Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11]C)[CH:8]=[C:7]([Cl:13])[C:3]=1[C:4]([OH:6])=[O:5].B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([Cl:13])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COc1cc(Cl)c(C(=O)O)c(Cl)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)c1c(Cl)cc(O)cc1Cl
Temperature: -78 °C
Reaction time: 16 h

Procedure:
2,6-Dichloro-4-methoxy-benzoic acid (500 mg, 2.3 mmol) was taken up in CH2CO2 and cooled to −78° C. BBr3 (6.9 ml of a 1 M solution in CH2Cl2) was added to the solution at −78° C. The solution was warmed to 25° C. and stirred at that temperature for 16 h. The solution was quenched with 3 N NaOH. The aqueous layer was extracted with CH2Cl2. The aqueous layer was cooled (0° C.) and acidified with conc. HCl (pH=1-2). The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried (Na2SO4). Filtration and concentration gave the crude phenol which was used without further purification.
Reaction SMILES: [I:1][CH3:2].[N:3]1[CH:8]=[CH:7][C:6]([C:9]([N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)=[O:10])=[CH:5][CH:4]=1>C(OCC)(=O)C>[I-:1].[CH3:2][N+:3]1[CH:4]=[CH:5][C:6]([C:9]([N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)=[O:10])=[CH:7][CH:8]=1
Reactant: CI
Reactant: O=C(c1ccncc1)N1CCc2ccccc2C1
Solvent: CCOC(C)=O
Product: C[n+]1ccc(C(=O)N2CCc3ccccc3C2)cc1
Product: [I-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.6 %

Procedure:
2 ml, equivalent to 4.26 g (30.2 mmol) of iodomethane and 6 g (25.2 mmol) of 2-[(4-pyridyl)carbonyl]-1,2,3,4-tetrahydroisoquinoline are introduced into 200 ml of ethyl acetate, and the mixture is stirred for 24 h at room temperature. A yellow precipitate forms, which is filtered off and washed with ether. 8.3 g of product are obtained, this being used without further treatment in the following stage.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:13](Cl)(Cl)Cl.CO>C(N(CC)CC)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:13])=[O:9])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: ClC(Cl)Cl
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
p-Nitrobenzoic acid (1.67 g) is suspended into chloroform (20 ml) and thereto are added triethylamine (1.40 ml) under ice-cooling and further 1-(p-chlorobenzenesulfonyoxy)-6-chloro-1,2,3-benzotriazole (3.44 g). When the mixture is stirred at room temperature for 15 minutes, yellow precipitates are produced and the mixture is further stirred for 5 hours. To the mixture are added methanol (0.6 ml) and triethylamine (1.4 ml), whereby the precipitates are dissolved. After stirring for 1 hour, chloroform is distilled off and the residue extracted with ethyl acetate. The extract is washed with water, an aqueous sodium hydrogen carbonate, 1 N hydrochloric acid and water in order and dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off. The resulting crystals aare recrystallized from isopropyl alcohol to give yellow crystals of methyl p-nitrobenzoate (1.4 g), melting point: 93°-94° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)=[C:4]([CH3:17])[CH:3]=1.N1C=CN=C1.[C:23]([Si:27]([CH3:30])([CH3:29])Cl)([CH3:26])([CH3:25])[CH3:24]>CN(C)C=O.C(OCC)(=O)C>[Si:27]([O:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)=[C:4]([CH3:17])[CH:3]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cc(O)cc(C)c1-c1cccc(C=O)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(O[Si](C)(C)C(C)(C)C)cc(C)c1-c1cccc(C=O)c1
Yield: 77.5 %

