Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]N(C)C=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH:16]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[H-].[Na+].CI>CCCCCC.O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([C:16]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[CH3:1])(=[O:14])=[O:15])=[CH:9][CH:8]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CI
Product: Cc1ccc(C(C)(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Reaction time: 0.25 h
Yield: 93 %

Procedure:
An N,N-dimethylformamide (5 ml) solution of the 2-[[(4-chlorophenyl)sulfonyl](2,5-difluorophenyl)methyl]-5-methylpyridine (52 mg, 0.132 mmol) obtained in Example 15 was added dropwise to an N,N-dimethylformamide (5 ml) suspension of sodium hydride (60% in oil) (30 mg, 0.75 mmol) under ice cooling. After the reaction mixture was stirred for 15 minutes under ice cooling, methyl iodide (12 μl, 0.198 mmol) was added thereto. After stirring at room temperature for 1 hour, water was added to the reaction mixture under ice cooling. The resulting mixture was concentrated under reduced pressure. To the residue was added water and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=8:1 eluate was concentrated under reduced pressure. The residue thus obtained was solidified with hexane and collected by filtration to give the title compound (50 mg, 0.122 mmol, 93%) as a white powder.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.[CH2:9]([O:16][C:17](ON1C(=O)CCC1=O)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>CO>[CH2:9]([O:16][C:17]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CO
Product: O=C(N[C@H]1CC[C@H](O)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of trans-4-aminocyclohexanol (35.5 g, 306.6 mmol) in methanol (621 mL) at 0° C. under nitrogen was added N-(benzyloxycarbonyloxy)succinimide (72.8 g, 291.9 mmol). The reaction mixture was slowly warmed to room temperature and after 1 d, poured into 0.25 M aqueous hydrochloric acid solution (2.13 L). The resulting slurry was stirred vigorously for 1 h and then filtered. The filtered solid was washed with water to obtain the title compound (65.65 g, 90%) as a white solid. 13C NMR (400 MHz, (CD3)2SO) δ 155.3, 137.2, 128.3, 127.7, 127.6, 68.1, 65.0, 49.1, 33.9, 30.3. 1H NMR (400 MHz, (CD3)2SO) δ 7.29 (m, 5H), 7.10 (d, J=7.9 Hz, 1H), 4.96 (d, J=2.3 Hz, 2H), 4.76 (d, J=4.0 Hz, 1H), 3.29 (s, 1H), 3.17 (br s, 1H), 1.71 (m, 4H), 1.22 (t, J=9.7 Hz, 4H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.O>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([C:33]5[CH:32]=[N:31][C:30]([F:29])=[CH:35][CH:34]=5)[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Reactant: CC1(C)OB(c2ccc(F)nc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(F)nc4)ccc2OCC3)c(F)c1
Temperature: 80 °C
Yield: 83.8 %

