Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([N+:20]([O-])=O)[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].[Cl:25][C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([NH:20][S:32]([C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[CH:27]=3)(=[O:34])=[O:33])[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc(Cl)c([N+](=O)[O-])c2)cc1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc(Cl)c(NS(=O)(=O)c3cccc(Cl)c3)c2)cc1

Procedure:
4-[4-Chloro-3-(3-chloro-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=463.1 (M+H+), was prepared in analogy to example 1, steps A to D. Step A was performed using 4-chloro-3-nitro-benzoyl chloride and yielded 4-(4-chloro-3-nitro-benzoylamino)-benzoic acid ethyl ester. This was reduced to 4-(4-Chloro-3-nitro-benzoylamino)-benzoic acid ethyl ester in step B. This was coupled with 3-chloro-benzenesulfonyl chloride in step C, yielding 4-[4-chloro-3-(3-chloro-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:13]([OH:15])=[O:14])=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.[NH:16]1[CH:20]=[CH:19][C:18](B(O)O)=[N:17]1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C.C(Cl)Cl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH:10]1([CH2:9][O:8][C:7]2[N:6]=[C:5]([C:13]([OH:15])=[O:14])[CH:4]=[CH:3][C:2]=2[C:20]2[CH:19]=[CH:18][NH:17][N:16]=2)[CH2:12][CH2:11]1
Reactant: OB(O)c1cc[nH]n1
Reactant: O=C(O)c1ccc(Br)c(OCC2CC2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1ccc(-c2cc[nH]n2)c(OCC2CC2)n1
Yield: 66.7 %

Procedure:
Under an atmosphere of nitrogen, a solution of 5-bromo-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid (Example 9 d, 0.4 g, 1.5 mmol), 1H-pyrazol-3-ylboronic acid (CAN 376584-63-3, 0.2 g, 1.8 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride methylene chloride complex (CAN 95464-05-4, 60 mg, 0.07 mmol) and sodium carbonate (1.3 g, 12 mmol) in DMF (10 mL) was heated to 100° C. for 5 h. The reaction mixture was poured into water and extracted with ethyl acetate (30 mL). The aqueous layer was adjusted to pH=2 by addition of 1 N hydrochloric acid and the resulting mixture was extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (silica gel, 15 g, eluting with 30% ethyl acetate in petroleum ether) to yield the title compound (0.23 g, 1 mmol, 60.3%) as white solid; MS (EI): m/e 260.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.C([Li])CCC.C([Cu])#N.C(OC([N:24]1[C:28]2=[N:29][CH:30]=[C:31]([Cl:33])[CH:32]=[C:27]2[C:26]([CH2:34]Cl)=[CH:25]1)=O)(C)(C)C.N>O1CCCC1.CCCCCC.O>[Cl:33][C:31]1[CH:32]=[C:27]2[C:26]([CH2:34][C:7]3[C:2]([F:1])=[N:3][C:4]([F:8])=[CH:5][CH:6]=3)=[CH:25][NH:24][C:28]2=[N:29][CH:30]=1
Reactant: Fc1cccc(F)n1
Reactant: CC(C)(C)OC(=O)n1cc(CCl)c2cc(Cl)cnc21
Agent: N#C[Cu]
Agent: N
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(Cc2c[nH]c3ncc(Cl)cc23)c(F)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To 2,6-Difluoropyridine (58, 3.40 g, 0.0295 mol) in tetrahydrofuran (200.0 mL), under an atmosphere of nitrogen at −78° C., 2.50 M of n-butyllithium in hexane (12.0 mL) was added slowly. After 60 minutes, CuCN.2LiCl (0.75 M in tetrahydrofuran, 40.0 mL) was added to the reaction mixture. After 5 minutes, 5-chloro-3-chloromethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (535, 4.20 g, 0.0139 mol, prepared as described in Example 49, Scheme 164) in tetrahydrofuran (20 mL) was added to the reaction. The reaction was stirred at −78° C. overnight, then poured into water and ammonia (10 mL), and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 15% ethyl acetate in hexane to give a white solid (P-0155, 300 mg, 7.7%). MS (ESI) [M−H+]−=278.1.
Reaction SMILES: Br[CH2:2][N:3]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[S:4]1(=[O:6])=[O:5].[C:15]1([N:21]2[CH2:25][CH2:24][C:23](=[O:26])[NH:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.O>O1CCCC1>[C:15]1([N:21]2[CH2:25][CH2:24][C:23](=[O:26])[N:22]2[CH2:2][N:3]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:4]2(=[O:6])=[O:5])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CBr
Reactant: O=C1CCN(c2ccccc2)N1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCN(c2ccccc2)N1CN1C(=O)c2ccccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
N-Bromomethylsaccharin (13.8 g), 1-phenyl-3-pyrazolidinone (11.9 g) and triethylamine (5.5 g) were dissolved in tetrahydrofuran (200 ml), and stirred in a stream of nitrogen at room temperature for 2 hours. The reaction mixture was added to water (200 ml), and extracted with 100 ml each of ethyl acetate two times. After drying the extract over anhydrous Glauber's salt, the solvent was distilled away. The thus obtained crude product was recrystallized from ethyl acetate to yield 16 g of N-(1-phenyl-3-pyrazolidinone-2-ylmethyl)saccharin (Compound (I)-(18)). Melting Point: 209°-213° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[N:4]=[CH:3]1.S(O)(O)(=O)=O.[NH2:26][OH:27].Cl>O>[CH3:1][C:2]([CH3:20])([CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[NH2:4])[CH:3]=[N:26][OH:27]
Reactant: NO
Reactant: CCCCCCC1CC=CCCC=CCC(C)(C)C=N1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCCCC(N)CC=CCCC=CCC(C)(C)C=NO
Yield: 200.5 %

