Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:11]=[C:12](Br)[S:13][C:14]=1[N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:32])[CH2:22][N:23]2[C:27]3=[N:28][CH:29]=[CH:30][CH:31]=[C:26]3[CH:25]=[CH:24]2)[CH2:17][CH2:16]1.O1CCO[CH2:36][CH2:35]1>>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:11]=[C:12]([CH2:35][CH3:36])[S:13][C:14]=1[N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:32])[CH2:22][N:23]2[C:27]3=[N:28][CH:29]=[CH:30][CH:31]=[C:26]3[CH:25]=[CH:24]2)[CH2:17][CH2:16]1
Reactant: C1COCCO1
Reactant: O=C(Cn1ccc2cccnc21)N1CCN(c2sc(Br)nc2-c2nc3ccccc3[nH]2)CC1
Product: CCc1nc(-c2nc3ccccc3[nH]2)c(N2CCN(C(=O)Cn3ccc4cccnc43)CC2)s1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A vial was charged with Example 38 (50 mg), 1,1′-bis(diphenylphosphin)ferrocen dichloropalladium-(II)-chlorid complex (in DCM 1/1, 3.91 mg) and dioxane (1.5 mL) at RT under argon, sealed and evacuated and backfilled with argon three times. Diethylzinc (1.5M in toluene) was added. The resulting orange suspension was shaken at 100° C. for 1.5 h. The reaction mixture was allowed to cool down, was quenched with water (0.5 mL) dropwise and evaporated to dryness. The resulting brown solid was purified by preparative LC-MS (I) to afford 17 mg of beige solid. LC-MS (A): tR=0.65 min; [M+H]+: 472.3.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8](Cl)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH:14]([S:17][CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][OH:26])=[CH:23][CH:22]=1)([CH3:16])[CH3:15].[OH-].[K+].O>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:26][CH2:25][C:24]2[CH:23]=[CH:22][C:21]([O:20][CH2:19][CH2:18][S:17][CH:14]([CH3:16])[CH3:15])=[CH:28][CH:27]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)SCCOc1ccc(CO)cc1
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)SCCOc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
In 15 ml of N,N-dimethylformamide were dissolved 1.2 g of 2-t-butyl-4,5-dichloro-3(2H)-pyridazinone and 1.2 g of p-(2-isopropylthioethoxy)benzyl alcohol, and then 0.31 g of powdery potassium hydroxide was added thereto. The resulting mixture was stirred overnight at room temperature, poured into water, extracted with diethyl ether, washed with water, dried over anhydrous sodium sulfate and then freed of the diethyl ether by distillation under reduced pressure. The resulting solid was recrystallized from n-hexane to obtain 1.2 g of the aimed compound, m.p. 82.0°~84.5° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[CH:12]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)[NH:11][CH:10]=[C:9]2[CH:27]=[O:28])[CH2:2][CH2:3][CH3:4]>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[C:12]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)=[N:11][CH:10]=[C:9]2[CH:27]=[O:28])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc2c(cc1OC)C(Cc1cccc(OC)c1)NC=C2C=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCCCOc1cc2c(C=O)cnc(Cc3cccc(OC)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.4 %

Procedure:
To a stirred solution of 6-butoxy-7-methoxy-1-(3-methoxy-benzyl)-1,2-dihydro-isoquinoline-4-carbaldehyde (200 mg, 0.53 mmol) in chloroform (6 mL) was added manganese (IV) oxide (536 mg, 5.34 mmol). The reaction mixture was stirred at room temperature for 15 hrs, filtered through a Celite® pad, and washed with chloroform. The filtrate was concentrated in vacuo to afford 6-butoxy-7-methoxy-1-(3-methoxy-benzyl)-isoquinoline-4-carbaldehyde (200 mg, 99% yield). The crude product was without further purification.
Reaction SMILES: [CH2:1]([PH:5](=[O:7])[OH:6])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.C[Si](Cl)(C)C.[CH2:20]=[C:21]([CH2:32][CH2:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>ClCCl>[CH2:1]([P:5]([CH2:20][CH:21]([C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[CH2:32][CH2:33][C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:35])(=[O:6])[OH:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[PH](=O)O
Reactant: C=C(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCP(=O)(O)CC(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 40.6 %

