Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([C:6]1[CH:38]=[CH:37][CH:36]=[CH:35][C:7]=1[O:8][C:9]1[C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:22][C:12]2[NH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[N:15][C:11]=2[CH:10]=1)=O)C.[F:39]C1C=CC=CC=1O>>[F:39][C:6]1[CH:38]=[CH:37][CH:36]=[CH:35][C:7]=1[O:8][C:9]1[C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:22][C:12]2[NH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[N:15][C:11]=2[CH:10]=1
Reactant: CCOC(=O)c1ccccc1Oc1cc2nc(-c3ccccn3)[nH]c2cc1Oc1ccc(S(C)(=O)=O)cc1
Reactant: Oc1ccccc1F
Product: CS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2ccccc2F)cc1

Procedure:
The entitled compound was obtained as a colorless solid in the same method as in Example 196 (step 4) to (step 6) or in accordance with the method or by combining it with an ordinary method but using 5-fluoro-4-(4-methanesulfonyl-phenoxy)-2-nitro-phenylamine obtained in Example 14 and 2-fluorophenol.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:8][C:7]=1[Br:21].[H-].C([Al+]CC(C)C)C(C)C.CO.Cl>C(Cl)Cl>[C:15]1([S:12]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][CH:3]=[O:2])=[C:7]([Br:21])[CH:8]=2)(=[O:13])=[O:14])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)CCc1ccc(S(=O)(=O)c2ccccc2)cc1Br
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CO
Solvent: ClCCl
Product: O=CCCc1ccc(S(=O)(=O)c2ccccc2)cc1Br
Temperature: -78 °C
Yield: 73.5 %

Procedure:
To a solution of 3-(4-benzenesulfonyl-2-bromo-phenyl)-propionic acid methyl ester (6.73 g, 17.6 mmol) in DCM (100 mL) was added diisobutyl aluminum hydride (1.0M in toluene, 17.6 mL) at −78° C. under Argon. The reaction was maintained at −78° C. for 90 minutes, and MeOH (7 mL ca.) was then added at −78° C. The mixture was allowed to warm to room temperature. HCl (2M) was added and the mixture was extracted twice with DCM. The combined organic extracts were washed with water, dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified via flash chromatography (hexane/EtOAc, 8/2) affording 3-(4-benzenesulfonyl-2-bromo-phenyl)-propionaldehyde (4.57 g, 74% yield).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([F:27])([O:6][C:7]([F:26])([F:25])[C:8]([C:21]([F:24])([F:23])[F:22])([F:20])[O:9][C:10]([F:19])([F:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:4][OH:5].Cl[CH2:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[CH2:37])=[CH:34][CH:33]=1>>[F:1][C:2]([F:28])([F:29])[C:3]([F:27])([O:6][C:7]([F:25])([F:26])[C:8]([C:21]([F:24])([F:23])[F:22])([F:20])[O:9][C:10]([F:18])([F:19])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:4][O:5][CH2:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[CH2:37])=[CH:34][CH:33]=1
Reactant: C=Cc1ccc(CCl)cc1
Reactant: OCC(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F
Product: C=Cc1ccc(COCC(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F)cc1
Yield: 70.2 %

Procedure:
As in Example 1, 96.4 grams (0.2 mol) of 2,5-bis-trifluoromethyl-2,4,4,5,7,7,8,8,9,9,9-undecafluoro-3,6-dioxanonanol was reacted with 30.6 grams (0.2 mol) of p-chloromethylstyrene, yielding as a fraction at 96°-97° C. and 1.4×10-4 mmHg 84 grams (yield 70%) of p-(4,7-bistrifluoromethyl-4,6,6,7,9,9,10,10,11,11,11-undecafluoro-2,5,8-trioxaundecyl)styrene. ##STR13##
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16](OC)=[O:17])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1.C1(C)C=CC=CC=1>[OH:17][CH2:16][C:15]1[CH:20]=[CH:21][C:12]([CH2:11][CH2:10][C:8]2[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][CH:7]=2)=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc(CCc2csc(NC(C)=O)n2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1nc(CCc2ccc(CO)cc2)cs1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
To a stirred solution of methyl 4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}benzoate (1.8 g) in dry tetrahydrofuran (36 ml) was added dropwise 1.0 M diisobutylaluminium hydride solution in toluene (20.7 ml) at −78° C. over 15 minutes under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1.5 hours, and then the reaction was quenched with water (1 ml). The mixture was stirred at room temperature for 30 minutes, dried over anhydrous magnesium sulfate, and filtered through a pad of Celite. The solvent was evaporated in vacuo. The residual solid was washed with ethyl ether to give N-(4-{2-[4-(hydroxymethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (1.03 g) as a colorless solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[CH:8]=2)[NH:3]1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH:29]=O)[CH:27]=2)[CH:22]=[N:21]1.N1CCCCC1>CO>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26](/[CH:29]=[C:10]3/[C:2](=[O:1])[NH:3][C:4]4[C:9]/3=[CH:8][C:7]([C:11]([NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:12])=[CH:6][CH:5]=4)[CH:27]=2)[CH:22]=[N:21]1
Reactant: O=Cc1ccc2cn[nH]c2c1
Reactant: O=C1Cc2cc(C(=O)Nc3ccccc3)ccc2N1
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2ccc(C(=O)Nc3ccccc3)cc2/C1=C\c1ccc2cn[nH]c2c1
Temperature: 60 °C
Yield: 24.2 %

