Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:22][Si:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][O:26][CH2:27]Cl>CN(C)C=O.O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)/[C:7](=[O:11])[N:8]2[CH2:27][O:26][CH2:25][CH2:24][Si:23]([CH3:30])([CH3:29])[CH3:22])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C/c1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
To a solution of E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one prepared in example 1a (2.3 g, 7.9 mmol) in N,N-dimethyl-formamide (20 mL) at 0° C. was added NaH (60% in mineral oil) (0.32 g, 7.9 mmol) (Aldrich), followed by the dropwise addition of 2-(trimethylsilyl)ethoxymethyl chloride (1.32 g, 7.9 mmol) in tetrahydrofuran (20 mL). The reaction mixture was stirred at 0° C. for 0.5 h, then poured into ice-water. The crude was extracted with ethyl acetate twice. The combined organic layer was dried over Na2SO4. The solvent was removed and the residue was purified by chromatography (EtOAc:hexanes=1:5) to give E/Z-6-chloro-3-(3-chloro-benzylidene)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indole-2-one as yellow oil (Yield 3.0 g, 90%).
Reaction SMILES: FC(F)(F)S(O[C@H:7]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1)[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])(=O)=O.[NH2:28][C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=1)[C:32]([O:34][CH3:35])=[O:33]>C(Cl)Cl>[CH3:35][O:34][C:32]([C:31]1[CH:30]=[C:29]([NH:28][C@@H:7]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=2)[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH:38]=[CH:37][CH:36]=1)=[O:33]
Reactant: COC(=O)c1cccc(N)c1
Reactant: Cc1cccc(C[C@@H](OS(=O)(=O)C(F)(F)F)C(=O)OCc2ccccc2)c1
Solvent: ClCCl
Product: COC(=O)c1cccc(N[C@@H](Cc2cccc(C)c2)C(=O)OCc2ccccc2)c1

Procedure:
A solution of benzyl (R)-2-trifluoromethanesulfonyloxy-3-(3-methylphenyl)-propionate (0.59 g, 1.47 mmol) and methyl 3-aminobenzoate (0.44 g, 2.94 mmol) in CH2Cl2 (20 mL) is stirred overnight at room temp for 2 days. Solvent is evaporated, and the residue is chromatographed (silica, 33% CH2Cl2/hexane) to yield benzyl (S)-2-(3-methoxycarbonylphenylamino)-3-(3-methylphenyl)-propionate, as a clear oil.
Reaction SMILES: CN(CCN(C)C)C.C([Li])(CC)C.Br[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH3:24])[CH:19]1[N:25]([CH3:28])[CH2:26][CH2:27][C:18]21[CH3:29].[CH:30]([N:33]([C:37](=[O:43])[C:38](OCC)=[O:39])[CH:34]([CH3:36])[CH3:35])([CH3:32])[CH3:31]>CCOCC>[CH:34]([N:33]([CH:30]([CH3:32])[CH3:31])[C:37](=[O:43])[C:38](=[O:39])[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH3:24])[CH:19]1[N:25]([CH3:28])[CH2:26][CH2:27][C:18]21[CH3:29])([CH3:36])[CH3:35]
Reactant: CCOC(=O)C(=O)N(C(C)C)C(C)C
Reactant: CN1CCC2(C)c3cc(Br)ccc3N(C)C12
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: CC(C)N(C(=O)C(=O)c1ccc2c(c1)C1(C)CCN(C)C1N2C)C(C)C
Temperature: -78 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
To a solution of TMEDA (2.85 ml) in anhydrous ether (5.0 ml) was added at -78° C. under N2 atmosphere, sec-butyllithium (14.5 ml). The resulting solution was subsequently treated with a solution of 5-bromo-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indole (3.80 g) in anhydrous ether (10 ml). The mixture was held at this temperature for 3 hours and then added to a solution of diisopropylamino-oxo-acetic acid, ethyl ester (7.5 g) in anhydrous ether (15 ml). After stirring at -78° C. for 4 hours, the reaction mixture was quenched with 50 ml of aqueous NH4Cl solution. The organic and aqueous phases were separated and the organic phase washed successively with saturated aqueous NaHCO3 and brine. The organic phase was dried (Na2SO4), filtered and concentrated to an oil which was purified by HPLC (silica gel, 10% MeOH in ethyl acetate as eluent). 2.8 g of 1,2,3,3a,8,8a-Hexahydro-α-oxo- 1,3a,8-trimethyl-5-pyrrolo[2,3-b]indole acetic acid, diisopropyl amide was obtained as a foam. Trituration with hexane and drying under reduced pressure yielded an analytically pure sample.
