Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[C:16]([F:24])[CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:12][C:9]2[CH:10]=[CH:11][C:2]([Cl:1])=[C:3]3[C:8]=2[N:7]=[CH:6][CH:5]=[CH:4]3)(=[O:21])=[O:22])=[C:16]([F:24])[CH:15]=1
Reactant: Nc1ccc(Cl)c2cccnc12
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1F
Product: O=S(=O)(Nc1ccc(Cl)c2cccnc12)c1ccc(Cl)cc1F
Yield: 33.7 %

Procedure:
In a similar fashion using route 14 general procedure 26, 5-chloroquinolin-8-amine (Intermediate 27) (50 mg, 0.28 mmol), 4-chloro-2-fluorobenzenesulfonyl chloride (96 mg, 0.42 mmol) gave the title compound (35 mg, 35%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH:3]=[CH2:4].C(=O)([O-])[O-].[K+].[K+].[Cl:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([Cl:20])[CH:19]=1>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:13][C:14]1[CH:15]=[C:16]([C:3]([C:2]([F:6])([F:5])[F:1])=[CH2:4])[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: C=CC(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F

Procedure:
3,3,3-Trifluoropropene (3.2 g), potassium carbonate (4.6 g) and bis-(triphenylphosphine)-palladium chloride (0.2 g) is added to a solution of 3,5-dichlorophenylboronic acid in THF (20 ml) under nitrogen. After 3 hours at reflux, the reaction is quenched with ethyl acetate (50 ml) and water (50 ml). The organic phase is then extracted with water and with a saturated aqueous solution of NaCl, dried over Na2SO4 and concentrated in vacuo. The crude product is purified on silica gel (35×45 mm) using heptane (150 ml) as eluant to yield 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (2.7 g), as a colorless oil. MS (HPLC/MS): no ionisation. Retention time: 5.10 min.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:26]=[CH:25][C:13]([O:14][CH:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([OH:18])=[O:17])=[C:12]([CH2:27][CH2:28][CH3:29])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[C:36](O)([CH3:39])([CH3:38])[CH3:37].CCN(CC)CC>C1C=CC=CC=1.CN(C=O)C.C(Cl)Cl.CCOC(C)=O>[Si:1]([O:8][CH2:9][C:10]1[CH:26]=[CH:25][C:13]([O:14][CH:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([O:18][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:17])=[C:12]([CH2:27][CH2:28][CH3:29])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CCCc1cc(CO[Si](C)(C)C(C)(C)C)ccc1OC(C(=O)O)c1ccccc1
Reactant: CC(C)(C)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCc1cc(CO[Si](C)(C)C(C)(C)C)ccc1OC(C(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 73.8 %

Procedure:
To a solution of 929 mg (2.24 mmol) of the product of Step L in benzene were added oxalyl chloride (234 mL, 2.69 mmol) and one drop of DMF at 0° C. The solution was stirred at rt for 45 minutes. After concentration the residue was dissolved in CH2Cl2 (10 mL). The solution was added to a solution of tert-butyl alcohol (253 mL, 2.69 mmol) and Et3N in CH2Cl2 (10 mL) at 0° C. The solution was stirred at rt for 3 hours. The mixture was poured into EtOAc (50 mL) and washed with H2O (1×) and brine, and dried over anhydrous MgSO4. Concentration gave 778 mg of the title compound as a slightly yellow glass.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-])=O)[N:4]([CH2:14][C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=2)[C:18]([O:20][CH3:21])=[O:19])[N:3]=1.[NH4+].[Cl-]>CO.[Zn]>[NH2:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:2]=[N:3][N:4]2[CH2:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1cccc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: COC(=O)c1cccc(Cn2ncc3c(N)cccc32)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
A suspension of methyl 3-((3-iodo-4-nitro-1H-indazol-1-yl)methyl)benzoate (1.00 g, 2.29 mmol) and MeOH (45 mL) was cooled to 0° C. Zinc dust (0.748 g, 11.4 mmol) was added followed by saturated aqueous NH4Cl (23 mL). The mixture was stirred at 0° C. for 2 hours, then warmed to ambient temperature and stirred for an additional 3 hours. The mixture was diluted with MeOH and filtered. To the filtrate was added saturated aqueous NH4OAc and the mixture was concentrated to remove bulk MeOH. The concentrated mixture was extracted with EtOAc and the combined organic extracts were washed with saturated aqueous NaHCO3 and brine, then dried over Na2SO4, filtered and concentrated. The product was purified by column chromatography (25 to 100% EtOAc/hexane) to afford 0.398 g (61%) of the title compound as a sticky orange foam.
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[CH:10]=[N:11][C:12]([Cl:22])=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Cl:22][C:12]1[N:11]=[CH:10][C:9]([NH:7][CH3:6])=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH:13]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cnc(Cl)cc1-c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1cnc(Cl)cc1-c1ccccc1Cl
Yield: 99 %

