Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([N:12]=[C:13]=[S:14])[C:9]([CH3:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH2:16]([NH2:19])[CH2:17][NH2:18]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:11]=[C:10]([NH:12][C:13]([NH:18][CH2:17][CH2:16][NH2:19])=[S:14])[C:9]([CH3:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Cc1c(N=C=S)cc(F)c2cccnc12
Reactant: NCCN
Solvent: Cc1ccccc1
Product: Cc1c(NC(=S)NCCN)cc(F)c2cccnc12
Reaction time: 0.17 h

Procedure:
N-(5-Fluoro-8-methyl-7-quinolinyl/-N'-2-aminoethylthiourea. A solution of 5-fluoro-8-methyl-7-quinolinylisothiocyanate (0.38 g) in toluene (40 mL) is added dropwise to a solution of 1,2-ethylenediamine (0.78 g) in toluene (40 mL). A white precipitate is observed after the reaction stirs for 10 minutes at room temperature. The precipitate is filtered and dried in vacuo to afford N-(5-fluoro-8-methyl-7-quinolinyl)-N'-2-aminoethylthiourea as a white solid.
Reaction SMILES: [Mg].C([Mg]Cl)(C)C.Br[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15].[Si:16]([O:23][CH2:24]/[CH:25]=[N:26]/[S@:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C1COCC1.C1(C)C=CC=CC=1>[Si:16]([O:23][CH2:24][C@H:25]([NH:26][S@:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28])[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[S@](=O)/N=C/CO[Si](C)(C)C(C)(C)C
Reactant: Fc1ccc(Br)c(F)c1
Agent: CC(C)[Mg]Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)[S@](=O)N[C@@H](CO[Si](C)(C)C(C)(C)C)c1ccc(F)cc1F
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a first flask was added magnesium turnings (197 mg, 8.11 mmol) and THF (7 mL). A 2.0 M solution of isopropyl magnesium chloride in THF (16 μL, 0.032 mmol) was added followed by 1-bromo-2,4-difluorobenzene (0.10 mL). The temperature of the reaction mixture raised to 30° C. Additional 1-bromo-2,4-difluorobenzene (0.91 mL) was added dropwise at such a rate that the internal temperature did not exceed 32° C. After addition, the reaction mixture was stirred at 26-28° C. for 30 minutes. To a second flask was added (S,E)-N-(2-(tert-butyldimethylsilyloxy)ethylidene)-2-methylpropane-2-sulfinamide (1.50 g, 5.41 mmol) and toluene (32 mL) under N2. The reaction mixture was cooled to −78° C. The Grignard reagent prepared in the first flask was slowly transferred to the reaction mixture in the second flask using a syringe. The reaction was allowed to slowly warm up to 0° C. The reaction was quenched by the addition of saturated aqueous NH4Cl solution. The organic layer was separated. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried and concentrated. The residue was purified by column chromatography (hexane/EtOAc, 6:1) to give (S)—N—((R)-2-(tert-butyldimethylsilyloxy)-1-(2,4-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (1.14 g, 54%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19](=[O:39])[C:20]4[C:25]([O:26][C:27]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:24]3[N:34]([CH3:38])[N:35]=[C:36](I)[C:23]3=[CH:22][CH:21]=4)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:41][CH2:42]OC(C)=O>C1(C)C=CC=CC=1.C1CCCCC1.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]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19](=[O:39])[C:20]4[C:25]([O:26][C:27]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:24]3[N:34]([CH3:38])[N:35]=[C:36]([CH:41]=[CH2:42])[C:23]3=[CH:22][CH:21]=4)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1nc(I)c2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c21
Reactant: CCOC(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCCCC1
Product: C=Cc1nn(C)c2c1ccc1c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of {1-[4-(3-iodo-1-methyl-6-oxo-8-phenyl-1,6-dihydro-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (27 mg, 0.0417 mmol), tetrakis(triphenylphosphine)palladium(0) (4.8 mg, 0.004 mmol) and vinyltributylin (0.0183 mL, 0.063 mmol) in toluene (2 mL) was stirred at 90° C. under nitrogen. After 3 hours, reaction mixture cooled to RT and was subjected to flash chromatography (SiO2, gradient 20 to 40% EtOAc in cyclohexane) to afford the title compound (23.4 mg) as a yellow gum. LCMS (Method H): RT=4.67 min, [M+H]+=548.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]([O:21][CH3:22])=[O:20])[C:8]([CH3:28])=[CH:7][C:5]=2[N:6]=1.[Cl:29][C:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[CH:32][N:31]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>O1CCOCC1.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:24]([O:23][C@@H:18]([C:9]1[C:8]([CH3:28])=[CH:7][C:5]2[N:6]=[C:2]([C:34]3[CH:33]=[CH:32][N:31]=[C:30]([Cl:29])[CH:35]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH3:22])=[O:20])([CH3:27])([CH3:26])[CH3:25]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: OB(O)c1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 95 °C

