Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC([O:4][C:5]([Cl:8])(Cl)Cl)=O.[Cl:9][C:10]1[C:11]([NH:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][O:29][CH2:30][CH3:31])=[CH:23][C:22]=2[CH3:32])=[N:12][CH:13]=[N:14][C:15]=1[CH3:16].C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[Cl:9][C:10]1[C:11]([N:17]([C:5]([Cl:8])=[O:4])[CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][O:29][CH2:30][CH3:31])=[CH:23][C:22]=2[CH3:32])=[N:12][CH:13]=[N:14][C:15]=1[CH3:16]
Reactant: CCOCCc1ccc(OCCNc2ncnc(C)c2Cl)c(C)c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOCCc1ccc(OCCN(C(=O)Cl)c2ncnc(C)c2Cl)c(C)c1
Temperature: 5 °C
Reaction time: 3 h

Procedure:
An amount 2.0 g of trichloromethyl chloroformate (TCF) was dissolved in 30 ml of toluene and cooled to 5° C. or lower. To the solution was added dropwise a solution of 5.0 g of 5-chloro-N-{2-[4-(2-ethoxyethyl)2-methylphenoxy]ethyl}-6-methyl-4-pyrimidine amine and 1.8 g of triethylamine dissolved in 20 ml of toluene, and after the dropwise addition, the mixture was stirred at room temperature for 3 hours. After completion of the reaction, 20 ml of water was added, and the mixture was stirred at room temperature for one hour to decompose excessive TCF.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[N:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:19]2[CH:20]=[CH:21][C:22]([CH3:26])=[C:23]([CH:25]=2)[NH2:24])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:33][C:34]([CH3:39])([CH3:38])[C:35](Cl)=[O:36]>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[N:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:19]2[CH:20]=[CH:21][C:22]([CH3:26])=[C:23]([NH:24][C:35](=[O:36])[C:34]([CH3:39])([CH3:38])[CH3:33])[CH:25]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2nc(-c3ccc(C)c(N)c3)c(-c3ccc(F)cc3)n2n1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: COc1ccc2nc(-c3ccc(C)c(NC(=O)C(C)(C)C)c3)c(-c3ccc(F)cc3)n2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
A stirred solution of 5-(3-(4-fluorophenyl)-6-methoxyimidazo[1,2-b]pyridazin-2-yl)-2-methylaniline (0.025 g, 0.072 mmol) in acetonitrile (1 mL) containing pyridine (0.215 mmol) is added trimethylacetylchloride (0.072 mmol). The mixture is stirred at room temperature for 4 hours, then concentrated to dryness and purified via chromatography (hexanes to EtOAc) to afford the title compound (0.028 g, 90%) as a yellow solid: Rf 0.28 (1:1 EtOAc:hexanes); LCMS (m/z)=433.5 [M+H]+, tR=2.74 min. (compound same as Example 114)
Reaction SMILES: C(C1C=C(C(N)C)C=CC=1C1C=C(F)C=CC=1OC)C=C.BrC1C=CC(C(N)C)=C(Cl)C=1.ClC1C=CC(OC)=C(B(O)O)C=1.FC1C=C(C2C=C(F)C=CC=2OC)C=CC=1C(NS(C1C(C(F)(F)F)=NN(C)C=1)(=O)=O)C.[Cl:77][C:78]1[CH:79]=[CH:80][C:81]([O:94][CH3:95])=[C:82]([C:84]2[CH:89]=[CH:88][C:87]([CH:90]([NH2:92])[CH3:91])=[C:86]([F:93])[CH:85]=2)[CH:83]=1.[F:96][C:97]1[CH:98]=[C:99]([S:104](Cl)(=[O:106])=[O:105])[CH:100]=[CH:101][C:102]=1[F:103]>>[Cl:77][C:78]1[CH:79]=[CH:80][C:81]([O:94][CH3:95])=[C:82]([C:84]2[CH:89]=[CH:88][C:87]([CH:90]([NH2:92])[CH3:91])=[C:86]([F:93])[CH:85]=2)[CH:83]=1.[Cl:77][C:78]1[CH:79]=[CH:80][C:81]([O:94][CH3:95])=[C:82]([C:84]2[CH:89]=[CH:88][C:87]([CH:90]([NH:92][S:104]([C:99]3[CH:100]=[CH:101][C:102]([F:103])=[C:97]([F:96])[CH:98]=3)(=[O:106])=[O:105])[CH3:91])=[C:86]([F:93])[CH:85]=2)[CH:83]=1
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Agent: C=CCc1cc(C(C)N)ccc1-c1cc(F)ccc1OC
Agent: CC(N)c1ccc(Br)cc1Cl
Agent: COc1ccc(Cl)cc1-c1ccc(C(C)N)c(F)c1
Product: COc1ccc(Cl)cc1-c1ccc(C(C)NS(=O)(=O)c2ccc(F)c(F)c2)c(F)c1

