Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C1COCC1>[I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: BrCc1ccccc1I
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: Ic1ccccc1CN1CCNCC1

Procedure:
Synthesized according to General Procedure A: 2-iodobenzyl bromide (4{27}, 4.92 g, 16.8 mmol, 1 equiv.), piperazine (8.70 g, 101.0 mmol, 6 equiv.), THF (36.7 mL). Purification with flash column chromatography on silica gel (4:1 EtOAc:MeOH) afforded 5{27} (4.43 g, 89%) as a light yellow liquid. 1H-NMR (400 MHz, CDCl3): δ 7.80 (dd, 1H, J=1.2, 8.0 Hz) 7.39 (dd, 1H, J=1.2, 7.6 Hz), 7.30-7.26 (m, 1H), 6.91 (dt, 1H, J=1.2, 7.2 Hz), 3.47 (s, 2H), 2.86 (t, 4H, J=4.8 Hz), 2.46 (br s, 4H), 1.76 (br s, 1H). 13C-NMR (100 MHz, CDCl3): δ 140.4, 139.3, 130.2, 128.6, 127.8, 100.6, 66.9, 54.3, 46.0.
Reaction SMILES: [CH2:1]([N:4]([CH3:30])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:19]([C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=2)(O)[CH:20]=[CH2:21])=[C:16]([OH:18])[CH:17]=1)[CH:2]=[CH2:3].O>CC1C=CC=CC=1C>[CH2:1]([N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]2[C:15]([C:19]([C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[CH:20][CH2:21][O:18]2)=[CH:14][CH:13]=1)[CH3:30])[CH:2]=[CH2:3]
Reactant: C=CCN(C)CCCCCCOc1ccc(C(O)(C=C)c2ccc(Br)cc2)c(O)c1
Solvent: Cc1ccccc1C
Solvent: O
Product: C=CCN(C)CCCCCCOc1ccc2c(c1)OCC=C2c1ccc(Br)cc1
Yield: 72 %

Procedure:
A solution of 0.26 g of (RS)-5-[6-(allyl-methyl-amino)-hexyloxy]-2-[1-(4-bromo-phenyl)-1-hydroxy-allyl]-phenol in 50 ml of o-xylene is boiled at 170° C. on a water separator for 2 hrs., evaporated and the residue is purified over silica gel with methylene chloride/methanol 95:5. There is obtained 0.18 g of allyl-[6-[4-(4-bromo-phenyl)-2H-chromen-7-yloxy]-hexyl]-methyl-amine, MS: m/e 456 (M+H+, 1 Br).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[NH:10][C:4]=2[CH:3]=1.[CH3:17][O:18][C:19](Cl)=[O:20]>CN(C=O)C.C(OCC)(=O)C.O>[CH3:17][O:18][C:19]([N:10]1[C:4]2[CH:3]=[C:2]([Br:1])[N:7]=[CH:6][C:5]=2[CH:8]=[C:9]1[C:11]1[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=1)=[O:20]
Reactant: Cn1cc(-c2cc3cnc(Br)cc3[nH]2)cn1
Reactant: COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)n1c(-c2cnn(C)c2)cc2cnc(Br)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
6-Bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine (Preparation 22, 100 mg, 0.36 mmol) was dissolved in dry DMF (1 ml). The solution was degassed and a solution of sodium bis(trimethylsilyl)amide (0.55 ml of a 1M solution in THF, 0.55 mmol) was added. After 20 minutes reaction, methylchloroformate (52 mg, 0.55 mmol) was added and the reaction stirred for 2 hours at room temperature. The reaction was diluted with ethyl acetate and water. The organic solution was washed with brine, dried over sodium sulphate and concentrated in vacuum. The crude product was purified on silica gel column chromatography eluting with 20% hexane in ethyl acetate followed by 2% methanol in ethyl acetate to afford the title compound as a white powder (95 mg, 79%). 1H NMR (500 MHz, CDCl3) 3.96 (s, 3H), 4 (s, 3H), 6.57 (s, 1H), 7.63 (s, 1H), 7.64 (s, 1H), 8.1 (s. 1H), 8.53 (s, 1H)
Reaction SMILES: [C:1]([O:14][C@H:15]([CH2:97][O:98][C:99](=[O:111])[CH2:100][CH2:101][CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][CH2:107][CH2:108][CH2:109][CH3:110])[CH2:16][S:17][CH2:18][C@H:19]([NH:79]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:20](=[O:78])[NH:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH2:34][NH:35][C:36](=[O:77])[CH:37]([CH2:56][S:57][C:58]([C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[NH:38]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].N1CCCCC1>C(#N)C>[C:1]([O:14][C@H:15]([CH2:97][O:98][C:99](=[O:111])[CH2:100][CH2:101][CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][CH2:107][CH2:108][CH2:109][CH3:110])[CH2:16][S:17][CH2:18][C@H:19]([NH2:79])[C:20](=[O:78])[NH:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH2:34][NH:35][C:36](=[O:77])[CH:37]([NH2:38])[CH2:56][S:57][C:58]([C:71]1[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=1)([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCCOCCOCCOCCCNC(=O)C(CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21)OC(=O)CCCCCCCCCCC
Solvent: CC#N
Solvent: C1CCNCC1
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCCOCCOCCOCCCNC(=O)C(N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1)OC(=O)CCCCCCCCCCC
Reaction time: 0.5 h

