
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 37.5 %

Procedure:
A solution of 2-bromo-4-chloro-6-fluoroaniline (25.0 g, 111 mmol) in 200 mL of anhydrous DCM, in a 2 liter round-bottom flask equipped with a bubbler, was treated with nitrosonium tetrafluoroborate (14.3 g, 123 mmol), at ambient temperature. After 1 hour complete consumption of the aniline was observed. The reaction mixture was cooled to 0° C. prior to the addition of potassium cyanide (14.5 g, 223 mmol). With rapid stirring, an aqueous solution of cupric sulfate hexahydrate (55.6 g, 223 mmol in 125 mL of water) was slowly added producing a large volume of gas evolution. After stirring for 40 minutes, the ice bath was removed and the reaction was allowed to warm to ambient temperature. After 1 hour at ambient temperature, the reaction mixture was diluted with additional DCM and then slowly quenched by the addition of aqueous saturated sodium bicarbonate until additional gas evolution is no longer observed. The resulting heterogeneous mixture was then filtered through a large pad of celite, washing with DCM as needed. The organic filtrate was then washed twice with saturated brine prior to drying over sodium sulfate. Filtration and solvent removal provided material which was subjected to silica gel chromatography eluting with 0-25% DCM in heptane. Collection of product containing fractions and removal of solvent yielded 9.76 grams of 2-bromo-4-chloro-6-fluorobenzo-nitrile, which gave LC/MS and proton NMR spectra consistent with theory.
Reaction SMILES: Cl.CN(C)[C@H]1[C@H](O)C(C)(C)OC2C=CC=CC1=2.Cl.[C:19]([NH:23][C@H:24]1[C@H:29]([OH:30])[C:28]([CH3:32])([CH3:31])[O:27][C:26]2[CH:33]=[CH:34][CH:35]=[CH:36][C:25]1=2)(C)([CH3:21])[CH3:20].Cl.O1CCN([C@H]2[C@H](O)C(C)(C)OC3C=CC=CC2=3)CC1>>[CH:19]([NH:23][C@H:24]1[C@H:29]([OH:30])[C:28]([CH3:32])([CH3:31])[O:27][C:26]2[CH:33]=[CH:34][CH:35]=[CH:36][C:25]1=2)([CH3:21])[CH3:20]
Reactant: CC(C)(C)N[C@@H]1c2ccccc2OC(C)(C)[C@H]1O
Agent: CC1(C)Oc2ccccc2[C@@H](N2CCOCC2)[C@@H]1O
Agent: CN(C)[C@@H]1c2ccccc2OC(C)(C)[C@H]1O
Agent: Cl
Product: CC(C)N[C@@H]1c2ccccc2OC(C)(C)[C@H]1O

Procedure:
3,4-Epoxy-3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran (10000g.) prepared as described by R. Livingstone, J. Chem. Soc., 76, (1962), was treated with isopropylamine (12 ml: an excess) in refluxing ethanol (50 ml.) for 16 hours. The solution was then evaporated to dryness in vacuo to give an off-white solid (13.00g.). This residue was dissolved in diethyl ether and treated with ethereal hydrogen chloride to give a crystalline hydrochloride (12.06g). Re-crystallisation from ethanol/diethyl ether yielded trans-4-isopropyl-amino-3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran-3-ol hydrochloride as colourless crystals, m.p. 172° - 174°. Similarly prepared were trans-4-dimethylamino-3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran-3-ol hydrochloride as colourless crystals m.p. 175° - 176°, trans-4-t-butylamino-3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran-3-ol hydrochloride as colourless crystals m.p. 239°-241°, trans-4-morpholino-3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran-3-ol hydrochloride m.p. 181°-187°.
Reaction SMILES: Cl.[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:18]4[CH2:23][NH:22][CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])[CH2:4][CH2:3]1.CCN(CC)CC.[CH3:39][N:40]([CH3:44])[C:41](Cl)=[O:42]>CN(C=O)C>[CH:2]1([NH:5][C:6](=[O:7])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:18]4[CH2:23][N:22]([C:41]([N:40]([CH3:44])[CH3:39])=[O:42])[CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)[CH2:3][CH2:4]1
Reactant: CN(C)C(=O)Cl
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CNC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CN(C(=O)N(C)C)C2
Temperature: 20 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
To a stirring solution of (S)-1-cyclopropyl-3-(3-fluoro-4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride (Example 149) (115 mg, 0.279 mmol) and NEt3 (43 μL, 0.307 mmol) in DMF (2 ml) was added dimethylcarbamoyl chloride (35 μL, 0.307 mmol). Reaction mixture was stirred at room temperature (20° C.) overnight before being concentrated in vacuo and purified by prep. HPLC at high pH to afford a white solid (75 mg, 56%).
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[NH:4][C:3]=1[C:15](=[O:18])[CH2:16][CH3:17].C(O)C.[NH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[NH:4][C:3]([C:15](=[O:18])[CH2:16][CH3:17])=[C:2]([C:29]3[CH:30]=[CH:31][C:26]([S:23]([NH2:22])(=[O:25])=[O:24])=[CH:27][CH:28]=3)[C:6]=2[CH3:7])=[CH:9][CH:10]=1
Reactant: CCC(=O)c1[nH]c(-c2ccc(Cl)cc2)c(C)c1Br
Reactant: NS(=O)(=O)c1ccc(B(O)O)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: CCO
Solvent: Cc1ccccc1
Product: CCC(=O)c1[nH]c(-c2ccc(Cl)cc2)c(C)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Yield: 6.7 %