Procedure:
A solution of 1.26 g (3.55 mmol) [6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-carbamic acid tert-butyl ester and 3.34 ml (42.8 mmol) trifluoroacetic acid in 11 ml dichloromethane was stirred at room temperature for 2 h. Addition of 2 M aqueous sodium carbonate solution was followed by extraction with two portions of dichloromethane. The combined organic layers were dried with sodium sulfate and concentrated to give 0.89 g (99%) of the title compound as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C@H:6]1[O:8][CH2:7]1.[NH2:16][C:17]([CH3:36])([CH3:35])[CH2:18][C:19]1[CH:34]=[CH:33][C:22]([O:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][CH:25]=2)=[CH:21][CH:20]=1>C(O)C>[NH2:1][C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C@@H:6]([OH:8])[CH2:7][NH:16][C:17]([CH3:36])([CH3:35])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][CH:25]=2)=[CH:33][CH:34]=1
Reactant: Nc1c(OC[C@@H]2CO2)cccc1[N+](=O)[O-]
Reactant: CC(C)(N)Cc1ccc(Oc2ccc(C(N)=O)cc2)cc1
Solvent: CCO
Product: CC(C)(Cc1ccc(Oc2ccc(C(N)=O)cc2)cc1)NC[C@H](O)COc1cccc([N+](=O)[O-])c1N
Temperature: 55 °C
Yield: 61.7 %

Procedure:
A suspension of (S)-3-(2-amino-3-nitrophenoxy)-1,2-epoxypropane (5 g, 23.8 mmol) and 4-(4-(2-amino-2-methylpropyl)phenoxy)benzamide (20.3 g 71.1 mmol) in absolute ethanol (200 mL) was heated to 55° C. for 12 h. All solids went into solution at 50° C. Upon completion of the reaction, the solvent was evaporated to dryness. The residue was redissolved in ethyl acetate and washed with a saturated solution of sodium bicarbonate. The layers were separated and the aqueous phase was extracted with ethyl acetate. The two organic layers were combined and washed with brine. The phases were separated and the organic layer was dried over sodium sulfate, filtered, and the solvent evaporated. column chromatography eluting with 20% MeOH/CHCl3 gave 7.26 g (62%) of product. NMR. MS.
Reaction SMILES: Cl.[F:2][C:3]([F:30])([F:29])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.[CH3:31][S:32]([NH2:35])(=[O:34])=[O:33]>N1C=CC=CC=1>[F:2][C:3]([F:30])([F:29])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:35][S:32]([CH3:31])(=[O:34])=[O:33])=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Reactant: CS(N)(=O)=O
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)NC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1

