Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1>Cl.C(OCC)C>[O:7]([CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][O:8]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1=COCCC1
Reactant: Oc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: c1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
Phenol (10 g, 106 mmol) was dissolved in 3,4-dihydro-2H-pyran (29 mL, 318 mmol) and one drop concentrated HCl was added at RT. The reaction was stirred at RT overnight. Ethyl ether (500 mL) was added to dilute the reaction. The organic layer was washed with water (2×100 mL), saturated sodium bicarbonate (2×100 mL), brine (2×100 mL) and dried over MgSO4. Evaporation gave title compound (17 g, 100%) as a colorless oil.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[Na].F[C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18]>C1COCC1.CC(O)C>[CH:1]([O:4][C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])([CH3:3])[CH3:2]
Reactant: CC(C)O
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [Na]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of isopropanol (225 mL) and small chunks of sodium metal (1.92 g, 83.6 mmol) were heated to reflux for 2.5 hours, until the sodium was consumed. The resulting solution was added while still hot to a solution of 4-fluoro-3-nitro-benzenesulfonamide (8.37 g, 38.0 mmol, example 2, step b) in THF/iPrOH (1/1, v/v, 150 mL) over a 10 minute period and stirred at room temperature for 3.5 hours. The reaction mixture was partitioned between EtOAc and brine and 1 N aqueous HCl. The organic phase was then washed with brine, dried with Na2SO4 and evaporated to give the title compound.
Reaction SMILES: C([O:3][C:4](/[C:6](=[C:11](\[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)/[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)/[CH2:7][C:8]([OH:10])=[O:9])=[O:5])C.[OH-].[Na+]>C(O)C.O>[Cl:28][C:25]1[CH:24]=[CH:23][C:22](/[C:11](=[C:6](/[CH2:7][C:8]([OH:10])=[O:9])\[C:4]([OH:5])=[O:3])/[C:12]2[CH:13]=[CH:14][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[CH:16][CH:17]=2)=[CH:27][CH:26]=1
Reactant: CCOC(=O)/C(CC(=O)O)=C(\c1ccc(Cl)cc1)c1ccc(S(C)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(/C(=C(\CC(=O)O)C(=O)O)c2ccc(Cl)cc2)cc1
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To a suspension of 50 g (0.118 mole) of (Z)-3-ethoxycarbonyl-4-(4-chlorophenyl)-4-(4-methanesulphonylphenyl)-3-butenoic acid, prepared in example 3, in 1000 ml of ethanol is added a solution of 10.4 g (0.26 mole) of sodium hydroxide in 25 ml of water. The mixture is heated under reflux for 6 hours, the precipitate is filtered off and washed with ethanol. The solid is then taken up into 500 ml of a 1N sodium hydroxide solution and the insoluble is filtered off. The aqueous phase is washed with dichloromethane and then acidified with hydrochloric acid to pH=1. After one hour's stirring, the precipitate obtained is filtered under suction, washed with water and dried to give 38.4 g of (Z)-2-[1-(4-chlorophenyl)-1-(4-methanesulphonylphenyl)-methylene]succinic acid in the form of crystals with a melting point of 199-200° C.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][O:19][CH3:20])[CH2:13]2)[N:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]3[O:37][C:38]4[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][C:39]=4[N:40]=3)=[CH:31][CH:30]=2)[O:23]1.N[C:48]1N=CN=C2N([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)N=C(C3C=CC(NC4OC5C=CC=CC=5N=4)=C(F)C=3)C=12>>[C:18]([OH:19])(=[O:23])[CH3:17].[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:12]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][O:19][CH3:20])[CH2:13]3)[N:3]=[C:2]([C:29]3[CH:30]=[CH:31][C:32]([NH:35][C:36]4[O:37][C:38]5[CH:44]=[CH:43][C:42]([CH2:45][CH3:48])=[CH:41][C:39]=5[N:40]=4)=[CH:33][CH:34]=3)[C:10]=12