Procedure:
The reaction mixture of (S)-methyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (370 mg, 0.769 mol), 2-chloropyridine-4-boronic acid (157 mg, 0.99 mmol), 2N K2CO3 (1.9 mL), Pd(PPh3)4 (80 mg, 0.077 mmol) in dioxane (10 mL) was heated at 95° C. for 2 h. The reaction mixture was diluted by EtOAc, washed by sat. NaHCO3, extracted by EtOAc, the organic phase was dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in hexanes to give the product. LCMS-ESI+: calc'd for C26H24Cl2N2O3S: 515.1 (M+H+). Found: 515.1 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[C:5]([CH3:40])([CH3:39])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([N+]#[C-])(S(C1C=CC(C)=CC=1)(=O)=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:2].Cl.[OH2:43]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:41])[C:5]([CH3:40])([CH3:39])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:43])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:2]
Reactant: O
Reactant: [C-]#[N+]C(CCCCCCC(C)(C)C(=O)OCC)(CCCCCCC(C)(C)C(=O)OCC)S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)CCCCCCC(=O)CCCCCCC(C)(C)C(=O)OCC
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 40 %

Procedure:
To a solution of 208i (12.0 g, 20.3 mmol) in CH2Cl2 (200 mL) was added concd HCl (47 mL). The reaction mixture was stirred for 80 min at room temperature and diluted with water (200 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×70 mL). The combined organic layers were washed with saturated NaHCO3 solution (3×40 mL) and brine (50 mL), dried over anhydrous MgSO4, and concentrated in vacuo to yield the crude product (7.52 g). Purification by column chromatography (silica gel, ethyl acetate/hexanes=1/9) gave 209i (3.5 g, 40.0%) as a colorless oil. 1H NMR (CDCl3): δ (ppm): 4.14 (q, J=7.1, 4H), 2.41 (t, J=7.0, 4H), 1.66-1.45 (m, 8H), 1.35-1.20 (m, 12H), 1.25 (t, J=7.1, 6H), 1.17 (s, 12H). 13C NMR (CDCl3): δ (ppm): 211.24, 177.89, 60.01, 42.69, 42.07, 40.64, 29.86, 29.07, 25.13, 24.73, 23.74, 14.24. HRMS (LSIMS, gly): Calcd for C25H47O5 (MH+): 427.3423, found: 427.3430.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[CH:14][C:13]3[N:19]=[C:20]([CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28])[N:21]([CH3:22])[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:36]C1C=CC2C3N(CC(C)C)C(C)=NC=3C=NC=2C=1)C1C=CC=CC=1.C1C=C(Cl)C=C(C(OO)=O)C=1>ClCCl>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N+:15]([O-:36])=[CH:14][C:13]3[N:19]=[C:20]([CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28])[N:21]([CH3:22])[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCOCc1nc2cnc3ccc(OCc4ccccc4)cc3c2n1C
Reactant: Cc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)C
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COCCOCc1nc2c[n+]([O-])c3ccc(OCc4ccccc4)cc3c2n1C
Reaction time: 3 h

Procedure:
A modification of the general method described in Part B of Example 3 was followed using 8-benzyloxy-2-[2-methoxy(ethoxymethyl)]-1-methyl-1H-imidazo[4,5-c]quinoline (5.4 g, 14 mmol) in lieu of 7-benzyloxy-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline. Dichloromethane (100 mL) was used as the solvent, and after three hours an analysis by TLC indicated the reaction was incomplete. Additional mCPBA (0.5 equivalents) was added, and the reaction was terminated after one additional hour. After the work-up the product was purified by column chromatography on silica gel (eluting with 90:10 dichloromethane:methanol to provide 1.5 g of 8-benzyloxy-2-[2-methoxy(ethoxymethyl)]-1-methyl-5-oxido-1H-imidazo[4,5-c]quinolin as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][CH3:18])[C:13](O)=[S:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=1.C(N(CC)CC)C.[I-].C[N+]1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][CH3:18])[C:13]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:26]=2)=[S:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CCCC(NS(=O)(=O)c1ccc(Cl)cc1)C(O)=S
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCC(NS(=O)(=O)c1ccc(Cl)cc1)C(=S)Nc1ccc(CC(=O)OCC)cc1
Yield: 23.5 %

