Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.[OH-].[Na+].[CH3:13][C:14]([CH3:16])=[O:15]>O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1/[CH:4]=[CH:13]/[C:14](=[O:15])[CH3:16]
Reactant: O=Cc1c(F)cccc1F
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)/C=C/c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 100ml reaction bottle equipped with magnetic stir bar was charged 5.0 g (35.2 mmole) of 2,6-difluorobenzaldehyde in 20 ml acetone and to this was added 3.4 g of 50% aqueous NaOH (42 mmole) in 60 ml water (exothermic) and stirred at room temperature. The reaction was monitored by GLC and after 2 hours the reaction was worked up. The reaction mixture was extracted with 50 ml CHCl3, washed with 50 ml H2O, dried over anhydrous MgSO4, filtered, and the solvent removed in vacuuo on a rotary evaporator to afford 5.7 g of trans-4-(2,6-difluorophenyl)-3-buten-2-one as a yellow oil in 81% purity by GC. and 89.5% isolated yield.
Reaction SMILES: [C:1]([O-])(=O)C.[Na+].[NH2:6][C:7]1[CH:8]=[C:9]([C:20]2[CH:21]=[N:22][C:23]([N:26]3[CH2:31][CH2:30][C:29]([CH2:37][CH3:38])([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH2:27]3)=[N:24][CH:25]=2)[CH:10]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:12]=1[NH2:13].[CH2:39]([N:41](CC)[C:42]([NH2:44])=[O:43])[CH3:40].[N+](C1C=CC(CSC(=N)N)=CC=1)([O-])=O>O.S(=O)(=O)(O)O.COCCOC>[CH2:37]([C:29]1([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:30][CH2:31][N:26]([C:23]2[N:22]=[CH:21][C:20]([C:9]3[CH:10]=[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)[C:12]4[NH:13][C:1]([NH:44][C:42]([NH:41][CH2:39][CH3:40])=[O:43])=[N:6][C:7]=4[CH:8]=3)=[CH:25][N:24]=2)[CH2:27][CH2:28]1)[CH3:38]
Reactant: CCOC(=O)C1(CC)CCN(c2ncc(-c3cc(N)c(N)c(-c4ccccn4)c3)cn2)CC1
Reactant: CC(=O)[O-]
Reactant: CCN(CC)C(N)=O
Agent: N=C(N)SCc1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)OCC)CC4)nc3)cc(-c3ccccn3)c2[nH]1
Temperature: 80 °C
Yield: 59.9 %

Procedure:
To a solution of sodium acetate (0.606 g, 7.38 mmol) in water (8.0 mL), concentrated sulphuric acid was added dropwise till pH ˜3.5 followed by addition of ethyl 1-(5-(3,4-diamino-5-(pyridin-2-yl)phenyl)pyrimidin-2-yl)-4-ethylpiperidine-4-carboxylate (0.55 g, 1.23 mmol) to get a yellow suspension. The solution of N,N-diethylurea-2-(4-nitrobenzyl)-2-thiopseudourea (0.454 g, 1.23 mmol) in DME (15.0 mL) was added to the resulting mixture. The homogenous mixture was stirred and heated to 80° C. for 5 h. After completion the reaction (by TLC), the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue thus obtained was triturated with water, EtOAc and Et2O respectively obtain the product (0.40 g, 60%). 1H NMR (TFA-d1): δ 10.03 (br s, 1H), 9.91 (s, 1H), 9.86 (m, 1H), 9.47 (m, 1H), 9.27 (m, 2H), 8.96 (s, 1H), 5.57 (m, 2H), 5.43 (q, J=7.20 Hz, 2H), 5.09 (m, 4H), 4.84 (m, 2H), 4.62 (q, J=7.20 Hz, 2H), 3.59 (m, 2H), 2.76-2.83 (m, 4H), 2.44 (t, J=7.20 Hz, 3H), 2.32 (t, J=7.20 Hz, 3H) and 1.98 (t, J=7.60 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[S:6][CH:5]=[N:4][CH:3]=1.[O:7]1CCO[CH2:9][CH2:8]1.[Br:13]CCO>CC(C)=O>[Br-:13].[OH:7][CH2:8][CH2:9][N+:4]1[CH:3]=[C:2]([CH3:1])[S:6][CH:5]=1
Reactant: OCCBr
Reactant: Cc1cncs1
Reactant: C1COCCO1
Solvent: CC(C)=O
Product: Cc1c[n+](CCO)cs1
Product: [Br-]
Reaction time: 0.5 h