Procedure:
The procedure described in Example 1(b) is repeated, except that 113 g (0.41 mol) of 3,3-dimethyl-12-hexyl-1-aza-1,5,9-cyclododecatriene, 33 g (0.202 mol) of hydroxylamine sulfate, 50 g of concentrated hydrochloric acid and 250 ml of water are used. Working up yields 125 g (0.405 mol) of 2,2-dimethyl-11-n-hexyl-11-amino-undeca-4,8-dienal oxime; yield 99% of theory.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](O)=[O:9])=[CH:6][N:5]=[C:4]2[N:11]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:12]=[CH:13][C:3]=12.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:57][C:58]1[CH:59]=[C:60]([NH:65][C:66](=[O:86])[C:67]2[CH:72]=[CH:71][C:70]([CH2:73][N:74]3[CH2:79][CH2:78][N:77]([CH2:80][CH3:81])[CH2:76][CH2:75]3)=[C:69]([C:82]([F:85])([F:84])[F:83])[CH:68]=2)[CH:61]=[CH:62][C:63]=1[CH3:64]>CN(C=O)C.O>[Cl:1][C:2]1[C:7]([C:8]([NH:57][C:58]2[CH:59]=[C:60]([NH:65][C:66](=[O:86])[C:67]3[CH:72]=[CH:71][C:70]([CH2:73][N:74]4[CH2:79][CH2:78][N:77]([CH2:80][CH3:81])[CH2:76][CH2:75]4)=[C:69]([C:82]([F:85])([F:84])[F:83])[CH:68]=3)[CH:61]=[CH:62][C:63]=2[CH3:64])=[O:9])=[CH:6][N:5]=[C:4]2[N:11]([S:14]([C:17]3[CH:18]=[CH:19][C:20]([CH3:21])=[CH:22][CH:23]=3)(=[O:15])=[O:16])[CH:12]=[CH:13][C:3]=12
Reactant: CCN1CCN(Cc2ccc(C(=O)Nc3ccc(C)c(N)c3)cc2C(F)(F)F)CC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)c(C(=O)O)cnc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN(Cc2ccc(C(=O)Nc3ccc(C)c(NC(=O)c4cnc5c(ccn5S(=O)(=O)c5ccc(C)cc5)c4Cl)c3)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
To a solution of 4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (50 mg, 0.14 mmol) in DMF (1 mL) were added HATU (162 mg, 0.43 mmol), DIEA (0.12 mL, 0.71 mmol) and N-(3-amino-4-methylphenyl)-4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide (60 mg, 0.14 mmol). The reaction mixture was stirred for overnight at room temperature after which, it was poured to water and the produced solid was filtered. The crude solid was dried with nitrogen gas flow. The title compound (85 mg, 0.11 mmol) was used next reaction without further purification. MS m/z: 753 [M+1].
Reaction SMILES: [NH:1]([CH3:20])[C@H:2]([C:15]([NH:17][O:18][CH3:19])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.[C:21]([N:31]([CH3:39])[C@H:32]([C:36]([OH:38])=O)[CH:33]([CH3:35])[CH3:34])([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].O>C1COCC1>[C:21]([N:31]([CH3:39])[C@H:32]([C:36]([N:1]([CH3:20])[C@H:2]([C:15]([NH:17][O:18][CH3:19])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:12])[CH3:13])[CH:5]=1)=[O:38])[CH:33]([CH3:34])[CH3:35])([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22]
Reactant: CN[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(=O)NOC
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CONC(=O)[C@H](Cc1ccc(O)c(C(C)(C)C)c1)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 56.6 %