Procedure:
9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (4.16 g, 10 mmol), 2-Fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (2.67 g, 12 mmol), Cs2CO3 (6.50 g, 20 mmol) Pd(dppf)Cl2 (730 mg, 1.0 mmol) and CH3CN—H2O (1 1, 40 mL) were added in a 50 mL of sealed tube, and the mixture was heated at 80° C. for 60 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (50 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative TLC to give 2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (4.0 g, yield: 84%). 1HNMR (DMSO-d6, 400 MHz): δ8.68 (s, 1H), 8.43 (t, J=4.8 Hz, 2H), 8.12-8.01 (m, 1H), 8.00-7.92 (m, 1H), 7.84 (t, J=2.8 Hz, 1H), 7.58-7.50 (m, 2H), 7.26 (s, 2H), 4.39 (s, 2H), 3.24 (s, 2H), 2.23 (s, 3H). ESI-MS: m/z=478 [M+H+]
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[N:8][CH:9]=1.Br[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([NH2:25])=[O:24].O>CN(C)C=O>[F:3][C:4]1[CH:5]=[CH:6][C:7](=[N:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[N:8]([CH:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]([NH2:25])=[O:24])[CH:9]=1
Reactant: NC(=O)C(Br)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(F)cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N=c2ccc(F)cn2C(C(N)=O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (0.040 g, 0.0017 mol) was suspended in N,N-dimethylformamide (15 mL) and was cooled at 0° C. N-(5-fluoropyridin-2-yl)-4-methylbenzenesulfonamide (compound a, 0.37 g, 0.0014 mol) was added and was stirred for 15 minutes. 2-Bromo-2-phenylacetamide h (0.3 g, 0.001 mol) was added then the reaction was warmed to room temperature and was stirred for 24 hours. The reaction was poured into water and extracted with ethyl acetate (3×50 mL) then dried then chromatographed on silica (50% ethyl acetate/hexanes) to give 2-(5-fluoro-2-(tosylimino)pyridin-1(2H)-yl)-2-phenylacetamide (compound j) Rf 0.42, 50% ethyl acetate/hexanes; MS m/z 400 (M+H).
Reaction SMILES: [CH2:1]([C:3]1([CH2:15][CH3:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]#[CH:14])[CH:11]=2)[S:6][CH2:5][CH2:4]1)[CH3:2].C(N(CC)CC)C.I[C:25]1[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:15]([C:3]1([CH2:1][CH3:2])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]#[C:14][C:25]3[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=3)[CH:11]=2)[S:6][CH2:5][CH2:4]1)[CH3:16]
Reactant: C#Cc1ccc2c(c1)C(CC)(CC)CCS2
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(CC)(CC)CCS3)cc1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
A mixture of 0.338 g (1.47 mmol) of (4,4-diethylthiochroman-6-yl)acetylene, 24 mg (0.13 mmol) of copper (I) iodide, and 2.54 g (25 mmol) of triethylamine were degassed with argon for 15 minutes. To the suspension was added 0.57 g (2.07 mmol) of ethyl 4-iodobenzoate (Compound 22) and then 0.12 g (0.17 mmol) of bis(triphenylphosphine)palladium (II) chloride. The suspension was degassed with argon for an additional 5 minutes, the tube was sealed and the mixture stirred at 55° C. for 16 hours.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].Br[CH2:16][C:17]1[CH:28]=[CH:27][C:20]([CH:21]=[CH:22][C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:11]([C:8]1[CH:7]=[CH:6][C:5]([O:14][CH2:16][C:17]2[CH:28]=[CH:27][C:20]([CH:21]=[CH:22][C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=2)=[C:4]([CH2:3][CH2:2][CH3:1])[C:9]=1[OH:10])(=[O:12])[CH3:13]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: COC(=O)C=Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCc2ccc(C=CC(=O)OC)cc2)ccc(C(C)=O)c1O
Yield: 53.2 %

Procedure:
A mixture of 1.0 g (5.15 g) of 2,4-dihydroxy-3-propylacetophenone, 1.58 g (6.18 mmol) of methyl 4-bromomethylcinnamate and 0.85 g (6.18 mmol) of anhydrous potassium carbonate in 20 ml of acetone was stirred at reflux for 18 hours. Ether extraction gave 1.01 g of the title compound as a light yellow powder mp 121°-125° C.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:17]4[CH:29]=[C:28]([C:30]5[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=5)[S:27][C:18]=4[N:19]=[C:20]([C:22]([O:24]CC)=[O:23])[N:21]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.Cl>CO.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:11][CH2:12][N:13]([C:16]3[C:17]4[CH:29]=[C:28]([C:30]5[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=5)[S:27][C:18]=4[N:19]=[C:20]([C:22]([OH:24])=[O:23])[N:21]=3)[CH2:14][CH2:15]2)=[O:9])=[CH:37][CH:38]=1
Reactant: CCOC(=O)c1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2cc(-c3ccc(F)cc3)sc2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)c1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2cc(-c3ccc(F)cc3)sc2n1
Yield: 43.1 %