Procedure:
To the mixture of 5-methylthiazole (10 g) and dioxane (20 ml) was added 2-bromoethanol (15 g), and the resulting mixture was heated under reflux for 4 hours. To the mixture left standing at room temperature for about 0.5 hour was added acetone (100 ml) with stirring to crystallize pale yellow solids. The supernatant was discarded, and acetone (50 ml) and ether (150 ml) were added with stirring to give white to pale yellow solids, which were collected by filtration, washed with ether and dried under reduced pressure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH2:19]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:13][CH2:19][CH:18]([O:21][CH3:22])[O:17][CH3:16])=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(CBr)OC
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(CNc1ccc(OCc2ccccc2)cc1)OC
Temperature: 100 °C

Procedure:
A mixture of 4-benzyloxyaniline (10 g), bromoacetaldehyde dimethyl acetal (12.2 g), potassium carbonate (13.8 g) and dimethylformamide (150 mL) was heated at 100° C. for 5 hours. After cooling, the reaction solution was filtered and concentrated. The residue was purified by MPLC (eluent: heptane/ethyl acetate 4:1). The product with the molecular weight of 287.36 (C17H21NO3); MS (ESI): 288 ([M+H]+), was obtained in this way.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].I[C:27]1[CH:28]=[C:29]([C:34]([F:37])([F:36])[F:35])[C:30]([NH2:33])=[N:31][CH:32]=1>>[F:37][C:34]([F:35])([F:36])[C:29]1[C:30]([NH2:33])=[N:31][CH:32]=[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:28]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1ncc(I)cc1C(F)(F)F
Product: Nc1ncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1C(F)(F)F

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl -5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 g, 1.0 mmol) and 5-iodo-3-trifluoromethyl-pyridin-2-ylamine (example B.48) (288 mg, 1.0 mmol) according to general procedure II. Obtained as an off-white solid (370 mg, 72%). MS (ISP) 516.2 [(M+H)+]; mp 230° C.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[O:18]C)(=[O:8])=[O:7])[CH3:3].B(Br)(Br)Br.CO.C(OC(C)C)(C)C>C(Cl)Cl>[CH3:3][N:2]([CH:4]=[N:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[OH:18])(=[O:7])=[O:8])[CH3:1]
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)N=CN(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Solvent: CC(C)OC(C)C
Product: CN(C)C=NS(=O)(=O)c1ccc([N+](=O)[O-])cc1O
Reaction time: 5 h

Procedure:
A solution of 2.82 g (9.8 mmol) of N-dimethylaminomethylene-2-methoxy-4-nitro-benzenesulfonamide in 70 ml of DCM is mixed slowly at room temperature with 13 ml of a 1 molar solution of boron tribromide in DCM. After 5 hours, 3 ml of the 1 molar solution of boron tribromide in DCM is added again, and it is stirred for another 16 hours. The batch is mixed with MeOH and diisopropyl ether. The precipitate that is formed is suctioned off, washed with EtOH and diisopropyl ether and dried. 1.94 g (7.1 mmol, corresponding to 72% of theory) of the product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:9])[C:5](F)=[N:6][CH:7]=1.[C:10]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([O:18][CH2:19][CH3:20])=[O:17])=[N:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Fc1cc(Cl)cnc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1ncc(Cl)cc1F
Temperature: 110 °C
Reaction time: 4.5 h
Yield: 78.2 %

