Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH3:29])([CH3:28])[CH2:3][NH:4][CH:5]([C:9]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](=[O:26])[C:16]2[C:11](=[CH:12][C:13]([Cl:27])=[CH:14][CH:15]=2)[N:10]=1)[CH:6]([CH3:8])[CH3:7].C(N(CC)CC)C.[F:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=O)=[CH:40][C:39]=1[CH3:47]>ClCCl>[CH2:19]([N:18]1[C:17](=[O:26])[C:16]2[C:11](=[CH:12][C:13]([Cl:27])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:5]([N:4]1[CH2:3][C:2]([CH3:29])([CH3:28])[N:1]=[C:42]1[C:41]1[CH:45]=[CH:46][C:38]([F:37])=[C:39]([CH3:47])[CH:40]=1)[CH:6]([CH3:8])[CH3:7])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)C(NCC(C)(C)N)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: Cc1cc(C(=O)Cl)ccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C2=NC(C)(C)CN2C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)ccc1F
Temperature: 25 °C
Yield: 42.6 %

Procedure:
To a solution of (±)-2-[1-(2-amino-2-methyl-propylamino)-2-methyl-propyl]-3-benzyl-7-chloro-3H-quinazolin-4-one (250 mg, 0.61 mmol) in dichloromethane (10 mL) was added triethylamine (295 μL, 2.12 mmol), followed by 4-fluoro-3-methylbenzoyl chloride (105 mg, 0.61 mmol). The resultant solution was stirred at ambient temperature for 2 hours, then evaporated under reduced pressure to a crude white solid. The resultant solid was treated with glacial acetic acid (10 mL) then the resultant suspention was heated at reflux for 48 hours. The reaction was cooled to ambient temperature then evaporated under reduced pressure to a crude oil. The oil was quenched with saturated aqueous sodium bicarbonate (10 mL) and brine (5 mL). The aqueous layer was extracted with dichloromethane (2×5 mL) and the combined extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5-10% ethyl acetate/hexanes) to furnish (±)-3-benzyl-7-chloro-2-{1-[2-(4-fluoro-3-methyl-phenyl)-4,4-dimethyl-4,5-dihydro-imidazol-1-yl]-2-methyl-propyl}-3H-quinazolin-4-one (138 mg, 43%) as a white solid: LCMS 531 (M++H)
Reaction SMILES: [OH2:1].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([CH2:27][CH2:28][C@H:29]([OH:35])[C:30]([CH3:34])([CH3:33])[C:31]#[N:32])(C(C)(C)C)(C)C>>[OH:1][CH2:27][CH2:28][C@H:29]([OH:35])[C:30]([CH3:34])([CH3:33])[C:31]#[N:32]
Reactant: O
Reactant: CC(C)(C#N)[C@@H](O)CC[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC(C)(C#N)[C@@H](O)CCO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
12.18 g (46.61 mmol) of tetrabutylammonium fluoride hydrate is added to a solution that consists of 3 g (11.65 mmol) of 5-tert-butyldimethylsilyl-2,2-dimethyl-3(S)hydroxy-pentane-nitrile of the title compound of Example 8b, dissolved in 40 ml of tetrahydrofaran, and it is stirred for 16 hours at room temperature. Then, it is evaporated to the dry state in a vacuum. The residue is purified by RP-18 chromatography (mobile solvent: acetonitrile/water gradient).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Br.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[C:20]([NH:24][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27])[S:21][C:22]=2[CH3:23])=[CH:14][CH:13]=1.Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[N:19]=[C:20]([N:24]3[C:25]([CH3:29])([CH3:28])[CH2:26][O:27][C:31]3=[O:33])[S:21][C:22]=2[CH3:23])=[CH:16][CH:17]=1
Reactant: Cc1sc(NC(C)(C)CO)nc1-c1ccc(Br)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc(N2C(=O)OCC2(C)C)nc1-c1ccc(Br)cc1
Reaction time: 2 h
Yield: 1270.7 %

