Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].CCCCCCC.[S:16](=O)(=[O:19])([OH:18])[OH:17].C(C(CCCC)C([O-])=O)C.[K+:31]>C(OCC)(=O)C>[K+:31].[OH:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[S:16]([O-:19])(=[O:18])=[O:17]
Reactant: O=S(=O)(O)O
Reactant: Oc1ccc(O)cc1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=S(=O)([O-])c1cc(O)ccc1O
Temperature: 12.5 °C
Reaction time: 0.21 h
Yield: 96.6 %

Procedure:
Hydroquinone (20 g, 0.1816 mol) and n-heptane (60 mL) was taken in a round bottom flask, after cooling the flask to about 10-15° C., sulfuric acid (36 N, 17.8 g) was added dropwise at the same temperature and stirring continued further for about 10-15 min. The temperature was slowly raised to 50-60° C. then stirred for 3-8 h. The reaction mass was then cooled to 25-35° C., n-heptane was decanted and ethyl acetate (200 mL) added to dissolve the solid formed. A solution of potassium 2-ethylhexanoate (36.4 g, 0.1996 mol) in ethyl acetate (200 mL) was added slowly. The reaction was further stirred for an hour. The precipitated crude solid was filtered, washed with ethyl acetate to give 40 g of 2,5-dihydroxybenzenesulfonic acid potassium salt.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:4]=2[N:3]=1.[F:12][C:13]([F:27])([F:26])[C:14]1[C:15]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:16][CH:17]=[CH:18][CH:19]=1>>[CH3:11][C:8]1[CH:9]=[CH:10][C:4]2[N:3]=[C:2]([N:23]3[CH2:24][CH2:25][N:20]([C:15]4[C:14]([C:13]([F:27])([F:12])[F:26])=[CH:19][CH:18]=[CH:17][N:16]=4)[CH2:21][CH2:22]3)[NH:6][C:5]=2[CH:7]=1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: Cc1ccc2nc(Cl)[nH]c2c1
Product: Cc1ccc2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1

Procedure:
The reaction of 2-chloro-6-methyl-1H-benzoimidazole (0.261 g, 1.57 mmol, Example14b) with 1-(3-trifluoromethylpyridin-2-yl)piperazine (0.54 g, 1.6 mmol, Maybridge) under the conditions of Example 3c afforded the title compound as a white solid. M.p. 216-217° C. MS (ESI, pos. ion) m/z: 362 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([OH:15])=O)=[CH:7]2)([O-:3])=[O:2].[CH2:16]([NH2:19])[CH2:17][CH3:18].[Cl-].[Na+]>CN(C)C=O.O>[CH2:16]([NH:19][C:13]([C:8]1[NH:9][C:10]2[C:6]([CH:7]=1)=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)=[O:15])[CH2:17][CH3:18]
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: CCCN
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 5-nitro-1H-indole-2-carboxylic acid (6.95 g, 33.7 mmol) in N,N-dimethylformamide (DMF)/pyridine (1/1, 150 ml) N,N′-carbonyl-diimidazole (5.47 g, 33.71 mmol) was added. The mixture was stirred at 80° C. for 1 h. At 0° C. propylamine (9.96 g, 168.56 mmol) was added. The mixture was stirred at 0° C. for 1 h and then at room temperature for 16 h. The solution was diluted with water (2 I). After addition of sodium chloride the product precipitated. After filtration the residue was washed with water and pentane, and dried in a vacuum oven at 50° C. to give the product as a yellow powder.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.[N:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(N(CC)CC)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:17][CH2:18][N:19]([C:32](=[O:33])[C:31]3[CH:30]=[CH:29][C:28]([C:25]4[CH:24]=[CH:23][N:22]=[CH:27][CH:26]=4)=[CH:36][CH:35]=3)[CH2:20][CH2:21]1)(=[O:14])=[O:15])[CH:7]=[CH:6]2
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(-c2ccncc2)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.7 %

Procedure:
To a solution of 1-(6-chloronaphthalene-2-sulfonyl)piperazine hydrochloride (90 mg), 4-(4-pyridyl)benzoic acid (52 mg), triethylamine (35 mg) and HOBt (39 mg) in DMF (10 ml) was added WSC hydrochloride (55 mg) under ice-cooling and the solution was stirred at room temperature 4 hours and concentrated. To the residue was added ethyl acetate and sodium bicarbonate solution. The organic layer was separated, washed with water, and extracted with 1 N hydrochloric acid. The extract was made alkaline with sodium hydroxide solution and extracted with dichloromethane. The extract was dried and concentrated, and the residue was crystallized with ether to give colorless crystals of the title compound (122 mg).