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([O:7][C:8](=[O:29])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[C:21]([O:26]C)[C:20]=2[F:28])=[O:18])=[CH:12][CH:11]=1)[CH3:6]>ClCCl>[Cl:25][C:24]1[C:19]([C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([CH2:9][C:8]([O:7][CH2:5][CH3:6])=[O:29])=[CH:15][CH:14]=2)=[O:18])=[C:20]([F:28])[C:21]([OH:26])=[CH:22][CH:23]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2c(Cl)ccc(OC)c2F)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(NC(=O)c2c(Cl)ccc(O)c2F)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
Boron tribromide (393 μl, 4.16 mmol) was added dropwise to a solution of ethyl[4-({[6-chloro-2-fluoro-3-(methyloxy)phenyl]carbonyl}amino)phenyl]acetate (506 mg, 1.39 mmol) in dichloromethane (30 ml) at −78° C. under argon and the reaction was stirred overnight whilst slowly warming to 0° C. The reaction was quenched by the careful addition of water, stirred for 1 hour, further diluted with ethyl acetate, filtered, phases separated, the organic layer dried (Na2SO4) and solvent evaporated and the residue purified by flash chromatography (Biotage SP4, 25+M silica column, 0→80% ethyl acetate/petrol, clean fractions collected) to afford the title compound as a colourless foam (157 mg, 32%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:18])[CH2:9][NH:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][CH:7]=1.O=P(Cl)(Cl)Cl>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:18][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)NCC(=O)c1cccc(Cl)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCOC(=O)c1ncc(-c2cccc(Cl)c2)o1
Yield: 51.6 %

Procedure:
A mixture of the product from Step 79b (1.28 g, 4.70 mmol, 1 eq), benzene (8 mL), and POCl3 (2.0 mL, 21 mmol) is heated under reflux for 65 h and cooled. The mixture is then evaporated and extracted between CHCl3 and water. The organic layer is separated, dried over MgSO4, filtered, and evaporated. The residue is crystallized from EtOH to give the title product (0.61 g, 51%). MS (ESI) for C12H10ClNO3 m/z 252 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][C:6]=2[S:5][C:4]([C:16]2[N:21]=[C:20]([CH2:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])[CH:19]=[CH:18][CH:17]=2)=[N:3]1.FC(F)(F)C(O)=O>>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([F:14])([F:13])[F:15])=[CH:11][C:6]=2[S:5][C:4]([C:16]2[N:21]=[C:20]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:19]=[CH:18][CH:17]=2)=[N:3]1
Reactant: CC(C)(C)OC(=O)CCc1cccc(-c2nc(=O)c3ccc(C(F)(F)F)cc3s2)n1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCc1cccc(-c2nc(=O)c3ccc(C(F)(F)F)cc3s2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
A mixture of tert-butyl 3-[6-(4-oxo-7-trifluoromethyl-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propanoate (0.35 g, 0.8 mmol) and trifluoroacetic acid (5.0 ml) was stirred at 0° C. for 2 hrs. The reaction mixture was concentrated under reduced pressure and combined with diisopropyl ether to precipitate crystals, which were collected by filtration and dried to give the titled compound (0.27 g, 88%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:26])C=1>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N+:12]=2[O-:26])=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=c1nc(-c2ccncc2)sc2ccccc12
Solvent: ClC(Cl)Cl
Product: O=c1c2ccccc2sc(-c2ccncc2)[n+]1[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.1 %

Procedure:
2-(4-pyridyl)-4H-1,3-benzothiazine-4-one (1.00 g, 4.1 mmol) was dissolved in chloroform (20 ml). To the mixture was added 3-chloroperbenzoic acid (ca. 77%, 0.92 g, 4.1 mmol). The reaction mixture was stirred at room temperature for 24 hr and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography and eluted with ethyl acetate-methanol (20:1, v/v) and recrystallized from diisopropylether-methanol to give the titled compound (0.18 g, 16%) as crystals.
