Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([P:4](Cl)Cl)[CH2:2][CH3:3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1>C(Cl)(Cl)Cl>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:3]([C:11]2[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=2)[CH2:2][CH2:1][PH2:4])=[CH:10][CH:9]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CCCP(Cl)Cl
Solvent: ClC(Cl)Cl
Product: PCCC(c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
Bis(p-chlorophenyl)propylphosphine was prepared by reacting 0.2 mole of propyldichlorophosphine with a 0.4 mole of p-chlorophenylmagnesium bromide. The product was isolated by chloroform extraction and distillation as previously described. The portion boiling between 160° and 165° C. under a pressure of 2 mm. Hg was collected. The analysis corresponded to bis(p-chlorophenyl)propylphosphine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](Cl)=[C:7]3[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:8]3=[N:9][C:10]=2[CH:11]=1.[CH2:19]([N:21]([CH2:30][CH3:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH2:29])[CH3:20].C1(O)C=CC=CC=1.[ClH:39]>CC(C)=O>[ClH:1].[ClH:39].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([NH:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:30][CH3:31])[CH2:19][CH3:20])=[C:7]3[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:8]3=[N:9][C:10]=2[CH:11]=1
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2n1
Reactant: CCN(CC)CCCCCCCN
Agent: Cl
Solvent: Oc1ccccc1
Solvent: CC(C)=O
Product: CCN(CC)CCCCCCCNc1c2ccc(Cl)cc2nc2ccc(OC)nc12

Procedure:
A mixture of 2.8 g. of 7,10-dichloro-2-methoxypyrido [3,2-b]quinoline, 2.0 g. of 7-diethylaminoheptylamine and 6.5 g. of phenol is stirred on a steam bath for 3 hours. The reaction is cooled, 20 ml. of 95% alcohol is added and this mixture is poured into a mixture of 200 ml. of acetone and 2.5 ml. of concentrated hydrochloric acid. The resulting solution is cooled in ice. The solid is collected and recrystallized from n-propanol:ethyl acetate (50:50), giving the desired product as yellow crystals, mp. 170°-174° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)OC(C)(C)C)=[CH:4][C:3]=1[NH:16][C:17]1[N:21]([C:22]2[CH:27]=[C:26]([NH:28][CH3:29])[N:25]=[CH:24][N:23]=2)[N:20]=[C:19]([CH3:30])[CH:18]=1.C(Cl)Cl>C(O)(C(F)(F)F)=O>[CH3:1][C:2]1[C:3]([NH:16][C:17]2[N:21]([C:22]3[CH:27]=[C:26]([NH:28][CH3:29])[N:25]=[CH:24][N:23]=3)[N:20]=[C:19]([CH3:30])[CH:18]=2)=[CH:4][C:5]([NH2:8])=[CH:6][CH:7]=1
Reactant: CNc1cc(-n2nc(C)cc2Nc2cc(NC(=O)OC(C)(C)C)ccc2C)ncn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1cc(-n2nc(C)cc2Nc2cc(N)ccc2C)ncn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Tert-butyl 4-methyl-3-(3-methyl-1-(6-(methylamino)pyrimidin-4-yl)-1H-pyrazol-5-ylamino)phenylcarbamate 38 (2.0 g) is dissolved in a mixed solvent of TFA:DCM/1:1 (20 mL). The mixture is stirred at room temperature for 4 hours, then concentrated in vacuo. The residue is dissolved in EtOAc and washed with aqueous NaHCO3. The organic layer is separated, dried with MgSO4, then concentrated in vacuo to provide 6-methyl-N1-(3-methyl-1-(6-(methylamino)pyrimidin-4-yl)-1H-pyrazol-5-yl)benzene-1,3-diamine 39.
Reaction SMILES: [Cl:1][C@H:2]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:3](O)=[O:4].S(Cl)([Cl:14])=O>>[Cl:1][C@H:2]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:3]([Cl:14])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)CC[C@@H](Cl)C(=O)O
Product: COC(=O)CC[C@@H](Cl)C(=O)Cl
Temperature: 75 °C
Reaction time: 1 h