Procedure:
To a solution of 4′-hydroxy-2′,6′-dimethylbiphenyl-3-carbaldehyde (9.0 g, 39.8 mmol) and imidazole (2.98 g, 43.8 mmol) in N,N-dimethylformamide (100 mL) was added tert-butyldimethylchlorosilane (6.6 g, 43.8 mmol) at room temperature with stirring, and the mixture was stirred at room temperature for 4 hrs. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=4/1) to give the title compound (10.5 g, yield 77%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([C:26]([NH:28][NH:29][C:30](=O)[C:31]([F:34])([F:33])[F:32])=O)=[CH:12][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:14][CH:15]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:45])=CC=1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:12][C:11]=1[C:26]1[S:45][C:30]([C:31]([F:34])([F:33])[F:32])=[N:29][N:28]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C(=O)NNC(=O)C(F)(F)F)c2)cc1
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(-c3nnc(C(F)(F)F)s3)c2)cc1
Yield: 59.8 %

Procedure:
A solution of 2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)-N′-(2,2,2-trifluoroacetyl)-[1,1′-biphenyl]-2-carbohydrazide (502 mg) and Lawesson's reagent (825 mg) in THF (10 mL) was stirred at 80° C. for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (299 mg) as a pale-yellow solid. The present compound was used for the next reaction without purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:23][C:24]([C:26]2[CH:27]=[N:28][N:29]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[C:30]=2[CH3:31])=[O:25])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([O:15][Si](C(C)(C)C)(C)C)[CH2:11][CH2:10]1)#[N:2].[H-].[Na+].Br[CH2:42][C:43]([O:45]CC)=[O:44].O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([N:23]([C:24]([C:26]2[CH:27]=[N:28][N:29]([C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)[C:30]=2[CH3:31])=[O:25])[CH2:42][C:43]([OH:45])=[O:44])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:10][CH2:11][CH:12]([OH:15])[CH2:13][CH2:14]1)#[N:2]
Reactant: CCOC(=O)CBr
Reactant: Cc1c(C(=O)Nc2ccc(N3CCC(O[Si](C)(C)C(C)(C)C)CC3)c(C#N)c2)cnn1-c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N(CC(=O)O)c2ccc(N3CCC(O)CC3)c(C#N)c2)cnn1-c1ccc(F)cc1
Yield: 10.2 %

Procedure:
N-(3-Cyano-4-(4-tert-butyldimethylsilyloxypiperidin-1-yl) phenyl)-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide (3.3 g) and sodium hydride (60% content, 0.3 g) were reacted in dimethylformamide (30 ml) under ice-cooling for 1 h. Dimethylformamide solution (10 ml) containing ethyl bromoacetate (1.4 g) was added and the mixture was stirred under ice-cooling for 1 h and, after allowed to warm to roan temperature, stirred for another 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. Tetrabutylammonium fluoride (3.0 g), tetrahydrofuran (20 ml) and acetonitrile (20 ml) were added to the residue and the mixture was stirred at 80° C. for 1 h. The solvent was evaporated under reduced pressure. To the residue was added dilute hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. A mixed solvent of toluene-ethyl acetate was added to the residue to allow crystallization. The crystals were recrystallized from hydrous isopropanol to give the title compound (0.3 g), melting point: 155–158° C.
Reaction SMILES: [O:1]1[C:5]([CH:6]=O)=[CH:4][N:3]=[CH:2]1.[CH3:8][C:9]([S:12]([NH2:14])=[O:13])([CH3:11])[CH3:10]>C1COCC1.C(O[Ti](OCC)(OCC)OCC)C>[CH3:8][C:9]([S:12](/[N:14]=[CH:6]/[C:5]1[O:1][CH:2]=[N:3][CH:4]=1)=[O:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)S(N)=O
Reactant: O=Cc1cnco1
Agent: CCO[Ti](OCC)(OCC)OCC
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)/N=C/c1cnco1
Temperature: 65 °C
Yield: 58.7 %