Procedure:
1-(5′-Chloro-3-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine was prepared in a similar manner to 1-(2-allyl-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine (Example 34) using 1-(4-bromo-2-chloro-phenyl)-ethylamine instead of 1-(4-bromo-2-fluoro-phenyl)-ethylamine and 5-chloro-2-methoxyphenyl boronic acid instead of 5-fluoro-2-methoxyphenyl boronic acid. The title compound was prepared in a similar manner to 1-methyl-3-trifluoromethyl-1H-pyrazole-4-sulfonic acid [1-(3,5′-difluoro-2′-methoxy-biphenyl-4-yl)-ethyl]-amide (Example 30) using 1-(5′-chloro-3-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine and 3,4-di-fluorophenyl sulfonyl chloride instead of 1-methyl-3-trifluoromethyl-1H-pyrazole-4-sulfonyl chloride. 1H NMR (400 MHz, CDCl3): δ 7.55-7.41 (m, 2H), 7.28 (q, 1H), 7.17 (d, 1H), 7.12-6.99 (m, 4H), 6.89 (d, 1H), 5.16 (d, 1H), 4.73 (dq, 1H), 3.80 (s, 3H), 1.55 (d, 3H) ppm; MS (ESI) m/z: 478.0 [M+Na]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:21]([OH:25])[C:22](O)=[O:23])=[O:18])[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:40]([C:49]([CH3:52])([CH3:51])[CH3:50])[C:41](=[O:48])[C@@H:42]1[CH2:46][C@H:45]([Br:47])[CH2:44][NH:43]1)=O)(C)(C)C>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C@H:21]([OH:25])[C:22]([N:43]1[CH2:44][C@@H:45]([Br:47])[CH2:46][C@H:42]1[C:41]([NH:40][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:48])=[O:23])=[O:18])[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O
Reactant: CC(C)(C)OC(=O)N(C(=O)[C@@H]1C[C@H](Br)CN1)C(C)(C)C
Product: CC(C)(C)NC(=O)[C@@H]1C[C@H](Br)CN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1

Procedure:
A procedure similar to that described in Example 1 was repeated, except that (2S,3S)-3-(N2 -benzyloxycarbonyl-L-asparaginyl)amino-2-hydroxy-4-phenylbutyric acid (prepared as described in Preparation 1) and (4S)-N-t-butoxycarbonyl-4-bromo-N-t-butyl-L-prolinamide (prepared as described in Preparation 8) were used as starting materials, in relative proportions similar to those used in that Example, to obtain the title compound as colorless powdery crystals, melting at 100°-105° C.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].Cl[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:14]([CH2:27][CH3:28])[N:15]=[C:16]2[C:25]=1[C:24]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:18]=[C:17]2[NH2:26].[I-].[Na+]>CN(C=O)C>[NH2:26][C:17]1[C:16]2=[N:15][N:14]([CH2:27][CH3:28])[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[C:25]2[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:18]=1
Reactant: CCn1nc2c(N)nc3ccccc3c2c1CCCCCl
Reactant: CS(N)(=O)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1nc2c(N)nc3ccccc3c2c1CCCCNS(C)(=O)=O
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 23.1 %