Procedure:
A mixture of (R)-2-chloro-4-methoxycarbonylbutyric acid (3.85 g) and thionyl chloride (2.4 ml) was stirred at 75° C. for 1 hour and the excess thionyl chloride was removed by distillation to give (R)-2-chloro-4-methoxycarbonylbutyryl chloride as an oil. A solution of this oil in ethyl acetate (10 ml) was then added dropwise to a stirred and ice-cooled mixture of 3-amino-5,6,7,8-tetrahydro-2-naphthol hydrobromide (5.20 g), sodium bicarbonate (4.48 g), water (20 ml) and ethyl acetate (30 ml). The whole was stirred at 0° C. for 1.5 hour and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate. The combined organic layer was washed with water and dried over magnesium sulfate. Evaporation of the solvent gave methyl (R)-4-chloro-4-[N-(3-hydroxy-5,6,7,8-tetrahydro-2naphthyl)carbamoyl]butyrate as an oil (6.20 g). A mixture of this oil, powdered potassium carbonate (2.95 g) and dimethylformamide (20 ml) was then stirred at room temperature for 1.5 hour. Dilution with water gave methyl (S)-3-(3,4,6,7,8,9-hexahydro-3-oxo-2H-naphtho[2,3-b][1,4]oxazin-2-yl)propionate was crystals (2.52 g, 40.9%). Purification by column chromatography on silica gel with ethyl acetate-hexane (3:2, v/v), followed by recrystallization from ethyl acetate-ethyl ether gave colorless crystals (2.22 g, 36.0%), m.p. 138°-139° C. [α]D26 -7.8° (c=0.3, CHCl3).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([C:10]([OH:12])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:37][C@@H:38]([CH2:46][C:47]1[CH:52]=[CH:51][C:50]([OH:53])=[CH:49][CH:48]=1)[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>CN(C=O)C>[C:1]([C:5]1[S:9][C:8]([C:10]([NH:37][C@H:38]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:46][C:47]2[CH:52]=[CH:51][C:50]([OH:53])=[CH:49][CH:48]=2)=[O:12])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(C(=O)O)s1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1ccc(C(C)(C)C)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
Prepared using General Procedure 7. Into a solution of 5-(tert-butyl)thiophene-2-carboxylic acid (1.93 g, 10.0 mmol) in DMF (20 mL) were added HATU (4.56 g, 12.0 mmol) and TEA (4.18 mL, 30.0 mmol). The mixture was stirred at room temperature for 30 min and (S)-tert-butyl 2-amino-3-(4-hydroxyphenyl)propanoate (2.37 g, 10.0 mmol) was added. After 1 h, the reaction mixture was poured into 400 mL of ice-water and the solid was filtered. The solid was dissolved in DCM and EA, dried over MgSO4, concentrated, and purified by chromatography (EA/hexanes) to provide 3.6 g (89%) of tert-butyl (5-(tert-butyl)thiophene-2-carbonyl)-L-tyrosinate. LCMS-ESI (m/z) calculated for C22H29NO4S: 403.2. found: 426.1 [M+Na]+, tR=9.07 min (Method 2).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[CH3:19]O>>[N+:1]([C:4]1[CH:12]=[C:8]([C:9]([O:11][CH3:19])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1O
Temperature: 100 °C
Reaction time: 24 h
Yield: 72 %

Procedure:
In methanol (250 ml) was suspended 5-nitrosalicylic acid (50.0 g, 273 mmol), and to the mixture was added sulfuric acid (6 ml). The mixture was stirred at 100° C. for 24 hours and the cooled to room temperature. The precipitated insoluble materials were filtered, which were washed with hydrous methanol (containing 20% of water) and methanol, and dried under reduced pressure to give methyl 5-nitrosalicylate (38.5 g, 195 mmol, 72%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](Cl)=[O:26])[CH:4]=[N:3]1.Cl.[CH3:29][NH:30][CH2:31][C:32]([O:34][CH3:35])=[O:33]>>[CH3:35][O:34][C:32](=[O:33])[CH2:31][N:30]([CH3:29])[C:25]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7](=[O:24])[NH:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:17]=[C:11]2[CH:10]=1)=[O:26]
Reactant: Cn1ncc(C(=O)Cl)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Reactant: CNCC(=O)OC
Agent: Cl
Product: COC(=O)CN(C)C(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1

