Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[N:18]=[CH:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[Cl:50][C:51]1[CH:62]=[CH:61][CH:60]=[CH:59][C:52]=1[O:53][CH:54]1[CH2:58][CH2:57][NH:56][CH2:55]1>CN(C=O)C.O>[Cl:50][C:51]1[CH:62]=[CH:61][CH:60]=[CH:59][C:52]=1[O:53][CH:54]1[CH2:58][CH2:57][N:56]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:19]2[N:18]=[CH:17][N:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:20]=2)=[O:22])[CH2:55]1
Reactant: O=C(O)CNC(=O)c1cn(-c2ccccc2)cn1
Reactant: Clc1ccccc1OC1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Cl)C1)c1cn(-c2ccccc2)cn1
Reaction time: 0.03 h
Yield: 34.7 %

Procedure:
DIPEA (167.9 mg, 1.3 mmol) was added to a stirred solution of [(1-phenyl-1H-imidazole-4-carbonyl)-amino]-acetic acid (prepared from Intermediate 68 by means of Step 3 of the General Scheme) (80 mg, 0.32 mmol) in DMF (2 mL) followed by HOBt (48.3 mg, 0.35 mmol) and EDCI (124 mg, 0.65 mmol). After 2 minutes of stirring, 3-(2-chloro-phenoxy)-pyrrolidine hydrochloride (prepared by the method used for the synthesis of Intermediate 72) (76 mg, 0.32 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate, and concentrated under reduced pressure. Purification by recrystallisation from a mixture of DCM in hexane afforded 48 mg (34.7% Yield) of 1-phenyl-1H-imidazole-4-carboxylic acid {2-[3-(2-chloro-phenoxy)-pyrrolidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 425, 93.15%. 1H NMR (300 MHz, DMSO-d6): δ 8.4 (s, 1H), 8.3 (s, 1H), 8.1-8.0 (t, 1H), 7.8-7.7 (t, 2H), 7.5-7.4 (m, 2H), 7.4-7.2 (m, 2H), 7.06-7.0 (m, 1H), 5.3-5.1 (d, 1H), 4.2-4.0 (m, 2H), 4.0-3.5 (m, 4H), 2.3-2.2 (m, 1H), 2.2-2.0 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:23])[C@@H:20]([CH3:22])[NH2:21])=[CH:14][CH:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.C(N(CC)CC)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl>C(OCC)(=O)C.CN(C1C=CN=CC=1)C>[CH3:22][C@H:20]1[NH:21][C:32](=[O:34])[N:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][C:7]3[C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH:10]=[CH:9][CH:8]=3)=[CH:13][CH:14]=2)[C:19]1=[O:23]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1noc2cccc(Oc3ccc(NC(=O)[C@@H](C)N)cc3)c12
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1noc2cccc(Oc3ccc(N4C(=O)N[C@H](C)C4=O)cc3)c12
Reaction time: 0.08 h
Yield: 87.8 %

Procedure:
N1-{4-[(3-methyl-1,2-benzisoxazol-4-yl)oxy]phenyl}-D-alaninamide (Intermediate 14, 337 mg) was dissolved in 8.0 ml of ethyl acetate. Triethylamine (0.33 ml, 2.38 mmol) was added followed by a solution of triphosgene (161 mg, 0.54 mmol) in 2.0 ml of ethyl acetate. After 5 minutes stirring, DMAP (66 mg, 0.54 mmol) was added and the reaction mixture was stirred at room temperature for 10 minutes. After quenching with a saturated aqueous solution of NaHCO3, the reaction mixture was extracted two times with ethyl acetate. The gathered organic layers were dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with a gradient Cy-Hex/EtOAc from 100/0% to 0/100%. This afforded the title compound (160 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)N([O])C(C)(C)CCC1.OS([O-])(=O)=O.[K+]>C(OC(C)C)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[O:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CC(=O)OC(C)C
Product: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Temperature: 2.5 °C