Procedure:
A mixture of 3.85 g of 5-chloro-2,3-difluoropyridine, 8.80 g of diethyl malonate, 25 ml of dimethyl sulfoxide and 17.9 g of cesium carbonate was stirred for 4.5 hours at 110° C. under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, then, to this was added ice water, and extracted with ethyl acetate. The organic layer was washed with saturated brine twice, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure, to obtain 5.83 g of diethyl (5-chloro-3-fluoro-2-pyridyl)malonate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[N:4][N:5]([CH2:8][C:9]([OH:11])=O)[C:6]=1[CH3:7].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:47][C:48]1[CH:53]=[CH:52][C:51]([N:54]2[C:62]3[CH2:61][CH2:60][CH:59]([C:63]([O:65][CH3:66])=[O:64])[NH:58][C:57]=3[CH:56]=[N:55]2)=[CH:50][CH:49]=1>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[N:4][N:5]([CH2:8][C:9]([N:58]2[CH:59]([C:63]([O:65][CH3:66])=[O:64])[CH2:60][CH2:61][C:62]3[N:54]([C:51]4[CH:50]=[CH:49][C:48]([F:47])=[CH:53][CH:52]=4)[N:55]=[CH:56][C:57]2=3)=[O:11])[C:6]=1[CH3:7]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: COC(=O)C1CCc2c(cnn2-c2ccc(F)cc2)N1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C1CCc2c(cnn2-c2ccc(F)cc2)N1C(=O)Cn1nc(C(F)(F)F)c(Cl)c1C
Temperature: 80 °C
Reaction time: 5 h
Yield: 11 %

Procedure:
To a solution of 2-[4-chloro-5-methyl-3-(trifluoromethyl)pyrazol-1-yl]acetic acid (20 mg, 0.073 mmol) in DMF (2 mL) was added Et3N (50 μL, 0.219 mmol), HATU (55 mg, 0.145 mmol) followed by methyl 1-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[4,3-b]pyridine-5-carboxylate (20 mg, 0.073 mmol) at room temperature. The resulting solution was then stirred at 80° C. for 5 h. The reaction mixture was then cooled to room temperature, H2O (10 mL) was added and the mixture was extracted with EtOAc (2×15 mL). The combined EtOAc layers were dried (MgSO4), filtered, concentrated in vacuo and the resulting crude product was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the desired product as white powder (0.004 g, 0.008 mmol, 7%). 1H NMR (400 MHz, CD3OD) δ 8.28 (s, 1H), 7.52 (2H, dd, J=5, 9 Hz), 7.26 (2H, t, 8.6, J=17.2 Hz), 5.3 (2H, dd, J=17.2, 69.2 Hz), 3.83 (s, 3H), 2.80-2.82 (m, 2H), 2.29 (s, 3H), 2.15-2.17 (m, 2H); MS: (ES) m/z calculated for C21H18ClF4N5O3 [M+H]+ 500.1, found 500.1.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19]>CN(C=O)C>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: C=CCCCBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCCC(C(=O)OCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 14 h
Yield: 101.1 %

Procedure:
A mixture of sodium hydride (60% in mineral oil, 2.4 g, 60.5 mmol, 1.1 eq) and diethyl malonate (8.34 mL, 55 mmol, 1 eq) in DMF (200 mL) was cooled to 0° C. and 5-bromo-1-pentene (6.5 mL, 55 mmol, 1 eq) was added dropwise. The reaction mixture was warmed to rt, stirred for 14 hours and then partitioned between ether and water. The layers were separated, the aqueous layer was extracted with ether (2×250 mL) and the combined organic phases were washed with water (2×) and brine, dried over MgSO4 and concentrated to give E1.1 as a colorless oil (12.7 g, 100% yield). 1H NMR (400 MHz, CDCl3): δ 5.71 (m, 1 H), 4.92 (m, 2 H), 4.12 (q, J=7.1 Hz, 4 H), 3.25 (t, J=7.58 Hz, 1 H), 2.01 (m, 2 H), 1.83 (m, 2 H), 1.36 (m, 2 H), 1.20 (t, J=7.1 Hz, 6 H).
Reaction SMILES: [F:1][C:2]([F:17])([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)[C:3](OC)=O.[CH3:18][C:19]1[CH:23]=[C:22]([C:24]2[N:29]=[N:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=2)[S:21][N:20]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1.CCOC(C)=O>[F:1][C:2]([F:17])([C:3]1[N:28]2[N:29]=[C:24]([C:22]3[S:21][N:20]=[C:19]([CH3:18])[CH:23]=3)[CH:25]=[CH:26][C:27]2=[N:30][N:31]=1)[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2
Reactant: COC(=O)C(F)(F)c1ccc2ncccc2c1
Reactant: Cc1cc(-c2ccc(NN)nn2)sn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc3nnc(C(F)(F)c4ccc5ncccc5c4)n3n2)sn1
Temperature: 150 °C