Procedure:
This compound was prepared in the same manner as described in example 92 starting from 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carbonyl chloride (Example 92, step a) (263 mg, 691 μmol) and methyl 2-(methylamino)acetate hydrochloride (482 mg, 3.45 mmol). Additional TEA (349 mg, 481 μl) was added to the reaction mixture. The final product was isolated as white solid (146 mg, 46%); MS: m/z=448.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8](B3OC(C)(C)C(C)(C)O3)=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:21].Br[C:23]1[CH:24]=[N:25][CH:26]=[C:27]([CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][C@H:31]2[C:35]([CH3:43])([CH3:42])[O:36][SiH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH:28]=1>>[C:38]([SiH2:37][O:36][C:35]([CH3:43])([CH3:42])[C@@H:31]1[CH2:32][CH2:33][CH2:34][N:30]1[CH2:29][C:27]1[CH:28]=[C:23]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[N:2]([CH3:1])[C:3](=[O:21])[CH2:4][CH2:5]3)[CH:24]=[N:25][CH:26]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@@H]1CCCN1Cc1cncc(Br)c1
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: CN1C(=O)CCc2cc(-c3cncc(CN4CCC[C@H]4C(C)(C)O[SiH2]C(C)(C)C)c3)ccc21

Procedure:
In analogy to the procedure described for the preparation of intermediate A-3 [C], 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-1) has been coupled to 3-bromo-5-[(S)-2-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidin-1-ylmethyl]-pyridine to give the title compound as an off white waxy solid. MS: 352.3 (M+H+).
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:20][C:19]2[C:21]3[C:26]([CH:27]=[CH:28][C:18]=2[N:17]=1)=[CH:25][C:24]1[C:29]2[C:34]([CH2:35][O:36][C:23]=1[CH:22]=3)=[CH:33][C:32]([C:37]1[NH:41][C:40]([C@@H:42]3[CH2:46][C@H:45]([CH2:47][O:48][CH3:49])[CH2:44][N:43]3[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[N:39][CH:38]=1)=[CH:31][CH:30]=2)=O)C1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(O)C.[Pd]>[CH3:49][O:48][CH2:47][C@@H:45]1[CH2:44][N:43]([C:50]([O:52][C:53]([CH3:56])([CH3:54])[CH3:55])=[O:51])[C@H:42]([C:40]2[NH:41][C:37]([C:32]3[CH:33]=[C:34]4[CH2:35][O:36][C:23]5[CH:22]=[C:21]6[C:26]([CH:27]=[CH:28][C:18]7[N:17]=[C:16]([C@@H:12]8[CH2:13][CH2:14][CH2:15][NH:11]8)[NH:20][C:19]=76)=[CH:25][C:24]=5[C:29]4=[CH:30][CH:31]=3)=[CH:38][N:39]=2)[CH2:46]1
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CCCN7C(=O)OCc7ccccc7)[nH]c65)cc3-4)[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CCCN7)[nH]c65)cc3-4)[nH]2)N(C(=O)OC(C)(C)C)C1
Reaction time: 4 h

Procedure:
A mixture of tert-butyl (2S,4S)-2-[5-(2-{(2S)-1-[(benzyloxy)carbonyl]pyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate (724 mg, 0.96 mmol) and 70 mg 10% Pd/C in 20 mL ethanol was hydrogenated at 1 atm overnight. Additional 10% Pd/C (300 mg) and a portion of solid NaHCO3 was added and hydrogenation continued for 4 hours. Filtration through celite and concentration of the filtrate under reduced pressure gave the product as a dark brown solid, 454 mg. Purification by reverse phase HPLC gave 65 mg purified product.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:30]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:16]3=[N:17][CH:18]=[C:19]([C:21]4[N:25]([CH2:26][CH2:27][C:28]#[N:29])[N:24]=[N:23][N:22]=4)[CH:20]=[C:15]3[N:14]=2)=[CH:9][CH:8]=1)(C)(C)C.O.C(OCC)(=O)C>C(O)(=O)C.O1CCCC1>[CH:31]1([N:30]2[C:16]3=[N:17][CH:18]=[C:19]([C:21]4[N:25]([CH2:26][CH2:27][C:28]#[N:29])[N:24]=[N:23][N:22]=4)[CH:20]=[C:15]3[N:14]=[C:13]2[C:10]2[CH:9]=[CH:8][C:7]([OH:6])=[CH:12][CH:11]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2nc3cc(-c4nnnn4CCC#N)cnc3n2C2CCCCC2)cc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#CCCn1nnnc1-c1cnc2c(c1)nc(-c1ccc(O)cc1)n2C1CCCCC1
Yield: 86.9 %