Procedure:
A solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (1.0 eq.) in isopropyl acetate (5 vol) was cooled to 0° C. and TEMPO (0.05 eq.) was added. A solution of bleach (12.5 wt %, 1.2 eq., 2.6 vol) was then slowly added over 1 hr while maintaining the temperature at 0-5° C. The mixture was stirred and monitored by HPLC for completion, then aqueous 10% KHSO4 (2.5 vol) was added, stirred for 10 minutes, and then the phases were separated. The organic phase was washed with aqueous 5% Na2SO3 (2 vol) then brine (1 vol) then dried azeotropically and concentrated to afford the title compound as a solid. The solid was triturated with acetonitrile (1.0 vol) to remove residual color and impurities. 1H-NMR (400 MHz, DMSO): δ 4.54 (m, 1H), 3.82 (m, 1H), 3.67 (m, 1H); 3.15 (m, 1H); ≈2.50 (m, 1H, coincides with DMSO); 1.42 and 1.39 (2s rotamers, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][CH:6]1[C:15]2[CH:14]=[C:13]([O:16][CH2:17][CH2:18][NH2:19])[CH:12]=[CH:11][C:10]=2[CH2:9][CH2:8][CH:7]1[N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.[CH:29]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31][CH2:30]1.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][CH:6]1[C:15]2[CH:14]=[C:13]([O:16][CH2:17][CH2:18][NH:19][S:33]([CH:29]3[CH2:32][CH2:31][CH2:30]3)(=[O:35])=[O:34])[CH:12]=[CH:11][C:10]=2[CH2:9][CH2:8][CH:7]1[N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=S(=O)(Cl)C1CCC1
Reactant: NCCOc1ccc2c(c1)C(Cc1ccc(Cl)c(Cl)c1)C(N1CCCC1)CC2
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=S(=O)(NCCOc1ccc2c(c1)C(Cc1ccc(Cl)c(Cl)c1)C(N1CCCC1)CC2)C1CCC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2-(8-(3,4-Dichlorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethanamine (120 mg, 0.286 mmol), para-(N,N-dimethylamino) pyridine (1.40 g, 19.7 mmol), and cyclobutanesulfonyl chloride (46.5 mg, 0.30 mmol) were dissolved in CH2Cl2 (20 ml) and stirred for 14 h at room temperature. 0.5N HCl was added, the organic phase separated and the aqueous phase extracted with CH2Cl2. The combined organic layers were washed with water, NaHCO3 solution, and saturated NaCl solution, dried over Na2SO4, and concentrated to afford a residue that was purified by flash chromatography (silica gel, MeOH/CH2Cl23:97→5:95). The white solid product (164 mg, 32%) was transferred to an HCl salt and precipitated from diisopropyl ether.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[I-].[K+].Br[CH:17]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)=[CH:24][CH:23]=1)[C:18]([O:20][CH3:21])=[O:19]>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH3:21][O:20][C:18](=[O:19])[CH:17]([O:11][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=1)[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][C:33]2[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=2)=[CH:26][CH:27]=1
Reactant: COC(=O)C(Br)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C(Oc1ccc(C(C)(C)C)cc1)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Yield: 97.6 %

Procedure:
As described in Example 30, a mixture of 3.13 g of p-tert.-butylphenol, 0.755 g of 60% sodium hydride-oil dispersion, 3.5 g of potassium iodide, one ml of hexamethylphosphoramide and 7.9 g of methyl bromo{p-[3-(p-chlorophenoxy)propoxy]phenyl}acetate in 70 ml of tetrahydrofuran is refluxed for 18 hours and worked-up to give 9.0 g of an oil. The oil is chromatographed over silica gel with dichloromethane as eluent to give 7.4 g of oil which is crystallized from petroleum ether-ether to give 5.7 g of white crystals, mp 98°-101° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[N:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[Cl-].[NH4+]>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:28](=[O:29])[C:27]5[CH:31]=[CH:32][CH:33]=[N:34][C:26]=5[C:25]([F:36])([F:24])[F:35])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: O=C(O)c1cccnc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1cccnc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.7 %