Procedure:
Diisopropylethylamine (10.0 mL, 57.4 mmol) was added under nitrogen to a mixture of 2-{[4-(4-bromophenyl)-5-methyl-1,3-thiazol-2-yl]amino}-2-methylpropan-1-ol hydrobromide (5.2 g, 1.2 mmol), prepared in the previous step, and 120 mL of methylene chloride at room temperature. A white solid formed. The mixture was cooled to ice bath temperature and triphosgene (5.2 g, 1.8 mmol) in 60 mL of methylene chloride was added dropwise over approximately 2 h. After the addition, the reaction became homogeneous. The reaction was stirred at ice bath temperature for approximately 2 h and then at room temperature overnight. The reaction was extracted with aqueous sodium hydroxide and the solvent removed under reduced pressure to give 5.6 g of a solid. Purification of the solid on a Horizon™ Flash Collector (the Biotage FLASH 25+™ cartridge) using a linear gradient of 36% methylene chloride in hexane to 75% methylene chloride in hexane gave the title compound (2.77 g, 63%) as a white solid, mp 175-176.5° C.; MS (ESI) m/z 367 [M+H]+. Anal. Calcd for C15H15BrN2O2S: C, 49.06; H, 4.12; N, 7.63. Found: C, 48.94; H, 4.19; N, 7.56.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:20](Cl)(=[O:22])[CH3:21]>ClCCl>[C:20]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C(C)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
4'-Hydroxyacetophenone (10 g, 73.4 mmole) was suspended in 200 ml dichloromethane in a 500 ml one neck round bottom flask under nitrogen at 0° C. The suspension was treated with diisopropylethylamine (14.7 ml, 84.5 mmole) followed by acetyl chloride (6.0 ml, 84.5 mmole) in 1×50 ml dichloromethane slowly dropwise. The reaction mixture was stirred 30 minutes at 0° C. and then for 1 hour at room temperature. The mixture was washed with 1×100 ml 10% hydrochloric acid and the organics were dried over magnesium sulfate. The dried organics were conentrated in vacuo to a yellow oil. The oil was distilled via kugelrohr (high vacuum, 165° C.) to give 12.25 g (94%) of 4'-acetoxy-acetophenone as a white solid. Melting Point: 47°-49° C. 4'-Acetoxy-acetophenone (10 g, 56.2 mmole) was dissolved in acetic anhydride (10.6 ml, 112.2 mmole) in an oven dried 50 ml two neck round bottom flask under nitrogen. The solution was cooled to 0° C. and boron trilfuoride gas was bubbled into the reaction mixture until it was saturated. The reaction was stirred 1 hour at room temperature and was poured into 600 ml diethyl ether. The orange precipitate was collected, washed with fresh diethyl ether, and was dried to afford 6.6 g (43%) of a boron difluoride complex. Melting Point: 130°-132° C.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[C:12]3[CH:13]=[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:15]([F:17])=[CH:16][C:11]=3[O:10][CH2:9][CH2:8][N:7]2[C:24]=1[C:25]([OH:27])=O)(=[O:3])[NH2:2].[N:28]1([CH2:33][CH2:34][NH2:35])[CH2:32][CH2:31][CH2:30][CH2:29]1>>[F:17][C:15]1[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:21])[CH3:22])=[CH:13][C:12]2[C:6]3[N:7]([C:24]([C:25]([NH:35][CH2:34][CH2:33][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:27])=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=3)[CH2:8][CH2:9][O:10][C:11]=2[CH:16]=1
Reactant: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C(=O)O
Reactant: NCCN1CCCC1
Product: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C(=O)NCCN1CCCC1