Procedure:
A solution of intermediate 62 (78 mg, 0.15 mmol) in glacial acetic acid (3 mL), tetrahydrofuran (1 mL), and water (1 mL) was heated to 100° C. for 3 h under a nitrogen atmosphere. Ethyl acetate (40 mL) was added and the organic phase washed with water (2×20 mL), NaHCO3 (2×20 mL), and brine (1×). The organic phase was dried (Na2SO4) and concentrated on a rotary evaporator to afford intermediate 63 as a white solid (54 mg, 89%). ESI-MS m/e 415.1 (M+1).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:15]([O:20][CH2:21][CH2:22][OH:23])(=[O:19])[CH2:16][CH2:17][CH3:18].CS(C)=O.CCN(CC)CC>C(Cl)Cl>[C:15]([O:20][CH2:21][CH:22]=[O:23])(=[O:19])[CH2:16][CH2:17][CH3:18]
Reactant: CCCC(=O)OCCO
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCCC(=O)OCC=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
To a mechanically stirred suspension of P2O5 (42.53 g, 150 mmol) in dry DCM (100 ml) at 0° C., was slowly added 30 (11.0 g, 83 mmol), followed by DMSO (13 g, 11.8 ml, 166 mmol). After stirring at 0° C. for 1 h, the ice bath was removed and the mixture further stirred at ii for 1.5 h. It was then cooled to 0° C., and then Et3N (42 g, 58 ml, 416 mmol) was slowly added. The reaction was then left with stirring for 6 hours at room temperature. The reaction was quenched by adding 1.0 M HCl (60 ml) at 0° C., and left with stirring for 30 minutes at 0° C. The organic layer was then washed with water (2×250 ml), dried, filtered and evaporated to afford 24 (6.60 g, 51 mmol, 61%) as a yellow liquid, that was used in the next step without any further purification.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[C:22]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=[C:19]([CH2:29][NH2:30])[CH:18]=1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:30]([CH2:29][C:19]3[CH:18]=[C:17]([CH3:16])[C:22]([O:23][CH2:24][C:25]([F:28])([F:26])[F:27])=[CH:21][N:20]=3)[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(CN)ncc1OCC(F)(F)F
Agent: Cl
Product: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)ncc1OCC(F)(F)F
Yield: 22 %

Procedure:
The title compound is prepared in 22% yield (42 mg, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (170 mg, 0.61 mmol, Step-1 of Intermediate-1) and (4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanamine hydrochloride (230 mg, 0.51 mmol, Amine-57) in a similar manner to Step-2 of Intermediate-1.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[N:17])=[CH:11][CH:10]=2)[O:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].I[CH2:30][CH2:31][CH2:32]I>C1COCC1>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:18])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:16]#[N:17])[CH2:32][CH2:31][CH2:30]3)=[CH:11][CH:10]=2)[O:5]1
Reactant: CC1(C)OB(c2ccc(CC#N)cc2)OC1(C)C
Reactant: ICCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(C3(C#N)CCC3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
To a solution of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile (7.0 g, 29 mmol) in THF at 0° C. was added NaHMDS (1.0 M, 120 mL, 120 mmol). After stirring for 20 min 1,3-diiodopropane (26 g, 86 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0° C., quenched with MeOH (5.0 mL) and the residue was purified by column chromatography (silica, ethyl acetate/hexanes gradient) to afford the desired product (4.0 g, 47%) as a yellow oil: ESI MS m/z 286 [C17H22BNO2+H]+.
Reaction SMILES: C(C1C=C(COC2C=C([O:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])(=[O:21])=[O:20])C=C(C)C=2)C=CC=1)#N.Cl.Cl.CN.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.C(O)C>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[S:19]([OH:21])(=[O:20])=[O:18]
Reactant: Cc1cc(OCc2cccc(C#N)c2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Agent: CN
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: O=S(=O)(O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.3 %