Procedure:
A solution of (23R,27R)-23-(((9H-fluoren-9-yl)methoxy)carbonylamino)-1-(9H-fluoren-9-yl)-3,6,22-trioxo-5-(tritylthiomethyl)-2,11,14,17-tetraoxa-25-thia-4,7,21-triazaoctacosane-27,28-diyl didodecanoate in acetonitrile (0.1M) was stirred at room temperature. Piperidine (final conc. 20%) was then added and the reaction stirred for 30 minutes. After concentration, the product was purified by flash chromatography on an ISCO COMBIFLASH® system using an initial gradient of 0-100% EtOAc, then 0-10% MeOH/DCM to give (22R,26R)-4,22-diamino-5,21-dioxo-1,1,1-triphenyl-10,13,16-trioxa-2,24-dithia-6,20-diazaheptacosane-26,27-diyl didodecanoate.
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]2[NH:22][C:21](=[O:23])[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=3)[N:19]=2)=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+].Cl>C(O)C.O>[CH3:32][O:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH2:24][N:20]1[C:21](=[O:23])[NH:22][C:18]([CH2:17][CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:33])=[O:3])=[CH:14][CH:13]=2)=[N:19]1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCCc2nn(Cc3cccc(OC)c3)c(=O)[nH]2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cccc(Cn2nc(CCCc3ccc(OC(C)(C)C(=O)O)cc3)[nH]c2=O)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
2-(4-{3-[1-(3-Methoxy-benzyl)-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl]-propyl}-phenoxy)-2-methyl-propionic acid ethyl ester (1.55 g, 3.42 mmol) was dissolved in a mixture of ethanol (7.5 mL) and water (7.5 mL). Solid sodium hydroxide (0.36 g, 8.73 mmol) was added in one portion and the solution was warmed to 70° C. and stirred for 1 h. The solution was cooled to rt and the pH adjusted to 7 with 6N HCl. The solution was concentrated to an oil, which was partitioned between 1N HCl (10 mL) and ethyl acetate (15 mL). The aqueous layer was then reextracted with ethyl acetate (15 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo at 50° C. to afford the title compound as an oil (1.41 g, 97.0%). 1H NMR (DMSO-d6) δ 13.0 (broad s, 1 H), 11.47 (s, 1 H), 7.23 (t, 1 H, J=8 Hz), 7.03 (d, 2 H, J=8 Hz), 6.82 (d, 1 H, J=2 Hz), 6.75 (m, 5 H), 4.73 (s, 2 H), 3.70 (s, 3 H), 3.35 (broad s, 1 H), 2.48 (t, 2 H, J=8 Hz), 2.36 (t, 2 H, J=8 Hz), 1.80 (quint, 2 H, J=7 Hz), 1.46 (s, 6 H); 13C NMR (DMSO-d6, 20° C.) δ 175.8, 160.0, 155.0, 154.1, 146.8, 139.8, 135.0, 130.3, 129.7, 120.1, 119.1, 113.8, 113.2, 78.9, 55.6, 47.8, 40.6, 40.5, 34.0, 28.4, 27.5, 26.2, 25.7; IR (CHCl3) 1707, 1603, 1509, 1159 cm−1; Anal. Calcd. for C23H27N3O5: C, 64.93; H, 6.40; N, 9.88. Found: C, 65.02; H, 6.65; N, 9.57.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[C:16]([NH2:18])=[O:17])[N:12]([CH2:19][CH:20]([CH3:22])[CH3:21])[N:11]=[CH:10]3)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.N1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>C1COCC1>[F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[C:16]([N:18]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[O:17])[N:12]([CH2:19][CH:20]([CH3:22])[CH3:21])[N:11]=[CH:10]3)=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(N)=O)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(=O)N3CCOCC3)cc21
Reaction time: 18 h
Yield: 93 %

