Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@@:18]1([N:26]2[C:36]3[N:35]=[C:33]([NH2:34])[NH:32][C:30](=[O:31])[C:29]=3[N:28]=[CH:27]2)[O:25][C@H:22]([CH2:23][OH:24])[C@@H:20]([OH:21])[CH2:19]1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]CCCCCCCCC.C(Cl)(=O)C1C=CC=CC=1.C(Cl)(=O)CCCCCCCCCCCCCCC.C(=O)(O)[O-].[Na+]>>[C:1]([C@@:18]1([N:26]2[C:36]3[N:35]=[C:33]([NH2:34])[NH:32][C:30](=[O:31])[C:29]=3[N:28]=[CH:27]2)[O:25][C@H:22]([CH2:23][OH:24])[C@@H:20]([OH:21])[CH2:19]1)(=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCCCCCCC(=O)[C@]1(n2cnc3c(=O)[nH]c(N)nc32)C[C@H](O)[C@@H](CO)O1
Agent: CCCCCCCCCCCCCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(Cl)c1ccccc1
Product: Nc1nc2c(ncn2[C@@]2(C(=O)c3ccccc3)C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Temperature: 0 °C

Procedure:
This compound was prepared using the procedure for palmitoyl-2'-deoxyguanosine, substituting the appropriate amount of benzoyl chloride for palmitoyl chloride, and substituting a 1:1 mixture of ice water and saturated aqueous sodium bicarbonate solution in the workup.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]1[C@H:17]([O:18][CH3:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:20]#[N:21])=[CH:13][CH:14]=2)[C:9]1([CH2:24][CH3:25])[CH2:22][CH3:23])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=[O:28].[K+].[K+].OO>CS(C)=O.O.C(OC(C)C)(=O)C.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>[C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]1[C@H:17]([O:18][CH3:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:20](=[O:28])[NH2:21])=[CH:13][CH:14]=2)[C:9]1([CH2:22][CH3:23])[CH2:24][CH3:25])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCC1(CC)c2cc(C#N)ccc2C[C@@H](OC)[C@@H]1NC(=O)OC(C)(C)C
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CC(=O)OC(C)C
Product: CCC1(CC)c2cc(C(N)=O)ccc2C[C@@H](OC)[C@@H]1NC(=O)OC(C)(C)C
Yield: 104 %

Procedure:
To a solution of trans-(7-cyano-1,1-diethyl-3-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid tert-butyl ester (8.5 g, 24 mmol) in DMSO (105 mL) was added K2CO3 (4.98 g, 36 mmol), and the mixture was stirred until all solids were dissolved. To the solution was added 30% hydrogen peroxide (12.2 mL, 120 mmol) in 0.5 mL portions over 45 min at a rate to keep the temperature 30-35° C. The reaction mixture was diluted with water (200 mL) and isopropyl acetate (500 mL), and sodium metabisulfite was added (10 g) to reduce excess peroxides. Layers were separated and the aqueous layer was extracted with isopropyl acetate (3×150 mL) and 10% MeOH/isopropyl acetate (2×100 mL). The combined organic layers were washed with water (3×150 mL) and saturated NaCl (100 mL), dried with Na2SO4 and concentrated to give the title compound (9.4 g). (m/z): [M+H]+ calcd for C21H32N2O4 377.24; found 377.6.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[NH:8][C:9]([CH3:13])=[CH:10][C:11](=O)[C:6]=2[C:5](=[O:14])[N:4]([CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]([N:21]([CH3:23])[CH3:22])[CH3:20])[C:3]1=[O:24].[N:25]1[CH:30]=CC=C[CH:26]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl>[CH3:1][N:2]1[C:7]2[N:8]=[C:9]([CH3:13])[CH:10]=[C:11]([N:25]([CH3:30])[CH3:26])[C:6]=2[C:5](=[O:14])[N:4]([CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]([N:21]([CH3:23])[CH3:22])[CH3:20])[C:3]1=[O:24]
Reactant: c1ccncc1
Reactant: Cc1cc(=O)c2c(=O)n(CCCC[C@@H](C)N(C)C)c(=O)n(C)c2[nH]1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(N(C)C)c2c(=O)n(CCCC[C@@H](C)N(C)C)c(=O)n(C)c2n1
Temperature: 55 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
To a mixture of (R)-1,7-dimethyl-3-(5-(N,N-dimethylamino)hexyl)pyrido[2,3-d]pyrimidine-2,4,5(1H,3H,8H)-trione (315 mg, 0.947 mmol), pyridine (1 ml, 12.4 mmol) and dichloromethane (20 ml), cooled in an ice bath, was added trifluoromethanesulfonic anhydride (0.315 ml, 1.87 mmol) dropwise. After stirring for 2 hours, the cooling bath was removed. A 30% (v:v) solution of dimethylamine in tetrahydrofuran (7 ml) was added and the solution was transferred to a pressure tube (1″×8″). The tube was sealed and heated to 55° C. for 2 hours. After cooling to room temperature the solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the solution filtered through a pad of celite. The filtrate was rinsed with saturated sodium bicarbonate solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate-methanol-triethylamine (85:10:5) to afford (R)-1,7-Dimethyl-5-(N,N-dimethylamino)-3-(5-(N,N-dimethylamino)hexyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)dione (300 mg, 88% yield for 2 steps) as an oil. 1H NMR (300 MHz, CDCl3) δ 0.99 (d, 3H), 1.20-1.50 (m, 3H), 1.52-1.74 (m, 3H), 2.28 (s, 6H), 2.42 (s, 3H), 2.99 (s, 6H), 3.64 (s, 3H), 4.03 (t, 2H), 6.39 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:4][C:5](=O)[CH3:6])[CH2:3][CH2:2]1.[CH3:8][C:9]([S:12]([NH2:14])=[O:13])([CH3:11])[CH3:10]>C1COCC1>[CH:1]1([CH2:4]/[C:5](=[N:14]/[S:12]([C:9]([CH3:11])([CH3:10])[CH3:8])=[O:13])/[CH3:6])[CH2:3][CH2:2]1
Reactant: CC(=O)CC1CC1
Reactant: CC(C)(C)S(N)=O
Solvent: C1CCOC1
Product: C/C(CC1CC1)=N\S(=O)C(C)(C)C
Temperature: 25 °C