Procedure:
To the solution of 1-(3-bromo-5-(4-chlorophenyl)-4-methyl-1H-pyrrol-2-yl)propan-1-one (compound 53b, 1.0 g, 3.06 mmol) in a mixture of toluene:ethanol (5:15 ml) was added 4-aminosulfonylbenzene boronic acid (0.67 g, 3.37 mmol) and potassium carbonate (1.26 g, 9.19 mmol) at a temperature of about 25° C. in a sealed tube and a nitrogen gas was bubbled through the resulting reaction mixture for 15 minutes. To the reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.17 g, 0.153 mmol) under nitrogen atmosphere and the reaction mixture was heated at about 90° C. to 95° C. for 18 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite. The celite cake was washed with 10% methanol in dichloromethane (3×25 ml). The combined filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 40% ethyl acetate in hexanes as an eluent to obtain the title compound (0.082 g, 6.65%).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:25])[CH2:15][CH2:16][CH2:17][S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.C(N(CC)CC)C.[C:50]1([CH2:56][CH2:57][CH2:58][CH2:59][CH:60]=[O:61])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>C(Cl)Cl>[CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:25])[CH:15]([CH2:16][CH2:17][S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:60]([OH:61])[CH2:59][CH2:58][CH2:57][CH2:56][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCSc1ccccc1)N1C(=O)OCC1Cc1ccccc1
Reactant: O=CCCCCc1ccccc1
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1OCC(Cc2ccccc2)N1C(=O)C(CCSc1ccccc1)C(O)CCCCc1ccccc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 68.6 %

Procedure:
To a solution containing (+)-4-benzyl-3-(4-phenylsulfanylbutanoyl)oxazolidin-2-one (2 g, 5.63 mmol) in anhydrous CH2Cl2 (30 mL) under nitrogen atmosphere at 0° C. is added di-n-butyl boron triflate (1 M in CH2Cl2, 6.6 mL, 6.59 mmol). To the resulting brown solution is added triethylamine (1 mL, 7.38 mmol). The pale yellow solution is cooled to -78° C. and a solution of 5-phenyl-1-pentanal (1 g, 6.25 mmol) in CH2Cl2 (5 mL) is added via syringe. The mixture is stirred at -78° C. for 1 hour and at 0° C. for 45 minutes then is quenched by the dropwise addition of 3:1 methanol/pH 7 phosphate buffer (40 mL) followed by 2:1 methanol/30% H2O2 (30 mL). The biphasic mixture is stirred at 0° C. for 1 hour then is combined with an identical reaction performed on 1.3 g-scale and evaporated to 50% volume in vacuo. The residue is partitioned between 5% NaHCO3 (200 mL) and diethyl ether (200 mL) and the layers are separated. The aqueous phase is extracted with diethyl ether (200 mL). The combined organic extracts are washed successively with 5% NaHCO3 (3×100 mL), 5% Na2S2O3 (3×100 mL), water (100 mL), brine (100 mL), dried over anhydrous MgSO4, filtered and concentrated to afford a yellow oil which is chromatographed on silica gel (pet-ether/EtOAc 9:1→4:1) to provide (+)-4-benzyl-3-[3-hydroxy-7-phenyl-2-(2-phenylsulfanylethyl)heptanoyl]-oxazolidin-2-one (2 g, 43%) as a colorless oil. TLC analysis [pet-ether/EtOAc, 4:1, Rf (oxazolidinone)=0.50, Rf (aldol product)=0.20]. [α]23D +7.2° (c 1.3, CHCl3). 1H NMR (300 MHz, CDCl3) δ 1.50-1.60 (m, 7H), 1.90 (m, 1H), 2.20 (m, 1H), 2.31 (d, J=3.6 Hz, 1H), 2.58 (t, J=7.5 Hz), 2.67 (dd, J=13.3, 9.9 Hz), 2.85 (m, 1H), 3.00 (m, 1H), 3.32 (dd, J=13.3, 3.4 Hz), 3.88 (m, 1H), 4.20 (m, 2H), 4.65 (m, 1H), 7.1-7.35 (m, 15H) ppm. Mass spectrum (FAB) m/z 517 (M)+.
Reaction SMILES: FC(F)(F)COC1C(C(N)=O)=NC=CC=1.[Cl:16][C:17]1[C:18]([C:25]([O:27]C)=[O:26])=[N:19][N:20]([CH:22]([CH3:24])[CH3:23])[CH:21]=1>>[Cl:16][C:17]1[C:18]([C:25]([OH:27])=[O:26])=[N:19][N:20]([CH:22]([CH3:23])[CH3:24])[CH:21]=1
Reactant: COC(=O)c1nn(C(C)C)cc1Cl
Agent: NC(=O)c1ncccc1OCC(F)(F)F
Product: CC(C)n1cc(Cl)c(C(=O)O)n1