Procedure:
A solution of 5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (compound 10g, prepared as described in Example 46) in THF was treated with carbonyldiimidazole (1.2 equivalents) at room temperature under nitrogen atmosphere. After stirring for 18 hours, the reaction was treated with morpholine (1 equivalent). After an additional 18 hours, the solvent was allowed to slowly evaporate and the residue was purified in a Sep Pak cartridge eluting with a gradient of 100% CH2Cl2 to MeOH/CH2Cl2 to provide compound 11g-2 as an oil in 93% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:40])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:53][S:54]([NH2:57])(=[O:56])=[O:55].[H-].[Na+].Cl>CN(C)C=O.O>[CH3:53][S:54]([NH:57][C:35]([C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:40])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])=[CH:32][CH:33]=1)=[O:36])(=[O:56])=[O:55]
Reactant: CS(N)(=O)=O
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(=O)NS(C)(=O)=O)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 6.9 %

Procedure:
A solution of rac 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid prepared in Example 232 (0.14 g, 0.24 mmol) and CDI (97 mg, 0.6 mmol) in N,N-dimethylformamide (5 mL) was heated at 60° C. for 2 h, then to this solution was added a mixture of methanesulfonamide (0.14 g, 1.43 mmol) and NaH (60% in mineral oil, 63 mg, 1.58 mmol), which had been stirred at room temperature for 2 h. The resulting mixture was stirred at room temperature for 1 h, then poured into water. The mixture was acidified to “pH” 1-2 by addition of aqueous HCl solution, then partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-methanesulfonylaminocarbonyl-phenyl)-amide as a white solid (11 mg, 7%).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4].Cl.[NH2:12][C:13]([NH2:15])=[NH:14]>CS(C)=O>[N:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]1[N:4]=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=2)[N:12]=[C:13]([NH2:15])[N:14]=1
Reactant: N#Cc1ccccn1
Reactant: N=C(N)N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1nc(-c2ccccn2)nc(-c2ccccn2)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.0 g (approximately 60% dispersion in paraffin oil, about 25 mmol) of sodium hydride is added in portions to a mixture of 5.21 g (50 mmol) of 2-cyanopyridine and 2.39 g (25 mmol) of guanidine hydrochloride in 100 ml of dimethyl sulfoxide. Stirring is carried out for 2 hours at room temperature, and then for 23 hours at 75° C. The mixture is cooled and poured into 100 ml of ice-water and filtered, yielding 4,6-di-pyrid-2-yl-[1,3,5]triazin-2-ylamine in the form of a white solid after drying in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].CO[C:12]1[CH2:17][CH:16]=[C:15]([CH2:18][CH3:19])[CH2:14][CH:13]=1.II>O1CCCC1.ClC1C=CC=CC=1.C(O)(=O)C.CCCCCCC.C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=1
Reactant: Cc1cccc(Cl)c1N
Reactant: CCC1=CCC(OC)=CC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: II
Solvent: Clc1ccccc1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: CCc1ccc(Nc2c(C)cccc2Cl)cc1
Temperature: -35 °C
Reaction time: 3 h