Procedure:
A 25 mL round bottomed flask was charged with Ti(OEt)4 (technical grade, 0.37 mL, 1.4 mmol) and 1-cyclopropylpropan-2-one (79.0 mg, 0.81 mmol) in THF (1.45 mL), under an argon atmosphere. Then 2-methylpropane-2-sulfinamide (88.7 mg, 0.73 mmol) was added and the reaction mixture was heated to reflux overnight. After cooling to room temperature the reaction mixture was poured onto brine (1.7 mL), with rapid stirring. The resulting suspension was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to afford crude 2-methyl-propane-2-sulfinic acid [2-cyclopropyl-1-methyl-eth-(E)-ylidene]-amide which was taken directly to the next step without purification.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28]C2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.CN(CC1CCCCC1)C1C=CC(OC)=C(Cl)C=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[Cl:24][C:18]1[CH:17]=[C:16]([N:15]([CH2:25][CH:26]2[CH2:28][CH2:29][CH2:30][CH2:31]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:3])=[O:32])=[CH:8][N:9]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCCC2)c2ccc(OC)c(Cl)c2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: COc1ccc(N(C)CC2CCCCC2)cc1Cl
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Product: COc1ccc(N(CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)cc1Cl

Procedure:
The title compound was prepared via {2-[3-(cyclohexylmethyl)-3-(3-chloro-4-methoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using (methyl-cyclohexylmethyl-(3-chloro-4-methoxy-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: C(OCC)C.C([Mg]Br)C.[C:10]1([S:16]([N:19]2[C:27]3[C:22](=[CH:23][C:24]([F:29])=[CH:25][C:26]=3[F:28])[C:21](I)=[CH:20]2)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:31]([N:38]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH:39]([CH3:42])[CH:40]=[O:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1>[CH2:43]([N:38]([CH:39]([CH3:42])[CH:40]([C:21]1[C:22]2[C:27](=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=2)[N:19]([S:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:18])=[O:17])[CH:20]=1)[OH:41])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CC(C=O)N(Cc1ccccc1)Cc1ccccc1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2cc(F)cc(F)c21
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C(O)c1cn(S(=O)(=O)c2ccccc2)c2c(F)cc(F)cc12)N(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 76.8 %