Reaction SMILES: [C:1]([NH:5][C:6]1[N:11]=[C:10]([N:12]2[C:16]3[CH:17]=[C:18]([NH2:21])[CH:19]=[CH:20][C:15]=3[N:14]=[CH:13]2)[CH:9]=[N:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl.[C:41](O)(=[O:44])[CH:42]=[CH2:43]>ClCCl.O>[C:1]([NH:5][C:6]1[N:11]=[C:10]([N:12]2[C:16]3[CH:17]=[C:18]([NH:21][C:41](=[O:44])[CH:42]=[CH2:43])[CH:19]=[CH:20][C:15]=3[N:14]=[CH:13]2)[CH:9]=[N:8][CH:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC(=O)O
Reactant: CC(C)(C)Nc1cncc(-n2cnc3ccc(N)cc32)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc2ncn(-c3cncc(NC(C)(C)C)n3)c2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of 1-[6-(tert-butylamino)pyrazin-2-yl]-1H-benzimidazol-6-amine (22 mg, 0.08 mmol) in anhydrous dichloromethane (2 mL) under N2 was added triethylamine (33 μL, 0.24 mmol), EDAC.HCl (22 mg, 0.12 mmol), 4-(1-pyrrolidino)pyridine (cat.) and acrylic acid (8 μL, 0.12 mmol). The resulting mixture then stirred at RT for 3 days and was the diluted with H2O (10 mL), the organic phase separated and the aqueous phase extracted with CH2Cl2 (10 mL). The combined organic layers were dried (Na2SO4) and the solvent removed in vacuo. The residue was purified by column chromatography using dichloromethane-methanol (98:2-93:7) as eluant to separate the pure product (10 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([I:9])[CH:3]=1.Br[CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:11]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][C:4]=1[I:9])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: Nc1ccc(Cl)cc1I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Clc1ccc(NC(c2ccccc2)c2ccccc2)c(I)c1
Temperature: 45 °C
Yield: 95.5 %

Procedure:
To a solution of 4-chloro-2-iodoaniline (16.5 g, 65.1 mmol) in DMF (250 mL) at rt were added □-bromodiphenylmethane (21.5 g, 84.6 mmol) and iPr2NEt (23 mL, 130 mmol) and the reaction mixture was heated at 45° C. overnight. After the volatile was removed under reduced pressure, the residue was dissolved in EtOAc, washed with water (3×) and brine and dried over MgSO4. Purification on SiO2 column chromoatography (hexanes to 5% EtOAc/hexanes) gave the desired Benzhydryl-(4-chloro-2-iodo-phenyl)-amine (26.1 g, 97% yield) as a yellowish solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([CH2:21][OH:22])[C:9]=2[CH3:23])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:26]([O:28][C:29](=[O:34])[C:30](Br)([CH3:32])[CH3:31])[CH3:27]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:26]([O:28][C:29](=[O:34])[C:30]([O:22][CH2:21][C:10]1[C:9]([CH3:23])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[N:11]=1)([CH3:32])[CH3:31])[CH3:27]
