Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[CH2:5][CH2:6][CH2:7][NH:8][CH3:9].[C:11]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18]([O:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29](O)=[O:30])[CH2:23][CH2:22]1)=[O:19].C(N(CC)C(C)C)(C)C.O>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:10])[CH2:5][CH2:6][CH2:7][NH:8][CH2:9][C:29](=[O:30])[CH2:28][CH2:27][N:24]1[CH2:25][CH2:26][CH:21]([O:20][C:18](=[O:19])[NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:22][CH2:23]1
Reactant: CNCCCC(=O)OC
Reactant: O=C(O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COC(=O)CCCNCC(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Yield: 127.4 %

Procedure:
To a stirred mixture of 4-methylaminobutyric acid methyl ester hydrochloride (546 mg, 3.26 mmol) and 3-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]propionic acid (1.20 g, 3.26 mmol) in DCM (15 mL) was added N,N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1.36 g, 3.58 mmol) followed by N,N-diisopropylethylamine (1.42 mL, 8.15 mmol). LC-MS (Method 2-90) showed product was present (Rt 3.11 min; m/z 482.4 [M+H]+). Water and DCM were added and the layers were separated. The organic layer was washed with water (2×) and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (2.0 g, 100% yield) as a light yellow oil.
Reaction SMILES: [F:1][C@@:2]([C:10]([F:13])([F:12])[F:11])([CH2:6][CH2:7][CH2:8][CH3:9])[C:3](O)=[O:4].C1C=C(C([Cl:22])=O)C(C(Cl)=O)=CC=1>>[F:1][C@@:2]([C:10]([F:13])([F:12])[F:11])([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([Cl:22])=[O:4]
Reactant: CCCC[C@](F)(C(=O)O)C(F)(F)F
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Product: CCCC[C@](F)(C(=O)Cl)C(F)(F)F
Temperature: 80 °C
Reaction time: 24 h
Yield: 93.9 %

Procedure:
A mixture of 8.0 g of (S)-(-)-2-fluoro-2-(trifluoromethyl)hexanoic acid and 24.0 g of phthalyl chloride was stirred at 80° C. for 24 hours. Subsequently, the reaction mixture was distilled under reduced pressure, thereby obtaining 8.2 g of (R)-(-)-2-fluoro-2-(trifluoromethyl)hexanoyl chloride having the physical properties as mentioned hereinbefore.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([OH:13])(=O)[CH2:8][CH2:9][CH:10]=[CH2:11].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl.CN(C=O)C>[C:15]1([NH:14][C:7](=[O:13])[CH2:8][CH2:9][CH:10]=[CH2:11])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccccc1
Reactant: C=CCCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCCC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.1 %

Procedure:
To a stirred solution of oxalyl chloride (2.0 M in CH2Cl2, 11.5 mL, 23.1 mmol) in CH2Cl2 (100 mL) and DMF (1 drop) at 0° C. was added 4-pentenoic acid (2.25 mL, 22.0 mmol). This was allowed to warm to ambient temperature. Upon cessation of gas evolution, the mixture was returned to 0° C. and a solution of aniline (2.00 mL, 22.0 mmol) and TEA (6.72 mL, 26.3 mmol) in CH2Cl2 (5 mL) was added dropwise. After warming to ambient temperature, the reaction was allowed to proceed for 3 h. The mixture was concentrated under reduced pressure, and then partitioned between HCl (1 N, 10 mL) and EtOAc (30 mL) and the layers separated. The aqueous portion was extracted with EtOAc (3×15 mL) and the organic layers combined, washed with brine, dried over MgSO4, and filtered. Concentration under reduced pressure gave a yellowish solid, which was recrystallized with toluene to obtain 42 as white crystals (1.97 g, 11.24 mmol, 51%). TLC Rf 0.68 (50% EtOAc/hexanes); 1H-NMR (300 MHz, CDCl3) δ 7.49 (d, 2H), 7.29 (t, 2H), 7.08 (t, 1H), 5.88 (m, 1H), 5.10 (dd, 2 H), 4.42 (br s, 4 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10]CC)=[O:9])=[N:6][CH:7]=1.[OH-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(F)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 1.3 h
Yield: 99 %

