Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C@@H:19]1([NH2:29])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1>>[N+:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH2:12][NH:29][C@@H:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH2:21][CH2:20]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: N[C@H]1CCCc2ccccc21
Product: O=[N+]([O-])c1ccc(Oc2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1

Procedure:
The product from Example 48A and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:24]([O:27][CH2:28][CH2:29]Br)(=[O:26])[CH3:25]>CN(C=O)C.O>[C:7]1([C:13]([CH2:29][CH2:28][O:27][C:24](=[O:26])[CH3:25])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: CC(=O)OCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CCOC(C)=O)(C(=O)OCC)c1ccccc1
Temperature: 25 °C
Yield: 100.8 %

Procedure:
A solution of potassium tert.butoxide (448 g, 4M) in DMF (2 l) under nitrogen at room temperature was treated dropwise with diethyl phenylmalonate (945 g, 4M). 1-Acetoxy-2-bromoethane (668 g, 4M) was added. The reaction was allowed to cool to room temperature after 45 mins and was diluted with water (5 l) then extracted with IPE (2 l, 500 ml). The extracts were washed, dried and evaporated to give the title compound (1300 g). Bp 130°/0.05 mm.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:21]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>CN(C1C=CN=CC=1)C.C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:21]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([NH:12][C:11]2[CH:13]=[CH:14][C:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)=[CH:9][CH:10]=2)=[O:30])=[CH:32][CH:33]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: Nc1ccc(-c2ncccc2Cl)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccc(-c3ncccc3Cl)cc2)cc1
Reaction time: 1 h

Procedure:
The product from Example 41A (17.5 mg, 0.0855 mmol), DMAP (catalytic amount), and pyridine (21 μL, 0.26 mmol) were combined in CH2Cl2 (0.5 mL) and treated with 4-tert-butylbenzoyl chloride (33 μL, 0.17 mmol). After stirring for 1 hour, the mixture was diluted with saturated NaHCO3 (1 mL) and extracted with CH2Cl2 (3×1 mL). The organic layer was dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (50% diethyl ether in hexanes) to provide the title compound. 1H NMR (300 MHz, CDCl3)δ 8.59 (dd, 1H), 7.91 (br s, 1H), 7.83 (d, 2H), 7.81 (dd, 1H), 7.78 (d, 4H), 7.51 (d, 2H), 7.21 (dd, 1H), 1.36 (s, 9H); MS (m/z) 365.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.C([Mg]Br)C.[O:30]1[C:35]2[CH:36]=[CH:37][CH:38]=[C:39]([CH:40]=[O:41])[C:34]=2[O:33][CH2:32][CH2:31]1>ClCCl>[O:30]1[C:35]2[CH:36]=[CH:37][CH:38]=[C:39]([CH:40]([C:2]3[N:3]=[CH:4][N:5]([C:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:6]=3)[OH:41])[C:34]=2[O:33][CH2:32][CH2:31]1
Reactant: O=Cc1cccc2c1OCCO2
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC[Mg]Br
Solvent: ClCCl
Product: OC(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cccc2c1OCCO2