Procedure:
Methanesulfonamide (1.14 g, 12.0 mmol) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 480 mg, 12.0 mmol) in DMF (5 mL); the reaction was stirred for five minutes. 1-(4-Chlorobutyl)-2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-amine (0.70 g, 2.4 mmol, prepared as described in Example 19) in DMF (2 mL) and sodium iodide (90 mg, 0.6 mmol) were sequentially added. The reaction was heated at 80° C. for one hour and 90° C. for three hours, allowed to cool to ambient temperature, and poured into ice water (70 mL). A precipitate was removed by filtration, and the filtrate was washed with diethyl ether. A precipitate formed in the aqueous layer over a period of 24 hours and was isolated by filtration and washed with water to provide 200 mg of N-[4-(4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl]methanesulfonamide as tan crystals, mp 192-194° C.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[F:10].[Li]CCCC.[C:16]([S:20]([N:22]=[CH:23][CH2:24][CH:25]([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:21])([CH3:19])([CH3:18])[CH3:17].[NH4+].[Cl-]>C1COCC1.O.CCOCC>[CH3:18][C:16]([CH3:19])([S:20]([NH:22][CH:23]([C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[F:10])[CH2:24][CH:25]([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:21])[CH3:17]
Reactant: COc1cccc(F)c1Br
Reactant: CCOC(=O)C(C)CC=NS(=O)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(C)CC(NS(=O)C(C)(C)C)c1c(F)cccc1OC
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A cooled (−78° C.) solution of commercially available 2-bromo-1-fluoro-3-methoxybenzene (2.642 g; 12.90 mmol) in anh. THF (60 ml), under nitrogen, was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (8.05 ml; 12.90 mmol). The resulting solution was further stirred at −78° C. for 5 min. A solution of ethyl 4-((tert-butylsulfinyl)imino)-2-methylbutanoate (2.550 g; 10.30 mmol) in anh. THF (20 ml) was then added dropwise to the cooled reaction mixture, and stirring at −78° C. was continued for 45 min. The resulting reaction mixture was treated successively with aq. sat. NH4Cl (75 ml), Et2O (250 ml) and water (75 ml). The separated organic layer was then washed with brine (75 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=30/1) afforded ethyl 4-(1,1-dimethylethylsulfinamido)-4-(2-fluoro-6-methoxyphenyl)-2-methylbutanoate as a yellow oil. LC-MS (conditions A): tR=0.81 min. and [M+H]+: 374.02 g/mol; tR=0.83 min. and [M+H]+: 374.34 g/mol (mixture of diastereoisomers).
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:70][NH:71][C:72](=[O:75])[CH2:73][NH2:74]>CN(C=O)C>[CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:74][CH2:73][C:72]([NH:71][CH3:70])=[O:75])=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CNC(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NCC(=O)NC)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.4 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and N1-methylglycinamide (12.5 mg, 0.1 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (9 mg, 30%). LC-MS m/z 592 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1)[CH3:2].[F:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[S:21]([C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)(=[O:23])=[O:22])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc([C@@H]2CCCN2)cc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: CCc1ccc(C2CCCN2S(=O)(=O)c2ccc(F)cc2)cc1

Procedure:
The title compound, white solid, m.p. 93° C. and MS: m/e=334.2 (M+H+) was prepared in accordance with the general method of example 1e from (S)-2-(4-ethyl-phenyl)-pyrrolidine and 4-fluoro-benzenesulfonyl chloride.
Reaction SMILES: [ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:29]1([CH2:35][CH2:36][CH2:37][CH2:38]OS(C)(=O)=O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([CH2:38][CH2:37][CH2:36][CH2:35][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CS(=O)(=O)OCCCCc1ccccc1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Agent: Cl
Product: O=C1N(CCCCc2ccccc2)CN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2

Procedure:
The title compound, white solid, m. p. 115° C. and MS: m/e=502.5 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and methanesulfonic acid 4-phenyl-but-1-yl ester.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:23])=[O:22])=[CH:17][CH:16]=2)[C:6]=1[CH3:24].[OH-].[Na+]>C1COCC1.CO>[CH3:23][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:7]2[C:8]3=[N:9][CH:10]=[CH:11][CH:12]=[C:13]3[C:5]([CH2:4][C:3]([OH:25])=[O:2])=[C:6]2[CH3:24])=[CH:16][CH:17]=1)=[O:22]
Reactant: COC(=O)Cc1c(C)n(Cc2ccc(S(C)=O)cc2)c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)c2cccnc2n1Cc1ccc(S(C)=O)cc1
Reaction time: 2 h