Procedure:
A solution of 3.0 g 2-Chloro-6-methyl-aniline in 3.5 ml of tetrahydrofuran and 31 ml of chlorobenzene is cooled down to −40 to −45° C. At this temperature, 4.01 g of titanium-tetrachloride is added to the solution, followed by the addition of 6.18 g of 1-Methoxy-4-ethylcyclohexa-1,4-diene. The reaction mixture is allowed to warm up to approx. −35° C. and stirred for 3 hours at this temperature. A solution of 8.06 g of iodine in 16.4 ml of tetrahydrofuran and 1.8 ml of acetic acid is added to the reaction mixture and the temperature is allowed to warm up to 0° C. The mixture is stirred for 30 minutes at 0° C. and 2 hours at 25° C. Then 2.68 g of iodine is added to the reaction mixture and stirring is continued for additional 24 hours at 25° C. Again, 2.68 g of iodine is added and stirring is continued for additional 72 hours at 25° C. The reaction is finally quenched by pouring the reaction mixture onto a mixture of 250 ml of aqueous sodium bisulfite (38-40%) and 450 ml of saturated aqueous sodium carbonate. The water phase is extracted with ethyl acetate (1×200 ml and 2×100 ml), the ethyl acetate phases are unified and washed with 100 ml of brine. The organic phase was dried over anhydrous sodium sulfate and evaporated in vacuo to give a dark viscous liquid. The liquid was dissolved in heptane/toluene and the solution was filtered over silicagel to obtain, after evaporation of the solvent, 2.0 g of crude product. The product can be used directly in the next step. Alternatively, it can be purified e.g. by column chromatography on silica gel with heptane/toluene (7:3) as eluent to yield pure N-(2′-Chloro-6′-methyl-phenyl)-4-ethylaniline.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[C:4]([C:6]1[C:7]([CH3:20])=[CH:8][N:9]2[C:14]=1[CH:13]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=[CH:10]2)=O>O1CCCC1>[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][C:6]1[C:7]([CH3:20])=[CH:8][N:9]2[C:14]=1[CH:13]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=[CH:10]2
Reactant: CCOC(=O)c1ccn2cc(C)c(C(=O)c3ccc(Cl)cc3Cl)c2c1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccn2cc(C)c(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 59.3 %