Procedure:
A scintillation vial was charged with 2-oxo-N-phenylindoline-5-carboxamide (22 mg, 0.087 mmol), 1H-indazole-6-carbaldehyde (14 mg, 0.096 mmol), piperidine (1 uL, 0.008 mmol) and MeOH (2 mL). The reaction was then heated to 60° C. for 2 hrs. A yellow precipitate formed which was further precipitated by cooling to room temperature and adding more MeOH (2 mL). The yellow solid was then filtered and washed with MeOH (10 mL) to give 8.0 mg, 24% of the title compound. 1H NMR (400 MHz, d6-DMSO) δ 13.42 (s, 1H), 11.02 (s, 1H), 10.16 (s, 1H), 9.01 (s, 1H), 8.39 (s, 1H), 8.14 (s, 2H), 8.03 (d, J=7.3 Hz, 1H), 7.89-7.82 (m, 2H), 7.79 (d, J=6.5 Hz, 2H), 7.36 (t, J=6.6 Hz, 2H), 7.11-7.09 (m, 1H), 6.96 (d, J=6.9 Hz, 1H); MS ESI 381.1 [M+H]+, calcd for [C23H16N4O2+H]+ 381.14.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]/[CH:10]=[CH:11]\[CH:12]([OH:14])[CH3:13])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:21](Cl)(=[O:23])[CH3:22]>C(Cl)Cl>[C:21]([O:14][CH:12]([CH3:13])/[CH:11]=[CH:10]\[S:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: COc1ccc(S/C=C\C(C)O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(S/C=C\C(C)OC(C)=O)cc1

Procedure:
1 g (4.76 mmol) of rac-(Z)-4-[(p-methoxyphenyl)thio]-3-buten-2-ol are dissolved in 50 ml of methylene chloride. whereupon the solution is treated with 0.77 ml (9.5 mmol) of pyridine and cooled to 0° . There is added dropwise thereto a solution of 0.5 ml (7.1 mmol) of acetyl chloride in 10 ml of methylene chloride and the mixture is stirred at 0° for 1 hour. The reaction mixture is washed successively with 50 ml of 1N hydrochloric acid, 50 ml of 5 percent sodium bicarbonate solution and 50 ml of saturated sodium chloride solution, dried over sodium sulphate and evaporated. By chromatography on silica gel with hexane/ethyl acetate (9:1) there is obtained pure rac-4-[[(Z)-3-acetoxy-1-butenyl]thio]anisole; IR: 1735 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.C1C=CC=CC=1.[CH3:24][CH:25]([N:27]1[C:31]([NH2:32])=[CH:30][CH:29]=[N:28]1)[CH3:26]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:30]3[CH:29]=[N:28][N:27]([CH:25]([CH3:26])[CH3:24])[C:31]=3[N:32]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(Cl)cc1
Reactant: CC(C)n1nccc1N
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2)nc2c1cnn2C(C)C