Procedure:
A solution of 25.2 g. of 4-[15-(trifluoromethyl)pentadecylamino]benzoyl chloride hydrochloride and 5.6 g. of methanesulfonamide in 250 ml. of pyridine is stirred under reflux for 2 hours and then concentrated in vacuo. The residue is partitioned between water and diethyl ether; the aqueous layer acidified with 1 N hydrochloric acid, and the organic layer separated, dried over magnesium sulfate and evaporated. Crystallization of the residual white solid from 60% aqueous acetic acid and then from methylene chloride-hexane affords the product as a white solid.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([N:8]2[C:12]3[N:13]=[CH:14][N:15]=[C:16]([S:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[CH:10]=[CH:9]2)[C@H:5]([OH:24])[C@@H:4]1[OH:25].CO[C:28](OC)([CH3:30])[CH3:29].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:29][C:28]1([CH3:30])[O:24][C@H:5]2[C@H:6]([N:8]3[C:12]4[N:13]=[CH:14][N:15]=[C:16]([S:17][C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=5)[C:11]=4[CH:10]=[CH:9]3)[CH2:7][C@@H:3]([CH2:2][OH:1])[C@H:4]2[O:25]1
Reactant: OC[C@@H]1C[C@@H](n2ccc3c(Sc4ccccc4)ncnc32)[C@H](O)[C@@H]1O
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)O[C@@H]2[C@H](CO)C[C@@H](n3ccc4c(Sc5ccccc5)ncnc43)[C@@H]2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
(1S,2R,3S,5R)-3-(Hydroxymethyl)-5-[4-(phenylsulfanyl)-7H-pyrrolo[2,3-d]-pyrimidin-7-yl]cyclopentane-1,2-diol (320 mg, 0.0895 mmol), 2,2-dimethoxypropane (0.0549 mL, 0.446 mmol), and p-toluenesulfonic acid monohydrate (17.0 mg, 0.0895 mmol) were dissolved in acetone (2.20 mL) and stirred at rt overnight. Then the reaction was quenched with saturated sodium bicarbonate solution and approximately half the solvent was removed in vacuo. The resulting residue was diluted with water and extracted with DCM (3×). Combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound as a white foam (35.5 mg, 99%), which was used without further purification. LC/MS: Rt=1.72 min, ES+ 389 (FA standard).
Reaction SMILES: [NH2:1][C@H:2]([C:15]([O:17]C)=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.[C:19](=O)([O-])[O-].[Na+].[Na+].C(Cl)(=O)OCC.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCOCC1.O.C1COCC1.O>[C:11]([C:6]1[CH:5]=[C:4]([CH2:3][CH:2]([NH:1][CH3:19])[CH2:15][OH:17])[CH:9]=[CH:8][C:7]=1[OH:10])([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)c(C(C)(C)C)c1
Reactant: O=C([O-])[O-]
Agent: CCOC(=O)Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1COCCO1
Solvent: O
Solvent: C1CCOC1
Product: CNC(CO)Cc1ccc(O)c(C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
To a solution of Tyr(3-tBu)-OMe (3.0 g, 11.9 mmol) in 1,4-dioxane/water (12 ml/12 ml), sodium carbonate (1.9 g, 17.9 mmol) and then ethyl chlorocarbonate (1.26 ml, 13.1 mmol) were added under cooling with ice and stirred for 2 hours. The reaction mixture was mixed with water, extracted with chloroform, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure. To a solution of the thus obtained residue (3.85 g) in THF (120 ml), lithium aluminum hydride (2.83 g, 59.7 mmol) was added little by little and stirred at 60° C. for 5 hours. The reaction mixture was poured into ice water, stirred and then filtered with Celite for removing insoluble material. The filtrate was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The thus obtained residue was subjected to silica gel column chromatography (methylene chloride:methanol=3:1), giving 3-(3-tert-butyl-4-hydroxyphenyl)-2-methylaminopropanol (T23) (1.9 g, 67%, in 2 steps).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][C:15]=2[F:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][Si](C=[N+]=[N-])(C)C>CO.C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:25])=[O:22])=[CH:16][C:15]=2[F:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(CC(=O)O)cc2F)CC1
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.2 %