Procedure:
To a solution of N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (95 mg, 0.307 mmol) in N,N-dimethylformamide (5 mL) were added 2-(trifluoromethyl)nicotinic acid (65 mg, 0.337 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (65 mg, 0.337 mmol) and 1-hydroxybenzotriazole (46 mg, 0.337 mmol), and the mixture was stirred at room temperature for 2 hr, heated to 50° C. and stirred for 2 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→100/0), and precipitated from ethyl acetate/diisopropyl ether to give the title compound (79.6 mg, 54%) as a pale-green powder.
Reaction SMILES: C(O)(=O)C.C(N=C1CC(C)CCN1)C.[ClH:15].[CH3:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][CH3:26])[CH:18]=1>>[ClH:15].[CH3:16][CH:17]1[CH2:22][CH2:21][NH:20][C:19](=[N:23][CH2:24][CH2:25][CH3:26])[CH2:18]1
Reactant: CCCNc1cc(C)ccn1
Agent: CCN=C1CC(C)CCN1
Agent: Cl
Solvent: CC(=O)O
Product: CCCN=C1CC(C)CCN1

Procedure:
The method of preparation of 2-(ethylimino)-4-methylpiperidine acetate was used to convert 4-methyl-2-(propylamino)pyridine hydrochloride to the title compound The product was obtained as a clear colorless oil which crystallized under EtOAc. The analysis of the product was found to be consistent with the proposed structure. MH+=155; 1H NMR (D2O): 3.45-3.20 (m, 2H); 3.05 (t, J=6 Hz, 2H); 2.60-2.45 (m, 1H); 2.20-2.00 (m, 1.95-1.70 (m, 2H); 1.60-1.40 (m, 2H); 1.40-1.25 (m, 1H); 0.90 (d, J=6 Hz, 3H); 0.80 (t, J=6 Hz, 3H).
Reaction SMILES: [Si:1]([N:8]1[C@@H:11]([CH2:12]O)[CH2:10][C:9]1=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[SH:46][C:47]1[N:52]=[CH:51][CH:50]=[CH:49][N:48]=1>C1COCC1>[Si:1]([N:8]1[C@@H:11]([CH2:12][S:46][C:47]2[N:52]=[CH:51][CH:50]=[CH:49][N:48]=2)[CH2:10][C:9]1=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Sc1ncccn1
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C[C@@H]1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)N1C(=O)C[C@@H]1CSc1ncccn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94.9 %

Procedure:
To a solution of 1-(tert-butyldimethylsilyl)-4(R)-(hydroxymethyl)azetidin-2-one (2.75 g, 12.77 mmol) in THF (80 mL) was added PPh3 (6.70 g, 25.54 mmol). The reaction was cooled at 0° and DEAD (3.3 mL, 25.54 mmol) was added dropwise. After 5 min. 2-mercaptopyrimidine (3.60 g, 31.92 mmol) was added. After stirring for 15 min at 0° and 60 h at room temperature, the reaction mixture was concentrated. The residue was treated with EtOAc/hexane (1/1) and the resulting solid was filtered and rinsed with Et2O. The filtrate was concentrated and purified by flash chromatography (SiO2, 25% EtOAc/hexane) to provide 1-(tert-butyldimethylsilyl)-4(R)-(pyrimidin-2-ylsulfanylmethyl)azetidin-2-one (3.75 g, 95% yield) as clear oil. 1H NMR (400 MHz, CDCl3) δ 8.70 (d, J=4.8 Hz, 2H), 7.20 (t, J=4.9 Hz, 1H), 4.08-4.01 (m, 2H), 3.41-3.36 (m, 1H), 3.99 (dd, J=14.3, 10.8 Hz, 1H), 2.98 (dd, J=15.6, 2.5 Hz, 1H), 1.18 (s, 9H), 0.53 (s, 3H), 0.49 (s, 3H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][S:2]1(=[O:11])=[O:10].CI.[C:14](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:14][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][S:2]1(=[O:10])=[O:11]
Reactant: O=S1(=O)Cc2ccccc2N1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CN1c2ccccc2CS1(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.6 %