Procedure:
The title compound was prepared in the same manner as described for intermediate 61 using ethyl 4-(4-chlorophenyl)-2,4-dioxobutanoate (610 mg, 2.397 mmol), benzene (5 mL), 1-(1-methylethyl)-1H-pyrazol-5-amine (300 mg, 2.397 mmol), and acetic acid (4 mL). The crude product was purified by column chromatography (Silica gel, eluent: 0 to 100% EtOAc/hexanes) to give 621 mg (75%) of product. LCMS E-S (M+H)=344.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.48-1.57 (m, 3H), 1.64-1.74 (m, 6H), 4.56 (q, J=7.1 Hz, 2H), 5.46 (m, 1H), 7.49-7.55 (m, 2H), 8.15-8.18 (m, 2H), 8.21 (s, 1H), 8.42 (s, 1H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:15][N:16]1[C:22](=[O:23])[N:21]2[CH2:24][C@H:17]1[CH2:18][CH2:19][C@H:20]2[C:25]1[O:29][N:28]=[C:27]([CH:30]2[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]2)[N:26]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH2:8]([O:15][N:16]1[C:22](=[O:23])[N:21]2[CH2:24][C@H:17]1[CH2:18][CH2:19][C@H:20]2[C:25]1[O:29][N:28]=[C:27]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[N:26]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2noc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1N2C[C@@H](CC[C@H]2c2nc(C3CCNCC3)no2)N1OCc1ccccc1
Reaction time: 2 h
Yield: 143.4 %

Procedure:
CF3COOH (4 mL) was added to the solution of tert-butyl 4-(5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate (960 mg, 2.0 mmol) in 16 mL of CH2Cl2 at 0° C. The mixture was stiffed at 0° C. for 2 hrs, then concentrated to give (2S,5R)-6-(benzyloxy)-2-(3-(piperidin-4-yl)-1,2,4-oxadiazol-5-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (1.1 g) as a brown oil, which was used directly in the next step. ESI-MS (EI+, m/z): 384.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][NH2:10].[Br:11][C:12]1[S:16][C:15]2=[N:17][C:18]([C:20](O)=[O:21])=[CH:19][N:14]2[CH:13]=1>>[Br:11][C:12]1[S:16][C:15]2=[N:17][C:18]([C:20]([NH:10][CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])=[O:21])=[CH:19][N:14]2[CH:13]=1
Reactant: NCc1c(Cl)cccc1Cl
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Product: O=C(NCc1c(Cl)cccc1Cl)c1cn2cc(Br)sc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate XLIV, using (2,6-dichlorophenyl)methanamine and 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid as starting materials.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:20])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(c4ccc(Cl)cc4)CC3)cnc12
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(c4ccc(Cl)cc4)CC3)cnc12
Yield: 46.4 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-[4-(4-chlorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.09 g, 0.19 mmol) obtained in step 2 and methanesulfonamide (0.090 g, 0.950 mmol), the title compound (0.05 g, 47%) was obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([S:10](F)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].Cl.[CH3:15][NH:16][CH3:17].C(N(CC)C(C)C)(C)C>O1CCCC1.Cl>[C:1]([C:4]1[CH:5]=[C:6]([S:10]([N:16]([CH3:17])[CH3:15])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(S(=O)(=O)F)c1
Reactant: CNC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cccc(S(=O)(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.6 %

Procedure:
To a solution of 40.44 g (0.20 mol) of 3-acetylbenzenesulfonyl fluoride in 200 ml of dry tetrahydrofuran is added 20.4 g (0.25 mol) of dimethylamine hydrochloride and 43.6 ml (0.25 mol) of N,N-diisopropylethylamine. The mixture is stirred at room temperature for 48 hours, diluted with 250 ml of 1N HCl and extracted with CH2Cl2. The extract is dried (MgSO4) and the solvent removed. The residue is chromatographed (silica gel column) with CH2Cl2 -hexane (1:1). The fractions containing product are combined, the solvent removed and the residue crystallized from CH2Cl2 -hexane to give 28 g (62%) of white crystals, m.p. 73°-76° C.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5]([N:13]=[C:14]=[S:15])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)Cl>[CH2:1]([NH:4][C:14]([NH:13][C:5](=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[S:15])[CH2:2][NH:3][C:14]([NH:13][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[S:15]
Reactant: NCCN
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: O=C(NC(=S)NCCNC(=S)NC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.1 %