Procedure:
To a solution of N-Me-Tyr(3-tBu)-NHOMe (1.24 g, 4.42 mmol), Z-N-Me-Val-OH (1.76 g, 6.63 mmol) and CMPI (1.7 g, 6.63 mmol) in THF (30 ml), TEA (1.23 ml, 8.84 mmol) was added and stirred overnight. The mixture was mixed with water, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated to remove the solvent under reduced pressure. The thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:1) to give the titled compound (1.32 g, 57%).
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[OH:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1>>[C:6]([C:5]1[C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=[CH:11][C:4]=1[O:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)#[N:7]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CC(C)(C)OC(=O)N1CCC(COc2cccc([N+](=O)[O-])c2C#N)CC1

Procedure:
Prepared as in Example 158c from 2,6-dinitrobenzonitrile and tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate in 73% as a tan solid. 1H NMR (400 MHz, MeOD) δ 1.24 (qd, J=12.8, 4.4 Hz, 2H), 1.41 (s, 9H), 1.78 (br d, J=12.1 Hz, 2H), 2.02 (m, 2H), 2.77 (m, 2H), 4.00 (br d, J=13.1 Hz, 2H), 4.15 (d, J=6.3 Hz, 2H), 7.74 (dd, J=7.5, 1.5 Hz, 1H), 7.91 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:18][C:19]1[C:27]([F:28])=[C:26]([F:29])[C:25]([F:30])=[C:24]([F:31])[C:20]=1[C:21](Cl)=[O:22]>>[F:18][C:19]1[C:27]([F:28])=[C:26]([F:29])[C:25]([F:30])=[C:24]([F:31])[C:20]=1[C:21]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:22]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1c(F)c(F)c(F)c(F)c1F
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4c(F)c(F)c(F)c(F)c4F)nc23)CC1
Yield: 85.7 %

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.008 mL (0.053 mMol) 2,3,4,5,6-pentafluorobenzoyl chloride, 0.016 gm (84%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([O-:19])=O)[CH2:12]1)(=[O:10])=[O:9].[Li+].[CH3:21][C:22]1[CH:23]=[C:24]([CH:28]2[CH2:32][CH2:31][CH2:30][NH:29]2)[CH:25]=[CH:26][CH:27]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([N:29]2[CH2:30][CH2:31][CH2:32][CH:28]2[C:24]2[CH:23]=[C:22]([CH3:21])[CH:27]=[CH:26][CH:25]=2)=[O:19])[CH2:12]1)(=[O:9])=[O:10]
Reactant: O=C([O-])C1CCCN(S(=O)(=O)c2ccccc2Cl)C1
Reactant: Cc1cccc(C2CCCN2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C2CCCN2C(=O)C2CCCN(S(=O)(=O)c3ccccc3Cl)C2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23.1 %