Procedure:
A mixture of methyl 2,2-difluoro-2-(quinolin-6-yl)acetate (0.50 g, 2.1 mmol), 1-(6-(3-methylisothiazol-5-yl)pyridazin-3-yl)hydrazine (0.25 g, 1.2 mmol) and p-toluenesulfonic acid monohydrate (0.40 g, 2.1 mmol) in 5 mL of dioxane was heated at 150° C. for 1 hour in a microwave. The mixture was then diluted with 70 mL of EtOAc and 40 mL of satd. NaHCO3 solution. The organic phase was separated and washed with 40 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc to 10% MeOH/EtOAc) to give yellow glass. The product was further purified by a prep-HPLC to give yellow glass. MS (ESI pos. ion) m/z: 395 (MH+). Calc'd exact mass for C19H12F2N6S: 394.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][N:14]([CH3:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][C:22]([OH:24])=O.Cl.[Cl:27][C@H:28]1[C@@H:36]2[C@@H:32]([CH2:33][NH:34][CH2:35]2)[C:31]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:30][CH2:29]1.Cl>ClCCl.C(OCC)C.C(N(CC)CC)C>[ClH:27].[Cl:27][C@H:28]1[C@@H:36]2[C@@H:32]([CH2:33][N:34]([C:22](=[O:24])[CH2:21][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]([CH3:13])[CH3:25])[CH2:35]2)[C:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:30][CH2:29]1
Reactant: CN(C)c1ccccc1CC(=O)O
Reactant: Cl[C@@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: CN(C)c1ccccc1CC(=O)N1C[C@@H]2[C@H](Cl)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Temperature: 4 °C
Reaction time: 1 h
Yield: 54.7 %

Procedure:
0.17 g of carbonyldiimidazole is added to a solution, cooled to +4° C. of 0.19 g of (2-dimethylaminophenyl)acetic acid in 15 cm3 of dry dichloromethane. The mixture is stirred for one hour at 4° C. and then a solution of 0.35 g of (3aR, 7R,7aR)-7-chloro-4,4-diphenylperhydroisoindole hydrochloride in 10 cm3 of dry dichloromethane is added followed by a solution of 0.15 cm3 of triethylamine in 10 cm3 of dry dichloromethane. The reaction mixture is stirred at room temperature for 20 hours and then diluted with 120 cm3 of dichloromethane, washed with 80 cm3 of water and then with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 22 cm), eluting under a nitrogen pressure of 0.4 bar with an ethyl acetate and cyclohexane mixture (75/25 by volume) and collecting fractions of 20 cm3. Fractions 6 to 9 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The product, which is obtained in the form of a base, is converted to the hydrochloride by dissolving in 25 cm3 of ethyl ether, followed by the addition of 5 cm3 of a 3.2N solution of hydrochloric acid in ethyl ether, washing with ethyl ether and drying. 0.14 g of (3aR, 7R,7aR)-7-chloro-2-[(2-dimethylaminophenyl)acetyl]-4,4diphenylperhydroisoindole hydrochloride is obtained in the form of white crystals; melting point 190° C.
Reaction SMILES: Br[C:2]1[C:3]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][O:5][CH:6]=1.[CH2:13]([SH:17])[CH2:14][CH2:15][CH3:16].C(N(CC)CC)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:13]([S:17][C:2]1[C:3]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][O:5][CH:6]=1)[CH2:14][CH2:15][CH3:16]
Reactant: Brc1conc1-c1cccnc1
Reactant: CCCCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCCSc1conc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
To a degassed solution of dioxane (40 ml) containing 64 (1.0 g, 4.44 mmol), were added 1.2 eq (0.62 ml) of butane-1-thiol and 2 eq of triethylamine (1.52 ml). The resulting mixture was stirred for another 2 hours under N2. Successively were added 2.5 mol % of Pd2(dba)3 (100 mg) and 5 mol % of Xantphos (128 mg). After the addition, the resulting solution was stirred for 18 hours at 95° C. under N2. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether) to afford 3-(4-butylsulfanyl-isoxazol-3-yl)-pyridine (65A) as an oil (0.26 g, 25%). (TLC diethyl ether Rf 0.54). 1H-NMR (400 MHz, CDCl3): δ 9.24 (d, J=2 Hz, 1H), 8.72 (dd, J=5 Hz, 2 Hz, 1H), 8.49 (s, 1H), 8.31 (dt, J=8 Hz, 2 Hz, 1H), 7.45-7.41 (m, 1H), 2.61 (t, J=7 Hz, 2H), 1.52-1.43 (m, 2H), 1.39-1.29 (m, 2H), 0.83 (t, J=7 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[CH2:13]([O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][NH:22][CH2:23][C:24]2[O:25][CH:26]=[CH:27][CH:28]=2)=[CH:19][CH:18]=1)[CH2:14][CH3:15].C(N(CC)CC)C>C(Cl)Cl.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:22]([CH2:21][C:20]2[CH:19]=[CH:18][C:17]([O:16][CH2:13][CH2:14][CH3:15])=[CH:30][CH:29]=2)[CH2:23][C:24]2[O:25][CH:26]=[CH:27][CH:28]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCCOc1ccc(CNCc2ccco2)cc1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOc1ccc(CN(Cc2ccco2)S(=O)(=O)c2ccc(C#N)cc2)cc1
Reaction time: 2 h
Yield: 42 %