Procedure:
Using an analogous reaction to that described for Intermediate 5, step 2 methyl 4-chloro-1-isopropyl-1H-pyrazole-3-carboxylate was converted into the title compound. MS m/z=188.9 [M+H]+. Calculated for C7H9ClN2O2: 188.035. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41 (d, J=6.65 Hz, 6 H) 4.52 (quin, J=6.70 Hz, 1 H) 8.17 (s, 1 H) 12.89 (br. s., 1 H)
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH2:12][CH2:13]Cl)=[C:10](Cl)[C:9]2[C:4](=[C:5]([O:16][CH3:17])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[CH3:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22]>C(O)CCC>[NH3:3].[CH3:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[N:22]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([O:16][CH3:17])[C:4]=3[N:3]=[C:2]([CH3:1])[C:11]=2[CH2:12][CH2:13]1
Reactant: Cc1ccccc1N
Reactant: COc1cccc2c(Cl)c(CCCl)c(C)nc12
Agent: Cl
Solvent: CCCCO
Product: COc1cccc2c3c(c(C)nc12)CCN3c1ccccc1C
Product: N
Yield: 2 %

Procedure:
2-Methyl-3-(2-chloroethyl)-4-chloro-8-methoxyquinoline (54 g, 0.2 mol), o-methylaniline hydrochloride (28.7 g, 0.2 mol) and 1-butanol (500 ml) were heated to 17° C. in a pressure vessel for 10 hours, then the solvent evaporated. Conversion to free base and chromatography (silica gel, 2% methanolic ammonia in dichloromethane) gave 1-(2-methylphenyl)-4-methyl-6-methoxy-2,3-dihydropyrrolo[3,2-c]quinoline in the early fractions. Later fractions were recrystallised from ethyl acetate to yield 1-(2-methylphenyl)-4-methyl-6-hydroxy-2,3-dihydropyrrolo[3,2-c]quinoline, m.p. 144°-146°.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:4]=1[CH:19]([NH:21]C(=O)OC(C)(C)C)[CH3:20]>O1CCOCC1.CCOC(C)=O>[Cl:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:4]=1[CH:19]([NH2:21])[CH3:20]
Reactant: CC(NC(=O)OC(C)(C)C)c1c(Cl)c2ccccc2n1-c1cccc(F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(N)c1c(Cl)c2ccccc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 118.6 %

Procedure:
Hydrogen chloride (4.0 M) in 1,4-dioxane (0.5 mL, 20 mmol) was added to a solution of tert-butyl {1-[3-chloro-1-(3-fluorophenyl)-1H-indol-2-yl]ethyl}carbamate (36 mg, 0.092 mmol) in 1,4-dioxane (1.0 mL) and the reaction was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with saturated NaHCO3 solution and water. The combined extracts were dried over MgSO4 and concentrated to give the desired product (31.5 mg). LCMS calculated for C16H12ClFN(M-NH2)+: m/z=272.1. Found: 272.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+]>C1C=CC=CC=1.FC(F)(F)C(O)=O.O>[C:18]1([CH:17]2[C:8]3[NH:9][C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:7]=3[CH2:6][C@@H:4]([C:3]([O:2][CH3:1])=[O:16])[NH:5]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1Cc2c([nH]c3ccccc23)C(c2ccccc2)N1
Temperature: 25 °C
Yield: 80 %