Reactant: COCCN1CCC(n2nc(I)c3c(N)ncnc32)C1
Reactant: Cc1ccc2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6ccccc6o5)c(F)c4)c4c(N)ncnc43)CC2)CC1
Product: CC(=O)O
Product: CCc1ccc2oc(Nc3ccc(-c4nn(C5CCN(CCOC)C5)c5ncnc(N)c45)cc3)nc2c1

Procedure:
rac-N2-(4-{4-Amino-1-[1-(2-methoxyethyl)tetrahydro-1H-3-pyrrolyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5-ethyl-1,3-benzoxazol-2-amine monoacetate was prepared from rac-3-iodo-1-[1-(2-methoxyethyl)tetrahydro-1H-3-pyrrolyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.200 g, 0.319 mmol) and N2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-methyl-1,3-benzoxazol-2-amine (0.145 g, 0.399 mmol) in a manner similar to that used for the preparation of cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-1,3-benzoxazol-2-amine. The compound was formed as an off-white solid (0.038 g, 16%). 1H NMR (DMSO-d6, 400 MHz) 1.91 (s, 3H), 2.33 (m, 2H), 2.39 (s, 3H), 2.66 (m, 2H), 2.75-2.83 (m, 3H), 3.17 (t, 1H), 3.29 (s, 3H), 3.45 (t, 2H), 5.37 (m, 1H), 6.96 (d, 1H), 7.30 (s, 1H), 7.38 (d, 1H), 7.67 (d, 2H), 7.93 (d, 2H), 8.24 (s, 1H), 10.80 (s, 1H); RP-HPLC Rt 10.756 min, 100% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 485 (MH+).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:31])[CH2:15][NH:16][CH2:17]C(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:3].[CH3:32][N:33]([CH3:43])[C:34]1[CH:39]=[CH:38][C:37]([N:40]=[C:41]=[S:42])=[CH:36][CH:35]=1>>[CH3:3][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:31])[CH2:15][N:16]([C:41]([NH:40][C:37]1[CH:38]=[CH:39][C:34]([N:33]([CH3:43])[CH3:32])=[CH:35][CH:36]=1)=[S:42])[CH2:17][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:1]
Reactant: CN(C)c1ccc(N=C=S)cc1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNCC(c1ccccc1)c1ccccc1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN(Cc1ccccc1)C(=S)Nc1ccc(N(C)C)cc1

Procedure:
When in the procedure of Example 80 an appropriate amount of the product of Example 71 was substituted for the product of Example 70 and an appropriate amount of 4-dimethylaminophenylisothiocyanate was substituted for ethyl isocyanato acetate the title compound was obtained. Total yield, 0.84 g (80%).
Reaction SMILES: O.O.O.O.O.O.[Cr](Cl)(Cl)(=O)=O.[N+]([C:15]1[CH:20]=[C:19](S(O)(=O)=O)[C:18]([OH:25])=[C:17](N)[CH:16]=1)([O-])=O.C(O)[CH2:28][OH:29]>>[CH:28](=[O:29])[C:19]1[C:18](=[CH:17][CH:16]=[CH:15][CH:20]=1)[OH:25]
Reactant: OCCO
Reactant: Nc1cc([N+](=O)[O-])cc(S(=O)(=O)O)c1O
Agent: O=[Cr](=O)(Cl)Cl
Solvent: O
Product: O=Cc1ccccc1O

Procedure:
30.9 parts of the monoazo dye formed from diazotised 4-nitro-2-amino-1-hydroxybenzene and 2-hydroxynaphthalene are stirred up with 26.7 parts of chromic chloride hexahydrate in 400 parts by volume of ethylene glycol at 120° to 125° C. until no further unchromed dye is detectable. To the resulting solution of the 1:1 chrome complex dye at 80° to 85° C. are thereupon added 23.4 parts of 4-nitro-2-amino-1-hydroxybenzene-6-sulfonic acid and 45.3 parts of the monoazo dye formed from diazotised dehydrothio-p-toluidine-7-sulfonic acid and salicylaldehyde, and the mixture is held at this temperature until the addition reaction has finished. The pH value of the reaction mixture is adjusted to and maintained at 7 to 7.5 during the reaction by the addition of 5N sodium hydroxide solution. After completion of the reaction, the chromium-containing dye is precipitated by the addition of a saturated sodium chloride solution, filtered off and dried. It is in the form of a dark powder which dissolves in water to give a brown colour, and which dyes wool, polyamide material and leather in brown shades having good fastness properties.