Procedure:
To 2-(4-{4-[(t-butyl)oxycarbonyl]piperazinyl}-3-fluorophenyl)acetic acid (0.3 g, 1.0 mmol) in 2 mL methanol and 7 mL benzene was added trimethylsilyidiazomethane (0.65 mL, 1.30 mmol). After stirring at ambient temperature for 1 hour, the reaction mixture was concentrated to provide 0.36 g (99%) of the title compound. 1H NMR (CDCl3; 300 MHz) δ7.00 (m, 2H), 6.90 (t, J=8.3 Hz, 1H), 3.71 (s, 3H), 3.61 (t, J=4.9 Hz, 4H), 3.57 (s, 2H), 3.02 (t, J=5.0 Hz, 4H), 1.50 (s, 9H); ESI (M+H)+=353.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:9]=[CH:10][C:11]=2[O:12][C:13]([O:15][CH3:16])=[O:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:24]([O-])([O-:26])=[O:25].[K+]>OS(O)(=O)=O>[CH:1]1([C:6]2[C:11]([O:12][C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]([N+:24]([O-:26])=[O:25])=[C:8]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)CCc1ccc(OC(=O)OC)c(C2CCCC2)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)CCc1cc(C2CCCC2)c(OC(=O)OC)cc1[N+](=O)[O-]
Temperature: -2 °C
Yield: 78.9 %

Procedure:
Ethyl 3-(3-cyclopentyl-4-methoxycarbonyloxy-phenyl)propanoate (920 mg, 2.87 mmol) was dissolved in H2SO4 (2.2 mL) and the reaction mixture was cooled to −2° C. internal temperature. KNO3 (348 mg, 3.45 mmol) was added in portions over 1 h maintain the internal temperature at 0° C. After 1 h at 0° C. the reaction mixture was poured over ice (30 mL) and partitioned between dichloromethane/water and separated. The organic layer was washed twice with a saturated aqueous NaHCO3, dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (0-40% ethyl acetate/hexanes) afforded ethyl 3-(5-cyclopentyl-4-methoxycarbonyloxy-2-nitro-phenyl)propanoate (827 mg, 76% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.53 (s, 1H), 4.04 (q, J=7.1 Hz, 2H), 3.86 (s, 3H), 3.11 (t, J=7.6 Hz, 3H), 2.68 (t, J=7.6 Hz, 2H), 1.99-1.91 (m, 2H), 1.82-1.75 (m, 2H), 1.69-1.61 (m, 2H), 1.58-1.53 (m, 2H), 1.15 (t, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:39].[CH3:40][NH:41][CH2:42][CH2:43][NH2:44]>C1COCC1>[NH2:44][CH2:43][CH2:42][N:41]([CH3:40])[C:16]1[N:17]=[C:18]([C:19]2[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=2[CH3:35])[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[O:23])[C:13]2[CH:12]=[CH:11][C:10](=[O:39])[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:14]=2[N:15]=1
Reactant: CNCCN
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(N(C)CCN)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 15.9 %

Procedure:
To a solution of 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide (50 mg, 0.09 mmol) in THF (5 mL) was added N-methyl-1,2-ethanediamine (0.044 mL, 0.5 mmol). The resultant mixture was stirred at room temperature overnight. The mixture was concentrated under vacuo. Flash chromatography (90% CH2Cl2/7% MeOH/3% NH4OH) then provide the title compound (8.0 mg, 16%). LC-MS (ES) m/z 559 (M+H)+; 1H-NMR(MeOD) δ 2.35 (s, 3H), 2.65 (m, 1H), 2.86 (m, 1H), 2.92 (m, 1H), 3.26 (m, 1H), 3.35 (m, 1H), 3.40 (m, 1H), 3.77 (m, 1H), 6.36 (d, 1H), 7.14 (m, 2H), 7.25 (m, 2H), 7.52 (d, 1H), 7.59 (d, 1H), 7.62 (m, 1H), 7.71 (m, 2H), 7.92 (s, 1H), 8.06 (d, 1H).
Reaction SMILES: C([Li])CCC.[Cl-].[CH3:7][O:8][C:9]1[CH:34]=[C:33]([CH3:35])[C:12]([CH2:13][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:11]([CH3:36])[C:10]=1[CH3:37].[F:38]/[C:39](=[CH:48]\[CH:49]=[C:50](/[CH3:53])\[CH:51]=O)/[C:40](/[CH3:47])=[CH:41]/[C:42]([O:44][CH2:45][CH3:46])=[O:43]>O1CCCC1>[CH3:7][O:8][C:9]1[CH:34]=[C:33]([CH3:35])[C:12](/[CH:13]=[CH:53]/[C:50](/[CH3:51])=[CH:49]/[CH:48]=[C:39](\[F:38])/[C:40](/[CH3:47])=[CH:41]/[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:11]([CH3:36])[C:10]=1[CH3:37]
Reactant: COc1cc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1C
Reactant: CCOC(=O)/C=C(C)/C(F)=C/C=C(\C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(C)/C(F)=C/C=C(C)/C=C/c1c(C)cc(OC)c(C)c1C
Temperature: -30 °C