Procedure:
Ethyl 1-(2,4-dichlorobenzoyl)-2-methylindolizine-7-carboxylate (3.17 g) was dissolved in tetrahydrofuran (32 ml), and a 10M borane-dimethyl sulfide complex (9.5 ml) was dropwise added under ice-cooling. The mixture was stirred at room temperature for 3.5 hr, neutralized and partitioned between ethyl acetate and water. The organic layer was washed three times with water and then with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=19/1) to give the objective compound (1.81 g) as a pale-yellow oil.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[C:14]([CH2:15][CH2:16][CH2:17][CH3:18])=[CH:13][S:12][CH:11]=1.CN([CH:22]=[O:23])C>C1COCC1>[Br:9][C:10]1[C:14]([CH2:15][CH2:16][CH2:17][CH3:18])=[CH:13][S:12][C:11]=1[CH:22]=[O:23]
Reactant: CN(C)C=O
Reactant: CCCCc1cscc1Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCc1csc(C=O)c1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
To a solution of freshly prepared LDA (11.40 mmol) in THF (7 mL) at -78° C. was added slowly 3-bromo-4-butylthiophene of Example l(a) (2.50 g, 11.40 mmol) in THF (10 mL). After stirring for 15 min, DMF (0.94 mL, 12.10 mmol) in THF (2 mL) was dropwise added. The resulting mixture was stirred for 1 h at -78° C. and then allowed to warm to room temperature. The reaction was quenched with water and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with H2O, brine and dried (MgSO4). After removing the solvent under reduced pressure, column chromatography (silica gel, EtOAc/Hexane, 20:80) of the residue afforded the title compound as an oil (1.87 g, 60%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH:3]([CH3:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].Br[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH3:31])=[CH:26][CH:25]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH2:30]([C:27]1[CH:28]=[CH:29][C:24]([CH:4]([CH:3]([CH3:10])[C:2]([F:11])([F:12])[F:1])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:25][CH:26]=1)[CH3:31]
Reactant: CCOC(=O)CC(C)C(F)(F)F
Reactant: CCc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(c1ccc(CC)cc1)C(C)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under argon, a solution of 1.29 g (7.02 mmol) of (+/−)-ethyl 4,4,4-trifluoro-3-methylbutanoate in 2 ml of abs. toluene was added dropwise to 8.1 ml of a 1 M solution, cooled to −10° C., of lithium hexamethyldisilazide in toluene (8.1 mmol). After 10 min at −10° C., a mixture of 1.0 g (5.4 mmol) of 1-bromo-4-ethylbenzene, 36.4 mg (0.16 mmol) of palladium(II) acetate and 134 mg (0.34 mmol) of 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl in 5 ml of abs. toluene was added to this reaction mixture. After the addition had ended, the mixture was warmed to RT and then stirred first at RT for 1 h and then at 80° C. for a further 3 h. After cooling to RT, the precipitated salts were filtered off with suction, the residue was washed with toluene and the combined filtrates were concentrated under reduced pressure. This gave 1.26 g of crude product (80.9% of theory) which was reacted as such.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][CH2:13][CH:12]=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:24])C=1.ClC1C=C(C=CC=1)C(O)=O>ClCCl>[C:1]1([CH3:15])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH2:14][CH:13]3[CH:12]([O:24]3)[CH2:11]2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N2C=CCC2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C(O)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CC3OC3C2)cc1
Temperature: 5 °C

Procedure:
334.5 g (1.5 mol) of 1-(toluene-4-sulphonyl)-pyrroline are dissolved in 1.5 l of dichloromethane at room temperature and treated in the course of 15 minutes with a suspension of 408 g (about 1.65-1.77 mol) of 70-75% strength m-chloroperbenzoic acid in 900 ml of dichloromethane (cools during preparation). The mixture is heated under reflux for 16 hours (test for peroxide with KI/starch paper still indicates peroxide content), the suspension is cooled to 5° C., and the precipitated m-chlorobenzoic acid is, filtered off with suction and washed with 300 ml of dichloromethane (peroxide test with precipitate: negative; precipitate discarded). The filtrate is washed twice with 300 ml of 10% strength sodium sulphite solution in each case to destroy excess peroxide (test for peroxide is now negative), extracted with 300 ml of saturated sodium bicarbonate solution, washed with water, dried using sodium sulphate and concentrated to about a quarter of the volume. Test for peroxide again: negative. The mixture is concentrated and the solid residue is stirred with 400 ml of isopropanol with ice-cooling, and the precipitate is filtered off with suction and dried in vacuo at 70° C.
Reaction SMILES: C[O-].[Na+].[CH:4]([O:6][CH3:7])=[O:5].[F:8][C:9]([F:30])([F:29])[C:10]1[N:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][C:25](OC)=[O:26])[CH:13]=[CH:12][CH:11]=1.O>C1(C)C=CC=CC=1>[F:29][C:9]([F:8])([F:30])[C:10]1[N:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2/[C:24](=[CH:25]\[OH:26])/[C:4]([O:6][CH3:7])=[O:5])[CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)Cc1ccccc1COc1cccc(C(F)(F)F)n1
Reactant: COC=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)/C(=C/O)c1ccccc1COc1cccc(C(F)(F)F)n1
Reaction time: 6 h
Yield: 94.8 %