Reactant: Cc1c(CO)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)OCc1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1.6 g of [5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-yl]-methanol in 15 ml of DMF were added 870 mg of sodium hydride (60% in mineral oil) at room temperature. After 15 min 1.6 g of tetrabutylammonium iodide and 3.4 g of 2-Bromo-2-methyl-propionic acid ethyl ester were added and the reaction mixture was stirred for 16 h at room temperature. After dilution with saturated aqueous sodium hydrogen carbonate solution the reaction mixture was filtered through a chem Elut® cartridge by eluting with ethyl acetate The solvents were removed under reduced pressure and the crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.3 g.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([NH:11][C@@H:12]([CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:13]([NH:15][C@@H:16]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]2[S:46](=[O:48])(=[O:47])[N:45](C(C)(C)C)[C:44](=[O:53])[CH2:43]2)=[CH:38][CH:37]=1)[CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[C:25]=1[C:26]([O:28][CH3:29])=[O:27])=[O:14])(=[O:10])[CH3:9].FC(F)(F)C(O)=O>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([NH:11][C@@H:12]([CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[C:13]([NH:15][C@@H:16]([CH2:35][C:36]1[CH:37]=[CH:38][C:39]([CH:42]2[S:46](=[O:48])(=[O:47])[NH:45][C:44](=[O:53])[CH2:43]2)=[CH:40][CH:41]=1)[CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[C:25]=1[C:26]([O:28][CH3:29])=[O:27])=[O:14])(=[O:10])[CH3:9]
Reactant: COC(=O)c1c(O)cccc1OCCCCNC[C@H](Cc1ccc(C2CC(=O)N(C(C)(C)C)S2(=O)=O)cc1)NC(=O)[C@H](Cc1ccccc1)NC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c(O)cccc1OCCCCNC[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)cc1)NC(=O)[C@H](Cc1ccccc1)NC(C)=O
Temperature: 130 °C
Reaction time: 0.02 h

Procedure:
Methyl 2-[4-((2S)-2-[(2S)-2-(acetylamino)-3-phenylpropanoyl]amino-3-[4-(2-tert-butyl-1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]propylamino)butoxy-]6-hydroxybenzoate trifluoroacetate (salt) was submitted in two batches to deprotection conditions in the a microwave. The first batch (5.1 mg, 0.0061 mmol) was combined with crushed 3 Å molecular sieves (7.9 mg) and trifluoroacetic acid (0.75 mL) and heated at 130° C. 3 times for one minute each time. The second batch (18 mg, 0.021 mmol) was combined with crushed 3 Å molecular sieves (29 mg) and trifluoroacetic acid (2.6 mL) and heated at 130° C. twice for one minute each time. The reactions were combined and filtered through a glass frit. The filtrate was purified on a 50 mm Luna C18 column using a 10–70% acetonitrile in water gradient with 0.05% trifluoroacetic acid at 30 mL per minute over a 30 minute period. The major product was lyophilized to obtain a white solid (12 mg), which was further purified on a 50 mm Luna C18 column using a 0–50% acetonitrile in water gradient with 0.05% trifluoroacetic acid at 30 mL per minute over a 30 minute period. The desired fractions were combined and lyophilized to give a white solid (6 mg, 24%). 1H NMR (400 MHz, CD3OD): δ 7.50 (d, J=8.0 Hz, 2H), 7.30 (m, 6H), 7.17 (m, 2H), 6.55 (dd, J=7.3 Hz, J′=6.5 Hz, 2H), 5.17 (m, 1H), 4.36 (m, 2H), 4.09 (bs, 2H), 3.91 (s, 3H), 3.22–2.83 (m, 9H), 1.92 (m, 7H); LCMS found for C35H43N4O9S (M+H)+: m/z=695.2.