Procedure:
4-cyanobenzene-1-sulfonyl chloride (600 mg, 2.9 mmol) was added to a stirring solution of N-(4-propoxybenzyl)-1-(furan-2-yl)methanamine (Example 5-8b) (685 mg, 2.9 mmol) and triethylamine (455 mg, 4.5 mmol) in DCM (100 mL) and the reaction was stirred for 2 hours. The reaction was diluted with H2O (200 mL) and extracted with DCM (3×, 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated on the rotovap. The residue was purified by silica gel chromatography (10% ethyl acetate in hexanes) to afford 4-cyano-N-(4-propoxybenzyl)-N-(furan-2-ylmethyl)benzenesulfonamide (500 mg, 50%) as an off white solid. NMR (DMSO-d6, 400 MHz): δ 0.95 (t, J=7.2 Hz, 3H), 1.70 (m, J=6.4 Hz, 2H), 3.88 (t, J=6.4 Hz, 2H), 4.25 (s, 2H), 4.28 (s, 2H), 6.15 (d, J=3.2 Hz, 1H), 6.27 (m, 1H), 6.84 (d, J=6.8 Hz, 2H), 7.11 (d, J=8.8 Hz, 2H), 7.39 (m, 1H), 7.93 (d, J=6.4 Hz, 2H), 8.01 (d, J=6.4 Hz, 2H).
Reaction SMILES: [F:1][CH2:2][C:3]([NH:5][C:6]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[CH3:18])=[O:9])=O.B(F)(F)F.CCOCC>C(O)(=O)C>[F:1][CH2:2][C:3]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=2[CH3:18])[C:8](=[O:9])[C:7]2[C:6](=[CH:22][CH:21]=[C:20]([N+:23]([O-:25])=[O:24])[CH:19]=2)[N:5]=1
Reactant: Cc1cccc(NC(=O)c2cc([N+](=O)[O-])ccc2NC(=O)CF)c1C
Agent: FB(F)F
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1cccc(-n2c(CF)nc3ccc([N+](=O)[O-])cc3c2=O)c1C
Yield: 84.4 %