Procedure:
A mixture of 1,3-dihydro-2,1-benzisothiazole 2,2-dioxide (J. Heterocyclic Chem. 1986, 23, 1645., 401 mg, 2.37 mmol), methyl iodide (0.6 mL, 9.48 mmol) and potassium carbonate (328 mg, 2.37 mmol) in N,N-dimethylformamide (7 mL) was stirred for 4 h at room temperature. The reaction mixture was diluted with toluene/ethyl acetate (1/3), then washed with water for two times, and then the organic layer washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by preparative thin layer chromatography on silica gel developing with hexane/ethyl acetate (2/1) to afford 272 mg (63%) of the title compound as a slight brown syrup:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[CH2:8][C@H:9]1[CH2:14][N:13]([S:15]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)(=[O:17])=[O:16])[CH2:12][CH2:11][NH:10]1.Br[C:24]1[CH:29]=[CH:28][C:27]([C@:30]([OH:36])([CH3:35])[C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>O.CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.CC(OC)(C)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.CC(O)C.C1(C)C=CC=CC=1>[F:32][C:31]([F:33])([F:34])[C:30]([C:27]1[CH:26]=[CH:25][C:24]([N:10]2[CH2:11][CH2:12][N:13]([S:15]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:17])[CH2:14][C@@H:9]2[CH2:8][N:3]2[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]2[CH3:1])=[CH:29][CH:28]=1)([OH:36])[CH3:35]
Reactant: C[C@@](O)(c1ccc(Br)cc1)C(F)(F)F
Reactant: C[C@H]1COCCN1C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CC(C)O
Solvent: COC(C)(C)C
Solvent: O
Product: C[C@H]1COCCN1C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 0.05 h
Yield: 50.2 %

Procedure:
A 1-L pressure vessel was charged with (3S)-3-methyl-4-(((2S)-4-(2-thiophenylsulfonyl)-2-piperazinyl)methyl)morpholine (10.50 g, 30.4 mmol), 100 mL of toluene, (2R)-(4-bromophenyl)-1,1,1-trifluoropropan-2-ol (9.81 g, 36.5 mmol, Example 243, Step 1), and sodium tert-butoxide (7.30 g, 76 mmol). Nitrogen gas through the solution for 3 min then RuPhos Palladacycle (1.107 g, 1.520 mmol) and dicyclohexyl(2′,6′-diisopropoxy-[1,1′-biphenyl]-2-yl)phosphine, RuPhos (0.709 g, 1.520 mmol) were added. The vessel was sealed and heated at 60° C. for 12 h. The mixture diluted with water and extracted with EtOAc. The combined organics were dried with MgSO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (0-70% EA/Hex) to give a tan foam. To this foam was added 200 mL of IPA and stirred at rt for 1 h. The white solid that had formed was collected by filtration, dissolved in MeOH, then dried under high vac at 70° C. for 1 h to give pure 1,1,1-trifluoro-2-(4-((S)-2-(((S)-3-methylmorpholino)methyl)-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)propan-2-ol (8.15 g). This material was identical to peak 2 in example 45.
Reaction SMILES: [CH2:1]([N:5]([CH2:39][CH2:40][CH2:41][CH3:42])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=[O:20])=[CH:16][CH:15]=2)=[C:8]([O:21][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:7]=1)[CH2:2][CH2:3][CH3:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>O1CCCC1>[CH2:39]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=[O:20])=[CH:16][CH:15]=2)=[C:8]([OH:21])[CH:7]=1)[CH2:40][CH2:41][CH3:42]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(O)c1
Temperature: 25 °C
Yield: 93.5 %