Procedure:
A 3.0 M diethyl ether solution of ethylmagnesium bromide (7.3 ml, 21.8 mmol) is added under N2 at 0° C. to a 95 ml tetrahydrofuran solution of N-benzenesulfonyl-3-iodo-5,7-difluoro-indole (8.4 g, 20 mmol). The resulting mixture is stirred for 20 minutes at 0° C., allowed to warm to room temperature over 20 minutes, then recooled to 0° C. A 20 ml tetrahydrofuran solution of (S) N,N dibenzyl-2-aminopropanal (Syn. Lett., 1997,2, 223–224, 5.1 g, 22 mmol) is added to the reaction mixture and the resulting mixture is stirred 1 hour as it warmed to room temp. The reaction is quenched with aqueous NH4Cl, extracted with ethyl acetate, washed with brine, dried (Na2SO4), filtered, concentrated, and the residue is purified by flash chromatography (SiO2, ethyl acetate/hexane gradient) to yield 8.4 g of 2-(N,N-dibenzylamino)-1-(1-benzenesulfonyl-5,7-difluoro-1H-indol-3-yl)-propan-1-ol. (77%)
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[C:12]2[O:13][CH2:14][CH2:15][O:16][C:11]=2[C:10]([C:17]([OH:19])=O)=[CH:9][CH:8]=1>>[CH3:5][O:6][C:7]1[C:12]2[O:13][CH2:14][CH2:15][O:16][C:11]=2[C:10]([C:17]([Cl:3])=[O:19])=[CH:9][CH:8]=1
Reactant: COc1ccc(C(=O)O)c2c1OCCO2
Reactant: O=S(Cl)Cl
Product: COc1ccc(C(=O)Cl)c2c1OCCO2
Yield: 100.6 %

Procedure:
391 g of thionyl chloride and 138 g of 8-methoxy-1,4-benzodioxane-5-carboxylic acid were introduced into a balloon flask provided with a condenser. The mixture was heated to 50°-55° C. and the excess thionyl chloride was distilled off under vacuum. 151 g of 8-methoxy-1,4-benzodioxane-5-carbonyl chloride were obtained (yield: 100%).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH3:44])[C:18](=[O:43])[C:19]3[CH:29]=[C:28]([CH2:30][CH2:31][O:32][C:33]4[C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[N:36]=[CH:35][CH:34]=4)[CH:27]=[N:26][C:20]=3[N:21]([CH2:24][CH3:25])[C:22]=2[N:23]=1>C(Cl)Cl>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH3:44])[C:18](=[O:43])[C:19]3[CH:29]=[C:28]([CH2:30][CH2:31][O:32][C:33]4[C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[N+:36]([O-:9])=[CH:35][CH:34]=4)[CH:27]=[N:26][C:20]=3[N:21]([CH2:24][CH3:25])[C:22]=2[N:23]=1
Reactant: CCN1c2ncc(CCOc3ccnc4ccccc34)cc2C(=O)N(C)c2ccc(C)nc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCN1c2ncc(CCOc3cc[n+]([O-])c4ccccc34)cc2C(=O)N(C)c2ccc(C)nc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.6 %

Procedure:
Solid mCPBA (80-85%, m-chloroperbenzoic acid) (60 mg, 0.28 mmol) was added to a solution of 5,11-dihydro-2,5-dimethyl-11-ethyl-8-{2-(4-quinolinyloxy)ethyl}-6H-dipyrido[3,2-b:2′,3′-e] [1,4]diazepin-6-one (55 mg, 0.13 mmol) in CH2Cl2 (1.3 mL) at room temperature. The mixture was stirred at room temperature for 2.5 h then diluted with CH2Cl2. The resulting solution was successively washed with aqueous 10% Na2S2O3, aqueous saturated NaHCO3 and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (MeOH/EtOAc,2% to 5%) to give the title compound (59 mg, 99% yield) as a white solid: MS (ES) m/z 456 (MH)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([O:11][C:12](=[O:36])[NH:13][C@@H:14]([C:30](=[O:35])N(OC)C)[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][CH:17]=1)([CH3:10])([CH3:9])[CH3:8]>C1COCC1>[C:7]([O:11][C:12](=[O:36])[NH:13][C@H:14]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:21]=1)[CH:30]=[O:35])([CH3:10])([CH3:8])[CH3:9]
Reactant: CON(C)C(=O)[C@@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](C=O)Cc1ccc(OCc2ccccc2)cc1
Reaction time: 1 h
Yield: 99.3 %