Procedure:
To a solution 0.1 g Lithium 1-(2-chloro-benzenesulfonyl)-piperidine-3-carboxylate (0.32 mmol) in DMF:DCM (3:1) was added 0.047 g 2-(3-methyl phenyl)-pyrrolidine (0.29 mmol) and 0.27 mL DIPEA (1.6 mmol). The mixture was stirred for 10 minutes at room temperature and 0.147 g HATU (0.38 mmol) was added. The mixture was stirred overnight at room temperature, diluted with 15 mL brine and extracted with ethyl acetate (3×10 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to dryness to obtain the crude product which was further purified by column chromatography on silica eluting with 15% ethyl acetate in hexane to yield 0.03 g (20.8%) of the title compound. (MH+) 447.07.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]([CH3:17])=[CH2:16])[N:10]=[CH:9][N:8]=1)[C:2]#[C:3][CH2:4][CH3:5].[ClH:18].O>C(Cl)(Cl)Cl.[Cl-].C([N+](CCCCCCCC)(CCCCCCCC)C)CCCCCCC>[CH2:1]([O:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]([Cl:18])([CH3:17])[CH3:16])[N:10]=[CH:9][N:8]=1)[C:2]#[C:3][CH2:4][CH3:5]
Reactant: Cl
Reactant: C=C(C)COc1cc(OCC#CCC)ncn1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCC#CCOc1cc(OCC(C)(C)Cl)ncn1
Temperature: 0 °C
Reaction time: 7 h

Procedure:
In 5 ml of chloroform were dissolved 0.64 g of 4-(2-pentynyloxy)-6-(2-methyl-2-propenyloxy)pyrimidine and 0.06 g of trioctylmethylammonium chloride, to which 3 ml of concentrated hydrochloric acid was added dropwise at 0° C., followed by stirring at 0° C. for 30 minutes and at room temperature for 7 hours. The reaction mixture was then poured into water, which was extracted three times with t-butyl methyl ether. The combined organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution, a saturated aqueous sodium chloride solution, dried over anhydrous magnesium, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.12 g of 4-(2-pentynyloxy)-6-(2-chloro-2-methylpropyloxy)pyrimidine (the present compound (40)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]I)[CH:7]=[C:6]2[CH:18]=[O:19].N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1.C([SnH](CCCC)CCCC)CCC.[F-].[K+]>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:7]1=[C:6]2[CH:18]=[O:19]
Reactant: COc1ccc2c(c1)c(C=O)cn2CCCCCI
Agent: CCCC[SnH](CCCC)CCCC
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Agent: [F-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)c(C=O)c1n2CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 5-methoxy-1-(5-iodopentyl)indole-3-carboxaldehyde in toluene at reflux under argon is added dropwise over 2 h a solution of 1,1′-azobis(cyclohexanecarbonitrile) and tri-n-butyltin hydride in toluene. The mixture is stirred for 3 h, cooled to room temperature, and potassium fluoride and water are added. The mixture is stirred for 18 h and filtered through a pad of kieselguhr. The filter-cake is washed (ethyl acetate) and the filtrate is concentrated in vacuo and purified by column chromatography to give the product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])[CH:3]=1.[CH2:17]([C@@H:19]1[O:21][CH2:20]1)[Cl:18]>>[Cl:18][CH2:17][C@@H:19]([OH:21])[CH2:20][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])[CH:3]=1
Reactant: ClC[C@H]1CO1
Reactant: CCCC(CCC)COc1cccc(Br)c1
Product: CCCC(CCC)COc1cccc(C[C@H](O)CCl)c1