Procedure:
To a solution of 2-chlorobenzenesulfonic acid 3-[(3-cyanophenyl)methoxy]-5-methylphenyl ester (414 mg, 1.0 mmol), as prepared in step (a) of Example 6, in methylene chloride (10 mL) was added 37% HCl in ethanol (15 mL) at 0° C. The mixture was allowed to stand at 0° C. for 3 days. The solvent was evaporated and the residue was concentrated in vacuo from methylene chloride several times. The residue was dissolved in ethanol (10 mL), treated with methylamine hydrochloride (270 mg, 4.0 mmol) and Na2CO3 (212 mg, 2.0 mmol), and then stirred at room temperature for 2 days. The reaction mixture was partitioned between methylene chloride (150 mL) and 10% K2CO3. The organic phase was washed with 10% K2CO3 (50 mL) and dried over K2CO3. After removing the solvent in vacuo, HCl in methanol (30 mL) was added and the solvent was removed in vacuo. The residue was then purified by flash column chromatography (10% methanol/methylene chloride) and crystallized from methanol/ethyl acetate to give the title compound as white crystals (145 mg, 30%) 1H-NMR (300 MHz, DMSO-d6) δ 2.22 (s, 3 H), 3.01 (s, 3 H), 5.10 (s, 2 H), 6.53 (s, 1 H), 6.56 (s, 1 H), 6.87 (s, 1 H), 7.58 (t, 1 H, J=7.0 Hz), 7.63 (t, 1 H, J=7.6 Hz), 7.73 (m, 2 H), 7.86 (m, 3 H), 7.94 (d, 1 H, J=4.0 Hz), 9.05 (br s, 1 H), 9.55 (br s, 1 H), and 9.94 (br s, 1 H). Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for C22H21N2O4SCl: 445.1 (M+H). Found: 445.0.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[CH2:12](O)[CH3:13]>S(=O)(=O)(O)O>[CH2:12]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[OH:11])[CH3:13]
Reactant: CCO
Reactant: O=C(O)c1cc(F)ccc1O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(F)ccc1O
Temperature: 90 °C

Procedure:
To a solution of 5-fluorosalicylic acid (50 g) in absolute ethanol (500 ml), concentrated sulfuric acid (10 ml) was cautiously added. The solution was heated at 90° C. for 72 hours. The solvent was removed in vacuo, and the viscous residue was made basic (final pH=9) by portionwise addition of saturated aqueous sodium bicarbonate. The solution was then extracted with three 200 ml portions of methylene chloride. The combined organic extracts were dried (anhydrous sodium sulfate) and concentrated in vacuo to afford the title compound (quantitative yield) as a viscous colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:27][CH2:26][CH:25]([NH:28][CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Product: CC(C)(C)OC(=O)N1CCC(NCc2cccc(-c3ccnc(Cl)n3)c2)C1

Procedure:
Intermediate 1 was coupled with 3-Amino-pyrrolidine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 389.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=O.[CH3:13][C:14]1([CH3:28])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[O:15]1>>[CH3:19][C:18]1([CH3:20])[C:14]([CH3:13])([CH3:28])[O:15][B:16]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:10]([C:2]3[O:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[CH:3]=3)=[O:12])=[CH:23][CH:22]=2)[O:17]1
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Product: CC1(C)OB(c2ccc(NC(=O)c3cc4ccccc4o3)cc2)OC1(C)C
Yield: 83 %