Procedure:
Oxazole-5-carbaldehyde (1.0 g, 10.30 mmol), 2-methylpropane-2-sulfinamide (2.247 g, 18.54 mmol; CASRN 146374-27-8), and tetraethoxytitanium (8.460 g, 37.09 mmol) were placed in THF (15 mL) and heated to 65° C. for 12 h. The reaction was cooled and poured onto water. The solids were filtered off and the filtrate was extracted with EtOAc. The layers were separated and the organic layer was concentrated. The resulting residue was purified by SiO2 chromatography (20-25% EtOAc/hexane) to afford (E)-2-methyl-N-(oxazol-5-ylmethylene)propane-2-sulfinamide (20, 1.211 g, 6.047 mmol, 58.70% yield).
Reaction SMILES: [CH:1]([N:4]([CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11]CC)[C:5](=[O:8])[CH2:6][Cl:7])([CH3:3])C.[C:17]1(C)C(S(O)(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([N:4]([CH2:9][CH:10]1[O:11][CH2:16][CH2:15][O:14]1)[C:5](=[O:8])[CH2:6][Cl:7])[C:3]#[CH:17]
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: CCOC(CN(C(=O)CCl)C(C)C)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C#CCN(CC1OCCO1)C(=O)CCl

Procedure:
N-Isopropyl-N-(2,2-diethoxyethyl)-α-chloroacetamide (10 grams), propandiol-1,2 (2.9 ml) and trace amounts of toluenesulfonic acid were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at reflux until no more ethanol was given off. After this time sodium carbonate (1 gram) was added to the mixture with stirring and the resulting mixture was distilled to yield the desired product N-propargyl-N-(1,3-dioxolan-2-ylmethyl)-α-chloroacetamide having a boiling point of 155° to 160° C. at 1 mm of Hg pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=2[CH:17]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[C:22]([Cl:38])=[CH:21][N:20]=1>>[Cl:38][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[N:24][C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[CH:17]=2)=[N:20][CH:21]=1
Reactant: CCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CCN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)C(C)C)n3)cc21

Procedure:
Title compound was prepared from 8-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine in an analogous manner to Example 1221d. Product was isolated as a white solid (62 mg, 55%). LCMS: 542.20 (M+H), HPLC purity: 100%, MP: 202-204. 1H-NMR (CDCl3, 400 MHz) δ 10.34 (s, 1H), 8.42 (d, J=8.3 Hz, 1H), 8.04 (s, 1H), 7.98 (d, J=7.9 Hz, 1H), 7.55-7.49 (m, 2H), 7.43-7.34 (m, 2H), 7.28-7.27 (m, 2H), 3.66-3.63 (m, 2H), 3.26-3.22 (m, 1H), 2.35-2.32 (m, 2H), 2.12-2.06 (m, 2H), 1.38-1.34 (m, 12H), 1.10 (t, J=7.3 Hz, 3H).
Reaction SMILES: C[I:2].[C:3]([O:7][C:8]([NH:10][CH:11]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:12]([O:14][C@@H:15]1[CH:20]2[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]2)[CH2:16]1)=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:29]COCC>C(OCC)(=O)C>[I-:2].[C:3]([O:7][C:8]([NH:10][CH:11]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:12]([O:14][C@@H:15]1[CH:20]2[CH2:21][CH2:22][N+:17]([CH3:29])([CH2:18][CH2:19]2)[CH2:16]1)=[O:13])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CI
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(C(=O)O[C@H]1C[N+]2(C)CCC1CC2)c1ccccc1
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
Methyl iodide (8.6 μl, 0.14 mmol) was added to a solution of (R)-quinuclidin-3-yl 2-(tert-butoxycarbonylamino)-2-phenylacetate (C1) (50 mg, 0.14 mmol) in ethyl acetate (2 ml), and the reaction was stirred at RT overnight. Et2O (1 ml) was added, and the precipitate was collected by suction filtration and dried under vacuum at 40° C. The product was further purified by preparative HPLC to obtain (3R)-3-(2-(tert-butoxycarbonylamino)-2-phenylacetoxy)-1-methyl-1-azoniabicyclo[2.2.2]octane iodide (24.2 mg; 35% yield).
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([O:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([Cl:56])[C:51]=3[CH3:57])[N:48]=[CH:49][C:42]=12)[C:36](OC)=[O:37])([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1C=CC=CC=1)[C:14]1C=CC=CC=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([O:40][C:41]1[C:42]2[CH:49]=[N:48][N:47]([C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([Cl:56])[C:51]=3[CH3:57])[C:43]=2[N:44]=[CH:45][N:46]=1)[C:36]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([CH3:5])=[CH:11][N:10]=1)=[O:37])([C:26]([CH3:27])([CH3:28])[CH3:29])([CH3:20])[CH3:14]
Reactant: Cc1ccc(N)nc1
Reactant: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1cccc(Cl)c1C
Agent: C[Al](C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)[C@H](COCCO[Si](C)(C)C(C)(C)C)Oc2ncnc3c2cnn3-c2cccc(Cl)c2C)nc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 113 %