Procedure:
Dissolve ethyl 5-fluoropyridine-2-carboxylate (4.60 g, 27.2 mmol) in THF (34 mL) and methanol (34 mL). Add 1.0 N NaOH (32.6, 32.6 mmol) and stir at room temperature for 1.3 hours. Concentrate the reaction mixture. Then add 1.0 N HCl (32.6 mL), stir and concentrate. Take the solid up in 20% methanol, 3% AcOH and 77% dichloromethane and filter through a silica plus. Wash the plug with the solvent listed above until all of the product elutes off to give the title compound (3.8 g, 100%): MS ES+ 142.03 (M+H)+, HRMS calcd for C6H5NO2F 142.0304 (M+H)+, found 142.0306, time 0.46 min, 0.51; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min], tR=6.3 min, 100% purity.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C@@H:10]([OH:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[CH:18][CH:19]=2)[C@@H:10]([OH:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(O)cc2)[C@@H](O)C1
Reactant: COc1ccccc1COCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2O)cc1
Temperature: 120 °C
Reaction time: 26 h
Yield: 95.8 %

Procedure:
A solution of 16.50 g (56.24 mmol) of (3R,4R)-3-hydroxy-4-(4-hydroxy-phenyl)-piperidine-1-carboxylic acid tert-butyl ester in 40 ml of N,N-dimethylformamide was treated in succession with 12.68 g (59.06 mmol) of 1-(3-chloro-propoxymethyl)-2-methoxy-benzene (WO 97/09311) and 12.44 g (90.00 mmol) of potassium carbonate. This mixture was stirred at 120° C. for 26 hours. Subsequently, the salts were filtered off and washed with dichloromethane. The filtrate was concentrated in a high vacuum to eliminate most of the N,N-dimethylformamide, poured into 300 ml of an ice/water mixture and the aqueous phase was extracted three times with 100 ml of dichloromethane. The combined organic phases were washed once with a small amount of water, dried over magnesium sulphate, evaporated under reduced pressure and dried in a high vacuum. The thus-obtained crude product (31.64 g) was separated on silica gel using a 99:1 mixture of dichloromethane and methanol as the eluent and yielded 25.4 g (53.85 mmol, 95.8% of theory) of (3R,4R)-3-hydroxy-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a slightly yellow oil; MS: 489 (M+NH4+)+.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C(N(C(C)C)CC)(C)C.[F:14][C:15]([F:44])([F:43])[C:16]1[CH:17]=[C:18]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:19][N:20]([CH:24]1[CH2:30][CH2:29][CH2:28][NH:27][C:26]2[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:25]1=2)[C:21](=[O:23])[CH3:22]>C1(C)C=CC=CC=1>[C:21]([N:20]([CH2:19][C:18]1[CH:36]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:38]=[C:16]([C:15]([F:14])([F:44])[F:43])[CH:17]=1)[CH:24]1[CH2:30][CH2:29][CH2:28][N:27]([C:1]([Cl:4])=[O:2])[C:26]2[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:25]1=2)(=[O:23])[CH3:22]
Reactant: O=C(Cl)Cl
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCNc2cc(Cl)ccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)Cl)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
Add phosgene (1.1 mmol, 1.93 M solution in toluene) followed by diisopropyl ethylamine (1.1 mmol) to a toluene (15 mL) solution of N-(3,5-Bis-trifluoromethyl-benzyl)-N-(8-chloro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-acetamide (0.50 g, 1.1 mmol) under nitrogen. After stirring at room temperature for 1 h, remove solvent under vacuum. Chromatograph the crude product over silica gel using ethyl acetate/hexane (10-30%) to elute. This provides the title compound (0.55 g, 96%) as an oil which solidifies upon standing: MS (ES+): 527 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[C:10]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C1COCC1>[CH:10]1([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C1CCCC1
Reactant: COc1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(NC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 7.00 g (56.8 mmol) p-Anisidine, 9.56 g (114 mmol, 2.0 equiv) Cyclopentanone, and 4.10 g (68.2 mmol, 1.2 equiv) Acetic acid in 145 mL Methanol is added 125 mL (125 mmol, 2.2 equiv) 1N Sodium cyanoborohydride in THF and stirred 18 h at ambient temperature. The reaction mixture is concentrated in vacuo and the residue taken into 200 mL EtOAc, washed with H2O (150 mL), dried (MgSO4), filtered and concentrated in vacuo to give crude Cyclopentyl-(4-methoxy-phenyl)-amine as a brown oil. To a stirred solution of this material and 6.03 g (58.6 mmol, 1.05 equiv) Et3N in 70 mL DCM is added 11.47 g (56.8 mmol, 1 equiv) Bromoacetyl bromide in 50 mL DCM dropwise over 30 minutes at 0° C. The reaction mixture is stirred 1 h at 0° C. followed by warming to ambient temperature and stirring 18 h. The reaction mixture is washed with 1N HCl (3×50 mL), dried (MgSO4), filtered through a pad of 100 g silica gel eluted with EtOAc/Hexanes (3:17, 1.5 L), and concentrated in vacuo to give 10.22 g (32.7 mmol) of 2-Bromo-N-cyclopentyl-N-(4-methoxy-phenyl)-acetamide as an orange oil: 1H NMR (CDCl3, 300 MHz) δ7.09 (d, 2H, J=9.0), 6.90 (d, 2H, J=9.0), 4.84 (m,1H), 3.83 (s, 3H), 3.54 (s, 2H), 1.87 (m, 2H), 1.49 (m, 4H), 1.25 (m, 2H); TLC Rf =0.65 (EtOAc/Hexanes, 3:17).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:39][C:40]1[CH:41]=[CH:42][C:43]2[O:47][C:46]([S:48]([N:51]3[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]3)(=[O:50])=[O:49])=[CH:45][C:44]=2[CH:57]=1>CN(C)C=O>[Cl:39][C:40]1[CH:41]=[CH:42][C:43]2[O:47][C:46]([S:48]([N:51]3[CH2:56][CH2:55][N:54]([C:11](=[O:13])[C:10]4[CH:9]=[CH:8][C:7]([C:4]5[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=5)=[CH:15][CH:14]=4)[CH2:53][CH2:52]3)(=[O:49])=[O:50])=[CH:45][C:44]=2[CH:57]=1
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Reactant: O=S(=O)(c1cc2cc(Cl)ccc2o1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc(-c2ccncc2)cc1)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3o2)CC1
Reaction time: 8 h
Yield: 12.4 %