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8].C(O)=[O:11].C([O-])=O.Cl>CC#N.CO>[OH:11][CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8]
Reactant: Cc1oc(=O)oc1CBr
Reactant: O=CO
Agent: Cl
Agent: O=C[O-]
Solvent: CC#N
Solvent: CO
Product: Cc1oc(=O)oc1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
4,5-dimethyl-2-oxo-1,3-dioxole (5 g, 43.82 mmol), NBS (8.19 g, 46.01 mmol), and benzoyl peroxide (20 mg) were dissolved in CCl4 (30 mL) and heated to 80° C. for 1.5 h. The reaction mixture was cooled to r.t and the solid was filtered off. The filtrate was concentrated. The residue was purified by silica gel column to give 8.29 g of 4-bromomethyl-5-methyl-2-oxo-1,3-dioxole as a yellow oil. TEA (12 mL, 86.1 mmol) was added dropwise to a solution of 4-bromomethyl-5-methyl-2-oxo-1,3-dioxole (6 g, 31.09 mmol) and formic acid (3.36 mL) in CH3CN (96 mL) while keeping the temperature under 20° C. The mixture was stirred at r.t. for 2 h and concentrated. The product was partitioned between H2O and EtOAc (3×). The organic layer was dried with Na2SO4, concentrated and dried in vacuo to give crude formate. The resulting formate was dissolved in MeOH (40 mL) and 0.5 mL of concentrated HCl was added. The mixture was stirred at r.t. for 5 h, concentrated, and co-evaporated with toluene. The crude product was purified by silica gel column to give 2.8 g of 4-hydroxymethyl-5-methyl-2-oxo-1,3-dioxole in 69% yield. 1H NMR (300 MHz, CDCl3): d 4.40 (s, 2H), 2.60 (broad, s, 1H), 2.20 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.C1C=CC=CC=1.[CH3:24][CH:25]([N:27]1[C:31]([NH2:32])=[CH:30][CH:29]=[N:28]1)[CH3:26]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:30]3[CH:29]=[N:28][N:27]([CH:25]([CH3:26])[CH3:24])[C:31]=3[N:32]=2)=[CH:4][CH:3]=1
Reactant: CC(C)n1nccc1N
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(Cl)cc1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2)nc2c1cnn2C(C)C

Procedure:
The title compound was prepared in the same manner as described for intermediate 61 using ethyl 4-(4-chlorophenyl)-2,4-dioxobutanoate (610 mg, 2.397 mmol), benzene (5 mL), 1-(1-methylethyl)-1H-pyrazol-5-amine (300 mg, 2.397 mmol), and acetic acid (4 mL). The crude product was purified by column chromatography (Silica gel, eluent: 0 to 100% EtOAc/hexanes) to give 621 mg (75%) of product. LCMS E-S (M+H)=344.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.48-1.57 (m, 3H), 1.64-1.74 (m, 6H), 4.56 (q, J=7.1 Hz, 2H), 5.46 (m, 1H), 7.49-7.55 (m, 2H), 8.15-8.18 (m, 2H), 8.21 (s, 1H), 8.42 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.Cl[S:21]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][N:6]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)[S:21]([C:24]1[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=1)(=[O:23])=[O:22]
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(CNCc2ccc(F)c(F)c2)cc1