Procedure:
To a stirred solution of [1-(4-methanesulfinyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (0.340 g, 0.95 mmol) in THF/MeOH (8 ml of a 1:1 mixture) is added 1M NaOH (2 ml) and the reaction mixture is stirred for 2 hours. The solvent is removed in vacuo and the resulting oil is dissolved in water and acidified to pH2 using concentrated HCl. A precipitate forms which is filtered, washed with water and dried in vacuo to yield the titled product. (MH+ 343)
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.C(N(CC)CC)C.[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19]>ClCCl>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]3[S:1][CH:2]=[CH:3][C:4]2=3)=[O:26])=[CH:28][CH:29]=1)([O-:20])=[O:19]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: c1cc2c(s1)CCCCN2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCCCc2sccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 10.71 g of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine and 19.4 ml of triethylamine in 150 ml of dichloromethane under argon is added in small portions 4-nitrobenzoyl chloride (exothermic). The mixture is stirred for 3 hours at 25° C. and then washed with water, sodium bicarbonate solution, brine and dried (Na2SO4). The solvent is removed, the residue dried under vacuum and recrystallized by dissolving in hot ethyl acetate and diluting with hexane. Chilling overnight and filtering gives 16 g of light brown crystals, m.p. 141°-142° C.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[O:14])[CH:9]([CH2:24][CH2:25]O)[CH2:8]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:74]=[N+:75]=[N-:76])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][C:13]([N:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:27]=[CH:28][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:8][CH:9]2[CH2:24][CH2:25][N:74]=[N+:75]=[N-:76])=[O:14])=[CH:18][CH:19]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(COc1ccc(Cl)cc1)N1CCN(Cc2ccc(F)cc2)CC1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: [N-]=[N+]=NCCC1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-2-(2-hydroxyethyl)piperazine (0.134 g, 0.33 mmol) and triphenylphosphine (0.100 g) in THF (6 mL) at 0° C. was added diethyl azodicarboxylate (0.060 mL) and diphenylphosphoryl azide (0.081 mL). The mixture was stirred at ambient temperature for 2 days, then concentrated of volatiles in vacuo. Purification by flash column chromatography on silica gel afforded 0.047 g of 1-((4-chlorophenoxy)methyl)carbonyl-2-(2-azidoethyl)-4-(4-fluorobenzyl)piperazine as a clear, colorless oil; NMR (CDCl3) 7.3 (m, 4), 7.0 (t, 2), 6.9 (d, 2), 4.7 (m, 3), 4.4 (br d, 1), 4.3 (m, 1), 10 4.1 (m, 1), 3.5-3.1 (m, 4), 2.8 (d, 1), 2.7 (d, 1), 2.1 (m, 2), 1.8 (m, 1) ppm.
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][C:4]=1[CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[O-].[Na+].[CH:36]([C:38]1[CH:47]=[CH:46][C:41]([C:42]([O:44][CH3:45])=[O:43])=[CH:40][CH:39]=1)=O>O1CCCC1>[Cl:2][C:3]1[CH:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][C:4]=1/[CH:5]=[CH:36]\[C:38]1[CH:39]=[CH:40][C:41]([C:42]([O:44][CH3:45])=[O:43])=[CH:46][CH:47]=1
Reactant: COC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(Cl)c1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: C[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(/C=C\c2ccc(C(=O)OC)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 52.6 g of (2-chloro-4-methoxycarbonylbenzyl)-triphenylphosphonium bromide in 500 ml of tetrahydrofuran was treated at 0° C. with 115 ml of 2% methanolic sodium methylate solution. Then, a solution of 16.4 g of methyl 4-formylbenzoate was added dropwise within 10 minutes and the mixture was stirred at room temperature for 1 hour. The suspension was filtered over Dicalite and the filtrate was evaporated. The residue was chromatographed using ethyl acetate/hexane/methylene chloride and gave dimethyl (Z)-2-chlorostilbene-4,4'-dicarboxylate, MS: m/z 330 (M+), and dimethyl (E)-2-chlorostilbene-4,4'-dicarboxylate as colourless crystals, m.p. 134°-135° C., MS: m/z 330 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][CH:10]=[C:9]2[CH3:23])=[CH:4][CH:3]=1.[Cl:24]N1C(=O)CCC1=O>C1COCC1>[Cl:24][C:10]1[CH:11]=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]=1[CH3:23]
Reactant: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: Cc1c(Cl)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Temperature: 20 °C
Reaction time: 18 h
Yield: 9.7 %