Procedure:
The procedure described in Example 177 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-4-methylthiobutanoic acid (1 g) and ethyl 4-aminophenylacetate hydrochloride (599 mg) were condensed in chloroform (30 ml) in the presence of triethylamine (1.72 ml) and 1-methyl-2-chloropyridinium iodide (946.8 mg) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-methylthiobutanamide (306.3 mg).
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][O:19][CH3:20])=[C:13]([CH:21]([CH3:23])[CH3:22])[CH:12]=2)=[C:8]([CH3:24])[CH:7]=[C:6]([OH:25])[C:3]=1[CH2:4]O>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[CH3:20][O:19][CH2:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][C:9]2[C:8]([CH3:24])=[CH:7][C:6]([OH:25])=[C:3]([CH3:4])[C:2]=2[CH3:1])=[CH:12][C:13]=1[CH:21]([CH3:23])[CH3:22]
Reactant: COCOc1ccc(Cc2c(C)cc(O)c(CO)c2C)cc1C(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COCOc1ccc(Cc2c(C)cc(O)c(C)c2C)cc1C(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
A mixture of 2,4-dimethyl-6-hydroxy-3-(4′-methoxymethoxy-3′-iso-propylbenzyl)benzyl alcohol ((0.20 g, 0.58 mmol) and Pd—C (0.08 g, 10%) in ethyl acetate-acetic acid (3.5 mL, 95:5) was stirred at room temperature under a H2 atmosphere for 6 h. The reaction mixture was filtered through a Celite plug and the solvent was removed under reduced pressure to afford 4-(4′-methoxymethoxy-3′-iso-propylbenzyl)-2,3,5-trimethylphenol (0.19 g, 100%) as colorless oil: 1H NMR (300 MHz, CD3OD): δ 6.94 (m, 1H), 6.91 (d, J=13.2 Hz, 1 H), 6.68 (dd, J=13.2, 2.4 Hz, 1 H), 6.55 (s, 1 H), 5.17 (s, 2 H), 3.95 (s, 2 H), 3.47 (s, 3 H), 3.30 (m, 1 H), 2.19 (s, 3 H), 2.16 (s, 3 H), 2.11 (s, 3 H), 1.17 (d, J=10.8 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=acetone-hexanes (3:7); Rf=0.60.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][S:40]([CH2:43][CH2:44][NH2:45])(=[O:42])=[O:41].O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:26])[F:27])=[N:20][C:21]([C:22](=[O:23])[NH:45][CH2:44][CH2:43][S:40]([CH3:39])(=[O:42])=[O:41])=[C:15]2[CH2:14]1)=[O:12])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: CS(=O)(=O)CCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)NCCS(C)(=O)=O)c2C1)Cc1cc(F)c(F)cc1F
Yield: 33.9 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.15 g, 0.27 mmol), 2-methanesulfonyl-ethylamine (65.5 mg, 0.41 mmol) and bis (2-oxo-3-oxazolidinyl)phosphonic chloride (0.104 g, 0.41 mmol) were dissolved in 5 mL of dichloromethane under stirring, and triethylamine (0.25 mL, 1.62 mmol) was then added to the solution. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-[1-(2-methanesulfonyl-ethylcarbamoyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 2b (60 mg, yield 34%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[CH3:19])[NH2:15]>>[NH2:15][C:14]1[CH:13]=[C:12]([O:11][CH3:10])[C:18]([CH3:19])=[CH:17][C:16]=1[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])=[O:5]
Reactant: O=Cc1ccccc1Cl
Reactant: COc1cc(N)ccc1C
Product: COc1cc(N)c(C(=O)c2ccccc2Cl)cc1C