Product: COc1ccc(CN(Cc2ccc(F)c(F)c2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-10 from N-(3,4-difluorobenzyl)(4-methoxyphenyl)-methanamine (example 5-36a) and methyl 4-(chlorosulfonyl)benzoate (example 5-10c). MS (M−H, 446); 1H NMR (400 MHz, DMSO-d6): δ ppm: 3.69 (s, 3H), 4.20 (s, 4H), 6.73 (d, J=8.8 Hz, 2H), 6.93 (m, 2H), 6.98 (d, J=8.8 Hz, 2H), 7.22 (m, 1H), 7.74(d, J=8.4 Hz, 2H), 7.99 (d, J=8.4 Hz, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C=O)C>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:15][CH:14]=3)[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: Oc1ccc(N2CCN(c3ccncc3)CC2)cc1
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(N2CCN(c3ccncc3)CC2)cc1
Reaction time: 1 h

Procedure:
A stirred suspension of 4-(4-(4-pyridyl)piperazin-1-yl)-phenol (1.34 g) in dry DMF (20 ml) was treated with sodium hydride (60% dispersion in mineral oil, 0.21 g) and the mixture stirred for 1 hour. To the resulting solution was added ethyl 4-bromobutyrate and the mixture was stirred for 16 hours. Solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water, filtered through phase separating paper (Whatman 1PS) and evaporated. The residue was purified by flash chromatography on silica, eluting with 1-5/92.5/6 v/v/v methanol/ethyl acetate/aqueous ammonia (SG 0.89) and recrystallised from ethyl acetate/hexane to give the title compound (0.7 g) as a solid: m.p. 84°-85° C.; NMR (CDCl3) δ 8.3(2H,d); 6.86(4H,c); 6.72(2H,d); 4.12(2H,q); 4.0(2H,t); 3.47(4H,m); 3.20(4H,m); 2.5(2H,t); 2.1(2H,m); 1.26(3H,t); m/e 370(M+H)+ ; calculated for C21H27N3O3C, 68.3; H, 7.4; N, 11.4. Found: C, 68.1; H, 7.4; N, 11.1%.
Reaction SMILES: [F:1][C:2]1([F:27])[CH2:5][N:4]([C:6]2[N:14]=[C:13]([N:15]3[C:19]4[CH:20]=[C:21]([C:24]#[N:25])[CH:22]=[CH:23][C:18]=4[N:17]=[CH:16]3)[N:12]=[C:11]3[C:7]=2[NH:8][C:9](=[O:26])[NH:10]3)[CH2:3]1.[O:28]1[CH2:32][CH2:31][CH:30]([CH2:33]O)[CH2:29]1>C(Cl)(Cl)Cl>[F:27][C:2]1([F:1])[CH2:3][N:4]([C:6]2[N:14]=[C:13]([N:15]3[C:19]4[CH:20]=[C:21]([C:24]#[N:25])[CH:22]=[CH:23][C:18]=4[N:17]=[CH:16]3)[N:12]=[C:11]3[C:7]=2[NH:8][C:9](=[O:26])[N:10]3[CH2:33][CH:30]2[CH2:31][CH2:32][O:28][CH2:29]2)[CH2:5]1
Reactant: N#Cc1ccc2ncn(-c3nc(N4CC(F)(F)C4)c4[nH]c(=O)[nH]c4n3)c2c1
Reactant: OCC1CCOC1
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc2ncn(-c3nc(N4CC(F)(F)C4)c4[nH]c(=O)n(CC5CCOC5)c4n3)c2c1
Yield: 18 %

Procedure:
White solid. 18% yield. Synthesized from 3-(6-(3,3-difluoroazetidin-1-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)-3H-benzo[d]imidazole-5-carbonitrile (0.12 mmol) and tetrahydro-3-furan-methanol following the general procedure for diversifying at the N9 position of the purinones based on a Mitsunobu reaction. 1H NMR (300 MHz, CDCl3+CD3OD) δ, ppm: 9.22 (s, 1H), 8.99 (s, 1H), 7.89 (d, 1H), 7.67 (d, 1H), 4.76 (t, 4H), 4.10-3.97 (m, 3H), 3.90-3.77 (m, 3H), 3.06-2.93 (m, 1H), 2.22-2.07 (m, 1H), 1.90-1.83 (m, 1H); IR (CHCl3), cm−1: 2979 (w), 1703 (s), 1367 (m), 1167 (m); MS (EI) m/z 453.1 (MH)+.