Procedure:
A solution of ethyl 4-(4-(2-(4-chlorophenoxy)acetyl)piperazin-1-yl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine-2-carboxylate (0.12 g, 0.22 mmol) in methanol/2M NaOH/CH2Cl2 (5:5:1, 5 ml) was stirred at room temperature for 3 hours after which it was neutralized with a 2N HCl solution in dioxane. The solvents were removed under reduced pressure, and the crude residue was purified by flash chromatography on silica gel (CH2Cl2/MeOH 8:1) to yield the title compound as a pale yellow solid (50 mg, 44%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([P:8]([C:13]2([C:16]#[N:17])[CH2:15][CH2:14]2)(=[O:12])[O:9]CC)=[CH:4][CH:3]=1.Br[Si](C)(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([P:8]([C:13]2([C:16]#[N:17])[CH2:14][CH2:15]2)(=[O:9])[OH:12])=[CH:4][CH:3]=1
Reactant: CCOP(=O)(c1ccc(Cl)cc1)C1(C#N)CC1
Agent: C[Si](C)(C)Br
Solvent: ClC(Cl)Cl
Product: N#CC1(P(=O)(O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 111.7 %

Procedure:
0.150 g (0.556 mmol) of ethyl (4-chlorophenyl)(1-cyanocyclopropyl)phosphinate was dissolved in 20 ml of chloroform, and 0.511 g (3.337 mmol) of bromotrimethylsilane was added. After stirring at room temperature for 18 hours, the solvent was removed, the residue was taken up in water and the solution was concentrated again by rotary evaporation. After column chromatography, 0.150 g (94.9% of theory) of (4-chlorophenyl)(1-cyanocyclopropyl)phosphinic acid was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[C:4]([Cl:13])[C:3]=1[OH:14].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[O:22][CH:23]=[CH:24][CH:25]=1>>[Cl:13][C:4]1[CH:5]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:2]([Cl:1])[C:3]=1[O:14][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[O:22][CH:23]=[CH:24][CH:25]=1
Reactant: Oc1c(Cl)cc(-c2cccs2)cc1Cl
Reactant: BrCCCCCc1ccco1
Product: Clc1cc(-c2cccs2)cc(Cl)c1OCCCCCc1ccco1

Procedure:
It is further contemplated that 2,6-dichloro-4-(2-thienyl)phenol can be caused to react with 2-(5-bromopentyl)furan (prepared from furan and 1,5-dibromopentane) in accordance with the procedure of Example 1(c) to give 2-{5-[2,6-dichloro-4-(2-thienyl)phenoxy]pentyl}furan [I; Y=(CH2)5, Z=HC, R=CH3, R1 =2-Cl, R2 =6-Cl, Het =2-thienyl].
Reaction SMILES: [Br-].[C:2]1([CH2:8][CH2:9][N+:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=[O:18])[CH3:17])[CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(O)C>[Pd]>[C:2]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][C:12]([C:16]([CH3:17])=[O:18])=[CH:11]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc[n+](CCc2ccccc2)c1
Agent: [Pd]
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)C1=CN(CCc2ccccc2)CCC1