Procedure:
In 10 ml of tetrahydrofuran was dissolved 488 mg (0.82 mmol) of 5-[2-[4-dibutylamino-2-(tert-butyldiphenylsiloxy)phenyl]vinyl]thiophene-2-carboaldehyde, and 2.5 ml of tetrabutylammonium fluoride (1 mol solution in tetrahydrofuran) was added dropwise thereto with stirring at room temperature. The mixture was stirred for 35 minutes. After the reaction mixture was poured into water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography to give 274 mg of a blackish brown crystal (yield: 93.6%).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:23]=[CH:22][C:8]([CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=3)[NH:12][CH:11]=2)=[C:7]([O:24][CH3:25])[CH:6]=1)#[N:4].I[CH3:27].[Cl-].[NH4+]>CN(C)C=O>[C:3]([C:5]1[CH:23]=[CH:22][C:8]([CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=3)[N:12]([CH3:27])[CH:11]=2)=[C:7]([O:24][CH3:25])[CH:6]=1)#[N:4]
Reactant: CI
Reactant: COc1cc(C#N)ccc1Cc1c[nH]c2ccc([N+](=O)[O-])cc12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1cc(C#N)ccc1Cc1cn(C)c2ccc([N+](=O)[O-])cc12
Reaction time: 1 h
Yield: 81 %

Procedure:
Sodium hydride (60% w/w dispersion in mineral oil, 0.12 g.) was added to a stirred solution of 3-(4-cyano-2-methoxybenzyl)-5-nitroindole (0.85 g.) in dry N,N-dimethylformamide (10 ml.) under a nitrogen atmosphere. After about one hour, iodomethane (0.645 g.) was added dropwise, and stirring continued at ambient temperature for 5 hours. The mixture was poured onto saturated aqueous ammonium chloride solution, extracted with ethyl acetate (2×20 ml.), the extract washed with water, brine, dried (MgSO4) and evaporated. The residue was crystallized from acetonitrile to give 3-(4-cyano-2-methoxybenzyl)-1-methyl-5-nitroindole (0.72 g., 81%) as a yellow solid, m.p. 200°-201° C.; partial NMR (250 MHz, DMSO-d6) 3.82(s, 3H, NMe); 3.92(s,3H, OMe); 4.12(s,2H, ArCH2)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH:17]3[C:22]([O:24][CH3:25])=[O:23])[C:7]=2[CH:26]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:34]/[CH:35]=[CH:36]/[C:37]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=1[F:44].CO>C(O)C.ClCCl>[F:44][C:38]1[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:37]=1/[CH:36]=[CH:35]/[CH2:34][N:19]1[CH2:20][CH2:21][C@H:16]([CH2:15][CH2:14][CH2:13][N:8]2[C:7]3[CH:26]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[O:11][CH2:10][C:9]2=[O:12])[C@H:17]([C:22]([O:24][CH3:25])=[O:23])[CH2:18]1
Reactant: COC(=O)C1CNCCC1CCCN1C(=O)COc2ccc(OC)cc21
Reactant: Fc1ccc(F)c(/C=C/CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: COC(=O)[C@@H]1CN(C/C=C/c2cc(F)ccc2F)CC[C@@H]1CCCN1C(=O)COc2ccc(OC)cc21
Temperature: 40 °C
Yield: 56.3 %