Reaction SMILES: N1CCOCC1.[CH3:7][C:8]1([O:11][CH2:10]1)[CH3:9].[Br:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2([C:25]#[N:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:17][CH:18]=1.C(=O)(O)[O-].[Na+]>O>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2([C:25]#[N:26])[CH2:20][CH2:21][N:22]([CH2:10][C:8]([OH:11])([CH3:9])[CH3:7])[CH2:23][CH2:24]2)=[N:17][CH:18]=1
Reactant: N#CC1(c2ccc(Br)cn2)CCNCC1
Reactant: CC1(C)CO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCN1
Product: CC(C)(O)CN1CCC(C#N)(c2ccc(Br)cn2)CC1
Temperature: 100 °C
Reaction time: 4.5 h
Yield: 91.4 %

Procedure:
Morpholine (catalytic amount) and isobutylene oxide (2.84 g) were added to 4-(5-bromopyridin-2-yl)piperidine-4-carbonitrile (3.4 g) of Reference Example 88(2) and water (35 ml), and the mixture was stirred at 100° C. for 4.5 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated brine dried over anhydrous sodium sulfate and concentrated in vacuo. Water was added to the residue and the precipitated solid was washed with water to give 4-(5-bromopyridin-2-yl)-1-(2-hydroxy-2-methylpropyl)piperidine-4-carbonitrile (3.95 g) as a light brown solid.
Reaction SMILES: [CH3:1]C1(C)[C@@H]2O[C@@H]2C2C=C(C#N)C=CC=2O1.[C:16]([C:18]1[CH:19]=[CH:20][C:21]2[O:26][C:25]([CH3:28])([CH3:27])[C@H:24]([OH:29])[C@@H:23]([N:30]([CH2:37][C:38]([O:40][CH2:41]C)=[O:39])C3C=CC=CC=3)[C:22]=2[CH:43]=1)#[N:17]>>[CH3:41][O:40][CH:38]([O:39][CH3:1])[CH2:37][NH:30][C@H:23]1[C:22]2[CH:43]=[C:18]([C:16]#[N:17])[CH:19]=[CH:20][C:21]=2[O:26][C:25]([CH3:27])([CH3:28])[C@@H:24]1[OH:29]
Reactant: CCOC(=O)CN(c1ccccc1)[C@H]1c2cc(C#N)ccc2OC(C)(C)[C@@H]1O
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@H]2O[C@H]21
Product: COC(CN[C@H]1c2cc(C#N)ccc2OC(C)(C)[C@@H]1O)OC
Yield: 90 %

Procedure:
A mixture of (1aR-cis)-1a,7b-dihydro-2,2-dimethyl-2H-oxireno-[c][1]benzopyran-6-carbonitrile (750 mg, 3.73 mmol, the title A compound of Example 3), dimethyl aminoacetal (1.2 mL) was heated in a sealed tube at 75° C. for two days. The reaction mixture was purified by flash column chromatography (ethyl acetate and hexane, 1:1) to give a colorless oil (1.0 g, 90%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:10]([CH3:17])([CH3:16])[CH:9]=2)=[CH:4][C:3]=1[CH3:18].[O:19]1COCO[CH2:20]1.S(=O)(=O)(O)O>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:14])([CH3:15])[CH2:11][C:10]([CH3:17])([CH3:16])[C:9]=2[CH:20]=[O:19])=[CH:4][C:3]=1[CH3:18]
Reactant: C1OCOCO1
Reactant: Cc1cc(C2=CC(C)(C)CC(C)(C)C2)ccc1F
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1cc(C2=C(C=O)C(C)(C)CC(C)(C)C2)ccc1F
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 200 g of glacial acetic-acid, 200 g of 1-fluoro-2-methyl-4-(3,3,5,5-tetramethyl-1-cyclohexen-1-yl)benzene and 35.4 g of 1,3,5-trioxane, a catalytic quantity (4.0 g) of concentrated sulfuric acid was added and the batch was heated to 106°-110° C. for 11/4 hours. The mixture was then cooled to 30° C. and partitioned between 100 ml of water and 200 ml of heptane. The bottom layer was discarded and to the remaining solution 100 ml of methanol was added. A solution of 96 g of 85% potassium hydroxide in 100 ml of water was then added and the reaction mixture was heated to 68°-72° C. for 13/4 hours. The batch was then cooled to 30° C. and the phases were allowed to separate. The bottom layer was discarded and the top layer was concentrated in vacuo until 25% of the total volume was distilled