Procedure:
(2-amino-4-methoxy-5-methylphenyl)-(2-chlorophenyl)-methanone (Xz) was prepared by reacting 2-chlorobenzaldehyde with 0.0226 moles of 3-methoxy-4-methyl aniline in a manner analogous to Example 1. MH+/Z=276.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]([Br:24])(Br)Br.C(N(CC)CC)C.[C:32]([O:36][C:37](=[O:49])[N:38]([CH2:40][C@H:41]1[CH2:46][CH2:45][C@H:44]([CH:47]=O)[CH2:43][CH2:42]1)[CH3:39])([CH3:35])([CH3:34])[CH3:33]>C(Cl)Cl>[C:32]([O:36][C:37](=[O:49])[N:38]([CH2:40][C@H:41]1[CH2:42][CH2:43][C@H:44]([CH:47]=[C:21]([Br:24])[Br:20])[CH2:45][CH2:46]1)[CH3:39])([CH3:35])([CH3:33])[CH3:34]
Reactant: CN(C[C@H]1CC[C@H](C=O)CC1)C(=O)OC(C)(C)C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C[C@H]1CC[C@H](C=C(Br)Br)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 257.6 g (982 mmol) triphenylphosphine in 1 l CH2Cl2 was treated with 162.8 g (491 mmol) tetrabromomethane (the reaction heated up to reflux and was then cooled with an ice bath) and after 40 min at RT with 157.4 ml (1129 mmol) triethylamine (the reaction heated up to reflux and became dark violet). After cooling (0° C.), 77.96 g (corresponds to 245.5 mmol) of crude trans-(4-Formyl-cyclohexylmethyl)-methyl-carbamic acid tert-butyl ester in 600 ml CH2Cl2 were added during 20 min. The solution was stirred for 20 h at RT, evaporated and filtered through silica gel (deactivated with hexane/0.5% Et3N) with hexane/Et2O 99:1 to 4:1 as eluent to yield 61.5 g (61%) of trans-[4-(2,2-Dibromo-vinyl)-cyclohexylmethyl]-methyl-carbamic acid tert-butyl ester, MS: 409 (M, 2Br).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Si](C)(C)C)(=O)=O.[F-].[Cs+].[P:21]([O:32]CCCC)([O:27][CH2:28][CH2:29][CH2:30][CH3:31])[O:22][CH2:23][CH2:24][CH2:25][CH3:26].C(#N)C>CCOC(C)=O>[C:7]1([P:21](=[O:32])([O:27][CH2:28][CH2:29][CH2:30][CH3:31])[O:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCCCOP(OCCCC)OCCCC
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCCOP(=O)(OCCCC)c1ccccc1

Procedure:
2-(trimethylsilyl)phenyl trifluoromethanesulfonate (25 mg, 0.083 mmol), Cesium Fluoride (70 mg, 0.461 mmol), Tributyl phosphite (83 mg, 0.335 mmol), Acetonitrile (1 ml): Reaction Time: 24 h; Rf: 0.4 (1:3 EtOAc:Pet. Ether); Thick oil; 16.3 mg, 72%; 1H NMR (400 MHz, CDCl3, TMS) δ 7.80 (dd, J=6.8, 13.3 Hz, 2H), 7.55 (t, J=7.5 Hz, 1H), 7.50-7.42 (m, 2H), 4.12-3.95 (m, 4H), 1.65 (quint, J=7.3 Hz, 4H), 1.39 (sext, J=7.3 Hz, 4H), 0.9 (t, J=7.3 Hz, 6H); 13C NMR (100 MHz, CDCl3, TMS) δ 132.3 (d, J=3.1 Hz), 131.7 (d, J=9.3 Hz), 128.4 (d, J=15.4 Hz), 128.3 (d, J=187.3 Hz), 65.8 (d, J=5.4 Hz), 32.4 (d, J=6.9 Hz), 18.7, 13.6; 31P NMR (162 MHz, CDCl3) δ 18.8; Mass (M+Na)+ 293; Known compound, Lit. X. Lu, J. Zhu, Synthesis 1987, 8, 726.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:16][C:17]1[C:18]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=2[S:20][CH:21]=1>>[Cl:26][C:24]1[CH:23]=[CH:22][C:19]2[S:20][CH:21]=[C:17]([CH2:16][N:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH:14]=[C:6]3[C:4]([OH:3])=[O:5])[C:18]=2[CH:25]=1
Reactant: Clc1ccc2scc(CBr)c2c1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Product: O=C(O)c1cc2ccccc2n1Cc1csc2ccc(Cl)cc12

Procedure:
Using general procedure B, 1H-indole-2-carboxylic acid ethyl ester was coupled with 3-bromomethyl-5-chloro-benzo[b]thiophene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 340.0 ([M−H]−).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:8])=[C:5]([CH3:7])[CH:6]=1.CO[CH2:11][Cl:12]>C(O)(=O)C>[CH3:1][C:2]1[S:3][C:4]([CH3:8])=[C:5]([CH3:7])[C:6]=1[CH2:11][Cl:12]
Reactant: Cc1cc(C)c(C)s1
Reactant: COCCl
Solvent: CC(=O)O
Product: Cc1sc(C)c(CCl)c1C
Temperature: 25 °C
Reaction time: 91 h