Procedure:
Butylphosphinic acid (2.0 g, 16 mmol) in 80 mL of dry dichloromethane was cooled to 0° C. under an atmosphere of nitrogen. Triethylamine (6.7 g, 66 mmol) was added followed by trimethylsilyl chloride (58 mL, 58 mmol, 1.0 M in dichloromethane). The mixture was stirred at 0° C. for 10 minutes and dibenzyl 2-methylenepentanedioate (2) (6.4 g, 20 mmol) in 20 mL of dichloroemthane was added. The cold bath was removed and the reaction warmed to room temperature and stirred overnight. The mixture was then cooled to 0° C. and quenched by the slow addition of 5% hydrochloric acid. The dichloromethane layer was then removed and washed with 5% hydrochloric acid and with brine. The organic layer was dried (MgSO4) and evaporated to give a clear light golden liquid. The liquid was purified by flash chromatography and eluted with 3:1 hexane/ethyl acetate containing 5% acetic acid. The desired fractions were combined and evaporated to give butyl[2,4-di(benzyloxycarbonyl)butyl]phosphinic acid (3,R=-butyl, R1=H) (2.9 g, 40%) as a clear and colorless oil. Rf 0.12 (3:1, Hex./EtOAc 5% AcOH).
Reaction SMILES: [F:1][B-](F)(F)F.[H+].[C:7]([C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)N)([CH3:10])([CH3:9])[CH3:8].N([O-])=O.[Na+]>O>[C:7]([C:11]1[CH:17]=[CH:16][CH:15]=[C:13]([F:1])[CH:12]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1cccc(N)c1
Reactant: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88956.8 %

Procedure:
To a vigorously stirred solution of tetrafluoroboric acid (73.26 mL; 0.4 mol; 48% wt % solution in water) in a large beaker at room temperature was slowly added 3-tert-butylaniline (15.0 g; 0.10 mmol). The resulting mixture was stirred at room temperature for 30 minutes, cooled to 0° C. and then a solution of sodium nitrite (11.09 g; 0.16 mol) in water (30 mL) was added. After addition was complete reaction mixture was stirred at 0° C. for 30 minutes, warmed to room temperature and further stirred for 20 minutes. The resulting beige slushy material was filtered, washed with tetrafluoroboric acid (20 mL) and ether (3×20 mL) to yield an off-white solid (13.54 g). The latter was dissolved in dichloromethane (300 mL) and heated at reflux for 2 hours until the solid was dissolved and no more gas (HF) evolution was observed. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to yield a dark oil that was purified by column chromatography eluting with ethyl acetate/hexanes (0 to 5% v/v gradient elution over 1 L) to yield the title compound as a pale yellow liquid (11.80 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:34][C:35]1[CH:42]=[C:41]([OH:43])[CH:40]=[CH:39][C:36]=1[C:37]#[N:38].[N:44]1[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50]O)[CH:45]=1>O1CCCC1>[F:34][C:35]1[CH:42]=[C:41]([O:43][CH2:50][C:46]2[CH:45]=[N:44][CH:49]=[CH:48][CH:47]=2)[CH:40]=[CH:39][C:36]=1[C:37]#[N:38]
Reactant: N#Cc1ccc(O)cc1F
Reactant: OCc1cccnc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(OCc2cccnc2)cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 85.8 %

Procedure:
A solution of triphenylphosphine (20 g) in tetrahydrofuran (300 mL) cooled at 0° C. is treated dropwise during 5 minutes with diisopropyl azodicarboxylate (15 mL) and stirred for 15 minutes at 0° C. It is then treated, dropwise, with a solution of 2-fluoro-4-hydroxybenzonitrile (7 g) and 3-pyridylmethanol (7 g) in tetrahydrofuran (200 mL) during 2 hours, and stirring is continued at ambient temperature for 18 hours. The mixture is concentrated in vacuo and the residue is dissolved in ethyl acetate (500 mL) and the solution is washed with hydrochloric acid (3×100 mL; 1 N) and the remaining organic layer is discarded. The combined acid washings are basified to pH 10 by treatment with solid sodium hydroxide and extracted with ethyl acetate (3×100 mL). This organic extract is dried over magnesium sulphate and concentrated in vacuo, and the residue is recrystallized from isopropyl ether, to give 2-fluoro-4-(3-pyridylmethoxy)benzonitrile (10 g), in the form of a white solid, m.p. 105-110° C.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(#N)C.[CH3:12][S:13][CH2:14]Cl>C(N(CC)CC)C>[C:1]([O:8][CH2:12][S:13][CH3:14])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)O
Reactant: CSCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCC(=O)OCSC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a three-necked 1000 ml. round-bottomed flask fitted with a mechanical stirrer, thermometer and reflux condenser is placed 63.8 g. of hexanoic acid in 200 ml. of acetonitrile. To the stirred mixture is added, at 20°-30° C., 55 g. of triethylamine over a period of 30 minutes. The reaction mixture is stirred at room temperature for an additional 60 minutes. Then is added, at 20°-24° C., 53 g. of chloromethyl methyl sulfide in a few minutes. The reaction mixture is warmed and allowed to reflux for 24 hours. The reaction mixture is cooled to 5°-0° C. and filtered. The solvent is stripped off under vacuum at 12 mm Hg pressure. The residue is taken up in diethyl ether and washed successively with a 10% solution of sodium bicarbonate and with water. The organic layer is dried over anhydrous sodium sulfate. Distillation gives the title ester; b.p. 57°-58° C./2 mm Hg, n20 1.4545.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][C@H:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>>[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH:19][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][C@H:14]3[CH3:18])[CH2:9]2)=[CH:7][C:2]=1[CH3:1])=[O:24]
Reactant: Cc1cc(N2CCC(N3CCC[C@H]3C)C2)ccc1N
Reactant: O=C(Cl)c1ccccc1F
Product: Cc1cc(N2CCC(N3CCC[C@H]3C)C2)ccc1NC(=O)c1ccccc1F