off. The remaining solution was diluted with 100 ml of heptane and 182 g of triethylamine. To the resulting mixture, a solution of 324 g of sulfur trioxide/pyridine complex in 535 g of dimethyl sulfoxide and 78.3 g of triethylamine was added at 30°-35° C. The batch was stirred at 30°-35° C. for 1/2 hour, then cooled to about 20° C. and quenched with 600 g of iced water. The phases were allowed to separate and the bottom layer was discarded. The top layer was diluted with 100 ml of methanol and 50% sodium hydroxide solution (90 g) was added. The reaction mixture was stirred for 11/2 hours at 30°-34° C. Water (100 ml) was added and the phases were allowed to separate at room temperature. The bottom layer was discarded and the top solution was concentrated in vacuo to remove the solvent. The residue was dissolved in 200 ml of ethanol, the solution was cooled to about 3° C., seeded and the product was allowed to crystallize overnight. The solids were filtered off, washed with 80 ml of cold ethanol and dried to constant weight. Yield: 100 g of 2-(4-fluoro-3-methylphenyl)-4,4,6,6-tetramethylcyclohex-1-enecarboxaldehyde; m.p. 50.5°-51.5° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[CH:23](B(O)O)=[CH2:24].C([O-])([O-])=O.[K+].[K+]>O.O1CCOCC1.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>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([CH:23]=[CH2:24])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CB(O)O
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F
Temperature: 100 °C
Yield: 37 %

Procedure:
A suspension of (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example A1) (6.8 g, 20 mmol), vinyl boronic acid [CAS-No. 4363-34-2] {Bull. Soc. Chim. Fr. 1966, (8), 2557-64} (4.312 g, 60 mmol) and K2CO3 (8.29 g, 60 mmol) in water (10 mL) and dioxane (50 mL) was purged by Ar-stream at 23° C. for 10 min, then tetrakis(triphenylphosphine)palladium(0) (693 mg, 0.6 mmol) was added and the mixture was heated to 100° C. for 20 h, filtered, evaporated and purified by column chromatography on silica gel (hexane/ethyl acetate 9:1) to yield a light yellow solid (2.476 g, 37%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[C:5]#[N:6].[CH2:12]([Sn](CC)(CC)CC)[CH3:13].[Cl-].[Li+]>CN(C=O)C>[CH2:12]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[C:5]#[N:6])[CH3:13]
Reactant: COc1ccc(C#N)cc1Br
Reactant: CC[Sn](CC)(CC)CC
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCc1cc(C#N)ccc1OC
Temperature: 135 °C

Procedure:
To a solution of 3-bromo-4-methoxybenzonitrile (8-1, 0.3 g, 1.42 mmol) in DMF (14 mL) was added tetraethyl tin (0.56 mL, 2.83 mmol), bis-tri-t-butylphosphine palladium (0.072 g, 0.141 mmol), and lithium chloride (0.18 g, 4.24 mmol) and the system was heated to 135° C. for 30 minutes in a microwave reactor. The mixture was partitioned between saturated NaHCO3 and EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by gradient elution on silica gel (0 to 10% EtOAc in hexanes) to yield the desired product (8-2) as a clear oil. ESI+ MS [M+H]+ C10H11NO: 162.1 found, 162.2 required.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.FBF.[NH:25]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH2:36][NH2:37])[CH2:26]1>>[NH2:37][CH2:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH:27]1[CH2:28][CH2:29][N:25]([C:11]2[C:12]([O:14][CH3:15])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:17])[CH2:26]1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: NCc1ccccc1C1CCNC1