Procedure:
A solution of 2M trimethyl aluminium in toluene (1.790 mL, 3.58 mmol) in toluene (15 mL) was added dropwise to a stirred suspension of 5-methylpyridin-2-amine (0.387 g, 3.58 mmol) in toluene (15 mL) cooled to 0° C., over a period of 2 minutes under nitrogen and the resulting suspension was stirred at 0° C. for 20 minutes. A solution of (2S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-chloro-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AE2) (1.05 g, 1.63 mmol) in toluene (10 mL) was added dropwise over 2 minutes, the mixture allowed to warm to ambient temperature and then heated to 60° C. for 20hrs. The reaction was cooled to ˜5° C. and a 10% solution of Rochelles salt (25 mL) added followed by ethyl acetate (30 mL). The organic phase was separated, washed with water (20 mL) and brine (20 mL), dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in iso-hexane to afford the product (1.1 g, 94%). 1H NMR (400 MHz, DMSO) δ 0.89 (9H, s), 2.03 (3H, s), 2.24 (3H, s), 3.70-3.79 (4H, m), 4.03-4.07 (1H, m), 4.12-4.16 (1H, m), 5.99-6.00 (1H, m), 7.33-7.47 (8H, m), 7.55-7.62 (5H, m), 7.67-7.69 (1H, m), 7.86-7.89 (1H, m), 8.17-8.18 (1H, m), 8.50 (1H, s), 8.53 (1H, s), 10.87 (1H, s); m/z (ESI+) (M+H)+=721; HPLC tR=3.63 min.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6](=[O:16])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([OH:3])=[O:2].[CH3:17][O:18][C:19](=[O:34])[CH:20]([NH:29][C:30](=[O:33])[CH2:31]O)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH3:17][O:18][C:19](=[O:34])[CH:20]([NH:29][C:30](=[O:33])[CH2:31][O:2][C:1](=[O:3])[CH2:4][O:5][C:6](=[O:16])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1
Reactant: COC(=O)C(Cc1ccc(O)cc1)NC(=O)CO
Reactant: O=C(O)COC(=O)CCc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COC(=O)C(Cc1ccc(O)cc1)NC(=O)COC(=O)COC(=O)CCc1ccc(O)cc1

Procedure:
A solution of 3-(4-hydroxy-phenyl)-propionic acid carboxymethyl ester 5 (10 grams, 44.64 mmol) and 2-(2-hydroxy-acetylamino)-3-(4-hydroxy-phenyl)-propionic acid methyl ester 3 (11.3 grams, 44.66 mmol) in anhydrous dichloro methane (100 mL) under a nitrogen atmosphere at 0° C. is added dropwise to a solution of 1,3-dicyclohexyl carbodiimide (23 grams, 111.47 mmol) in dichloro methane (60 mL). The resulting solids are filtered off. The organic phase is washed with 5% sodium bicarbonate (2×25 mL) and water (2×25 mL), dried over sodium sulphate, and distilled to give crude 8, which can be purified in an appropriate solvent.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][CH2:10][CH2:11][CH2:12][N:13]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:7][CH:6]=1.O.NN>C(O)C>[NH2:13][CH2:12][CH2:11][CH2:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][N:2]([CH3:26])[CH3:1])=[CH:25][CH:24]=1
Reactant: CN(C)CCc1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: CN(C)CCc1ccc(OCCCN)cc1