Procedure:
Metallation of 1-bromo-3-(2-propylpentyloxy)benzene followed by addition of (R)-(−)-epichlorohydrin gave (S)-1-chloro-3-(3-(2-propylpentyloxy)phenyl)propan-2-ol Yield (1.52 g, 58%): 1H NMR (400 MHz, DMSO-d6) δ 7.14 (t, J=7.8 Hz, 1H), 6.77-6.72 (m, 3H), 5.14 (d, J=5.6 Hz, 1H), 3.88-3.81 (m, 1H), 3.78 (d, J=5.6 Hz, 2H), 3.52 (dd, J=10.8, 4.4 Hz, 1H), 3.43 (dd, J=11.2, 5.6 Hz, 1H), 2.74 (dd, J=13.6, 5.2 Hz, 1H), 2.60, (dd, J=13.6, 7.6 Hz, 1H), 1.75-1.69 (m, 1H), 1.39-1.25 (m, 8H), 0.85 (t, J=7.0 Hz, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[C:16]([C:18]1[N:22]([CH3:23])[C:21](B(O)O)=[CH:20][CH:19]=1)#[N:17].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)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]>[C:16]([C:18]1[N:22]([CH3:23])[C:21]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=2)=[CH:20][CH:19]=1)#[N:17]
Reactant: NS(=O)(=O)c1ccc(Br)cc1C(F)(F)F
Reactant: Cn1c(C#N)ccc1B(O)O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cn1c(C#N)ccc1-c1ccc(S(N)(=O)=O)c(C(F)(F)F)c1
Reaction time: 16 h
Yield: 18.4 %

Procedure:
According to general procedure B, 4-bromo-2-(trifluoromethyl)benzenesulfonamide (170 mg, 0.56 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (100 mg, 0.67 mmol), potassium fluoride (107 mg, 1.85 mmol), and tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (83 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-(trifluoromethyl)benzenesulfonamide (34 mg, 18%) was provided after purification. MS (ESI) m/z 329. HPLC purity 98.6% at 210-370 nm, 9.1 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:36])(C[Si](OC(C)C)(C)C)[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[N:25][N:24]=[N:23]3)=[CH:18][CH:17]=2)[C:12]1=[O:27])[CH3:10].[C:37](=O)(O)[O-:38].[Na+]>CO.O1CCCC1.OO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:36])([CH2:37][OH:38])[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]([N:22]3[CH:26]=[N:25][N:24]=[N:23]3)=[CH:20][CH:21]=2)[C:12]1=[O:27])[CH3:10]
Reactant: O=C([O-])O
Reactant: CC(C)O[Si](C)(C)C[C@](O)(c1ccccc1F)[C@@H](C)n1ccn(-c2ccc(-n3cnnn3)cc2)c1=O
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](n1ccn(-c2ccc(-n3cnnn3)cc2)c1=O)[C@](O)(CO)c1ccccc1F
Temperature: 50 °C
Yield: 57.4 %

Procedure:
1-[(1R,2S)-2-(2-Fluorophenyl)-2-hydroxy-3-(isopropoxy dimethylsilyl)-1-methylpropyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (1 g) was dissolved in a mixture of methanol and tetrahydrofuran (1:1, 20 ml), to which an 30% aqueous solution of hydrogen peroxide (2 ml) and sodium bicarbonate (157 mg) were added. The mixture was heated at 50° C. for 4 hours, then cooled and extracted with ethyl acetate (100 ml). The extract was washed with water (30 ml), an aqueous solution of Na2S2O3 (30 ml×2) and a saturated aqueous solution of sodium chloride (30 ml) successively, dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent:hexane/ethyl acetate=1/4) and recrystallized from diethyl ether (20 ml) to give 1-[(1R,2S)-2-(2-fluorophenyl)-2,3-dihydroxy-1-methyl propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (440 mg) as a colorless crystalline powder.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:8]1(C)[CH:13]=CC(S(OCC#C)(=O)=O)=C[CH:9]=1>Cl[Cu].O>[CH:1]#[C:2][CH2:3][C:4]#[C:5][CH2:6][CH2:7][CH2:9][CH2:8][CH3:13]
Reactant: C#CCCCCC
Reactant: C#CCOS(=O)(=O)c1ccc(C)cc1
Agent: Cl[Cu]
Solvent: O
Product: C#CCC#CCCCCC
Reaction time: 0.25 h