Procedure:
2-carbamoyl-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (0.05 g) was reacted with 1-pyrrolidineethylamine similar to as described in Example 2 to afford 21.1 mg of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-N3-(2-pyrrolidin-1-ylethyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 470 (M)+. 1H NMR (400 MHz, DMSO) δ 11.20 (t, J=5.5 Hz, 1H), 8.61 (d, J=8.4 Hz, 1H), 8.42 (s, 1H), 7.90 (s, 1H), 7.03 (d, J=10.5 Hz, 1H), 5.47 (s, 1H), 5.02-4.84 (m, 2H), 4.64-4.43 (m, 2H), 3.65-3.49 (m, 2H), 3.16-2.81 (m, 6H), 1.95-1.79 (m, 4H), 1.49 (s, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22](O)=[O:23])=[CH:19][C:18]=2[CH:25]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C@H:27]1[CH2:32][CH2:31][C@H:30]([CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:29][CH2:28]1>>[CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22]([NH:26][C@H:27]3[CH2:28][CH2:29][C@H:30]([CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:32]3)=[O:23])=[CH:19][C:18]=2[CH:25]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc2oc(C(=O)O)cc2c1
Reactant: CC(C)(C)OC(=O)CC[C@H]1CC[C@H](N)CC1
Product: CC(C)(C)OC(=O)CC[C@H]1CC[C@H](NC(=O)c2cc3cc(C(=N)NC(=O)OCc4ccccc4)ccc3o2)CC1

Procedure:
In the same manner as in Example 15 (3), 5-(benzyloxycarbonylamidino)-2-benzofurancarboxylic acid (3.98 g, 11.8 mmol) and t-butyl trans-3-(4-aminocyclohexyl)propionate (2.70 g, 11.8 mmol) were condensed to give 5.04 g of t-butyl trans-3-[4-[[5-(benzyloxycarbonylamidino)-2-benzofuranyl]carbonylamino]cyclohexyl]propionate as a colorless solid (78%). In the same manner as in Example 85, this solid (4.90 g, 8.95 mmol) was subjected to hydrogen reduction to give 3.52 g of compound (161) as a colorless solid (95%), which was treated with methanesulfonic acid (0.82 g, 8.52 mmol) in tetrahydrofuran solvent to give 3.82 g of methanesulfonate of compound (161) as a colorless solid (88%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH:12]([CH2:26][NH2:27])[C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.C([O:40][C:41](=O)[C:42]1[C:47]([CH2:48]Br)=[CH:46][CH:45]=[CH:44][C:43]=1[O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])C>C(#N)C>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][N:13]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[CH:12]([CH2:26][N:27]3[CH2:48][C:47]4[C:42](=[C:43]([O:50][Si:51]([C:54]([CH3:56])([CH3:55])[CH3:57])([CH3:52])[CH3:53])[CH:44]=[CH:45][CH:46]=4)[C:41]3=[O:40])[C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CN2CCc3c(sc(N)c3C(=O)OC(C)(C)C)C2CN)cc1
Reactant: CCOC(=O)c1c(CBr)cccc1O[Si](C)(C)C(C)(C)C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2CCc3c(sc(N)c3C(=O)OC(C)(C)C)C2CN2Cc3cccc(O[Si](C)(C)C(C)(C)C)c3C2=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.3 %

Procedure:
To a solution of 2-amino-7-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (80 mg, 0.20 mmol) and diisopropyl ethylamine (35 μl, 0.40 mmol) in acetonitrile (10 ml) at room temperature was added a solution of 6-bromomethyl-2-(tert-butyl-dimethyl-silanyloxy)-benzoic acid ethyl ester (69 mg, 0.20 mmol). The solution was stirred for 12 hours at room temperature and the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and washed with water, 1 N hydrochloric acid, brine, dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was chromatographed on silica gel column eluted with 20% ethyl acetate/hexane to yield 42 mg (33%) of 2-amino-7-(7-(tert-butyl-dimethyl-silanyloxy)-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[O:8][C:7]=1[C:12]([F:15])([F:14])[F:13])=[O:5])[CH3:2].[Br:16]N1C(=O)CCC1=O.C(Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][Br:16])[O:8][C:7]=1[C:12]([F:15])([F:13])[F:14])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C)oc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(CBr)oc1C(F)(F)F
Temperature: 25 °C
Yield: 37.6 %