Agent: FBF
Product: COc1c(N2CCC(c3ccccc3CN)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
Starting from difluoroborane 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylate (1.13 g, 3.3 mmol) and 2-(3-pyrrolidinyl ) benzenemethanamine, a procedure analogous to that given in Example 1, provided the fluoroborate ester of the title compound.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[Cl:17][C:18]1[CH:19]=[C:20](/[CH:25]=[CH:26]/[C:27]#[N:28])[CH:21]=[CH:22][C:23]=1[Cl:24].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:10]([N:4]1[CH2:5][CH:25]([C:20]2[CH:21]=[CH:22][C:23]([Cl:24])=[C:18]([Cl:17])[CH:19]=2)[CH:26]([C:27]#[N:28])[CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#C/C=C/c1ccc(Cl)c(Cl)c1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 72.9 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (10.25 g, 43 mmol) in CH2Cl2 (55 mL) was added dropwise, over a 30 minutes period, to a stirred solution of (E)-3-(3,4-dichloro-phenyl)-acrylnitrile (5.70 g, 29 mmol) and trifluoroacetic acid (0.22 mL, 3 mmol) in CH2Cl2 (10 mL) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO2, CH2Cl2) afforded the title compound (7.0 g, 73%) as a colorless oil. ES-MS m/e: 332.3 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25](=[O:38])[C@H:26]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][C:28]#[CH:29].COC(=O)C(NC(OC(C)(C)C)=O)CC#C>C1COCC1.C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:23][O:24][C:25](=[O:38])[C@H:26]([NH:30][C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:27][C:28]#[C:29][C:18]1[CH:19]=[CH:20][C:15]([C:14]#[C:13][CH2:12][CH2:11][NH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:22])=[CH:16][CH:17]=1
Reactant: C#CC[C@@H](NC(=O)OC(C)(C)C)C(=O)OC
Reactant: O=C(NCCC#Cc1ccc(I)cc1)OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#CCC(NC(=O)OC(C)(C)C)C(=O)OC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@@H](CC#Cc1ccc(C#CCCNC(=O)OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
Compound 210, [4-(4-iodophenyl)-but-3-ynyl]carbamic acid benzyl ester (0.52 g, 1.283 mmol) was dissolved in a mixture of anhydrous THF and triethylamine (8 mL, 1/1, v/v). To the solution was added copper (I) iodide (0.025 g, 0.128 mmol). The mixture was stirred at room temperature for 15 min. The flask was then evacuated and re-filled with Argon. The procedure was repeated three more times to ensure no oxygen remained. The catalyst, dichlorobis(triphenylphosphine)palladium(II) (0.09 g, 0.128 mmol) was added into the mixture under Argon protection. The mixture was further stirred at room temperature for 30 min. The other starting material 220, 2-tert-butoxycarbonylamino-pent-4-ynoic acid methyl ester (0.32 g, 1.412 mmol), dissolved in THF (4 mL) was added dropwise over 15 min. The newly formed reaction mixture was further stirred overnight at room temperature. The solid in the reaction mixture was vacuum filtered. The filtrate was concentrated. The residue was re-dissolved in dichloromethane and purified by column chromatography, eluting with a mixture of ethyl acetate (0-25%) and hexanes (100-75%) to afford the product 230 (0.64 g, 99%) as a gummy, yellowish solid. 1H NMR (300 MHz, CDCl3): δ 1.46 (s, 9H), 2.64 (t, J=6.3 Hz, 2H), 2.95 (t, J=4.1 Hz, 2H), 3.42 (m, 2H), 3.79 (s, 3H), 4.56 (m, 1H), 5.12 (s, 2H), 5.38 (br s, 11), 7.29 (s, 4H), 7.35 (m, 5H). m/z (APCI) 502 [C29H32N2O6—H]+.