Procedure:
LiAlH4 (916 mg, 24.1 mmol) was added cautiously and portionwise during 15 min to a stirred solution of (R)-[2-(4-Benzyloxy-phenyl)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester (10.00 g, 24.1 mmol) in THF (150 mL) at 0° C. under an atmosphere of argon. The ice-bath was removed and the mixture was stirred for 1 h, then poured onto a mixture of ice and KHSO4 (1M aqueous). When the ice had melted the product was extracted into EtOAc. The combined extracts were washed with brine then dried (Na2SO4) and evaporated to give the aldehyde as pale yellow crystals (8.51 g, 99%), mp 100.3-101.7° C. (lit. mp 98-99° C.).[W. J. Thompson et al, Tetrahedron Lett., 1990, 31, 6819] 1H NMR (CDCl3) δ 9.63 (1H, s, CHO), 7.45-7.33 (5H, m), 7.09 (2H, d, J=8.7 Hz), 6.92 (2H, d, J=8.6 Hz), 5.05 (2H, s, OCH2Ph), 4.40 (1H, br s, Hα), 3.07 (2H, d, J=6.7 Hz, Hβ,β), 1.44 (9H, s, CMe3). 13C NMR (CDCl3) δ 199.6, 156.4, 144.4, 136.8, 130.4, 128.6, 128.5, 128.0, 127.9, 127.5, 115.1, 80.9, 70.0, 46.0, 34.6, 28.3.
Reaction SMILES: S1C=CCC1.[C:6]([O-:9])([O-:8])=O.[K+].[K+].C1OC2C(=CSC=2)OC1.BrCCBr.BrCC(Br)CCCCCCCCCCCCCC.BrCC(Br)CCCC.[C:51]([C:56]1[S:57][C:58](C(OCC)=O)=[C:59]2[O:64][CH2:63][CH2:62][O:61][C:60]=12)([O:53]CC)=[O:52].[OH-].[Na+]>O.CN(C=O)C>[C:6]([C:58]1[S:57][C:56]([C:51]([OH:53])=[O:52])=[C:60]2[O:61][CH2:62][CH2:63][O:64][C:59]=12)([OH:9])=[O:8]
Reactant: CCOC(=O)c1sc(C(=O)OCC)c2c1OCCO2
Reactant: O=C([O-])[O-]
Agent: C1=CSCC1
Agent: CCCCC(Br)CBr
Agent: CCCCCCCCCCCCCCC(Br)CBr
Solvent: CN(C)C=O
Solvent: BrCCBr
Solvent: O
Product: O=C(O)c1sc(C(=O)O)c2c1OCCO2

Procedure:
The salt either 5 or 6 is dissolved in water and acidified with 1 Molar HCI added slowly dropwise with constant stirring until the solution becomes acidic. Immediately following, thick white precipitate falls out. After filtration, the precipitate is washed with water and air-dried to give 2,5-dicarbethoxy-3,4-dihydroxythiophene (Z). The salt either (5, 2.5 grams) or 6 can be alkylated directly or the dihydrothiophene derivative (7) can be suspended in the appropriate 1,2-dihaloalkane or substituted 1,2-dihaloalkane and refluxed for 24 hours in the presence of anhydrous K2CO3 in anhydrous DMF. To prepare EDOT, either 1,2-dicholorethane (commercially available from Aldrich) or 1,2-dibromoethane (commercially from Aldrich) is used. To prepare the various substituted EDOT derivatives the appropriate 1,2-dibromoalkane is used, such as 1-dibromodecane, 1,2-dibromohexadecane (prepared from 1-hexadecene and bromine), 1,2-dibromohexane, other reported 1,2-dibromoalkane derivatives, and the like. The resulting 2,5-dicarbethoxy-3,4-ethylenedioxythiophene or 2,5-dicarbethoxy-3,4-alkylenedioxythiophene is refluxed in base, for example 10 percent aqueous sodium hydroxide solution for 1 to 2 hours, and the resulting insoluble material is collected by filtration. This material is acidified with 1 Normal HCl and recrystallized from methanol to produce either 2,5-dicarboxy-3,4-ethylenedioxythiophene or the corresponding 2,5-dicarboxy-3,4-alkylenedioxythiophene. The final step to reduce the carboxylic acid functional groups to hydrogen to produce the desired monomer is given in the references above.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Br:11])=[CH:6][C:5]=1[CH2:12]Br.[F:15][C:16]([F:28])([F:27])[O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([NH2:26])[CH3:25])=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Br:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([Cl:10])[CH:8]=1)[C:3](=[O:14])[N:26]([CH:24]([C:21]1[CH:20]=[CH:19][C:18]([O:17][C:16]([F:15])([F:27])[F:28])=[CH:23][CH:22]=1)[CH3:25])[CH2:12]2
Reactant: COC(=O)c1c(Cl)cc(Br)cc1CBr
Reactant: CC(N)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(c1ccc(OC(F)(F)F)cc1)N1Cc2cc(Br)cc(Cl)c2C1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 38.7 %