Procedure:
A stirred suspension of 4-(4-pyridyl)benzoic acid (133 mg, 0.67 mmol) in dimethylformamide (5 ml) was treated sequentially with 1-hydroxybenzotriazole hydrate (108 mg, 0.8 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (153 mg, 0.8 mmol) and 1-(5-chlorobenzofuran-2-ylsulphonyl) piperazine (201 mg, 0.67 mmol). After stirring overnight the solvent was removed in vacuo and the residue chromatographed (Merck Art 9385 silica, eluting with dichloromethane containing 2% v/v of methanol) to yield 1-(5-chlorobenzofuran-2-ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]piperazine as a colourless solid (40 mg), 1H NMR (CDCl3) δ=3.2-3.4 ppm (broad s, 4H), δ=3.6-4.0 ppm (broad s, 4H), δ=7.35 ppm (s, 1H), δ=7.5 ppm (m, 6H), δ=7.7 ppm (m, 3H), δ=8.7 ppm (d, 2H), MS (M+H)+ 482/484.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[C:18](OC1C=CC(Cl)=C(Cl)C=1Cl)(=[O:23])[CH2:19][C:20]([O-])=[O:21]>C1(C)C(C)=CC=CC=1>[OH:23][C:18]1[N:17]=[C:13]2[CH:12]=[C:11]([O:10][CH2:9][C:6]3[S:7][CH:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=3)[CH:16]=[CH:15][N:14]2[C:20](=[O:21])[CH:19]=1
Reactant: O=C([O-])CC(=O)Oc1ccc(Cl)c(Cl)c1Cl
Reactant: CC(C)c1csc(COc2ccnc(N)c2)n1
Solvent: Cc1ccccc1C
Product: CC(C)c1csc(COc2ccn3c(=O)cc(O)nc3c2)n1
Temperature: 140 °C
Yield: 63.6 %