Reaction SMILES: [Li].[C:2]([O:5][C:6]1[C:7]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:8][C:9]([OH:18])=[C:10]([C:13]=1[C:14]([CH3:17])([CH3:16])[CH3:15])[CH:11]=[O:12])(=[O:4])[CH3:3].Br[CH:24]([CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28].[Cl-].[NH4+]>O1CCCC1>[C:2]([O:5][C:6]1[C:7]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:8][C:9]([OH:18])=[C:10]([CH:11]([OH:12])[CH:24]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:30][CH2:31][CH:32]([CH3:33])[CH3:34])[C:13]=1[C:14]([CH3:15])([CH3:17])[CH3:16])(=[O:4])[CH3:3]
Reactant: CC(C)CCC(Br)CCC(C)C
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(O)c(C=O)c1C(C)(C)C
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)Oc1c(C(C)(C)C)cc(O)c(C(O)C(CCC(C)C)CCC(C)C)c1C(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
Lithium (2.8 g) was added to a solution of 5-acetoxy-4,6-di-tert-butyl-2-hydroxybenzaldehyde (24.3 g) and 5-bromo-2,8-dimethylnonane (47.0 g) in tetrahydrofuran (200 ml) under ice cooling under a nitrogen atmosphere and the mixture was stirred overnight. The reaction mixture was poured into ice water, neutralized with a saturated aqueous solution of ammonium chloride and subjected to extraction with diethyl ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel chromatography (10% ethyl acetate in n-hexane) to afford 4-acetoxy-3,5-di-tert-butyl-2-(2,2-diisoamyl-1-hydroxyethyl)phenol [17.0 g (yield, 46%)] as a colorless oil.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:19][C:20]([C@@H:22](/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](=[O:51])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C@@:23]([OH:34])([CH2:31][CH2:32][OH:33])[C:24]([O:26]C(C)(C)C)=[O:25])=[O:21])[C:14](=[O:18])[N:15]([CH3:17])[CH3:16])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].C(OC1C(OC(=O)C)=C(I)C=CC=1)(=[O:54])C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(#N)C.O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:19][C:20]([C@H:22]([C@@:23]([OH:34])([CH2:31][C:32]([OH:33])=[O:54])[C:24]([OH:26])=[O:25])/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](=[O:51])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:21])[C:14](=[O:18])[N:15]([CH3:16])[CH3:17])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC(=O)Oc1cccc(I)c1OC(C)=O
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCO)C(=O)OC(C)(C)C)C(=O)N(C)C)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CC#N
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CC(=O)O)C(=O)O)C(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.4 %

Procedure:
tert-Butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-dimethylcarbamoyl-ethylcarbamoyl]-2-hydroxy-2-(2-hydroxy-ethyl)-12-oxo-nonadec-4-enoate (96.8 mg, 0.133 mmol) was dissolved in acetonitrile (2.0 mL) and water (0.6 mL), and 4-acetamide-2,2,6,6-tetramethylpiperidine-1-oxyl (4.3 mg, 19.9 μmol) and diacetoxyiodobenzene (85.7 mg, 0.266 mmol) were added. The mixture was stirred at room temperature for 4 hours. An aqueous solution of citric acid was added to the reaction mixture, which was followed by extraction with ethyl acetate. The organic extract was washed with sodium thiosulfate and a saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in formic acid (4.0 mL) and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified with preparative HPLC to obtain the title compound (43.2 mg).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:9][C:10]1([CH3:29])[O:14][C:13](=[O:15])[N:12]([CH:16]2[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]2)[C@H:11]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O.ClCCCl>[I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH:19]1[CH2:18][CH2:17][CH:16]([N:12]2[C@@H:11]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:10]([CH3:9])([CH3:29])[O:14][C:13]2=[O:15])[CH2:21][CH2:20]1
