Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=O.[CH2:14]([O:16][C:17](=[O:33])[CH:18]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])P(OC)(OC)=O)[CH3:15]>>[CH2:14]([O:16][C:17](=[O:33])[C:18]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:4][C:3]1[CH:6]=[C:7]([O:12][CH3:13])[C:8]([O:10][CH3:11])=[CH:9][C:2]=1[F:1])[CH3:15]
Reactant: COc1cc(F)c(C=O)cc1OC
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)P(=O)(OC)OC
Product: CCOC(=O)C(=Cc1cc(OC)c(OC)cc1F)NC(=O)OC(C)(C)C

Procedure:
In a preferred method of preparing F-Dopa, 2-fluoro-4,5-dimethoxybenzaldehyde is reacted with tert-Butoxycarbonylamino-(dimethoxy-phosphoryl)-acetic acid ethyl ester to produce 2-tert-butoxycarbonylamino-3-(2-fluoro-4,5-dimethoxy-phenyl)-acrylic acid ethyl ester. In this method R is methyl, R1 is methoxy, X is fluorine, R2 is methyl, and Y is tert-butoxycarbonyl.
Reaction SMILES: [C:1]1([NH:7][C:8]2([CH2:14][NH:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:22]=O>ClCCl>[C:1]1([N:7]2[C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[CH2:14][N:15]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:22]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=O
Reactant: CCOC(=O)CNCC1(Nc2ccccc2)CCCCC1
Solvent: ClCCl
Product: CCOC(=O)CN1CN(c2ccccc2)C2(CCCCC2)C1
Temperature: 100 °C
Yield: 98 %

Procedure:
510 mg (1.75 mmol) of ethyl [(1-phenylaminocyclohexylmethyl)amino]-acetate are dissolved in 10 ml of dichloromethane and 10 ml of formaldehyde are added. The solution is heated to 100° C. with microwaves for 30 min. The medium is poured into dichloromethane and washed with water. The organic phases are collected and then dried over sodium sulfate. The solvents are evaporated. 520 mg of ethyl (1-phenyl-1,3-diazaspiro[4.5]dec-3-yl)acetate are obtained in the form of a colorless oil. Yield=98%.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@@H:4]([C:5]#[C:6][C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[CH3:18][CH2:19][CH2:20][CH2:21][CH2:22]O>>[CH3:1][C:2]1([CH3:17])[C@@H:4]([C:5]#[C:6][C:7]([O:9][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:8])[C@H:3]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CCCCCO
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](C#CC(=O)O)C1(C)C
Product: CCCCCOC(=O)C#C[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C