Procedure:
2-[3-[4-[2-(Dimethylamino)ethyl]phenoxy]propyl]-1H-isoindole-1,3-(2H)-dione (2.1 g) and hydrazine hydrate (1.2 ml) were heated at reflux in ethanol for 4 h. The solvent was evaporated and the residue was distilled to give the title compound as a clear yellow oil b.p. 170° (0.1 mm). TLC silica; ethyl acetate:water:isopropanol:0.88 ammonia 25:8:15:2; Rf 0.35.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:13]3[C:14](=[O:32])[NH:15][C:16](=[O:31])[C:17]=3[C:18]3[C:26]4[C:21](=[CH:22][C:23]([N+:27]([O-])=O)=[CH:24][CH:25]=4)[N:20]([CH3:30])[CH:19]=3)=[CH:8][N:9]2[CH3:12])=[CH:5][CH:4]=1)#[N:2].O.O.[Sn](Cl)Cl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:27][C:23]1[CH:22]=[C:21]2[C:26]([C:18]([C:17]3[C:16](=[O:31])[NH:15][C:14](=[O:32])[C:13]=3[C:7]3[C:6]4[C:10](=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[N:9]([CH3:12])[CH:8]=3)=[CH:19][N:20]2[CH3:30])=[CH:25][CH:24]=1
Reactant: Cn1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)NC2=O)c2ccc(C#N)cc21
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1cc(C2=C(c3cn(C)c4cc(C#N)ccc34)C(=O)NC2=O)c2ccc(N)cc21
Reaction time: 16 h
Yield: 78.3 %

Procedure:
3-(6-cyano-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-pyrrole-2,5-dione (9.0 g, 21 mmole) was suspended in ethanol (1.8 L) and treated with tin (II) chloride dihydrate (35 g, 156 mmole). This was mechanically stirred for 16 h at reflux. The reaction was cooled and reduced in volume to 1L. This was poured into a mixture of ethyl acetate (2 L) and saturated sodium bicarbonate solution (1 L) and well mixed. The organic layer was decanted and washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered, evaporated, and then purified by flash column chromatography (ethyl acetate). The product was further purified by crystalization from tetrahydrofuran/hexane to provide 6.5 g of 3-[4-(6-amino-1-methyl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-1-methyl-1H-indole-6-carbonitrile; mp 255-260° C.
Reaction SMILES: [C:1]([O:4][NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].[H-].[Na+].[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH:17]=[C:16]1[S:24](Cl)(=[O:26])=[O:25]>>[C:1]([O:4][N:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[S:24]([C:16]1[O:15][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH:17]=1)(=[O:25])=[O:26])(=[O:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: CC(=O)ONC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Product: CC(=O)ON(C(=O)OC(C)(C)C)S(=O)(=O)c1cc2ccccc2o1