Procedure:
To an ice cold solution of ethane-1,2-diamine (2.23 g, 37.1 mmol) in CH2Cl2 (100 mL) is added benzoyl isothiocyanate (12.41 g, 76 mmol) dropwise and the resulting suspension is stirred at room temp for 18 h. The reaction is filtered thru a ground glass frit and the resulting solid is washed with CH2Cl2 to give 10.2 g (71%) of the title compound as a white solid. LC/MS (Condition A): ret. T=3.67 min, (M+H)+ 387.13. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.98 (2 H, br. s.), 7.86-8.01 (4 H, m), 7.60-7.72 (2 H, m), 7.47-7.58 (4 H, m), 3.88-4.09 (4 H, m).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:28][CH3:29])=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH3:30][C:31]1[N:32]=[C:33]([Sn](CCCC)(CCCC)CCCC)[S:34][CH:35]=1.[Li+].[Cl-]>O1CCOCC1.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([C:33]4[S:34][CH:35]=[C:31]([CH3:30])[N:32]=4)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:28][CH3:29])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(C)cs1
Reactant: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(-c3nc(C)cs3)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Temperature: 25 °C
Yield: 36.1 %

Procedure:
To a suspension of (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (40 mg, 0.0808 mmol, example 58) in dioxane (1.5 ml) was added a solution of 4-methyl-2-(tributylstannyl)-thiazole (38 mg, 0.0970 mmol) in dioxane (0.5 ml) and argon was bubbled through the resulting mixture for 10 minutes. Then LiCl (10 mg, 0.242 mmol) and tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.00404 mmol) were added and the mixture was stirred at reflux for 3.5 h. The reaction mixture was allowed to cool to room temperature, diluted with DCM and filtered through a pad of silica gel. The filtrate was evaporated and the remaining light brown solid was purified by silica column chromatography (DCM/EtOAc 4:1) to obtain a white solid (15 mg) which was triturated with ether to obtain the title compound (9 mg, 22%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]([OH:23])=O)[CH2:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]([Cl:26])=[O:23])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C1=NN(c2ccc(F)cc2F)C(c2ccc(Br)cc2)C1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C1=NN(c2ccc(F)cc2F)C(c2ccc(Br)cc2)C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
5-(4-bromo-phenyl)-1-(2,4-difluoro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid (10.0 g, 26.2 mmol) prepared in Step 1 was added to thionyl chloride (100.0 mL). The reaction was stirred at 100° C. for 2 hours and then concentrated under reduced pressure. The resulting residue was concentrated under reduced pressure three times, along with using toluene, to give 5-(4-bromo-phenyl)-1-(2,4-difluoro-phenyl)-4,5-dihydro-1H-pyrazole-3-carbonyl chloride as a dark brown liquid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH3:26][N:27]([CH3:32])[CH2:28][CH2:29][CH2:30][NH2:31].C(N(CC)CC)C>CN1C(=O)CCC1>[CH3:26][N:27]([CH3:32])[CH2:28][CH2:29][CH2:30][NH:31][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9]
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Reactant: CN(C)CCCN
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CN(C)CCCNc1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21
Temperature: 140 °C
Yield: 43.5 %

Procedure:
A mixture of (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (Intermediate 67, 0.15 g), 3-dimethylaminopropylamine (1.26 g) and triethylamine (0.62 g) in NMP (6 mL) was stirred and heated at 140° C. for 48 hours. After cooling, the mixture was concentrated under vacuum and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 5-10%. The resultant product was repurified by preparative TLC, eluting with a mixture of methanol and DCM (10%) to give (1aRS,7bSR)-5-[2-(3-dimethylaminopropylamino)-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.08 g) as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=[C:4]([Cl:16])[C:3]=1[NH:17][C:18]1[NH:22][C:21]2[CH:23]=[C:24]([O:30][CH2:31][CH:32]([F:34])[F:33])[C:25]([C:27]([OH:29])=O)=[CH:26][C:20]=2[N:19]=1.[Br:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1.C1COCC1>CCOC(C)=O>[Br:35][C:36]1[CH:42]=[CH:41][C:39]([NH:40][C:27]([C:25]2[C:24]([O:30][CH2:31][CH:32]([F:33])[F:34])=[CH:23][C:21]3[NH:22][C:18]([NH:17][C:3]4[C:4]([Cl:16])=[CH:5][CH:6]=[C:7]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:13])([CH3:12])[CH3:14])[C:2]=4[Cl:1])=[N:19][C:20]=3[CH:26]=2)=[O:29])=[CH:38][CH:37]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(C(=O)O)c(OCC(F)F)cc3[nH]2)c1Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(C(=O)Nc4ccc(Br)cc4)c(OCC(F)F)cc3[nH]2)c1Cl