Procedure:
A solution of 6.06 ml. (14.4 mmol) of n-butyllithium (2.3 M in hexane) was added dropwise under argon, at -72° C., to a stirred suspension of 4.61 g. (10 mmol) of 4-methoxy-2,3,6-trimethylbenzyl triphenylphosphonium chloride in 25 ml. of dry tetrahydrofuran. After addition of reagent was complete the mixture was stirred at -30° C. until an orange solution was formed. The resulting solution was first cooled to -72° C. and then treated dropwise with a solution of 2.03 g. (9.0 mmol) of ethyl (E,Z,E)-4-fluoro-3,7-dimethyl-8-oxo-2,4,6-octatrienoate in 10 ml. of dry tetrahydrofuran. The reaction mixture was gradually allowed to come to 25° C. and further stirred at this temperature under argon for 2.0 hours. It was poured onto 100 ml. of cold water and extracted with methylene chloride (4×100 ml.). The combined organic extracts were washed with water (2×100 ml.) dried over anhydrous magnesium sulfate and concentrated to give 6.4 g. of oily crude product. This material was filtered through 300 g. of florisil and eluted with methylene chloride to yield 2.97 g. of yellow crystalline substance, which on crystallization from ether-petroleum ether (~1:9) afforded ethyl (E,Z,E,E)-9-(4-methoxy-2,3,6-trimethylphenyl)-4-fluoro-3,7-dimethyl-2,4,6,8-nonatetraenoate as yellow crystals, mp 92°-96° C.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[CH2:9]1)=O)(C)(C)C.C(OC(N1CC(OC2C=C(Cl)C=CC=2O)C1)=O)(C)(C)C.[H-].[Na+]>CN(C=O)C>[Cl:19][C:17]1[CH:16]=[CH:15][C:14]([O:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)=[C:13]([CH:18]=1)[O:12][CH:10]1[CH2:9][NH:8][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2OCCc2cccc(Cl)c2)C1
Agent: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cccc(CCOc2ccc(Cl)cc2OC2CNC2)c1
Reaction time: 0.08 h

Procedure:
Preparation of 3-[5-Chloro-2-[2-(3-chloro-phenyl)-ethoxy]-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester. To a solution of 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (60 mg, 0.20 mmol) in DMF (2 mL) was added NaH (10 mg, 0.24 mmol). After 5 min, the title compound of Step A (56 mg, 0.24 mmol) was added and the resulting mixture was heated at 65° C. for 18 h. The reaction was diluted with H2O and extracted EtOAc (3×). The organics were dried and purified by RP HPLC (Agilent) to give the title compound as an oil (47 mg, 54%). MS (ESI): mass calcd. for C22H25Cl2NO4, 438.3; m/z found, 382.0 [M-56+H]+. 1H NMR (CDCl3): 7.34-7.32 (m, 1H), 7.25-7.22 (m, 2H), 7.19-7.16 (m, 1H), 6.90 (dd, J=8.8, 2.0 Hz, 1H), 6.78 (d, J=8.8 Hz, 1H), 6.54 (d, J=2.4 Hz, 1H), 4.85-4.79 (m, 1H), 4.30-4.25 (m, 2H), 4.16 (t, J=6.7 Hz, 2H), 4.07-4.03 (m, 2H), 3.10 (t, J=6.7 Hz, 2H), 1.46 (s, 9H).
Reaction SMILES: CO[C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=3[NH:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:6]=1.[O:29]=[C:30]1[CH2:35][NH:34][CH2:33][CH2:32][NH:31]1>>[Cl:20][C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([NH:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:15]=1)[NH:12][C:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][CH2:3][N:34]3[CH2:33][CH2:32][NH:31][C:30](=[O:29])[CH2:35]3)[CH:6]=1)=[CH:19]2
Reactant: COC(=O)Cc1cccc(-c2cc3cc(Cl)cc(NC4CCOCC4)c3[nH]2)c1
Reactant: O=C1CNCCN1
Product: O=C1CN(CCc2cccc(-c3cc4cc(Cl)cc(NC5CCOCC5)c4[nH]3)c2)CCN1