Procedure:
A mixture of 4-iodo-1-tritylimidazole (commercially available) (8.64 g, 19.8 mmol) in dichloromethane (100 mL) at −10° C. was treated with ethyl magnesium bromide (6.3 mL, 19 mmol, 3M in THF) and allowed to react for 45 m. A solution of 2,3-dihydro-benzo[1,4]dioxine-5-carbaldehyde (Intermediate A2) (2.6 g, 15.9 mmol) in dichloromethane was added via syringe at −10° C. and stirred for 45 m. The mixture was quenched with water (50 mL) and a sat. solution of ammonium chloride (50 mL). The residue was isolated in a typical aqueous workup and purified by chromatography on silica gel with 3 to 5% NH3-MeOH:CH2Cl2 to give (2,3-dihydro-benzo[1,4]dioxin-5-yl)-(1-trityl-1H-imidazol-4-yl)-methanol (Intermediate A3) as a solid, 2.9 g (40%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:76][CH2:77][CH2:78][O:79][CH2:80][CH2:81][O:82][CH2:83][CH2:84][O:85][CH2:86][CH2:87][NH2:88]>O1CCCC1>[NH2:88][CH2:87][CH2:86][O:85][CH2:84][CH2:83][O:82][CH2:81][CH2:80][O:79][CH2:78][CH2:77][NH:76][C:35]([C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1)=[O:37]
Reactant: NCCOCCOCCOCCN
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(C(=O)NCCOCCOCCOCCN)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 20 mL round-bottomed flask, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1, 100 mg, 162 μmol), HBTU (61.5 mg, 162 μmol) and Hunig's base (105 mg, 142 μL, 811 μmol) were combined with dry tetrahydrofuran (2 mL) to give an off-white suspension at room temperature. It was stirred at room temperature for 30 min. 1,11-Diamino-3,6,9-trioxaundecane (15.6 mg, 15.2 μL, 81.1 μmol) was added. After stirring at room temperature overnight, the reaction mixture was absorbed on small amount of silica gel, loaded on a 24 g pre-packed silica gel column and eluted with ethyl acetate to give (2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-{2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy}-ethylcarbamoyl)-2-methoxy-phenyl]-amide, dimer as white solid (148 mg, 66% yield). LCMS (ES+) m/z calcd. for C70H74Cl4F4N8O9 [(M+H)+]: 1387. found: 1387.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[NH:10][C:6]=2[CH:5]=[C:4]([NH2:12])[CH:3]=1.Br[CH2:14][CH2:15][O:16][CH2:17][CH2:18]Br.CCN(C(C)C)C(C)C>C(O)CO.O>[Br:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[NH:10][C:6]=2[CH:5]=[C:4]([N:12]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:3]=1
Reactant: BrCCOCCBr
Reactant: Cc1nc2c(Br)cc(N)cc2[nH]1
Solvent: OCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1nc2c(Br)cc(N3CCOCC3)cc2[nH]1
Temperature: 100 °C
Reaction time: 20 h
Yield: 57.8 %

Procedure:
A mixture of 7-bromo-2-methyl-3H-benzo[d]imidazol-5-amine (25 g, 111 mmol), 1-bromo-2-(2-bromoethoxy)ethane (38 g, 166 mmol) and DIPEA (21 g, 166 mmol) in ethylene glycol (600 mL) was stirred at 100° C. for 20 h. It was cooled to rt, and diluted with water (200 mL) and extracted with DCM (300 mL×4). The combined organic layers were washed with brine, dried over sodium sulphate and evaporated. The residue was purified by column chromatography (eluted with petroleum ether/ethyl acetate=1/1) to give the product (19 g, 58%) as a yellow solid; LC/MS: MS (ES+) m/e 296 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 2.44 (s, 3H), 3.07 (t, J=4.8 Hz, 4H), 3.74 (t, J=4.8 Hz, 4H), 6.85 (d, J=2.1 Hz, 1H), 7.04 (d, J=2.1 Hz, 1H), 12.20 (s, 1H).
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH2:20][NH:21][C:22]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=O)[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].O(C1C=CC(P2(=S)SP(=S)(C3C=CC(OC4C=CC=CC=4)=CC=3)[S:44]2)=CC=1)C1C=CC=CC=1>C1COCC1>[S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH2:20][NH:21][C:22]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[S:44])[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: S=P1(c2ccc(Oc3ccccc3)cc2)SP(=S)(c2ccc(Oc3ccccc3)cc2)S1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=O)C4CCCCC4)cnc32)cc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=S)C4CCCCC4)cnc32)cc1
Reaction time: 15 h