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-(2-(R)-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 2-fluorobenzoyl chloride. LCMS: RT=1.70 minutes, MS: 382 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([O:18][CH3:19])=[O:17])=[CH:4][CH:3]=1.I[CH3:21].[H-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[N:11]([CH3:21])[C:10]([CH3:15])=[C:9]2[C:16]([O:18][CH3:19])=[O:17])=[CH:6][CH:7]=1
Reactant: CI
Reactant: COC(=O)C1=C(C)NC(=O)CC1c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)N(C)C(=O)CC1c1ccc(F)cc1
Temperature: 0 °C

Procedure:
The product from Example 2, Step 1 (1.5 g, 5.70 mmol, 1 equiv) and iodomethane (809 mg, 5.70 mmol, 1 equiv) were dissolved in DMF (20 mL) and cooled to 0° C. To this was added portionwise sodium hydride 60% in mineral oil (228 mg, 5.70 mmol, 1 equiv) and warmed to room temperature over 1 h. The reaction was quenched with water, and extracted with EtOAc. The organic phase was concentrated in vacuo. The product was obtained as a light yellow oil (1.58 g, quant.). MS (ES+) m/e 278 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH:3](O)[CH3:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.Cl>C1COCC1.O>[CH3:1][O:2][CH2:3][CH2:4][O:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:34][CH:35]=1
Reactant: COC(C)O
Reactant: COC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COCCOc1ccc(C(=O)OC)cc1
Temperature: 10 °C
Reaction time: 18 h
Yield: 104.6 %

Procedure:
4.3 mL (37.5 mmol) of methoxyethanol and 10.1 g (37.5 mmol) of triphenylphosphine are added to a solution of 61 g (30 mmol) of methyl 4-hydroxybenzoate in 120 ml of THF at room temperature. 7.7 mL (37.5 mmol) of diisopropyl azodicarboxylate (DIAD) in 110 mL of THF are incorporated slowly so that the temperature is maintained to 10° C. After 18 hours at room temperature, the reaction mixture is poured onto icy water and acidified with a 1N HCl solution. The aqueous phase is extracted with ethyl acetate and the organic phase is then washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. Chromatography of the residue using cyclohexane: ethyl acetate 4:1 yielded 6.6 g (98%) of pure methyl 4-(2-methoxyethoxy)benzoate as a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]2[CH2:19][CH2:20][S:21][C:3]=12.[CH2:22]([O:29][CH:30]1[CH2:33][CH:32]([S:34](Cl)(=[O:36])=[O:35])[CH2:31]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:7]1[C:2]([NH:1][S:34]([CH:32]2[CH2:33][CH:30]([O:29][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:31]2)(=[O:36])=[O:35])=[C:3]2[S:21][CH2:20][CH2:19][N:4]2[C:5](=[O:18])[C:6]=1[CH3:17]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCS2
Reactant: O=S(=O)(Cl)C1CC(OCc2ccccc2)C1
Solvent: c1ccncc1
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC(OCc3ccccc3)C2)c2n(c1=O)CCS2
Yield: 44.5 %

Procedure:
Using the same reaction conditions and workup as described for the preparation of Example 19A, 8-amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (I-19f: 0.15 g, 0.35 mmol) in pyridine (2 mL) was reacted with 3-benzyloxy-cyclobutanesulfonyl chloride (0.1 g, 0.39 mmol) to afford the crude product. Purification by column chromatography on silica gel (50% ethylacetate in hexane) afforded 0.1 g of the product (43% yield).
Reaction SMILES: [CH3:1][C:2]1([C:17]([O:19]C)=[O:18])[CH2:7][CH2:6][CH:5]([O:8][CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH2:4][CH2:3]1.[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]1([C:17]([OH:19])=[O:18])[CH2:3][CH2:4][CH:5]([O:8][CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:15])[CH3:16])[CH2:6][CH2:7]1
Reactant: COC(=O)C1(C)CCC(OCOCC[Si](C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C(=O)O)CCC(OCOCC[Si](C)(C)C)CC1
Yield: 90.9 %