Procedure:
To a solution of 5-methyl-2-trifluoromethyl-furan-3-carboxylic acid ethyl ester (0.95 g, 4.5 mmol) in CCl4 (12 mL) was added N-bromosuccinimide (0.84 g, 4.8 mmol) followed by AIBN (0.004 g, 0.01 mmol). After refluxing for 2 h, analytical HPLC analysis confirmed the reaction was complete. The reaction was cooled to rt, then CH2Cl2 and sat'd NaHCO3 (aq.) were added. The organic portion was separated and dried to provide the crude residue as a yellow oil. This material was purified by RP HPLC to provide the title compound (510 mg, 38%). MS (ESI): mass calcd. for C9H8BrF3O3, 300.0; m/z found, 302.9 [M+H]+. 1H NMR (CDCl3): 6.84 (s, 1H), 4.44 (s, 2H), 4.34 (q, J=7.2 Hz, 2H), 1.36 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([Cl:20])[CH:13]=1)P(OCC)(=O)OCC.[CH:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[C:22]1=O)[CH2:28]2.C([N-]C(C)C)(C)C.[Li+]>C1COCC1>[Cl:20][C:14]1[CH:13]=[C:12]([C:3]([O:2][CH3:1])=[C:22]2[CH:23]3[CH2:29][CH:27]4[CH2:26][CH:25]([CH2:30][CH:21]2[CH2:28]4)[CH2:24]3)[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1
Reactant: CCOP(=O)(OCC)C(OC)c1cc(Cl)cc(OC)c1
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=C1C2CC3CC(C2)CC1C3)c1cc(Cl)cc(OC)c1
Temperature: -68 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
Phosphonoate 8 (4.62 g, 14 mmol) and 2-adamantanone (2.58 g, 17 mmol) were dissolved in anhydrous THF (35 ml) under argon and cooled to -68° C. Dropwise addition of lithium diisopropylamide (18.6 mmol) in anhydrous THF (20 ml) at -68° C. generated the ylid, followed by subsequent olefination of the ketone. The reaction was slowly warmed to room temperature over 2 h and then stirred at 75° C. for 1 h. The solution was partitioned between EtOAc/NH4Cl, dried over Na2SO4, evaporated and purified by silica gel chromatography (2% EtOAc/hexanes), yielding 2.5 g (55%) of enol ether 9 as an oil.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:6]([O:7][CH3:8])[C:4]=1[OH:5].C(=O)([O-])[O-].[K+].[K+].Br[CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C=O)C>[CH:2]([C:3]1[CH:11]=[CH:10][CH:9]=[C:6]([O:7][CH3:8])[C:4]=1[O:5][CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:1]
Reactant: CCOC(=O)C(C)Br
Reactant: COc1cccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1c(C=O)cccc1OC
Temperature: 25 °C
Reaction time: 19.5 h
Yield: 93 %

Procedure:
o-vanillin (24.20 g) was dissolved in DMF (300 ml) and potassium carbonate (15.4 g) and ethyl 2-bromopropionate (24.8 ml) were added to the solution, followed by stirring the solution at room temperature for 19.5 hours. The reaction solution was filtered and the filtrate was concentrated. The obtained residue was distilled to obtain the desired compound (36.98 g, yield: 93%).
Reaction SMILES: [C:1]([S:5]([OH:8])(=[O:7])=[O:6])([F:4])([F:3])[F:2].C([O-])([O-])=O.[K+:13].[K+].C(=O)([O-])[O-]>>[C:1]([S:5]([O:8][K:13])(=[O:7])=[O:6])([F:4])([F:3])[F:2]
Reactant: [K+]
Reactant: O=S(=O)(O)C(F)(F)F
Agent: O=C([O-])[O-]
Product: O=S(=O)(O[K])C(F)(F)F