Procedure:
3.5 g of N-(2-fluoroacetamido-5-nitrobenzoyl)-2,3-dimethylaniline, 3.0 g of boron trifluoride etherate and 30 ml of acetic acid are treated in the same manner as described in Example 1-(2), whereby 2.8 g of 2-fluoromethyl-3-(2,3-dimethylphenyl)-6-nitro-4(3H)-quinazolinone are obtained as yellow prisms.
Reaction SMILES: [C:1]([C:3]1[C:4]2[N:13]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:12]=[C:11]([NH:19][C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([O:25]C)=[O:24])[C:5]=2[C:6]([O:9][CH3:10])=[N:7][CH:8]=1)#[N:2].CO.C1COCC1.[OH-].[Na+]>O>[C:1]([C:3]1[C:4]2[N:13]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:12]=[C:11]([NH:19][C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([OH:25])=[O:24])[C:5]=2[C:6]([O:9][CH3:10])=[N:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1cccc(Nc2cn(C3CCCC3)c3c(C#N)cnc(OC)c23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ncc(C#N)c2c1c(Nc1cccc(C(=O)O)c1)cn2C1CCCC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 92.2 %

Procedure:
To a mixture of methyl 3-((7-cyano-1-cyclopentyl-4-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl)amino)benzoate (90 mg) in a mixed solvent of methanol (1 mL) and THF (1 mL) was added 8N aqueous sodium hydroxide solution (0.288 mL), and the mixture was stirred at 80° C. for 4 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The aqueous layer was neutralized with 1N hydrochloric acid at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (80 mg).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl.[C:10]([O-:13])([O-])=O.[K+].[K+].ClC(O[CH2:20][CH3:21])=O>C1COCC1>[CH2:20]([C:10]([N:5]1[CH2:6][CH2:7][CH2:8][C:2](=[O:1])[CH2:3][CH2:4]1)=[O:13])[CH3:21]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)Cl
Reactant: O=C1CCCNCC1
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCC(=O)N1CCCC(=O)CC1
Temperature: 25 °C

Procedure:
To a cold (0° C.) stirred solution of 4-oxohomopiperidine.HCl (0.6 g, 4.05 mmol), K2CO3 (0.615 g, 4.46 mmol) in anhydrous THF (10 mL) will be ethyl chloroformate (0.44 mL, 4.05 mmol) dropwise. The reaction was warmed to RT for 2 hrs then quenched with H2O, extracted with EtOAc, and the organic layer dried over Na2SO4. Pure 1-ethylcarbonyl-4-oxohomopiperidine will be isolated via silica gel flash chromatography
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.FC1C=C([N+]([O-])=O)C=CC=1OC1C2SC(C(NCCN3CCOCC3)=O)=CC=2N=CN=1.[Cl:42][C:43]1[CH:44]=[C:45]([OH:52])[CH:46]=[CH:47][C:48]=1[N+:49]([O-:51])=[O:50]>>[Cl:42][C:43]1[CH:44]=[C:45]([CH:46]=[CH:47][C:48]=1[N+:49]([O-:51])=[O:50])[O:52][C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1Cl
Reactant: Clc1ncnc2ccsc12
Agent: O=C(NCCN1CCOCC1)c1cc2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Product: O=[N+]([O-])c1ccc(Oc2ncnc3ccsc23)cc1Cl
Yield: 72 %

Procedure:
Starting from the chloride 20 (scheme 4) and following the procedure described above for the synthesis of compound 24 (scheme 4, example 22) replacing 2-fluoro-4-nitrophenol with 3-chloro-4-nitrophenol, title compound 171 was obtained in 72% yield. LRMS (M+1) 307.7 (100%).
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[F:23][C:24]1[CH:25]=[C:26]([CH:31]([OH:35])[C:32](O)=[O:33])[CH:27]=[C:28]([F:30])[CH:29]=1>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][C:32](=[O:33])[CH:31]([C:26]2[CH:27]=[C:28]([F:30])[CH:29]=[C:24]([F:23])[CH:25]=2)[OH:35])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: O=C(O)C(O)c1cc(F)cc(F)c1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Product: CCCC(NC(=O)C(O)c1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was coupled with (3,5-Difluoro-phenyl)-hydroxy-acetic acid to afford the title compound: MS m/z 478.3 (M+1); Diastereomers were separated using a S,S-Whelk-O1 column (5 cm×25 cm), eluting with 70:30 heptane:iPrOH at a flow rate of 110 mL/min.