Procedure:
To a solution of N-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)cyclohexanecarboxamide (0.081 g, 0.196 mmol) in THF (1 mL) at ambient temperature was added 2,4-bis(4-phenoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (0.104 g, 0.196 mmol, TCI). After about 15 h, the reaction mixture was concentrated under reduced pressure. The residue was suspended in EtOAc/DCM (1:1) and filtered through a plug of silica gel (5 g) eluting with EtOAc/DCM (1:1, approximately 100 mL). Concentration of the filtrate provided the crude N-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)cyclohexanecarbothioamide. The crude thioamide was dissolved in THF (1 mL) and diacetoxymercury (0.0626 g, 0.196 mmol) was added. After about 30 min at ambient temperature, additional diacetoxymercury (0.0626 g, 0.196 mmol) was added. After about 4 h, the reaction mixture was diluted with EtOAc, filtered, concentrated under reduced pressure, and purified by silica gel chromatography eluting with a gradient of 50-95% EtOAc in heptane to provide 1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine as a yellow oil (0.020 g, 25%): LC/MS (Table 2, Method a) Rt=2.77 min; MS m/z: 395 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[C:7]([NH:9][C:10]1[N:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH2:14])=[O:13])=O)[CH2:2][CH3:3].[OH-].[Na+].Cl>N1C=CC=CC=1>[CH2:1]([O:4][C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[C:7]1[NH:14][C:12](=[O:13])[C:11]2[CH:15]=[CH:16][CH:17]=[N:18][C:10]=2[N:9]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccccc1C(=O)Nc1ncccc1C(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCCOc1ccccc1-c1nc2ncccc2c(=O)[nH]1
Yield: 89.8 %

Procedure:
A stirred mixture of 2-(2-propoxybenzamido)-nicotinamide (0.77 g) and pyridine (0.8 ml) in 2 Normal sodium hydroxide (20 ml) was heated under reflux for 30 minutes. The cooled reaction mixture was neutralized with 2 Normal hydrochloric acid to afford a precipitate which together with another precipitate similarly prepared from 2-(2-propoxybenzamido)nicotinamide (0.1 g) was recrystallized from ethanol-ether to afford white needles (0.65 g) which were washed with water to afford the title compound, 0.55 g, m.p. 110-111° C.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[S:28][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:30][N:31]=1>>[S:32]([C:29]1[S:28][C:27]([NH:26][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])=[N:31][CH:30]=1)(=[O:34])(=[O:33])[NH2:35]
Reactant: Nc1ncc(S(N)(=O)=O)s1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1cnc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C. 1) and 2-amino-thiazole-5-sulfonic acid amide [CAS-No. 63735-95-5] according to general procedure II. Light yellow solid. MS (ISP) 517.2 [(M−H)−]; mp 311° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([CH2:20]O)[O:17][C:16]2=[O:22])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([S:13][CH3:14])[N:10]=[N:9]1.[CH3:23][C:24]1[N:25]=[N:26][NH:27][N:28]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.CO>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([CH2:20][N:26]3[N:27]=[N:28][C:24]([CH3:23])=[N:25]3)[O:17][C:16]2=[O:22])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([S:13][CH3:14])[N:10]=[N:9]1
Reactant: CSc1cn(-c2ccc(N3C[C@H](CO)OC3=O)cc2F)nn1
Reactant: Cc1nn[nH]n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: ClCCl
Solvent: CO
Product: CSc1cn(-c2ccc(N3C[C@H](Cn4nnc(C)n4)OC3=O)cc2F)nn1
Yield: 47.8 %

Procedure:
(5R)-3-{3-Fluoro-4-[4-(methylthio)-1H-1,2,3-triazol-1-yl]phenyl}-5-(hydroxymethyl)-oxazolidin-2-one (Intermediate 48) (1.10 g, 3.39 mmol), 5-methyl-2H-tetrazole (0.347 g, 4.09 mmol), polystyrene-triphenylphosphine (phosphine loading 1.51 mmol/g, 3.79 g, 5.72 mmol) and diisopropyl azodicarboxylate (0.856 g, 4.11 mmol) were reacted as described for Example 29 to afford the title product (0.632 g) after chromatography on silica gel with 5% methanol in dichloromethane. The regioisomeric product (5R)-3-{3-Fluoro-4-[4-(methylthio)-1H-1,2,3-triazol-1-yl]phenyl}-5-[(5-methyl-1H-tetrazol-1-yl)methyl]-1,3-oxazolidin-2-one was also isolated (0.369 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:18][CH2:19][C:20]1[NH:24][N:23]=[N:22][N:21]=1)[C:13]([O:15]CC)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].O>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:18][CH2:19][C:20]1[NH:24][N:23]=[N:22][N:21]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@H](CCc1nnn[nH]1)NC(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(N[C@@H](CCc1nnn[nH]1)C(=O)O)OCc1ccccc1