Procedure:
A solution of methyl 4-[3-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylate (Intermediate 220) (150 mg, 0.414 mmol) in ethanol (2 mL) was treated with K2CO3 (63 mg, 0.455 mmol) followed by a solution of 2-[(1E)-3-chloroprop-1-en-1-yl]-1,4-difluorobenzene (Intermediate 124) (86 mg, 0.455 mmol) in ethanol (1 mL). The reaction was warmed to 40° C. for 18 hours. The reaction was partitioned between ethyl acetate and water. The aqueous layer was extracted with dichloromethane (2×20 mL). The organic extracts were combined, dried over MgSO4 and concentrated at reduced pressure to obtain a yellow oil. Chromatography on silica gel eluting with (0-2.5%) methanol in dichloromethane gave the title compound as a yellow oil (120 mg, 56%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:6][Sb-:7]([F:12])([F:11])([F:10])([F:9])[F:8].[Cl-:13].[Cr+3:14].N1C2C=CC=CC=2N=C1CNCC1NC2C=CC=CC=2N=1.[Cl-].[Cr+3].[NH:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[CH2:47][N:48]([CH2:55][C:56]1[NH:60][C:59]2[CH:61]=[CH:62][CH:63]=[CH:64][C:58]=2[N:57]=1)[CH2:49]CCCCC.[Cl-].[Cl-]>F[Sb-](F)(F)(F)(F)F.[Ag+].C1COCC1>[O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:6][Sb-:7]([F:12])([F:11])([F:10])([F:9])[F:8].[Cl-:13].[Cr+3:14].[NH:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[CH2:47][N:48]([CH2:55][C:56]1[NH:57][C:58]2[CH:64]=[CH:63][CH:62]=[CH:61][C:59]=2[N:60]=1)[CH3:49]
Reactant: CCCCCCN(Cc1nc2ccccc2[nH]1)Cc1nc2ccccc2[nH]1
Agent: [Ag+]
Agent: [Cr+3]
Agent: F[Sb-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CN(Cc1nc2ccccc2[nH]1)Cc1nc2ccccc2[nH]1

Procedure:
4b was synthesised by an analogous procedure to that described for 4a using silver hexafluoroantimonate (0.661 g, 1.92 mmol) and complex 3e (1 g, 1.92 mmol). Yield 1.32 g, 87%. +FAB-MS: (m/e): 483 ([M]+), 467 ([M-Me]+), 449 ([M-Cl]), 361 ([M-Cr, Cl, THF). −FAB-MS: (m/z): 235 ([M]−).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:10]([F:23])[C:9]=2F)=[CH:4][CH:3]=1.[F:25]C1C=C(B(O)O)C=CC=1OCCCCCCCC.BrC1C=CC(I)=C(F)C=1>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>[F:23][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:25])[CH:13]=[CH:12][C:11]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCOc1ccc(-c2ccc(Br)cc2)c(F)c1F
Reactant: CCCCCCCCOc1ccc(B(O)O)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Fc1cc(Br)ccc1I
Product: CCCCCCCCOc1ccc(-c2ccc(Br)cc2F)cc1F

Procedure:
This was prepared using a similar method to that described for compound 8. The product is a low melting solid and was used without further purification. Quantities: 3-fluoro-4-octyloxyphenylboronic acid (6) (6.83 g, 0.026 mol), 1-bromo-3-fluoro-4-iodobenzene (6.92 g, 0.023 mol), tetrakis(triphenylphosphine)palladium(0) (1 g, 0.87 mmol).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[C:13]=1[C:14]#[N:15]>C(Cl)Cl.N1C=CC=CC=1>[Br:20][C:16]1[C:13]([C:14]#[N:15])=[C:12]([NH:11][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:19]=[CH:18][CH:17]=1
Reactant: N#Cc1c(N)cccc1Br
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1c(Br)cccc1NS(=O)(=O)c1ccccc1
Reaction time: 2 h
Yield: 28 %

Procedure:
Benzenesulfonyl chloride (0.53 g) was added to a solution of 2-amino-6-bromobenzonitrile (Intermediate 22, 0.5 g) in DCM (15 mL) and pyridine (1 mL). The mixture was stirred for 2 hours, then a further aliquot of benzenesulfonyl chloride (0.53 g) was added and the mixture was stirred overnight. The reaction mixture was diluted with DCM, washed with 1N hydrochloric acid, and the organic solution was dried with sodium sulfate and filtered. The filtrate was evaporated under vacuum and the residue was purified by flash chromatography on silica, eluting with a mixture of DCM and methanol. The fractions containing the desired product were combined and evaporated to give the title compound as a white powder (0.24 g).