Reactant: Nc1ccccc1I
Reactant: CC1(C)OC(=O)N(C2CCC(=O)CC2)[C@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)OC(=O)N(C2CCC(Nc3ccccc3I)CC2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The starting material (see Intermediate M synthesis) was a mixture of S:R stereoisomers (˜3:1). To a vial charged with 2-iodoaniline (commercially available from Sigma-Aldrich, Milwaukee, Wis.) (0.100 g, 0.457 mmol) were added (S)-5,5-dimethyl-3-(4-oxocyclohexyl)-4-phenyloxazolidin-2-one (0.131 g, 0.457 mmol), DCE (1.826 mL) and AcOH (0.039 mL, 0.685 mmol). The mixture was stirred at room temperature for 15 minutes prior to the addition of sodium triacetoxyborohydride (0.213 g, 1.004 mmol). The pale yellow suspension was then stirred overnight at room temperature. Water was added to the mixture and the resulting mixture was transferred to a separatory funnel and extracted with DCM (2×). The combined organic layers were dried with Na2SO4, filtered, and dried under reduced pressure. The material thus obtained was purified with a 25 g SNAP column (Biotage) ramping EtOAc in heptane (10% DCM throughout, 0-50%) providing the desired product as a mixture of isomers according to LC-MS (2:1 cis:trans). m/z (ESI) 491.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=1[CH2:20]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=1[CH2:20][Cl:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cc(OC(F)(F)F)ccc1OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(OCc2ccccc2)c(CCl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2-Benzyloxy-5-trifluoromethoxy-phenyl)-methanol (510 mg) is dissolved in methylene chloride (5 ml) and thereto is added thionyl chloride (198 μl) and the mixture is stirred at room temperature for 2 hours. The reaction solution is concentrated under reduced pressure and the residue is purified by silica gel column chromatography (hexane:ethyl acetate=1:0→4:1) to give 1-benzyloxy-2-chloromethyl-4-trifluoromethoxy-benzene (360 mg). 1H-NMR (CDCl3): δ 4.67 (2H, s), 5.14 (2H, s), 6.91 (1H, d), 7.10-7.45 (7H, m)
Reaction SMILES: CN(C)[C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.P(Cl)(Cl)(Cl)=O.[CH:18]1[CH:19]=[CH:20][N:21]2[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[C:22]=12.O.O.O.C([O-])(=O)C.[Na+]>O.ClCCCl>[F:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([C:20]2[N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[C:22]3=[CH:18][CH:19]=2)=[O:11])=[CH:9][CH:8]=1
Reactant: CC(C)OC(=O)C1CCCn2cccc21
Reactant: CN(C)C(=O)c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC(C)OC(=O)C1CCCn2c(C(=O)c3ccc(F)cc3)ccc21

Procedure:
A solution of 758 mg. of N,N-dimethyl-4-fluorobenzamide and 0.44 ml. of phosphorous oxychloride in 50 ml. of 1,2-dichloroethane is refluxed for one hour. To this solution is added a solution of 500 mg. of isopropyl 5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylate in 10 ml. 1,2-dichloroethane. The reaction mixture is refluxed for 3 hours. A solution of 3.3 g. sodium acetate trihydrate in 9 ml water is added and refluxed for a further 10 hours. The organic phase is separated, washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The residue is purified by preparative t.l.c. using hexane:ethyl acetate (90:10). Crystallization from dichloromethane-hexane yields isopropyl 3-p-fluorobenzoyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylate (XI, R=H, L=p-F, R2 =iC3H7, n=1), m.p. 92° C.