Procedure:
Prepared analogously to Example 30b from ethyl (2S)-2-(benzyloxycarbonyl-amino)-4-(1H-tetrazol-5-yl)-butyrate and lithium hydroxide in a mixture of solvents from water and THF.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:22][C@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:20][C@H:17]1[CH:18]=[O:19])=[O:15])([CH3:12])([CH3:11])[CH3:10].[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1.O>[C:9]([O:13][C:14]([N:16]1[CH2:22][C@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:20][C@H:17]1[CH:18]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[OH:19])=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: Brc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 85.2 %

Procedure:
A solution of p-bromoiodobenzene (9.44 g, 33.4 mmol) in tetrahydrofuran (10 ml) was added dropwise to a solution of 1.6M butyl lithium-hexane solution (19.0 ml, 30.3 mmol) in tetrahydrofuran (50 ml) at -78° C. in a nitrogen stream over 15 minutes. The resulting reaction solution was stirred at -78° C. for 40 minutes and then a solution of (2S,4R)-N-t-butoxycarbonyl-4-(t-butyldimethylsiloxy)prolinal (5.0 g, 15.2 mmol) in tetrahydrofuran (17 ml) was added dropwise thereto over 10 minutes. The reaction solution was stirred at -78° C. for 1.5 hours. After addition of saturated aqueous ammonium chloride, the reaction solution was poured into a liquid mixture of ethyl acetate with water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting oily residue was subjected to silica gel Column chromatography (Wakogel™ C-300, 200 ml ethyl acetate-heptane 2:3→3:2) to give (2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-[(4-bromophenyl)hydroxymethyl]pyrrolidine (6.30 g, yield: 85.3%) as a pale yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:32])[CH:30]=[CH2:31]>C1COCC1>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)=[CH:3][C:2]([NH:1][C:29](=[O:32])[CH:30]=[CH2:31])=[CH:11][CH:10]=2)#[N:13]
Reactant: C=CC(=O)Cl
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(F)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.00 g (3.60 mmol) of 6-amino-4-(3-fluorophenylamino)quinoline-3-carbonitrile in 12 mL of THF under N2 was chilled in ice. Triethylamine (0.436 g, 4.32 mmol) was added followed by 0.393 g (4.32 mmol) of acryloyl chloride and the reaction was stirred at 25° C. overnight. The solvent was removed and the residue was slurried with water and filtered. The crude product was washed with water, dried, washed with hot ethyl acetate and dried in vacuo (50° C.). This yielded 0.862 g of N-[3-cyano-4-(3-fluorophenylamino)quinolin-6-yl]acrylamide as a brown solid: mass spectrum (electrospray, m/e): M+H 333.1.
Reaction SMILES: [CH2:1]1[N:6]([CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12])[CH2:5][CH2:4][N:3]([CH:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:2]1.Cl.Cl.CC(C)=[O:31].OS(O)(=O)=O.O=[Cr](=O)=O.S(=O)(=O)(O)O.[OH-].[Na+]>CC(C)=O.O.[O-2].[O-2].[O-2].[Cr+6].C(O)(C)C>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]2[CH2:2][CH2:1][N:6]([CH2:7][CH2:8][O:9][CH2:10][C:11]([OH:31])=[O:12])[CH2:5][CH2:4]2)=[CH:21][CH:22]=1
Reactant: CC(C)=O
Reactant: OCCOCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Agent: O=[Cr](=O)=O
Agent: [Cr+6]
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: O=C(O)COCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Reaction time: 17 h
Yield: 60.7 %