Procedure:
A solution of 1-(2-phenylethyl)-3-acetylpyridinium bromide (30.6 g, 0.1 mole) and triethylamine (10.1 g, 0.1 mole) in ethyl alcohol (50 mole) over 5% palladium on carbon (5 g) was hydrogenated at room temperature and pressure. Upon cessation of hydrogen uptake, the catalyst was filtered and the filtrate concentrated at reduced pressure. The semi-solid filtered and the filtrate concentrated under reduced pressure to leave a pale brown oil, methyl 1-(2-phenyl ethyl)-1,4,5,6-tetrahydro-3-pyridyl ketone (6).
Reaction SMILES: O=C1CCC(=O)[N:3]1[C:8]1[C:17]2[N:18]=[C:19]([CH2:33][O:34][CH2:35][CH3:36])[N:20]([CH2:21][C:22]([NH:25][C:26](=[O:32])[CH2:27][CH2:28][C:29](O)=[O:30])([CH3:24])[CH3:23])[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[C:56]([O:60][C:61](=[O:64])[NH:62][NH2:63])([CH3:59])([CH3:58])[CH3:57].C(N)CN>ClCCl.CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl.O>[NH2:3][C:8]1[C:17]2[N:18]=[C:19]([CH2:33][O:34][CH2:35][CH3:36])[N:20]([CH2:21][C:22]([NH:25][C:26](=[O:32])[CH2:27][CH2:28][C:29]([NH:63][NH:62][C:61]([O:60][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:64])=[O:30])([CH3:24])[CH3:23])[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CCOCc1nc2c(N3C(=O)CCC3=O)nc3ccccc3c2n1CC(C)(C)NC(=O)CCC(=O)O
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: NCCN
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)NC(=O)CCC(=O)NNC(=O)OC(C)(C)C
Reaction time: 96 h
Yield: 49.5 %

Procedure:
A solution of 4-({2-[4-(2,5-dioxopyrrolidin-1-yl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}amino)-4-oxobutanoic acid (3.16 g, 6.39 mmol) in dichloromethane (100 mL) was treated with triethylamine (2.67 mL, 19.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.67 g, 19.2 mmol), tert-butylcarbazate (2.46 g, 19.2 mmol) and N,N-dimethylpyridin-4-amine (78 mg, 0.64 mmol). The reaction mixture was stirred for 4 days and then was treated with 100 mL of water. The layers were separated and the aqueous portion was extracted with chloroform (50 mL). The combined organic layers were washed successively with water (50 mL) and brine (50 mL). The organic portion was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a white foam. The white foam was dissolved in dichloromethane (50 mL) and treated with ethylene diamine (1 mL). After stirring for 4 hours, the reaction mixture was treated with water (50 mL) and chloroform (50 mL) and the layers were separated. The aqueous portion was extracted with chloroform (2×25 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL). The organic layer was concentrated and purification of the crude product by chromatography on silica gel (gradient elution, 25%-100% CMA in chloroform) followed by crystallization from dichloromethane gave 1.67 g of tert-butyl 2-[4-({2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}amino)-4-oxobutanoyl]hydrazinecarboxylate as a white powder.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:25][CH3:26])=[C:11]([CH:13]2[C:15]3([C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[O:17][C:16]3([CH3:24])[CH3:23])[O:14]2)[CH:12]=1>ClCCCl>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:25][CH3:26])=[C:11]([CH:13]2[C:19](=[O:20])[C:18]([CH3:21])([CH3:22])[O:17][C:16]([CH3:24])([CH3:23])[C:15]2=[O:14])[CH:12]=1
Reactant: CCc1ccc(Br)cc1C1OC12C(=O)C(C)(C)OC2(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: CCc1ccc(Br)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
To an ice-cold solution of concentrated sulphuric acid (2 ml) is added a second solution of 2-(5-bromo-2-ethylphenyl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one (0.995 g, 2.82 mmol) in 1,2-dichloroethane (2 ml) dropwise over 5 minutes. This biphasic mixture is stirred vigorously for 1 hour at 0° C., then poured into ice-cold water (15 ml). This aqueous mixture is then concentrated under vacuum to remove all organic volatiles, producing a free-flowing solid. The solid is filtered, dried under vacuum, then washed with hexanes to afford 4-(5-bromo-2-ethylphenyl)-2,2,6,6-tetramethylpyran-3,5-dione (0.81 g) as a cream-coloured solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:11]([O:18][CH2:19][C@H:20]([C:22]([NH2:24])=[O:23])[NH2:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C.O>CS(C)=O.CCOC(C)=O>[CH2:11]([O:18][CH2:19][C@@H:20]([NH:21][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Br:1])[CH:9]=1)[C:22]([NH2:24])=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1ccc(F)cc1Br
Reactant: NC(=O)[C@H](N)COCc1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N[C@H](COCc2ccccc2)C(N)=O)cc1Br
Yield: 17.6 %