Procedure:
Amide coupling of benzofuran-2-carboxylic acid with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine was done according to Example 20, Step 4 to give benzofuran-2-carboxylic acid [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide in 83% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.3 (s, 12 H) 7.4 (m, 1 H) 7.5 (m, 1 H) 7.7 (d, J=8.3 Hz, 2 H) 7.7 (dd, J=8.5, 0.9 Hz, 1 H) 7.8 (m, 4 H) 10.6 (s, 1 H)
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11]O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.S(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[C:1]1([S:7]([CH:10]=[CH2:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(CCO)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C=CS(=O)(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
2-(phenylsulfonyl)ethanol (143.8 g, purity 96.2%, 743 mmol) was added to 71.9 g of toluene, and 30.0 g (38 mmol) of pyridine was added to the mixture. The resulting solution was heated to 60° C., then 110.5 g (929 mmol) of thionyl chloride added over 5 hours at 60 to 70° C., and the mixture was stirred for 2 hours at 70° C. Then, the mixture was diluted with 143.9 g of toluene and cooled to 45° C. Then 303.2 g of 7% sodium bicarbonate solution and 193.4 g of toluene were added, washed separated. Obtained organic layer was mixed with 303.2 g of 7% sodium bicarbonate solution and stirred and separated. 5 g of the organic layer was sampled and subjected to HPLC analysis, which revealed that (β-chloroethylsulfonyl)benzene was obtained in a yield of 98% and phenylvinylsulfone in a yield of 0.7%. (Internal Standard: methyl benzoate).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](O)=[C:8]([C:17]#[N:18])[C:7]1=[O:19])[CH3:2].O=P(Cl)(Cl)[Cl:22]>O>[Cl:22][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[C:7](=[O:19])[C:8]=1[C:17]#[N:18]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOCCn1c(=O)c(C#N)c(O)c2ccccc21
Solvent: O
Product: CCOCCn1c(=O)c(C#N)c(Cl)c2ccccc21
Temperature: 100 °C

Procedure:
To 1-(2-Ethoxy-ethyl)-4-hydroxy-2-oxo-1,2-dihydro-quinoline-3-carbonitrile (1 eq, 0,150 g, 0.58 mmole) was added POCl3 neat. The resulting solution was heated to 100° C. for 8 hours. Reaction mixture was added dropwise to water (20 mL) which had been heated to 80° C. then cooled to RT and extracted with ethyl acetate (25 mL×3). Combined, organic phase was Washed consecutively with water, brine before drying over sodium sulfate. Organic phase was evaporated and the residue was purified by flash chromatography to afford 4-Chloro-1-(2-ethoxy-ethyl)-2-oxo-1,2-dihydro-quinoline-3-carbonitrile as a yellow solid (0.109 g, 68%. LCMS calc M+H 277, obs M+H 277).
Reaction SMILES: [Li+].[OH-].[N+:3]([CH3:6])([O-:5])=[O:4].[F:7][C:8]([F:13])([F:12])[C:9](=[O:11])[CH3:10].[O-]S([O-])(=O)=O.[Mg+2]>[Cl-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.C(OCC)C.O>[F:7][C:8]([F:13])([F:12])[C:9]([CH3:10])([OH:11])[CH2:6][N+:3]([O-:5])=[O:4]
Reactant: CC(=O)C(F)(F)F
Reactant: C[N+](=O)[O-]
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: CCOCC
Solvent: O
Product: CC(O)(C[N+](=O)[O-])C(F)(F)F
Temperature: 22.5 °C
Reaction time: 48 h

Procedure:
To LiOH (0.193 g, 8.06 mmol) in a 3-neck roundbottom flask was added water (25 ml), nitromethane (3.76 ml, 81 mmol) and trifluoroacetone (7.95 ml, 89 mmol). Cetyltrimethylammonium chloride (3.8 g, 10.88 mmol) and MgSO4 (1.9 g, 16.12 mmol) were added and the resulting yellow solution stirred at 20-25° C. for 2 days. The reaction mixture was poured into diethyl ether (120 ml) and washed with water (3×200 ml) and brine (1×100 ml). The organic portion was dried over MgSO4 and concentrated in vacuo to afford the title compound as a yellow liquid. 1H NMR (CDCl3, 400 MHz): δ 4.7 (1H d), δ 4.5 (1H, d), δ 3.7 (1H, broad), δ 1.6 (3H, s).