Procedure:
To a stirred suspension of hydroxyzine dihydrochloride (70.0 g, 0.156 mol) in acetone (560 ml), Jones reagent (130 ml, 0.351 mol), which was made by adding sulphuric acid (115 ml) to a solution of chromium trioxide (133.7 g) in water (250 ml) and adding water to the total volume of 500 ml, was added dropwise in a period of 2 hours. The stirring was continued for further 17 hours at room temperature. Isopropanol (10 ml) was added dropwise and the mixture was stirred for 1 hour. 25% aqueous NaOH solution (250 ml) was added slowly to adjust pH to ca. 12. Celite (100 g) was then added and the suspension was stirred for 20 min. The mixture was filtered through a pad of celite (13×2 cm) and washed with 2:1 acetone-water (3×200 ml). Evaporation of the most acetone from the combined filtrate gave a aqueous suspension. The suspension was washed by ethyl acetate (100 ml) and 5% aqueous NaCl solution (100 ml) This washing procedure was repeated 5 times. Water (500 ml) was added to the isolated middle oily layer. 5% HCl aqueous solution was used to adjust pH to ca 2. After being washed with dichloromethane (2×200 ml), the aqueous solution was adjusted to pH=6 with 25% NaOH solution and extracted with dichloromethane (3×250 ml). The combined organic extract was treated with charcoal (10 g) and filtered through a pad of celite (13×2 cm). Evaporation of solvent afforded the titled compound as a pale white foam (36.8 g, yield 60%) δH (CDCl3 ; 300 MHz) 13.73 (1H, br), 7, 14-7.36 (9H, m), 4.24 (1H, s), 3.95 (2H, s), 3.68-3.78 (2H, m), 3.09 (4H, br), 2.89-2.98 (2H, m), 2.62 (4H, br); δC (CDCl3 ; 75.47 MHz) 175.09, 141.33, 140.53, 132.93, 128.95, 128.89, 128.83, 127.56, 74.65, 70.23, 66.56, 56.72, 53.09, 49.24; Found: M+, 388.1544. C21H25Cl1N2O3 requires M, 388.1554.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[N:26]=[C:27]=[S:28]>O1CCCC1.C(=O)([O-])O.[Na+]>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])[C:2]=1[NH:1][C:27](=[S:28])[NH:26][C:20]1[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=1[Cl:18]
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Reactant: S=C=Nc1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(NC(=S)Nc2ccc(Cl)cc2Cl)c1NCCCO
Temperature: 25 °C
Reaction time: 72 h
Yield: 83.7 %

Procedure:
A mixture of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (13.1 g, 50.6 mmol) and 2,4-dichloro-1-isothiocyanatobenzene (13.4 g, 65.8 mmol) in tetrahydrofuran (150 mL) was stirred at room temperature for 3 days. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, concentrated in vacuo, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with diisopropyl ether to give methyl 4-chloro-3-{[(2,4-dichlorophenyl)carbamothioyl]amino}-2-[(3-hydroxypropyl)amino]benzoate as a colorless powder (19.6 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]O)=[C:12]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:35])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24][Cl:35])=[C:12]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Cn1c(CO)c(-c2ccccc2F)c2cc(OCc3ccccc3)ccc2c1=O
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)Cn1c(CCl)c(-c2ccccc2F)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 95.3 %

Procedure:
To a suspension of 6-benzyloxy-4-(2-fluorophenyl)-3-hydroxymethyl-2-isobutyl-1(2H)-isoquinolinone (4.31 g, 10 mmol) in toluene (50 mL) was added thionyl chloride (1.5 mL, 20 mmol). The obtained mixture was refluxed under heating for 2 h. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 6-benzyloxy-3-chloromethyl-4-(2-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone (4.29 g, 95.3%) as crystals.