Procedure:
24.6 G. of 2,4,5-trimethyl-thiophene, 14.8 g. of freshly distilled chloromethyl methyl ether and 52 g. of glacial acetic acid were combined in a glass pressure bottle and stirred at room temperature for 4-178 hours. The resulting reaction mixture was poured into ice water, stirred for 10 min. and extracted with benzene. The combined benzene extracts were washed twice with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. The resulting 2,4,5-trimethyl-3-chloromethyl-thiophene was used for the next step without any further purification.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C@@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12](=[O:15])[CH2:13]Br)=[O:6])[CH2:3][CH2:2]1.[CH2:16]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:52])[C@@H:28]([NH:38][C:39]([C:41]2[CH:50]=[C:49]([OH:51])[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:42]=2)=[O:40])[CH2:29][CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])[CH2:23][CH2:22]1)=[O:20])[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:16]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:52])[C@@H:28]([NH:38][C:39]([C:41]2[CH:50]=[C:49]([O:51][CH2:13][C:12]([N:8]3[CH2:9][CH2:10][CH2:11][C@H:7]3[C:5](=[O:6])[NH:4][CH:1]3[CH2:3][CH2:2]3)=[O:15])[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:42]=2)=[O:40])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH2:23][CH2:22]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccccc3c2)CC1
Reactant: O=C(NC1CC1)[C@@H]1CCCN1C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CC3)c3ccccc3c2)CC1
Temperature: 80 °C

Procedure:
To a solution of 100 mg of (S)-1-(2-Bromo-acetyl)-pyrrolidine-2-carboxylic acid cyclopropylamide and 93 mg of 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-naphthalene-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 2 ml of DMF, 118 mg of cesium carbonate was added and the reaction mixture was heated to 80° C. for 5 h. Then, the reaction mixture was diluted with water and filtered through a chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure and the residue was dissolved in 1 ml of DCM and 0.2 ml of TFA. After 16 h at RT 10 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. Yield: 40 mg MS (ES+): m/e=652.
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([OH:16])=O)[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[F:18][C:19]1[C:20]([NH2:33])=[CH:21][C:22]2[CH:23]=[C:24]3[C:30]([CH3:32])([CH3:31])[CH2:29][CH2:28][N:25]3[C:26]=2[CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[F:17][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:33][C:20]4[C:19]([F:18])=[CH:27][C:26]5[N:25]6[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]6=[CH:23][C:22]=5[CH:21]=4)=[O:16])[CH2:12][CH2:13]3)=[CH:10][C:4]=2[O:3]1
Reactant: CC1(C)CCn2c1cc1cc(N)c(F)cc12
Reactant: O=C(O)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)CCn2c1cc1cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)c(F)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
To a mixture of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (346 mg, 1.4 mmol), 6-fluoro-1,1-dimethyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-7-amine (260 mg, 1.2 mmol) and HATU (543 mg, 1.4 mmol) in DMF (5 mL) was added triethylamine (0.40 mL, 2.9 mmol). The reaction was stirred at room temperature overnight and then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over MgSO4. After the removal of solvent, the residue was purified by column chromatography (10-20% ethyl acetate-hexanes) to afford 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-fluoro-1,1-dimethyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-7-yl)cyclopropanecarboxamide (342 mg, 65%). ESI-MS m/z calc. 442.2, found 443.5 (M+1)+. Retention time 2.30 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J=7.6 Hz, 1H), 7.30-7.25 (m, 3H), 7.20 (m, 1H), 7.12 (d, J=8.2 Hz, 1H), 6.84 (d, J=11.1 Hz, 1H), 6.01 (d, J=0.5 Hz, 1H), 3.98 (t, J=6.8 Hz, 2H), 2.37 (t, J=6.8 Hz, 2H), 1.75 (dd, J=3.8, 6.9 Hz, 2H), 1.37 (s, 6H) and 1.14 (dd, J=3.9, 6.9 Hz, 2H) ppm.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[N:3]=1.[I:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1>>[I:22][C:23]1[N:24]=[CH:25][N:26]([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)[N:3]=2)[CH:27]=1
Reactant: Ic1c[nH]cn1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cn1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)cn1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example A.2) (1.31 g, 4.0 mmol) and commercially available 4-iodo-imidazole (0.85 g, 4.4 mmol) according to the general procedure Ia. Obtained as a light brown solid (1.84 g, 95%). MS (ISP) 486.9 [(M+H)+]; mp 179° C.