Procedure:
4-[(4-Isopropyl-1,3-thiazol-2-yl)methoxy]-2-pyridinamine (378 mg, 1.52 mmol) dissolved in xylene (15 ml) was added with trichlorophenyl malonate (750 mg, 1.62 mmol) and refluxed by heating at 140° C. for 1 hour and 30 minutes. The reaction solution was returned to room temperature and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform→chloroform:methanol=100:1→80:1→50:1) to obtain 307 mg (64%) of the title compound.
Reaction SMILES: [C-:1]#[N:2].[K+].C(O)CO.O.C(=O)=O.[S:12]1[C:16]2[CH:17]=[C:18]([CH2:21]O)[CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1>O.CN(C=O)C>[S:12]1[C:16]2[CH:17]=[C:18]([CH2:21][C:1]#[N:2])[CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1
Reactant: OCc1ccc2ncsc2c1
Reactant: [C-]#N
Agent: O=C=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: OCCO
Product: N#CCc1ccc2ncsc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of potassium cyanide (0.68 g, 0.010 mol) in water (3.0 mL) was added under nitrogen to a cooled (with an ethylene glycol/water (4/1)/dry ice bath) solution of 1,3-benzothiazol-6-ylmethanol in DMF (30 mL). The reaction mixture was warmed to 0° C., and stirred for 30 min. Water was added and the reaction mixture was extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was flash chromatographed on a silica gel column with ethyl acetate in hexane from 10-30% to afford the desired product (1.07 g). Analytical LCMS: (M+H)+=175.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:5])[CH3:2].[O:33]1[CH:38]=[CH:37][CH2:36][CH2:35][CH2:34]1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][Si:16]([C:29]([CH3:31])([CH3:30])[CH3:32])([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:13]=2)[N:8]([CH:34]2[CH2:35][CH2:36][CH2:37][CH2:38][O:33]2)[N:7]=1)=[O:5])[CH3:2]
Reactant: C1=COCCC1
Reactant: CCOC(=O)c1n[nH]c2cc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc12
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nn(C2CCCCO2)c2cc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Ethyl6-tert-butyldiphenylsilyloxyindazole-3-carboxylate (1.461 g) which can be prepared according to the method described in Reference example 18, etc. was dissolved in toluene (16.5 mL; manufactured by Wako Pure Chemical Industries, Ltd.), added with 3,4-dihydro-2H-pyran (0.6 mL; manufactured by Tokyo Chemical Industry, Co., Ltd.) and toluene sulfonic acid-monohydrate (0.1293 g), followed by stirring overnight at 60° C. under nitrogen atmosphere. The reaction solution was poured to a saturated aqueous solution of sodium hydrogen carbonate and extracted once with ethyl acetate. The organic layer was washed twice with water and once with brine and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography “COLUMN-A”; n-hexane:ethyl acetate=96:4→75:25) to obtain the title compound (1.334 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[C:6]([Cl:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].Cl.[CH3:15][S:16]([CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:18])=[O:17].C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[Cl:10][C:6]1[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[N:24]1[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][S:16]([CH3:15])(=[O:17])=[O:18])[CH2:26][CH2:25]1
Reactant: COc1cc(F)c(Cl)cc1[N+](=O)[O-]
Reactant: CS(=O)(=O)CCN1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(Cl)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 91.3 %

Procedure:
To 1-chloro-2-fluoro-4-(methyloxy)-5-nitrobenzene (Example 104, Step B) (0.822 g, 4.0 mmol), 4-[2-(methylsulfonyl)ethyl]piperazine hydrochloride (Example 148, Step B) (0.915 g, 4.0 mmol), and K2CO3 (1.7 g, 12 mmol) was added DMSO (8 mL). The reaction was heated to 100° C. for two days. The reaction was determined to be complete by TLC. The reaction mixture was diluted with H2O and extracted with DCM and EtOAc sequentially for two iterations. The organic was dried (MgSO4), filtered, and rotovapped down. Purification by flash chromatography provided the title compound of Step A (1.38 g, 91%). MS (M+H, ES+) 378.
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1.Cl[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=1.[Cl-].C(C1C=CC=C(C(C)C)C=1[NH+]1CCN(C2C(C(C)C)=CC=CC=2C(C)C)C1)(C)C>CCCCCC.C1(C)C=CC=CC=1>[F:23][C:20]1[CH:21]=[C:22]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=2)[CH:17]=[CH:18][C:19]=1[F:24]
Reactant: COc1ccc([Mg]Br)cc1
Reactant: Fc1ccc(Cl)cc1F
Agent: CC(C)c1cccc(C(C)C)c1N1CC[NH+](c2c(C(C)C)cccc2C(C)C)C1
Agent: [Cl-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc(F)c(F)c2)cc1
Reaction time: 24 h
Yield: 92 %

Procedure:
Using a THF solution of p-methoxyphenylmagnesium bromide (2.34 mL, 0.64 M, 1.5 mmol), 4-chloro-1,2-difluorobenzene (148.6 mg, 1.0 mmol), FeF3.3H2O (8.34 mg, 0.05 mmol) and 1,3-bis(2,6-diisopropylphenyl)imidazolinium chloride (64.1 mg, 0.15 mmol) as starting materials, the reaction was performed at a scale of 1.0 mmol at 60° C. for 24 hours, and then at 80° C. for 12 hours, in the same manner as in Example 2. After performing silica gel column chromatography (toluene=15, 30 and 50% in hexane), the above compound was obtained as a white solid (0.215 g, yield=92%, purity=>99% (GC analysis)).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[C:11]1(=[O:21])[C:15]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:14][CH2:13][NH:12]1.[CH3:22]I>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:18]2[CH2:19][CH2:20][C:15]3([C:11](=[O:21])[N:12]([CH3:22])[CH2:13][CH2:14]3)[CH2:16][CH2:17]2)=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: O=C1NCCC12CCNCC2
Reactant: CI
Product: CN1CCC2(CCN(c3ccc(N)cn3)CC2)C1=O