Procedure:
PPA (0.223 mL, 50% in EtOAc, ˜0.38 mmol) is slowly added to a mixture of 2-{2,6-dichloro-3-[(2,2-dimethyl-propionylamino)-methyl]-phenylamino}-6-(2,2-difluoro-ethoxy)-1H-benzimidazole-5-carboxylic acid (0.150 g, 0.291 mmol), 4-bromoaniline (50 mg, 0.291 mmol), TEA (0.101 mL, 0.728 mmol) and THF (10 mL). The mixture is refluxed for 3 d, concentrated and purified via prep. HPLC (column: Zorbax stable bond C18, 5 μm, 30×100 mm, gradient: water+0.15% HCOOH/MeOH 95:5→10:90) to furnish the title compound.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[C:17]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.[C:28](Cl)(=[O:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[C:28]([N:2]([CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[C:17]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:1])(=[O:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCOC(=O)CC(=Cc1ccc(-c2cccc(CNC)c2)cc1)C(=O)OC
Reactant: CCCCCCC(=O)Cl
Product: CCCCCCC(=O)N(C)Cc1cccc(-c2ccc(C=C(CC(=O)OCC)C(=O)OC)cc2)c1

Procedure:
In a manner similar to that of Example 37(e), by reacting 1.5 g (4.2 mmol) of methyl ethyl 2-(3′-methylaminomethylbiphenyl-4-ylmethylene)succinate with 740 μl (4.8 mmol) of heptanoyl chloride, and after purification, 1.8 g (89%) of the expected product are obtained.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[OH-].[NH4+:12].O>C1COCC1>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:12])=[O:7])=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1ccc(I)cc1
Reaction time: 3 h
Yield: 97 %

Procedure:
Crude 4-iodobenzoyl chloride (11.4 g, 42.7 mmol) in THF (75 mL), prepared above, was treated with ammonium hydroxide (5 mL) followed by water (40 mL) at ambient temperature. The reaction mixture was stirred for 3 hours and then partitioned between EtOAc (50 mL) and brine (50 mL). The phases were separated and the organic phase was washed with 10% aqueous NaHCO3 solution (30 mL) and brine (30 mL), dried over Na2SO4, and filtered. The filtrate volume was reduced until a white solid precipitated from solution. The white solid was collected by filtration and washed with diethyl ether to provide the desired product (10.2 g, 41.4 mmol, 97%).
Reaction SMILES: CC1C=CC(S([O:11][C@H:12]([C@@H:15]2[CH:19]=[CH:18][CH2:17][O:16]2)[CH2:13]O)(=O)=O)=CC=1.[OH-].[NH4+:21]>>[NH2:21][CH2:13][C@H:12]([C@@H:15]1[CH:19]=[CH:18][CH2:17][O:16]1)[OH:11]
Reactant: [NH4+]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H](CO)[C@@H]2C=CCO2)cc1
Agent: [OH-]
Product: NC[C@@H](O)[C@@H]1C=CCO1
Temperature: 75 °C
Reaction time: 48 h

Procedure:
(S)-1-((S)-2,5-dihydrofuran-2-yl)-2-hydroxyethyl 4-methylbenzenesulfonate (14) (1.0 g, 3.52 mmol) was suspended in ammonium hydroxide (8 mL) then stirred and heated at 75° C. in a sealed tube for 6.5 hours during which time the two liquid phases became a single phase solution. The mixture was stood at ambient temperature for 2 days then the solvents were removed in vacuo. The residue was azeotroped with diethyl ether (3×10 mL) to obtain (R)-2-amino-1-((S)-2,5-dihydrofuran-2-yl)ethanol which was used without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]([C:13](=[O:16])[CH2:14]Br)=[CH:9][CH:8]=1>CCOCC.ClCCl>[C:7]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:8]=[CH:9][C:10]([C:13](=[O:16])[CH2:14][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:11][CH:12]=1
Reactant: C1COCCN1
Reactant: O=C(CBr)c1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a cooled (0° C.) solution of morpholine (5.99 g, 68.7 mmol) in ether (20 mL) was added the solution of 1-(4-biphenylyl)-2-bromoethanone (9.47 g, 34.4 mmol) in a mixture of ether (100 mL) and dichloromethane (100 mL) dropwise at 0° C. After the addition was over, the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (150 mL) and extracted with 5% NaHCO3 (150 mL) and brine (100 mL). The organic layer was dried (MgSO4) and concentrated to give 9.70 g (100%) of the title compound as a white solid. MS (ES) m/e 281.2 [M+H]+.