Procedure:
Sodium methoxide (0.725 g, 13 mmol) and methyl formate (0.8 ml, 13 mmol) were added portionwise to a stirred solution of methyl 2-(6-trifluoromethylpyrid-2-yloxymethyl)phenylacetate (2.0 g, 6.0 mmol) in dry toluene (15 ml) under a nitrogen atmosphere at room temperature. After 6 hours at room temperature, the mixture was poured into water and extracted with diethyl ether. The ether extracts were washed with water, dried and the ether removed to give (E)-methyl 2-[2-(6-trifluoromethylpyrid-2-yloxymethyl)phenyl]-3-hydroxyacrylate (2.01 g, 95%) as a yellow gum which was used in the next stage without further purification; 1H NMR (270 MHz)δ: 3.75(3H,s), 5.34(2H,s), 6.90(1H,d), 7.15-7.75(7H,m), 11.95(1H,d) ppm.
Reaction SMILES: [OH-].[Li+].[O:3]1[CH2:8][CH2:7][CH2:6][O:5][CH:4]1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]3[CH:23]=[C:22]([C:24]([O:26]C)=[O:25])[CH:21]=[CH:20][C:18]=3[N:19]=2)=[C:11]([F:28])[CH:10]=1>C1COCC1>[O:5]1[CH2:6][CH2:7][CH2:8][O:3][CH:4]1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]3[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[CH:20][C:18]=3[N:19]=2)=[C:11]([F:28])[CH:10]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2c1

Procedure:
Lithium hydroxide (1M in H2O, 0.80 mL, 0.80 mmol) and methyl 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)benzo[d]thiazole-6-carboxylate (0.25 g, 0.67 mmol) were stirred in THF (5 mL) for 3 d. The reaction mixture was concentrated under vacuum, the resulting oil was dissolved in a minimum amount of water, and the solution was made acidic with 5 N HCl (aq). The resulting suspension was filtered and the collected solid was dried to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)benzo[d]thiazole-6-carboxylic acid an off-white solid. MS (ESI) m/z: Calculated: 359.1; Observed: 360.4 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C@H:14]([N+:15]([O-])=O)[CH2:13][C:12]([CH2:18][NH:19][C:20]([C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=2)=[O:21])=[CH:11][CH2:10]1>[Zn].CO.C(O)(=O)C>[NH2:15][C@@H:14]1[CH2:13][C:12]([CH2:18][NH:19][C:20]([C:22]2[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)=[O:21])=[CH:11][CH2:10][C@H:9]1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: COC(=O)c1ccc(C(=O)NCC2=CC[C@@H](c3ccc(Cl)cc3Cl)[C@H]([N+](=O)[O-])C2)cc1
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: N[C@@H]1CC(CNC(=O)c2ccc(C(=O)O)cc2)=CC[C@H]1c1ccc(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 31.4 %

Procedure:
To a solution of Example 15A (35 mg, 0.076 mmol) in mixture of methanol/acetic acid (0.5 mL/0.5 mL), Zn powder (49 mg, 0.76 mmol) was added at room temperature. The reaction mixture was stirred for 30 minutes, filtered, concentrated under reduced pressure and purified by high pressure liquid chromotography (eluting with 0-70% acetonitrile/water and 0.1% trifluoroacetic acid) to provide the title compound (10 mg, 32%). 1H NMR (300 MHz, methanol-d4) δ ppm 8.06-8.16 (m, 2H), 7.88-7.97 (m, 2H), 7.52-7.59 (m, 1H), 7.37-7.49 (m, 2H), 7.10-7.24 (m, 1H), 5.78-5.87 (m, 1H), 3.97-4.06 (m, 2H), 3.83-3.95 (m, 1H), 3.49-3.62 (m, 1H), 2.25-2.61 (m, 4H). MS (ESI) m/z 419 (M+H)+.