Procedure:
To a 250-mL round-bottom flask containing a solution of methyl 1-methyl-4-[[2-(trimethylsilyl)ethoxy]methoxy]cyclohexane-1-carboxylate (3.6 g, 11.90 mmol, 1.00 equiv) in a mixed methanol/water (25 mL/4 mL) was added sodium hydroxide (2.38 g, 59.50 mmol, 5.00 equiv) and the resulting solution was heated to reflux overnight. After cooling, the pH value of the solution was adjusted to 4 with hydrochloric acid (2.0 M), extracted with 3×100 mL of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The desired 1-methyl-4-[[2-(trimethylsilyl)ethoxy]methoxy]cyclohexane-1-carboxylic acid (3.12 g, 91%) was obtained as a light yellow oil which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:5]([CH:6]=[O:7])=[C:4]([F:12])[CH:3]=1.Cl([O-])=[O:14].[Na+].O.O.P(O)(O)([O-])=O.[Na+].CC(=CC)C>C(O)(C)(C)C.O>[Br:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:5]([C:6]([OH:14])=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: [O-][Cl+][O-]
Reactant: COc1cc(Br)cc(F)c1C=O
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1cc(Br)cc(F)c1C(=O)O
Reaction time: 2 h
Yield: 68.5 %

Procedure:
To a solution of 4-bromo-2-fluoro-6-methoxy-benzaldehyde (3.4 g, 14.6 mmol) in tert-butanol (70 ml) and water (35 ml), sodium chlorite (2.64 g, 29.2 mmol), monosodium phosphate dihydrate (11.4 g, 72.9 mmol) and 2-methyl-2-butene (12.4 ml, 116.7 mmol) are added successively at room temperature and the mixture is stirred for 2 h. After completion of the reaction (monitored by TLC), the mixture is concentrated under reduced pressure and the residue is diluted with ice water (50 ml) and acidified to pH 5 by adding 2N hydrochloric acid. The mixture is extracted with methyl tert-butyl ether (2×100 ml). The methyl tert-butyl ether layer is extracted again with 10% aqueous sodium hydroxide (100 ml). The aqueous layer is acidified to pH 2 with 5N hydrochloric acid and extracted with dichloromethane (2×50 ml). The organic layer is washed with brine (50 ml), dried over sodium sulfate and evaporated to dryness to obtain 4-bromo-2-fluoro-6-methoxy-benzoic acid (2.5 g, 10.0 mmol, 68%).
Reaction SMILES: [CH2:1]([Mg]Cl)[CH3:2].[C:5]([O:9][C:10](=[O:23])[NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17](=[O:22])N(OC)C)[N:16]=1)([CH3:8])([CH3:7])[CH3:6]>O1CCCC1>[C:5]([O:9][C:10](=[O:23])[NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17](=[O:22])[CH2:1][CH3:2])[N:16]=1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CON(C)C(=O)c1csc(NC(=O)OC(C)(C)C)n1
Reactant: CC[Mg]Cl
Solvent: C1CCOC1
Product: CCC(=O)c1csc(NC(=O)OC(C)(C)C)n1
Temperature: -70 °C
Reaction time: 1 h
Yield: 54.9 %

Procedure:
A solution of ethyl magnesium chloride (126 mL, 0.252 mol, 2 M in tetrahydrofuran) was stirred and cooled to −70° C. on a dry ice/acetone bath. A solution of [4-(methoxy-methyl-carbamoyl)-thiazol-2-yl]-carbamic acid tert-butyl ester (14.5 g, 0.0504 mol) in tetrahydrofuran (200 mL) was added dropwise over approximately 5 minutes. The mixture was stirred for 1 hour. The cooling bath was removed and stirring continued for an additional 2 hours. The mixture was poured into a mixture of ice and saturated aqueous ammonium chloride solution and then extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over magnesium sulfate and evaporated to give an off white solid which was purified by chromatography over a 350 g pad of silica gel eluted with 4:1 ethyl acetate/dichloromethane to afford (4-propionyl-thiazol-2-yl)-carbamic acid tert-butyl ester (7.09 g, 55%) as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[CH:18]=[O:19].[BH4-].[Na+].O>CO>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:3]=1[CH2:18][OH:19]
Reactant: O=CC1=C(Cl)c2ccccc2OC1c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCC1=C(Cl)c2ccccc2OC1c1ccccc1