Procedure:
A mixture of 4-bromo-2-bromomethyl-6-chloro-benzoic acid methyl ester (0.409 g, 1.2 mmol), 1-(4-trifluoromethoxy-phenyl)-ethyl-amine (0.288 g, 10.4 mmol), and K2CO3 (0.331 g, 2.4 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-Bromo-7-chloro-2-[1-(4-trifluoromethoxy-phenyl)-ethyl]-2,3-dihydro-isoindol-1-one (0.202 g, 39%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.67 (d, 3H), 3.96 (d, 1H), 4.20 (d, 1H), 5.77 (q, 1H) 7.21 (d, 2H), 7.41 (m, 3H), 7.58 (s, 1H). GC-MS: m/z 434 (M)+, 420 (M−14)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[O:5][C:6]=1[CH:7]=[O:8].[CH3:19][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=2)[O:5][C:6]=1[CH:7]([OH:8])[CH3:19]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)oc1C=O
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)oc1C(C)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-methyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carbaldehyde (1.32 g, 5.16 mmol) and 50 mL tetrahydrofuran is stirred at 0° C. Methyl magnesium bromide (2.2 mL, 6.71 mmol, 3M) is added dropwise and the resulting mixture is allowed to stir at room temperature 30 min. The reaction is not complete, so an additional amount of methyl magnesium bromide (1 mL, 3 mmol) is added and the reaction stirred an additional 1 hr at room temperature. The mixture is cooled on an ice/water bath and aqueous ammonium chloride (10 mL) is added. The product is extracted with three 75 mL portions of ethyl acetate, the combined extracts are dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product is purified by silica gel chromatography eluting with a mixture of 1:1 hexanes:ethyl acetate to afford 1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethanol as an ivory solid, 1.12 g, 80%. MS (M++1) 272.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:22])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][Cl:20])=[CH:14][CH:13]=3)[C:6]=2[CH:21]=1.[C:23](Cl)(=[O:25])[CH3:24].O>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([NH:22][C:23](=[O:25])[CH3:24])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][Cl:20])=[CH:16][CH:17]=3)[C:6]=2[CH:21]=1
Reactant: CCc1nc2cc(N)c(Cl)cc2n1-c1ccc(CCCl)cc1
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCc1nc2cc(NC(C)=O)c(Cl)cc2n1-c1ccc(CCCl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.4 %

Procedure:
To a solution of 6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-ylamine (step 6 of Example 110, 100 mg, 0.3 mmol) in pyridine (7 mL) was added dropwise acetyl chloride (0.03 mL, 0.33 mmol) under nitrogen atmosphere at 0° C., and the reaction mixture was stirred at room temperature for 1.5 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with 2N aqueous NaOH (30 mL), brine (30 mL), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:3) to afford 110 mg (98%) of the title compound as white solids: 1H-NMR (CDCl3) δ: 8.66 (1H, s), 7.56 (1H, br.s), 7.45 (2H, d, J=8.2 Hz), 7.29 (2H, d, J=8.2 Hz), 7.12 (1H, s), 3.82 (2H, t, J=7.1 Hz), 3.19 (2H, t, J=7.1 Hz), 2.77 (2H, q, J=7.6 Hz), 2.26 (3H, s), 1.34 (3H, t, J=7.6 Hz).
Reaction SMILES: [CH2:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)[CH:2]=[CH2:3].[Cl:9][SiH:10]([Cl:12])[Cl:11]>[Pt].C1(C)C=CC=CC=1>[Cl:9][Si:10]([Cl:12])([Cl:11])[CH2:3][CH2:2][CH2:1][C:4]1[S:5][CH:6]=[CH:7][CH:8]=1
Reactant: C=CCc1cccs1
Reactant: Cl[SiH](Cl)Cl
Agent: [Pt]
Solvent: Cc1ccccc1
Product: Cl[Si](Cl)(Cl)CCCc1cccs1
Temperature: 60 °C