Procedure:
Into a 1 l vessel, there were charged 19.2 g of magnesium chips (0.8 mole) into 550 ml of tetrahydrofuran (THF) under nitrogen. To this mixture, there were added dropwise 84 g (0.77 mole) of ethyl bromide so as to maintain the THF in reflux. Once the ethyl magnesium bromide had been formed, 62.4 g (0.65 mole) of 1-heptyne were added dropwise at 10°, over 10 min, and the mixture was heated to 60° for 45 min. After cooling to 10°, 1.93 g (19.5 mmole) of CuCl were added thereto and the mixture was left at rest for 15 min. 138 G (0.65 mole) of propargyl p-toluenesulfonate were then added over 20 min to the reaction mixture maintained at 0°. The latter was left at rest for 30 min while surveying that the temperature did not rise above 5°. It was then heated to 15° to complete the reaction. The reaction mixture was hydrolyzed with 100 ml of water and the aqueous phase was separated and extracted with two fractions of 80 ml THF each. The combined organic extracts were then washed with an aqueous solution saturated with NaCl, two fractions of 50 ml each of a 5% aqueous solution of KCN and was then dried over Na2SO4. After filtration and evaporation, a concentrated solution of deca-1,4-diyne in THF was obtained, which was used in the following reaction step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[OH:17])[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:20]OCCl>CN(C)C=O.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:20])[CH:12]=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(O)c(OCc2ccccc2)c1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 300 g of 3-benzyloxy-4-hydroxybenzaldeyde (obtained as described in example 62) in 600 ml of dimethylformamide was added to a suspension of 34.6 g of sodium hydride in 346 ml of dimethylformamide under stirring in nitrogen atmosphere. After complete dissolution of sodium hydride 116 g of chloromethyl methyl ether were added; stirring was continued for 30 minutes. The mixture was then diluted with water and extracted with ethyl ether. The combined organic phase was dried over sodium sulfate, filtered and evaporated. The residue was distilled (b.p. 178°-183° C./0.1 mm Hg) to give 3-benzyloxy-4-methoxybenzaldehyde, m.p. 30° C. (from petroleum ether, b.p. 30°-70° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:11].N(/C(C)(C)C#N)=N\C(C)(C)C#N.[Br:24]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:24][CH:4]1[C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[Cl:1])[C:6](=[O:11])[O:5]1
Reactant: O=C1OCc2c(Cl)cccc21
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)/N=N/C(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1OC(Br)c2c(Cl)cccc21
Yield: 96.7 %

Procedure:
4-chloroisobenzofuran-1(3H)-one (10 g, 59.32 mmol), (E)-2,2′-(diazene-1,2-diyl)bis(2-methylpropanenitrile) (0.974 g, 5.93 mmol) and 1-bromopyrrolidine-2,5-dione (11.61 g, 65.25 mmol) were dissolved CCl4 (100 mL) and heated at reflux for 2 hours. The reaction was cooled and filtered, the filtrate was evaporated to the desired compound as a yellow gum (14.20 g, 97% yield); 1H NMR (400.132 MHz, CDCl3) δ 7.32 (1H, s), 7.61 (1H, t), 7.73 (1H, d), 7.88 (1H, d); m/z (LC-MS, ESI+), RT=2.28 (M+H not detected).