Procedure:
A solution of 2-bromo-4-fluorobenzonitrile (200 mg, 1.00 mmol), O-benzyl-D-serinamide (290 mg, 1.49 mmol) and DIEA (0.466 mL, 2.68 mmol) in DMSO (3 mL) was stirred at 100 C for 18 h. Water and EtOAc were added. The organic phase was separated, washed with 1N HCl, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column, eluted with 0-60% EtOAc in hexane to give (R)-3-(benzyloxy)-2-(3-bromo-4-cyanophenylamino)propanamide (66 mg).
Reaction SMILES: Br[C:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]3[O:15][CH2:14][CH2:13][CH2:12][C:11]=3[CH:16]=2)=[C:5]([CH:17]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:18]([O:20]C)=[O:19])[N:4]([CH3:27])[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH:34]12[CH2:40][CH:37]([CH2:38][CH2:39]1)[CH:36]=[C:35]2B(O)O.ClCCl>C(COC)OC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(O)C>[CH:34]12[CH2:40][CH:37]([CH2:38][CH2:39]1)[CH:36]=[C:35]2[C:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]3[O:15][CH2:14][CH2:13][CH2:12][C:11]=3[CH:16]=2)=[C:5]([CH:17]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[C:18]([OH:20])=[O:19])[N:4]([CH3:27])[N:3]=1
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2)CCCO3)c(Br)nn1C
Reactant: OB(O)C1=CC2CCC1C2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: Cn1nc(C2=CC3CCC2C3)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O
Temperature: 140 °C
Yield: 60.5 %

Procedure:
A solution of methyl 2-[3-bromo-4-(3,4-dihydro-2H-1-benzopyran-6-yl)-1-methyl-1H-pyrazol-5-yl]-2-(tert-butoxy)acetate (11i) (50 mg, 0.114 mmol), disodium carbonate (36 mg, 0.343 mmol), and bicyclo[2.2.1]hept-2-en-2-ylboronic acid (19 mg, 0.137 mmol) in a mixture of dimethoxyethane (0.45 mL), ethanol (0.19 mL) and water (0.13 mL) was bubbled with nitrogen for 5 minutes. [1,1′-Bis(diphenylphosphino) ferrocene]dichloropalladium(II), complex with dichloromethane (4.7 mg, 0.006 mmol) was added and the reaction mixture was heated at 140° C. for 2 hours. The solution was concentrated in vacuo. Water (2 mL) was added to the residue and the aqueous layer was washed with diethyl ether (2 mL), acidified with 1M hydrochloric acid until pH 3 and extracted with diethyl ether (2×3 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (dichloromethane/ethyl acetate 45/55+0.5% formic acid) to provide 2-(3-{bicyclo[2.2.1]hept-2-en-2-yl}-4-(3,4-dihydro-2H-1-benzopyran-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(tert-butoxy)acetic acid (example 15) (30 mg, 0.069 mmol, 60%) as a mixture of diastereoisomers.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11]C(C)=O.C(O)(=O)C.S(=O)(=O)(O)O.[N+:24]([O-])([OH:26])=[O:25]>O>[CH2:2]([C:3]1[CH:8]=[C:7]([N+:24]([O-:26])=[O:25])[CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH2:11])[CH3:1]
Reactant: O=[N+]([O-])O
Reactant: CCc1cccc(CC)c1NC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CCc1cc([N+](=O)[O-])cc(CC)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 58 parts of 2,6-diethylacetanilide in 100 parts of glacial acetic acid and 184 parts of concentrated sulfuric acid is treated at 10° with a mixture of 19.5 parts by volume of concentrated nitric acid and 13 parts by volume of concentrated sulfuric acid. After addition is completed, the mixture is stirred at 25°C for 1 hour. It is then poured into water and ice, and the solid filtered, washed with water and dried. The 2,6-diethyl-4-nitroacetanilide (30 parts) is treated with 150 parts by volume of refluxing 70% sulfuric acid solution for one hour, and the mixture poured onto ice and made basic with 5N sodium hydroxide solution. The solid 2,6-diethyl-4-nitroaniline is filtered, washed with water and recrystallized from methyl alcohol-water.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[CH:4]=[CH:3][CH:2]=1.[N:18]1([C:24]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:25]=2[CH:26]=[CH:27][NH:28]3)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[NH:28]1[C:29]2[C:25](=[C:24]([N:18]3[CH2:23][CH2:22][N:21]([CH:14]4[CH2:15][CH2:16][N:11]([C:9]5[CH:8]=[CH:7][CH:6]=[C:5]6[C:10]=5[N:1]=[CH:2][CH:3]=[CH:4]6)[CH2:12][CH2:13]4)[CH2:20][CH2:19]3)[CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:27]1
Reactant: O=C1CCN(c2cccc3cccnc23)CC1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: c1cnc2c(N3CCC(N4CCN(c5cccc6[nH]ccc56)CC4)CC3)cccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
To a solution of 0.270 g of 1-quinolin-8-yl-piperidin-4-one (Example A, Step 6, above) and 0.240 g of 4-piperazino-indole (commercially available) in 15 mL CH2Cl2 was added 0.327 g of sodium triacetoxyborohydride and 0.2 mL acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2Cl2. The organic phase was washed with water, dried over magnesium sulfate and evaporated. The product crystallized to give 0.200 g of the desired product. Mp: 256° C.; MS (ES) m/z (relative intensity): 412 (M++−H, 100).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[NH4+:18]>C(O)C>[NH2:18][C:2]1[N:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=S(=O)(Nc1nccs1)c1ccc(Cl)nc1
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)Nc2nccs2)cn1
Temperature: 120 °C
Reaction time: 96 h
Yield: 22 %