Reaction SMILES: [C-]#N.[Na+].Br[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)=[CH:8][C:7]=1[Cl:21].[CH3:22][N:23](C=O)C.O>[Cl-].[Na+].O>[O:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=[C:12]1[C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:22]#[N:23])=[C:7]([Cl:21])[CH:8]=1
Reactant: CN(C)C=O
Reactant: Clc1cc(-c2nc3ccccc3o2)ccc1CBr
Agent: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: N#CCc1ccc(-c2nc3ccccc3o2)cc1Cl

Procedure:
A slurry of NaCN (435 mg, 8.9 mmol), 2-[4-(bromomethyl)-3-chlorophenyl]-1,3-benzoxazole (940 mg, 2.9 mmol), DMF (30 mL) and H2O (30 mL) was stirred at rt for 12 h. The reaction mixture was poured into brine (250 mL) and filtered. The resultant colorless solid was purified by flash chromatography on silica gel (EtOAc:hexanes 1:9) to afford the desired [4-(1,3-benzoxazol-2-yl)-2-chlorophenyl]acetonitrile as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 8.32 (s, 1H), 8.19 (dd, 1H), 7.77–7.80 (m, 1H), 7.70 (d, 1H), 7.59–7.61 (m, 1H), 7.38–7.41 (m, 2H), 3.92 (s, 2H). MS (ESI) 269 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([CH3:16])[N:6]=[C:7]3[C:12]=2[CH:11]=[CH:10][CH:9]=[CH:8]3)[CH:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.B.CSC.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.[OH-].[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]([S:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=1)(=[O:27])=[O:26])[C@H:5]2[CH3:16]
Reactant: Cc1nc2ccccc2c2ccc(F)cc12
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: [Na+]
Solvent: CSC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccc(F)cc3[C@@H]2C)cc1
Yield: 53.3 %

Procedure:
A solution of 8-fluoro-6-methylphenanthridine (0.5 g, 2.4 mmol) and 4-methoxybenzenesulfonyl chloride (0.514 g, 2.49 mmol) in dichloromethane (5 mL) was added to a solution of borane-methyl sulfide (0.142 mL, 1.42 mmol, 10 M solution in methyl sulfide) and (R)-2-methyl-CBS-oxazaborolidine (0.47 mL, 0.4734 mmol, 1.0 M solution in toluene) in dry dichloromethane (6 mL) over the course of three hours at room temperature. The reaction mixture was stirred for twelve hours and then a solution of aqueous sodium hydroxide (10 mL, 1 N) was added. The aqueous layer was extracted with dichloromethane (3×). The organic layers were combined, washed with a solution of saturated, aqueous sodium chloride, and dried over anhydrous sodium sulfate. The organic solvent was removed in vacuo to yield the crude product as an orange solid. The crude product was purified by chromatography on silica gel (1:10 ethyl acetate:hexane) to afford the title compound as a white solid (0.489 g, 1.28 mmol, 54% ).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9]([OH:32])[CH:10]2[NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C@:20]2([CH3:31])[C:25]([CH3:27])([CH3:26])[C:24](=[O:28])[N:23]([CH3:29])[C:22]([NH2:30])=[N:21]2)[CH:14]=1)=[O:5])C.[Li+].[OH-]>C1COCC1.CO.O>[NH2:30][C:22]1[N:23]([CH3:29])[C:24](=[O:28])[C:25]([CH3:26])([CH3:27])[C@:20]([C:15]2[CH:14]=[C:13]([NH:12][CH:10]3[C@H:9]([OH:32])[CH2:8][C@@H:7]4[C@H:11]3[C@H:6]4[C:4]([OH:5])=[O:3])[CH:18]=[CH:17][C:16]=2[F:19])([CH3:31])[N:21]=1