Procedure:
To a stirred solution of 16 g 4-chloro-3-formyl-flav-3-ene in 500 ml dry methanol at room temperature is added 0.5 g sodium borohydride in small portions. After the addition is completed 500 ml water is added. The solution is filtered and extracted with chloroform. The combined organic extracts are dried over magnesium sulfate and evaporated. Chromatographically pure 4-chloro-3-hydroxymethyl-flav-3-ene is obtained as a yellowish oil; TLC (SiO2, CHCl3): 1 spot, RF 0.18.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.F[C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([C:30]([C:32]2[CH:41]=[C:40]([CH3:42])[C:35]3[NH:36][C:37](=[O:39])[O:38][C:34]=3[CH:33]=2)=[O:31])[CH:29]=1)[C:25]#[N:26]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([CH:27]=[C:28]([C:30]([C:32]5[CH:41]=[C:40]([CH3:42])[C:35]6[NH:36][C:37](=[O:39])[O:38][C:34]=6[CH:33]=5)=[O:31])[CH:29]=4)[C:25]#[N:26])[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(C(=O)c2cc(F)cc(C#N)c2)cc2oc(=O)[nH]c12
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C#N)cc(C(=O)c4cc(C)c5[nH]c(=O)oc5c4)c3)CC1)C(=O)N2

Procedure:
0.22 g (0.80 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 0.12 g (0.40 mmol) 3-fluoro-5-(4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-benzonitrile were heated to 300° C. for approx. 10 min. Then the mixture was dissolved in DMF and purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent was evaporated down. The residue was neutralised with 1N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(OC(=O)C)(=O)C.[Br:12][C:13]1[C:17]([Br:18])=[CH:16][S:15][CH:14]=1>C(O)(=O)C>[Br:12][C:13]1[C:17]([Br:18])=[CH:16][S:15][C:14]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Brc1cscc1Br
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1scc(Br)c1Br
Reaction time: 0.17 h

Procedure:
41.4 ml of fuming nitric acid was slowly added to 500 ml of acetic acid under ice-cooling, followed by stirring for 10 minutes, and a solution of 78 ml of acetic acid anhydride containing 50 g of 3,4-dibromothiophene was slowly added, followed by stirring at room temperature for 18 hours. Ice was added to the reaction solution, and the resulting crystals were collected by filtration, and washed with water and diethyl ether/n-hexane=1/5 successively, to give 40.2 g of the title compound.
Reaction SMILES: [C:1](=[O:38])([O:9][CH2:10]/[C:11](/[C:28]1[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=1)=[C:12](/[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)\[CH2:13][O:14][Si](C(C)(C)C)(C)C)[O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Br:8]>CC#N.C1(C)C=CC=CC=1>[C:1](=[O:38])([O:9][CH2:10]/[C:11](/[C:28]1[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:35])=[O:36])=[CH:30][CH:29]=1)=[C:12](/[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)\[CH2:13][OH:14])[O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Br:8]
Reactant: CC(C)(C)[Si](C)(C)OC/C(=C(\COC(=O)OCCCCCBr)c1ccc(S(C)(=O)=O)cc1)c1ccccc1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(/C(COC(=O)OCCCCCBr)=C(/CO)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-bromopentyl (2Z)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-(methylsulfonyl)phenyl]-3-phenylbut-2-enyl carbonate (1 eq) and PyrHF (excess) in MeCN (0.25 M) was stirred at rt for 2 h, diluted with 5 volumes of toluene, filtered through a pad of silica gel eluted with 70% EtOAc/hexanes to give the titled compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:6][C:7]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:8]=1[C:9](Cl)=[O:10]>CCOCC>[CH3:6][C:7]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:8]=1[C:9]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)=[O:10]
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Reactant: c1c[nH]cn1
Solvent: CCOCC
Product: Cc1cc(C)c(C(=O)n2ccnc2)c(C)c1
Reaction time: 5 h
Yield: 67.9 %

Procedure:
136 g (2.0 moles) of imidazole in 1,000 ml of ether are initially taken, and 146 g (0.8 mole) of 2,4,6-trimethylbenzoyl chloride are added dropwise to the stirred mixture in the course of 30 minutes at from 10° to 20° C. Stirring is continued for 5 hours at room temperature, and the precipitated imidazole hydrochloride is filtered off under suction, the filtrate is evaporated down and the residue is distilled to give 116.4 g (68% of theory) of N-(2,4,6-trimethylbenzoyl)-imidazole of boiling point 128° C./0.01 mbar.