Procedure:
To a solution of 1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole (Example 1) (1 g, 3.03 mmol) in THF (100 ml) at -70° C., N-chlorosuccinimide (488 mg, 3.65 mmol) was added over 10 minutes. The reaction mixture was warmed to 20° C. over 3 hours and stirred for 18 hours. More N-chlorosuccinimide (450 mg, 3.37 mmol) was added and the mixture was stirred for 6 hours. After dilution with aqueous potassium carbonate, the reaction mixture was extracted with ethyl acetate. The organic fractions were washed with water, dried (MgSO4), filtered and concentrated. The crude dark orange solid (1.3 g) was purified by chromatography (silica gel, hexane/ethyl acetate, 1/1) to give 3-chloro-1-(4-fluorophenyl)-2-methyl-5-[-4-(methylsulfonyl)phenyl]-1H-pyrrole (107 mg, 10%): mp (DSC) 172° C. Anal Calc'd. for C18H15NSClFO2 : C, 59.42; H, 4.16; N, 3.85. Found: C, 59.21; H, 4.10; N, 3.56.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])N.[CH:12]([C:15]([CH3:17])=O)([CH3:14])[CH3:13]>C(O)C.S(=O)(=O)(O)O>[CH3:17][C:15]1[C:12]([CH3:14])([CH3:13])[C:4]2[C:3](=[CH:11][CH:10]=[CH:9][C:5]=2[C:6]([OH:8])=[O:7])[N:1]=1
Reactant: CC(=O)C(C)C
Reactant: NNc1cccc(C(=O)O)c1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CC1=Nc2cccc(C(=O)O)c2C1(C)C
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A solution of 3-hydrazinobenzoic acid (30.0 g, 197 mmol), isopropylmethylketone (31.7 mL, 296 mmol) in ethanol (500 mL) and sulfuric acid (5 mL) was heated under reflux in an oil bath for 20 h. After cooling to ambient temperature the solvent was evaporated off under reduced pressure to a small volume of ˜200 mL. Collected the solid with a filter funnel, washed with iPrOH (3×30 mL) and ethyl ether (3×30 mL) and dried. Further drying of the solid in an oven at 45° C. under high vacuum for 18 h provided 32.59 g (81.3%) of the product.
Reaction SMILES: [CH:1]([N:4]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:7](=[O:21])[C:6]([C:22](O)=[O:23])=[CH:5]1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:58][CH2:59][C:60]1[CH:65]=[CH:64][C:63]([S:66](=[N:71][CH3:72])([N:68]([CH3:70])[CH3:69])=[O:67])=[CH:62][CH:61]=1>CN(C=O)C.O>[CH3:69][N:68]([CH3:70])[S:66]([C:63]1[CH:64]=[CH:65][C:60]([CH2:59][NH:58][C:22]([C:6]2[C:7](=[O:21])[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:20])[F:19])[CH:12]=3)=[C:9]([CH3:10])[N:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=2)=[O:23])=[CH:61][CH:62]=1)(=[N:71][CH3:72])=[O:67]
Reactant: Cc1c(-c2cccc(C(F)(F)F)c2)c(=O)c(C(=O)O)cn1C(C)C
Reactant: CN=S(=O)(c1ccc(CN)cc1)N(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[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: CN=S(=O)(c1ccc(CNC(=O)c2cn(C(C)C)c(C)c(-c3cccc(C(F)(F)F)c3)c2=O)cc1)N(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 1-isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-3-carboxylic acid (preparation 9.2, 186 mg, 0.55 mmol) in DMF (5 mL) is treated with DIPEA (300 μL, 1.72 mmol) and stirred at room temperature for 10 min. HBTU (312 mg, 0.82 mmol) is added, and the mixture is stirred for 20 min. A solution of 4-(aminomethyl)-N,N,N′-trimethylbenzenesulfonimidamide (preparation 60d, 156 mg, 0.69 mmol) in DMF (0.5 mL) is added and the mixture is stirred for 2 h. Water is added and the mixture is extracted with dichloromethane. The organic layer is dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by preparative reversed phase HPLC (Xbridge, gradient of acetonitrile in water, 0.1% TFA). Yield: 41 mg (11% of theory); ESI mass spectrum: [M+H]+=549; r.t. HPLC: 1.17 min (Z001_005).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([O:8][CH3:9])[CH:7]=1.[CH3:11][C:12]([CH3:14])=[O:13].[Li]CCCC>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]([OH:13])([CH3:14])[CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Br)ccc1I
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(Br)ccc1C(C)(C)O
Temperature: -78 °C
Reaction time: 2 h
Yield: 25.4 %

Procedure:
To a solution of 5-bromo-2-iodoanisole (668 mg, 2.14 mmol) and acetone (0.471 mL, 6.40 mmol) in tetrahydrofuran (7.62 mL) at −78° C. was added n-BuLi (2.5M in hexane, 0.940 mL, 2.35 mmol) in a dropwise manner. The reaction mixture was stirred at −78° C. for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride, warmed to room temperature and extracted with ethyl acetate (2×). The combined organic layers were dried over magnesium sulfate and filtered, and concentrated under reduced pressure yielding 680 mg of crude oil. Purification by column chromatography (0-10% ethyl acetate/heptanes) afforded the title compound (133 mg, 25% yield) as a clear, colorless oil. MS (ES+) 226.9 (M−H2O+H)+. 1H NMR (400 MHz, CDCl3) δ: 7.20 (d, 1H), 7.06-7.10 (m, 1H), 7.04 (d, 1H), 3.91 (s, 3H), 1.58 (s, 6H).