Procedure:
To the solution of 0.06 mol of L-tryptophan methyl ester and 0.05 mol of benzaldehyde in 150 ml of benzene, 0.5 ml of trifluoroacetic acid and 2 g of molecular sieves (4 Å) were added. The reaction mixture was refluxed for 1 hour, and then 0.138 mol (3 equiv.) of trifluoroacetic acid was added and the mixture was further refluxed for 3 hours. The reaction mixture was cooled down to room temperature and diluted with water and basified with 30% solution of NaOH. The organic layer was separated, dried over MgSO4 and the solvent was removed in vacuo. The residue was washed with diethyl ether, and the precipitate thus formed was filtered off to give the required product (80% yield).
Reaction SMILES: [C:1]1(=[O:20])[N:5]([CH:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:7](O)=[O:8])[C:4](=[O:19])[CH:3]=[CH:2]1.C(Cl)[Cl:22]>>[C:1]1(=[O:20])[N:5]([CH:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:7]([Cl:22])=[O:8])[C:4](=[O:19])[CH:3]=[CH:2]1
Reactant: CCCCCCCCCC(C(=O)O)N1C(=O)C=CC1=O
Reactant: ClCCl
Product: CCCCCCCCCC(C(=O)Cl)N1C(=O)C=CC1=O
Temperature: 72.5 °C

Procedure:
24.0 g (0.085 mole) maleimidoundecanoic acid were dissolved in 50 ml of dry CH2Cl2 in a 250 ml round bottomed flask fitted with a stirrer, reflux condenser and CaCl2 drying tube, and were treated with 31.0 g (0.24 mole) oxalyl and boiled under reflux for 15 hours at an oil bath temperature of 70 to 75° C. Subsequently, the CH2Cl2 was first distilled off under normal pressure, and the oxalyl chloride was distilled off at 0.01 mbar. On account of its susceptibility to hydrolysis, the dark-coloured residue was not purified further, but was immediately used for further syntheses. Yield: 2.5 g=100% theoretical. The maleimidoundecanoic acid chloride had a purity of 94% as determined by GC/MS.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][N:3]=1.BrN1C(=O)CCC1=O.[C:18]([O-:21])(=[O:20])[CH3:19].[K+].C1OCCOCCOCCOCCOCCOC1>C(Cl)(Cl)(Cl)Cl.C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][O:21][C:18](=[O:20])[CH3:19])[C:5]([Br:9])=[CH:4][N:3]=1
Reactant: CC(=O)[O-]
Reactant: Cc1cc(Br)ncc1Br
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C1CCC(=O)N1Br
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)OCc1cc(Br)ncc1Br
Temperature: 5 °C
Yield: 20.5 %

Procedure:
2.5-Dibromo-4-methylpyridine(26.06 g, 103.8 mmol) and N-bromosuccinimide (27.72 g, 155.7 mmol) in carbon tetrachloride (500 ml) were heated to reflux over a 150 W light bulb for 2 h. Cooling to 5° C., filtration and evaporation to dryness under reduced pressure gave the crude brominated products which were treated with potassium acetate (66.0 g, 673 mmol) and 18-crown-6 (3.00 g, 11.4 mmol) in acetonitrile (500 ml) at room temperature for 40 h. Filtration and evaporation of the filtrate to dryness gave the crude products which were dissolved in ethyl acetate, washed with saturated aqueous potassium bromide solution, the organic phase dried (Na2SO4) and evaporated to dryness under reduced pressure with purification by flash chromatography using hexane/ethyl acetate (6:1) as eluent giving the title compound (6.56 g. 19%) as a white solid: δH (CDCl3), 2.22 (3H, s, CH3), 5.12 (2H, s, CH2OAc), 17.50 (1H, s, 3-H), 18.45 (1H, s, 6-H); m/z (E.I.) 308 (MH+, 3%), 230 (100%): (Found: M+, 307.8926. C8H8NO2Br requires M. 307.89221.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]([CH2:13][OH:14])[CH2:10][CH2:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1.Cl>CC(O)C.ClC(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]([CH2:13][O:14][CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][O:16]3)[CH2:10][CH2:9][C:8]=2[CH:15]=1)([O-:3])=[O:2]
Reactant: C1=COCCC1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCC(CO)O2
Agent: Cl
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc2c(c1)CCC(COC1CCCCO1)O2
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To a stirred mixture of 38 parts of 3,4-dihydro-6-nitro-2H-1-benzopyran-2-methanol, 30 parts of 3,4-dihydro-2H-pyran and 750 parts of trichloromethane were added 3 drops of 2-propanol saturated with hydrogen chloride (slightly exothermic reaction). The whole was stirred for 3 hours in a water bath at room temperature. The whole was washed with a cold sodium hydroxide solution 10% and with water. The organic layer was dried, filtered and evaporated. The oily residue was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The oily residue was solidified in petroleumether. The product was filtered off and dried, yielding 34 parts (64%) of 3,4-dihydro-6-nitro-2-[[(tetrahydro-2H-pyran -2-yl)oxy]methyl]-2H-1-benzopyran; mp. 66.4° C. (intermediate 9).