Procedure:
N-[(tert-Butoxy)carbonyl]-1-benzofuran-2-sulfonamido acetate (56) is prepared from [(tert-butoxy)carbonyl]amino acetate, sodium hydride and 1-benzofuran-2-sulfonyl chloride according to Scheme 2. (3.1 g, 75%), 1H NMR (250 MHz, DMF) δ ppm 8.07 (1H, d, 0.9 Hz), 7.91 (1H, d, 7.3 Hz), 7.82 (1H, dd, 8.5, 0.8 Hz), 7.64 (1H, td, 7.8, 1.4 Hz), 7.41-7.52 (1H, m), 2.32 (3H, s), 1.37 (9H, s).
Reaction SMILES: [O-]CC.[Na+].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][CH:7]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=1)=[O:16]>C(O)C>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=2)=[O:16])=[CH:8][CH:7]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CSc1ccc(C(=O)CBr)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CSc1ccc(C(=O)CSc2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
To a stirring mixture of sodium ethoxide (13.32 g, 196 mmol) in ethanol (IL) in a 2 L RBF was added 4-chlorothiophenol (26.0 g, 179 mmol), followed by 2-bromo-1-[4-(methylsulfanyl)phenyl]ethanone (40 g, 163 mmol). The reaction mixture was heated to reflux until all solid dissolved, hot filtered through a fritted funnel, then allowed to cool slowly to room temperature, then to 0° C. in an ice bath. The title compound was isolated as pink needle-like crystals (43.9 g, 87%) by filtration. LCMS M+1=309.2.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[S:3]([C:6]1[CH:15]=[CH:14][C:9]2[NH:10][C:11](=O)[NH:12][C:8]=2[CH:7]=1)(=[O:5])=[O:4].O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:11]1[NH:10][C:9]2[CH:14]=[CH:15][C:6]([S:3]([C:2]([F:17])([F:16])[F:1])(=[O:5])=[O:4])=[CH:7][C:8]=2[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2ccc(S(=O)(=O)C(F)(F)F)cc2[nH]1
Product: O=S(=O)(c1ccc2[nH]c(Cl)nc2c1)C(F)(F)F

Procedure:
Reflux 5-trifluoromethylsulfonyl-1,3-dihydro-benzimidazol-2-one (380 mg) for 8 hours in POCl3 (10 mL). Evaporate the solvent in vacuo, then carefully neutralize with saturated NaHCO3, and extract with EtOAc. Dry over Na2SO4, concentrate under vacuum, and purify by flash chromatography (1:1 hexanes/EtOAc) to obtain 2-chloro-5-trifluoromethylsulfonyl-1H-benzimidazole. G. 1′-(5-trifluoromethylsulfonyl-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16](Br)[C:15]=3[O:24][CH2:25][CH3:26])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.[CH3:27][S:28]([C:31]1[CH:32]=[N:33][CH:34]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:36]=1)(=[O:30])=[O:29].C(#N)C.C(=O)([O-])[O-].[Na+].[Na+].O.ClCCl>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([C:35]4[CH:34]=[N:33][CH:32]=[C:31]([S:28]([CH3:27])(=[O:30])=[O:29])[CH:36]=4)[C:15]=3[O:24][CH2:25][CH3:26])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1Br
Reactant: CC1(C)OB(c2cncc(S(C)(=O)=O)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1-c1cncc(S(C)(=O)=O)c1
Temperature: 100 °C
Yield: 19.5 %

Procedure:
To a mixture of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-bromo-6-chloro-3-ethoxybenzonitrile (20 mg, 0.04 mmol) and 3-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (19 mg, 0.069 mmol) in acetonitrile (2 mL, 40 mmol) was added sodium carbonate (10 mg, 0.09 mmol) in water (0.5 mL, 30 mmol). The reaction was degassed with bubbling nitrogen. [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (2 mg, 0.002 mmol) was added and degassed more with N2. Reaction was heated at 100° C. for 2 hours. The crude product was purified on preparative LC-MS (acetonitrile, water, TFA) to give the desired product (0.004 g, 20%) as white amorphous solid. The product was isolated as a racemic mixture. LCMS calculated for C23H22ClN7O3S (M+H)+: m/z=512.1; found: 512.2. 1H NMR (500 MHz, DMSO) δ 9.20 (d, J=2.1 Hz, 1H), 9.12 (d, J=1.9 Hz, 1H), 8.61 (t, J=2.0 Hz, 1H), 8.12 (s, 1H), 7.80 (s, 1H), 6.36 (q, J=7.0 Hz, 1H), 3.54 (dt, J=14.0, 7.0 Hz, 1H), 3.37 (s, 3H), 3.36-3.30 (m, 1H), 2.58 (s, 3H), 1.81 (d, J=7.0 Hz, 3H), 0.92 (t, J=6.9 Hz, 3H).