Reactant: CCOC(=O)[C@H]1[C@@H]2C[C@@H](O)C(Nc3ccc(F)c([C@@]4(C)N=C(N)N(C)C(=O)C4(C)C)c3)[C@@H]21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC3[C@H]4[C@@H](C[C@H]3O)[C@@H]4C(=O)O)ccc2F)N=C1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (1S,3R,5R,6S)-2-[3-((S)-2-Amino-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-4-yl)-4-fluoro-phenylamino]-3-hydroxy-bicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester (example 100, 0.05 mmol) in THF (1 ml), MeOH (0.3 ml) and H2O (0.3 ml) was added LiOH (1N, 0.1 mmol) and the reaction mixture was stirred at room temperature for 4 h. The mixture was concentrated in vacuo, the residue diluted with aqueous HCl (0.5 N) until pH=5 and evaporated again. The solid residue was triturated with dichloromethane/MeOH (10:1), filtered and the filtrate was concentrated in vacuo to yield a mixture of isomers of the title compound as a white solid. MS (ESI): m/z=419.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:13]1([CH:19]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:20][CH2:21][N:22]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:24])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[C:42]1([CH:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:20][CH2:21][N:22]([CH:36]2[CH2:37][CH2:38][N:39]([S:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[CH2:40][CH2:41]2)[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:33])[F:35])[CH:27]=2)=[O:24])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)N(CCC(c1ccccc1)c1ccccc1)C1CCNCC1
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N2CCC(N(CCC(c3ccccc3)c3ccccc3)C(=O)Nc3cccc(C(F)(F)F)c3)CC2)cc1
Reaction time: 8 h
Yield: 55.2 %

Procedure:
27.5 mg (100 μmol, 2 eq.) of morpholinomethyl resin is preswollen in anhydrous tetrahydrofuran, then 4-methoxyphenylsulphonyl chloride (15.5 mg, 0.075 mmol, 1.5 eq.) then N-(3,3-diphenylpropyl)-N-(4-piperidinyl)-N′-[3-(trifluoromethyl)phenyl]urea (24.3 mg, 0.05 mmol) are added. The mixture is agitated overnight. The aminomethyl (20 mg) and SAX ion exchange resins are added and the mixture is agitated overnight. The resins are filtered and rinsed with dichloromethane. The oil obtained after evaporation is passed through a silica gel cartridge (500 mg, Interchim) eluting with ethyl acetate in order to obtain 18 mg (yield=56%) of a white solid after concentration.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[N:16]1[C:28]2[C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([O:29][CH2:30][C:31]([F:34])([F:33])[F:32])[C:22]=3[N:21]=[C:20](Cl)[C:19]=2[CH2:18][CH2:17]1>C(CN)O.O>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[N:16]1[C:28]2[C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([O:29][CH2:30][C:31]([F:34])([F:33])[F:32])[C:22]=3[N:21]=[C:20]([NH:21][CH2:22][CH2:23][OH:29])[C:19]=2[CH2:18][CH2:17]1
Reactant: Cc1cc(OCc2ccccc2)ccc1N1CCc2c(Cl)nc3c(OCC(F)(F)F)cccc3c21
Solvent: NCCO
Solvent: O
Product: Cc1cc(OCc2ccccc2)ccc1N1CCc2c(NCCO)nc3c(OCC(F)(F)F)cccc3c21
Temperature: 180 °C
Yield: 165.5 %

Procedure:
1-(2-Methyl-4-benzyloxyphenyl)-4-chloro-6-β,β,β-trifluoroethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(749 mg, 1.5 mmol) was dissolved in ethanolamine(10 ml), and the resultant was refluxed at 180° C. for 15 hours. The reaction mixture was dissolved in water, extracted with dichloromethane, and 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 purified by silica gel column chromatography(ethyl acetate) to obtain 650 mg of desired compound as solid in 83% of yield.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](=[O:14])[NH:4][CH:3]=1.[CH3:15][NH:16][CH3:17]>>[CH3:15][N:16]([CH3:17])[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](=[O:14])[NH:4][CH:3]=1
Reactant: COc1ccc2c(=O)[nH]cc(Br)c2c1
Reactant: CNC
Product: COc1ccc2c(=O)[nH]cc(N(C)C)c2c1
Yield: 116.2 %

Procedure:
A solution of 4-bromo-6-methoxyisoquinolin-1(2H)-one (1 g, 3.94 mmol) in dimethylamine (5 ml, 39.5 mmol) was heated to 105° C. for 48 h. After cooling, the reaction mixture was concentrated under reduced pressure to get 4-(Dimethylamino)-6-methoxyisoquinolin-1(2H)-one (0.8 g, 4.58 mmol, 85% yield). MS: MS m/z 219.20 (M++1).