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[CH:6]1[C:16]2[C:15](=[O:17])[NH:14][C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=3[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.Cl>C1(C)C=CC=CC=1>[Br:1][CH2:2][C:3]([N:11]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:16]=2[C:15](=[O:17])[NH:14][C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]1=2)=[O:4]
Reactant: O=C1Nc2ccccc2Nc2ccccc21
Reactant: O=C(Cl)CBr
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C1Nc2ccccc2N(C(=O)CBr)c2ccccc21

Procedure:
93 g (0.55 mol) of bromoacetyl chloride were added dropwise, with stirring, to a suspension of 105 g (0.5 mol) of 5,10-dihydro-11H-dibenzo[b,e][1,4]-diazepin-11-one in 1 liter of toluene, at 90° C. The mixture was then refluxed for a further 30 minutes, during which there was a strong development of hydrogen chloride. After cooling, the dark blue crystal slurry obtained was suction filtered;
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH2:9][CH2:8][C:6]=2[N:7]=1.[NH:16]1[CH2:21][CH2:20][C:19](=[N:22][O:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)[CH2:18][CH2:17]1.C(N(C(C)C)CC)(C)C>CS(C)=O.CCOC(C)=O>[CH:33]([O:32][C:30]([N:27]1[CH2:28][CH2:29][CH:24]([O:23][N:22]=[C:19]2[CH2:18][CH2:17][N:16]([C:2]3[N:3]=[CH:4][C:5]4[CH2:11][N:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH2:9][CH2:8][C:6]=4[N:7]=3)[CH2:21][CH2:20]2)[CH2:25][CH2:26]1)=[O:31])([CH3:35])[CH3:34]
Reactant: CS(=O)(=O)N1CCc2nc(Br)ncc2C1
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCNCC2)CC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3ncc4c(n3)CCN(S(C)(=O)=O)C4)CC2)CC1
Temperature: 25 °C

Procedure:
Crude 59a, 2d (51 mg) and diisopropylethylamine (0.07 mL) in 0.4 mL of DMSO was heated at 100° C. for 3 h. The mixture was cooled to room temperature, diluted with EtOAc (5 mL) and washed with brine (3×5 mL). The organic layer was dried, concentrated and purified by preparative HPLC to afford 59b: LC-MS 495.4 (MH+), tR=5.11 (Method 4). EC50: 328 nM.
Reaction SMILES: S(Cl)(Cl)=O.[NH:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[C:19](=O)[CH2:18][CH2:17][CH2:16]2>C(Cl)Cl>[N:5]1([C:19]2[C:20]3[C:15](=[CH:14][CH:13]=[CH:12][C:11]=3[OH:10])[CH2:16][CH2:17][CH:18]=2)[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: c1c[nH]cn1
Reactant: O=C1CCCc2cccc(O)c21
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Oc1cccc2c1C(n1ccnc1)=CCC2
Yield: 46.1 %

Procedure:
227 g (1.9 mols) of thionyl chloride are added dropwise to a mixture of 503 g (7.4 mols) of imidazole and 1.6 liter of methylene chloride at 5° C., while stirring. The mixture is subsequently stirred for 20 minutes and 157 g (0.97 mol) of 8-hydroxy-1-tetralone are then added. The reaction mixture is stirred for a further 2 hours and then filtered and the filtrate is poured into ice water. The organic phase is separated off and concentrated under reduced pressure. The residue is taken up in 1 liter of toluene and the solution formed is boiled under reflux for one hour. The mixture is concentrated again under reduced pressure and the residue which remains is dissolved in methylene chloride. The organic phase is washed with water and concentrated under reduced pressure. The residue is triturated with toluene, the product separating out as crystals. 95 g of 3,4-dihydro-1-(imidazol-1-yl)-8-hydroxynaphthalene of melting point 186° C. are obtained in this manner.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[C:14]([C:33]4[CH:48]=[CH:47][C:36]([C:37]([O:39][CH2:40][C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)=[O:38])=[CH:35][CH:34]=4)[N:15]3[CH2:18][CH2:19][CH2:20][CH2:21][N:22]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]3=[O:32])=[CH:11][CH:10]=2)=[O:8])=[CH:4][C:3]=1[CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51].