Procedure:
Under a N2 atmosphere, a mixture of 6-chloro-N-(thiazol-2-yl)pyridine-3-sulfonamide (0.7 g, 2.54 mmol), ammonium hydroxide (7.5 mL) and ethanol (7.5 mL), was stirred at 120° C. in a sealed tube for 4 days. The reaction was cooled to RT. After evaporating the solvents under reduced pressure, purification via silica gel chromatography using 5%-10% methanol in CH2Cl2 gave 6-amino-N-(thiazol-2-yl)pyridine-3-sulfonamide as a orange solid (0.14 g, 22%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=257.2; tR=0.2 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5](Cl)=[CH:4][CH:3]=1.[CH2:9]([Mg]Br)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>CCOCC>[CH2:9]([C:2]1[CH:7]=[CH:6][C:5]([CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:4][CH:3]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: Clc1ccc(Cl)cc1
Reactant: CCCCCC[Mg]Br
Solvent: CCOCC
Product: CCCCCCc1ccc(CCCCCC)cc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A 2 L round-bottomed flask is charged with 1,4-dichlorobenzene (118 g, 0.80 mol), [1,3 -bis(diphenylphosphino)propane]Ni(II) chloride (500 mg, 0.9 mmol), and dry ether (600 mL). The mixture is cooled to 0° C. and a 2 M solution of n-hexylmagnesium bromide in ether (1 L) is added dropwise. The cooling bath is removed, and the solution is slowly heated to reflux and allowed to boil for 24 h. The mixture is cooled to 0° C. and diluted with water (50 mL) and then with a 2 M aqueous hydrochloric acid solution (500 mL). The aqueous layer is separated, extracted with ether (2×200 mL), and the combined organic layers are washed with water (100 mL) and dried over magnesium sulfate. The solvent is removed in vacuo and the product is purified by distillation.