Procedure:
A teflon vessel was charged with 75% aqueous solution of CF3SO3H used in Example 1, and K2CO3 (free fluorine 31 ppm, free chlorine 18 ppm) was put into the solution such that the reaction between the acid and the carbonate proceeded under acidic conditions and terminated while pH of the reaction liquid was 2. Then the reaction liquid was dried in the same manner as in Example 1 to thereby obtain a white powder of CF3SO3K.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([CH3:15])[C:7]([C:16](OC)=[O:17])=[C:6]2[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[OH:17][CH2:16][C:7]1[C:8]([CH3:15])=[N:9][C:10]2[C:5]([C:6]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=2
Reactant: COC(=O)c1c(C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2c(CO)c(C)nc3cc(OC)c(OC)cc23)cc1OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.7 %

Procedure:
A solution of methyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-methylquinoline-3-carboxylate (0.4 g) in tetrahydrofuran (10 ml) was added dropwise to a suspension of lithium aluminium hydride (LiAlH4)(0.114 g) in tetrahydrofuran (10 ml) at room temperature. The mixture was stirred at room temperature for 1.5 hours, and water was added. The resulting mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, the solvent was evaporated, and the resulting crystals were collected by filtration and recrystallized from methanol to give 3-hydroxymethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-methylquinoline (0.326 g, 88%). mp. 200°-201° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](Br)=[CH:11][C:12]2[CH2:16][CH:15]([CH3:17])[S:14][C:13]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[B:25](OC)([O:28]C)[O:26]C.Cl>C1COCC1.CCOC(C)=O>[CH2:1]([O:8][C:9]1[C:10]([B:25]([OH:28])[OH:26])=[CH:11][C:12]2[CH2:16][CH:15]([CH3:17])[S:14][C:13]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COB(OC)OC
Reactant: CC1Cc2cc(Br)c(OCc3ccccc3)cc2S1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1Cc2cc(B(O)O)c(OCc3ccccc3)cc2S1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6-benzyloxy-5-bromo-2-methyl-2,3-dihydrobenzo[b]thiophene (1.0 g, 3.0 mmol) in THF at 0° C. is added n-BuLi (1.8 mL, 4.5 mmol, 2.5 M in hexane) and the mixture is stirred for 1.5 h at 0° C. B(OMe)3 (1.67 mL, 15 mmol) is added dropwise and it is warmed to RT and stirred for 1.5 h. 3M HCl solution is added slowly at 0° C. and EtOAc is added to extract the product. The organic phase is dried with MgSO4 and concentrated. The residue is purified by chromatography to give the title compound as a white solid: (M+H)+=301.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:15][C:16](O)=[O:17]>C1COCC1>[CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:4][C:3]=1[CH2:15][CH2:16][OH:17]
Reactant: Cc1oc(CCc2ccccc2)nc1CC(=O)O
Solvent: C1CCOC1
Product: Cc1oc(CCc2ccccc2)nc1CCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.7 %

Procedure:
BH3-THF complex (49 mL of a 1.0 M solution in THF) was added dropwise via addition funnel over 50 min to a solution of (5-methyl-2-phenethyl-oxazol-4-yl)-acetic acid (5.05 g, 20.6 mmol) in THF (35 mL). The reaction mixture was stirred at ambient temperature for 3 h, and then quenched with MeOH (12 mL). After heating at 50° c for 2 h, the reaction mixture was cooled to ambient temperature, and then partitioned between CH2Cl2 and 1N NaOH. The organic phase was washed with brine (1×50 mL), dried over MgSO4 and concentrated to obtain a residue which was purified by column chromatography (500 mL SiO2, 35% EtOAc/hexanes) to provide 3.99 g (84%) of the desired product as a clear, colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.33-7.20 (m, 5H), 3.84 (q, J=5.6 Hz, 2H), 3.06-2.67 (m, 4H), 2.62 (t, J=5.6 Hz, 2H), 2.22 (s, 3H); MS (EI+) 232.19 (M+H); 254.15 (M+H+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:15][CH2:16][C:17]([C:19]2[S:26][C:25]([CH3:27])=[C:24]3[C:20]=2[CH2:21][C@H:22]2[C:28]([CH3:30])([CH3:29])[C@H:23]23)=[O:18])[CH:5]=[C:6]([O:13][CH3:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][OH:12].CCN(C(C)C)C(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:15][CH2:16][C:17](=[O:18])[C:19]2[S:26][C:25]([CH3:27])=[C:24]3[C:20]=2[CH2:21][C@H:22]2[C:28]([CH3:30])([CH3:29])[C@H:23]23)[CH:5]=[C:6]([O:13][CH3:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:12][S:41]([CH3:40])(=[O:43])=[O:42]
Reactant: COc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(Cl)c1OCCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(Cl)c1OCCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 471.3 %