Procedure:
2-Allylthiophene (25 g), 13 g of anhydrous toluene (13 g), and 250 mg of Platinum Catalyst were combined under nitrogen in a three-neck flask equipped with a reflux condenser and a dropping funnel. Then, 30 g of trichlorosilane was added drop-wise to the mixture. Upon completion of the addition, the mixture was heated to 60° C. and maintained at that temperature for 2 h. Then, the mixture was distilled at 150° C. and 0.02 ton to give 2-(3-trichlorosilylpropyl)thiophene as a colorless liquid: 1H NMR (CDCl3) δ 7.16 (dd, 1H, J=5.1, 0.9 Hz); 6.95 (dd, 1H, J=4.8, 3.3 Hz); 6.83 (m, 1H); 2.96 (t, 2H, J=7.2 Hz); 1.98 (m, 2H); 1.46 (m, 2H).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:11]([O:18][CH3:19])=[N:12][CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[C:20]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]=O)[CH:21]=1>>[C:20]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:1]2[CH:2]([C:10]3[C:11]([O:18][CH3:19])=[N:12][CH:13]=[CH:14][C:15]=3[O:16][CH3:17])[CH2:3][CH2:4][CH2:5][C:6]2=[O:8])[CH:21]=1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Reactant: COC(=O)CCCC(N)c1c(OC)ccnc1OC
Product: COc1ccnc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2ccccc2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,4-dimethoxypyridin-3-yl)pentanoate with commercially available [1,1′-biphenyl]-3-carbaldehyde. Subsequent purification by preparative HPLC the target compound. LC-MS (conditions A): tR=0.83 min.; [M+H]+: 403.34 g/mol.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH:16]=[CH:15][C:9]3=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=[C:8]3[C:7](=[O:17])[C:6]=2[CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].[CH3:71][O:72][C:73]1[CH:80]=[C:79]([O:81][CH3:82])[CH:78]=[CH:77][C:74]=1[CH2:75][NH2:76]>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.O1CCOCC1>[Cl:14][C:12]1[CH:13]=[C:8]2[C:7](=[O:17])[C:6]3[CH:18]=[C:2]([NH:76][CH2:75][C:74]4[CH:77]=[CH:78][C:79]([O:81][CH3:82])=[CH:80][C:73]=4[O:72][CH3:71])[CH:3]=[CH:4][C:5]=3[CH:16]=[CH:15][C:9]2=[N:10][CH:11]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: O=c1c2cc(Br)ccc2ccc2ncc(Cl)cc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1COCCO1
Product: COc1ccc(CNc2ccc3ccc4ncc(Cl)cc4c(=O)c3c2)c(OC)c1
Temperature: 100 °C

Procedure:
7-bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (3.0 g, 9.40 mmol), tris(dibenzylideneacetone) dipalladium (0) (Pd2(dba3)) (43 mg, 0.047 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binapthyl (BINAP) (88 mg, 0.141 mmol), and sodium tert-butoxide (1.08 g, 11.3 mmol) were combined in a dry flask through which argon was purged. The flask was charged with 100 mL of dry dioxane, 2,4-dimethoxybenzylamine (1.41 mL, 9.40 mmol) was added, and the mixture was sparged with argon for 5 minutes. The reaction was heated to 100° C. and stirred under argon. After 2 h the reaction was concentrated and dissolved in 400 ml of ethyl acetate and washed with 100 mL of saturated aqueous ammonium chloride solution. The organic layer was separated, dried with magnesium sulfate, filtered, and concentrated. The resultant solids were slurried in 50 mL hot methanol, then allowed to cool to ambient temperature. The solids were filtered and dried to afford the title compound. LRMS (APCI) calculated for C23H20ClN2O3 [M+H]+, 407.1; found 407.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.[C:11](#[N:15])[CH2:12][C:13]#[N:14].O>C(O)C.N1CCCCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[C:12]([C:11]#[N:15])[C:13]#[N:14]
Reactant: N#CCC#N
Reactant: O=Cc1ccc(O)c(O)c1
Solvent: O
Solvent: C1CCNCC1
Solvent: CCO
Product: N#CC(C#N)=Cc1ccc(O)c(O)c1
Temperature: 70 °C
Yield: 85.3 %

Procedure:
To 11 g (80 mmol) of 3,4-dihydroxybenzaldehyde and 5.5 g (83 mmol) of malononitrile in 40 ml of ethanol, 7 drops of piperidine were added and the mixture was heated at 70° C. for 0.5-1 hour and then poured into water. The resulting solid precipitate was separated by filtration to give 12.7 g (86% yield) of a yellow solid, m.p. 225° C.