[F-].[Cs+].[OH:57][C:58]1[CH:59]=[C:60](B(O)O)[CH:61]=[CH:62][CH:63]=1.O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:31]=[C:30]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:32])[N:22]1[CH2:21][CH2:20][CH2:19][CH2:18][N:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([C:7]([C:5]3[S:6][C:2]([C:62]4[CH:61]=[CH:60][CH:59]=[C:58]([OH:57])[CH:63]=4)=[C:3]([CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])[CH:4]=3)=[O:8])[CH:17]=2)[CH:13]=[C:14]1[C:33]1[CH:48]=[CH:47][C:36]([C:37]([O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[O:38])=[CH:35][CH:34]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccc(C(=O)OCc5ccccc5)cc4)n(CCCCN4C(=O)c5ccccc5C4=O)c3c2)sc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccc(C(=O)OCc5ccccc5)cc4)n(CCCCN4C(=O)c5ccccc5C4=O)c3c2)sc1-c1cccc(O)c1
Yield: 81.6 %

Procedure:
A mixture of 5 (60 mg, 0.075 mmol), Pd(PPh3)4 (17 mg, 0.015 mmol), CsF (34 mg, 0.22 mmol), 3-hydroxyphenylboronic acid (16 mg, 0.12 mmol), and H2O (80 μL) in DME (8 mL) was degassed with N2 for 10 min and then refluxed. When the reaction was over by TLC monitoring, the mixture was poured into H2O (10 mL) and then extracted with 70 mL Et2O. The organic layer was washed with brine (2×10 mL), dried over MgSO4, and then concentrated in vacuo. MPLC purification (Hex:EtOAc/5:1) of the residue gave 6 as a yellow amorphous solid (50 mg, 82%). 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J=8.0 Hz, 2H), 8.04 (s, 1H), 7.74-7.61 (m, 7H), 7.56 (d, J=8.0 Hz, 2H), 7.49-7.26 (m, 6H), 7.13 (s, 1H), 7.03 (d, J=7.6 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.63 (s, 1H), 5.40 (s, 2H), 4.32 (t, J=7.2 Hz, 2H), 4.16-4.06 (m, 2H), 3.72 (s, 2H), 3.51 (t, J=6.8 Hz, 2H), 1.72-1.69 (m, 2H), 1.49-1.46 (m, 2H), and 1.26 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 188.62, 171.45, 168.65, 166.21, 157.16, 149.47, 143.69, 141.59, 138.00, 137.26, 137.23, 136.09, 134.28, 131.99, 131.82, 130.66, 130.37, 130.33, 130.12, 129.33, 128.90, 128.62, 128.53, 123.49, 121.88, 121.13, 120.87, 116.54, 116.46, 112.82, 104.20, 67.20, 61.46, 43.92, 37.36, 34.81, 27.45, 25.84, and 14.42.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]([OH:13])=O)[C:6]=2[C:14]=1[F:15].Cl.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:29])([CH3:28])[C:26]#[N:27])=[C:21]([F:30])[CH:20]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:26]([C:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][NH:17][C:11](=[O:13])[CH2:10][N:7]2[C:6]3[C:14]([F:15])=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)=[CH:20][C:21]=1[F:30])([CH3:29])[CH3:28])#[N:27]
Reactant: O=C(O)Cn1cnc2ccc(F)c(F)c21
Reactant: CC(C)(C#N)c1ccc(CN)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C#N)c1ccc(CNC(=O)Cn2cnc3ccc(F)c(F)c32)cc1F

Procedure:
N-[4-(1-Cyano-1-methylethyl)-3-fluorobenzyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide is synthesized according to example 14 with (6,7-difluoro-1H-benzimidazol-1-yl)acetic acid (150 mg, 0.707 mmol) prepared according to scheme 2, 2-[4-(aminomethyl)-2-fluorophenyl]-2-methylpropanenitrile hydrochloride (194 mg, 0.848 mmol) prepared according to scheme 8, Et3N (237 μL, 1.70 mmol) and HATU (323 mg, 0.848 mmol) in DMF (3.0 mL). The product is purified by HPLC: Gilson prep pumps, Flow rate: 30 ml/min, Column: Gemini (50 21.2×50 mm, Mobile phase: A=water (0.075% TFA) B=MeCN (0.075% TFA). Yield=25 mg as TFA salt, 0.05 mmol, 7%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.74-1.87 (m, 6H), 4.43 (d, J=5.66 Hz, 2H), 5.22 (s, 2H), 7.19-7.40 (m, 2H), 7.45-7.61 (m, 2H), 8.34 (s, 1H), 8.91-9.04 (m, 1H). MS [M+H], calcd: 387.1. found: 387.0.