Procedure:
To a solution of 3-[3-chloro-4-(3-hydroxy-propoxy)-5-methoxy-phenyl]-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (430 mg, 0.958 mmol) in DCM (20 mL) and DIPEA (0.262 mL, 1.53 mmol) is added methane sulfonylchloride (0.090 mL, 1.15 mmol) at 0° C. The reaction mixture is stirred at 0° C. for 30 min. The reaction mixture is diluted with DCM, washed with 0.1 N aq. NaOH followed by 10% aq. citric acid solution, dried over MgSO4 and evaporated to give methanesulfonic acid 3-{2-chloro-6-methoxy-4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propyl]-phenoxy}-propyl ester (2.38 g) as a brown oil; LC-MS: tR=1.14 min, [M+1]+=527.23.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[NH:14][C:13](=O)[C:12]=2[CH2:11][CH2:10]1.[CH2:28]([N:30](CC)CC)C.CS(Cl)(=O)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:25])([F:24])[F:26])[C:15]=3[N:14]=[C:13]([NH:30][CH3:28])[C:12]=2[CH2:11][CH2:10]1
Reactant: CCN(CC)CC
Reactant: Cc1cc(O)ccc1N1CCc2c1c1cccc(OC(F)(F)F)c1[nH]c2=O
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CNc1nc2c(OC(F)(F)F)cccc2c2c1CCN2c1ccc(O)cc1C
Temperature: -78 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
1-(2-Methyl-4-hydroxyphenyl)-4-oxo-6-trifluoromethoxy-2,3,4,5-tetra-hydropyrrolo[3,2-c]quinoline(2.3g, 6.1 mmol) was dissolved in dichloromethane. Triethylamine(2.6 ml, 18.0 mmol) was added and methanesulfonyl chloride(1.0 ml, 12.8 mmol) were added, and then the reaction mixture was stirred at -78° C. for 3 hours. The reaction mixture was slowly warmed up to -10° C., and stirred for 1 hours. After extracting the reaction mixture with dichloromethane, the organic layer was washed with water for 3 times. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized in dichloromethane/hexane to obtain 2.3 g of desired compound as solid in 72% of yield.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:8]([F:11])=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>OS(O)(=O)=O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:12]([F:15])([F:13])[F:14])[C:8]([F:11])=[CH:9][C:10]=1[N+:16]([O-:18])=[O:17])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(F)c(C(F)(F)F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1cc(C(F)(F)F)c(F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To 3-acetamido-6-fluorobenzotrifluoride (2.4 g, 10.85 mmol) in concentrated H2SO4 (10 mL) at 0° C. was added dropwise 70% HNO3 (1.5 mL, Baker). The mixture was stirred at 0° C. for 0.5 h, then at room temperature for 3 h and it was poured into ice water (20 g). The precipitate was collected by filtration, affording 2.6 g (90%) of crude 3-acetamido-6-fluoro-4-nitrobenzotrifluoride. It was crystallized from EtOH/H2O to give 2.1 g of pure compound as yellow needles. 1H NMR (CDCl3): δ 2.318 (s, 3H), 8.062 (d, 1H, J=9.6 Hz), 9.196 (s, 1H), 10.152 (s, 1H).