Procedure:
2-[3-(7-Tetrahydropyran-4-ylamino-5-chloro-1H-indol-2-yl)-phenyl]-acetic acid methyl ester prepared in Example 132 and 2-oxo-piperazine were reacted according to the same procedures as Example 32 and Steps A and B of Example 36 sequentially to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)(=[O:10])=[O:9])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.[C:20]([C:22]1[N:26]([CH3:27])[C:25](B(O)O)=[CH:24][CH:23]=1)#[N:21].[F-].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:20]([C:22]1[N:26]([CH3:27])[C:25]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]3[CH2:15][CH2:14]3)(=[O:10])=[O:9])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=2)=[CH:24][CH:23]=1)#[N:21]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: O=S(=O)(NCC1CC1)c1ccc(Br)cc1C(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cn1c(C#N)ccc1-c1ccc(S(=O)(=O)NCC2CC2)c(C(F)(F)F)c1
Reaction time: 16 h
Yield: 49.4 %

Procedure:
In analogous manner to general procedure B, 4-bromo-N-(cyclopropylmethyl)-2-(trifluoromethyl)benzenesulfonamide (200 mg, 0.56 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (100 mg, 0.67 mmol), potassium fluoride (107 mg, 1.85 mmol), and tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (83 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-(cyclopropylmethyl)-2-(trifluoromethyl)-benzenesulfonamide (106 mg, 53%) was provided after purification. MS (ESI) m/z 383. HPLC purity 100.0% at 210-370 nm, 10.8 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1.[F:21][C:22]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=1[CH:24]=[O:25]>CCCCCC.O.O1CCCC1>[Br:13][C:14]1[CH:19]=[C:18]([CH:24]([C:23]2[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:22]=2[F:21])[OH:25])[C:17]([Br:20])=[CH:16][N:15]=1
Reactant: Brc1ccc(Br)nc1
Reactant: O=Cc1cc(F)ccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: OC(c1cc(F)ccc1F)c1cc(Br)ncc1Br
Reaction time: 1 h
Yield: 52 %

Procedure:
Under an argon atmosphere, n-butyl lithium (a 1.59M hexane solution, 76 ml, 121 mmol) was added to a tetrahydrofuran (400 ml) solution of diisopropylamine (17 ml, 121 mmol) at −70° C. The reaction mixture was stirred for 1 hour. To the reaction mixture was added dropwise a tetrahydrofuran (100 ml) solution of 2,5-dibromopyridine and the resulting mixture was stirred for 2 hours. To the reaction mixture was added dropwise 2,5-difluorobenzaldehyde (15 ml, 139 mmol) and the mixture was stirred for 1 hour. After addition of water, the resulting mixture was concentrated under reduced pressure. The residue thus obtained was extracted with dichloromethane. The organic layer thus obtained was dried over magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was washed with dichloromethane:hexane to yield a pale yellow powder. The filtrate was subjected to silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=6:1 eluate was concentrated under reduced pressure. The residue thus obtained and the above-described pale yellow powder were combined to give the title compound (18.4 g, 48.6 mmol, 52%) as a pale yellow powder.