Procedure:
Intermediate B-20 was prepared by the general procedure for intermediate B-15, by using 2-chloro-5-nitropyridine, 2,8-diazaspiro[4,5]decan-1-one, and methyl iodide as starting materials. MS (M+1): 261.2
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[NH:9][CH:8]=[CH:7][C:6]2=O.S(Cl)([Cl:21])=O>CN(C=O)C>[ClH:21].[Cl:21][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COCCOc1cc2[nH]ccc(=O)c2cc1OC
Solvent: CN(C)C=O
Product: COCCOc1cc2nccc(Cl)c2cc1OC
Product: Cl
Yield: 95 %

Procedure:
A solution of 6-methoxy-7-(2-methoxyethoxy)-1,4-dihydroquinolin-4-one (500 mg, 2 mmol) in thionyl chloride (10 ml) and DMF (3 drops) was heated at reflux for 1 hour. Excess thionyl chloride was removed by evaporation and the residue azeotroped with toluene and then triturated with ether. The solid was collected by filtration and dried under vacuum to give 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinoline hydrochloride (590 mg, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH2:24][CH2:25][NH:26][S:27]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH:37]=O)(=[O:29])=[O:28])=[C:5]2[CH2:39][CH2:40][CH2:41][C:42]1[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][CH:43]=1.[NH:52]([CH2:55][CH3:56])[CH2:53][CH3:54].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:6]([CH2:24][CH2:25][NH:26][S:27]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][N:52]([CH2:55][CH3:56])[CH2:53][CH3:54])(=[O:29])=[O:28])=[C:5]2[CH2:39][CH2:40][CH2:41][C:42]1[CH:43]=[CH:44][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:50][CH:51]=1
Reactant: CCNCC
Reactant: COC(=O)c1ccc(CCCc2c(CCNS(=O)(=O)Cc3ccccc3C=O)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCN(CC)Cc1ccccc1CS(=O)(=O)NCCc1c(CCCc2ccc(C(=O)OC)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Yield: 41.3 %

Procedure:
As outlined in Example 17, Step 1 methyl 4-{3-[5-chloro-1-(diphenylmethyl)-2-(2-{[(2-formylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoate (Example 16, Step 5, 58 mg, 0.081 mmol) was reacted with HNEt2 (0.022 mL, 0.21 mmol) and NaBH(OAc)3 (56 mg, 0.26 mmol) in DCE (2 mL) to afford methyl 4-{3-[5-chloro-2-{2-[({2-[(diethylamino)methyl]benzyl}sulfonyl)amino]ethyl}-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoate (26 mg, 41%) and the side product methyl 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-(hydroxymethyl)benzyl]sulfonylamino}ethyl]-1H-indol-3-yl}propyl)benzoate (8.6 mg, 15%), both as white solids.
Reaction SMILES: [CH3:1][N:2]([CH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])C(=O)OC.NN.[OH-].[K+]>C(O)CO.O>[CH3:1][NH:2][CH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:19])=[O:20]
Reactant: COC(=O)N(C)CCc1ccc2[nH]cc(S(=O)(=O)c3ccccc3)c2c1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: CNCCc1ccc2[nH]cc(S(=O)(=O)c3ccccc3)c2c1
Temperature: 110 °C

Procedure:
To a stirred solution of methyl methyl{2-[3-(phenylsulfonyl)-1H-indol-5-yl]ethyl}carbamate (171 mg, 0.46 mmol) in ethylene glycol (5 ml) was added H2NNH2 (147 mg, 4.6 mmol), KOH (1.9 g 13.8 mmol), and heated to 110° C. for 12 hours. The mixture was cooled to room temperature, diluted with water (5 mL) and extracted with EtOAc. The combined organic layers were washed with water (7 mL), brine (10 mL), dried (MgSO4), filtered and concentrated under reduced pressure to a residue which is triturated with CH2Cl2 to afford an off white solid, (131 mg, 93%). Mp: 151-154° C., MS (ES−) 313 (M−H).