Procedure:
Using the procedure of Step A of Example 7, 3 g of tert.-butyl (1R,cis) 2,2-dimethyl-3-(2-carboxyethynyl)-cyclopropane-carboxylate and 2 ml of n-amyl alcohol were reacted and the residue was chromatographed over silica gel. Elution with an 8-2 hexane-isopropyl ether mixture yielded 2.7 g of tert.-butyl (1R,cis) 2,2-dimethyl-3-[pentyloxycarbonylethynyl]-cyclopropane-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=O.[CH2:12]1[CH:16]2[CH2:17][NH:18][CH2:19][CH:15]2[CH2:14][N:13]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([N:18]1[CH2:17][CH:16]2[CH2:12][N:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][CH:15]2[CH2:19]1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC2CN(C(=O)c3ccc(Cl)c(Cl)c3)CC2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of acid 3,4-dichlorobenzoic acid (0.45 g, 2.36 mmol), tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (0.5 g, 2.36 mmol) and HOBt (0.4 g, 2.83 mmol) in DMF (15 mL), EDCI.HCl (0.54 g, 2.83 mmol) and DIEA (1.5 g, 11.5 mmol) were added. The mixture was stirred at room temperature overnight and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the crude product which was used directly in the next step.
Reaction SMILES: C1(CCCC2C=C[N+]([O-:16])=CC=2)C=CC=CC=1.Cl[O-].[Na+].[Cl:20][C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[CH:26][CH2:27]2)=[CH:23][CH:22]=1>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[C@H:25]3[O:16][C@H:26]3[CH2:27][C:28]=2[CH:29]=1
Reactant: Clc1ccc2c(c1)CC=C2
Reactant: [O-][n+]1ccc(CCCc2ccccc2)cc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: Clc1ccc2c(c1)C[C@@H]1O[C@H]21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirring solution of 4-phenylpropylpyridine-N-oxide (278 mg, 1.31 mmol) in methylene chloride (20 mL) was added (R,R)-Jacobsen catalyst (237.0 mg, 0.3732 mmol) and a solution of sodium hypochlorite (2.0 M in water; 16 mL, 32 mmol) at 0° C. The resulting brown suspension was stirred at 0° C. for 15 minutes then a solution of 6-chloro-1H-indene (1) (2.81 g, 18.6 mmol) in methylene chloride (20 mL) was added via syringe with simultaneous addition of additional sodium hypochlorite (2.0M in water; 16 mL, 32 mmol). The reaction was stirred at 0° C. for one hour then the ice bath was removed and the reaction was stirred at room temperature for 1 hr. An aliquot was taken and TLC on silica (hexanes) showed all starting material consumed. The reaction was poured into brine and extracted with methylene chloride. The combined extracts were washed with saline, then dried over sodium sulfate, filtered, and evaporated under reduced pressure to leave crude product which solidified when placed under hi-vacuum. Yield ˜3.7 g of a brown solid. 1H NMR (400 MHz, DMSO) δ 7.55 (d, J=7.6 Hz, 1H), 7.32 (s, 1H), 7.23 (d, J=7.3 Hz, 1H), 4.36 (s, 1H), 4.16 (s, 1H), 3.03 (dd, J=45.8, 18.2 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]([C:14]1[NH:15][CH:16]=[CH:17][CH:18]=1)[CH3:13].[N:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]=[O:21].CO>O1CCCC1>[CH2:26]([O:25][C:23]([CH2:22][NH:19][C:20](=[O:21])[NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]([C:14]1[NH:15][CH:16]=[CH:17][CH:18]=1)[CH3:13])=[O:24])[CH3:27]
Reactant: CCOC(=O)CN=C=O
Reactant: CC(=C1C(=O)Nc2ccc(N)cc21)c1ccc[nH]1
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)Nc1ccc2c(c1)C(=C(C)c1ccc[nH]1)C(=O)N2
Reaction time: 8 h

Procedure:
A solution of 5-amino-3-[1-(pyrrol-2-yl)ethylidene]indolin-2-one (360 mg, 1.5 mmol) in tetrahydrofuran (15 mL) was treated with ethyl isocyanatoacetate (195 mg, 1.5 mmol) at ambient temperature. After stirring overnight, methanol (5 mL) was added and the reaction was concentrated. Chromatography on SiO2 (7.2 g) using 1:2 hexane/ethyl acetate afforded 5-(N′-(ethoxycarbonylmethyl)ureido)-3-[1-(pyrrol-2-yl)ethylidene]indolin-2-one; 1H NMR (400 MHz, DMSO-d6) δ 1.32 (t, 3H), 2.82 (s, 3H), 3.96 (d, 2H), 4.22 (q, 2H), 6.44 (m, 2H), 6.88 (d, 1H), 7.16 (m, 1H), 7.28 (d, 1H), 7.40 (m, 1H), 7.96 (m, 1H), 8.76 (s, 1H), 11.02 (s, 1H) ppm; (200 mg).
Reaction SMILES: [CH:1]1([NH:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:36])/[CH:26]=[CH:27]/[C:28]3[CH:33]=[CH:32][C:31]([CH2:34]Cl)=[CH:30][CH:29]=3)=[CH:20][CH:19]=2)=[CH:14][CH:13]=1>CN(C=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:36])/[CH:26]=[CH:27]/[C:28]3[CH:29]=[CH:30][C:31]([CH2:34][N:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9][OH:10])=[CH:32][CH:33]=3)=[CH:22][CH:23]=2)=[CH:14][CH:13]=1
Reactant: O=C(/C=C/c1ccc(CCl)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: OCCNC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccc(CN(CCO)C2CCCCC2)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
0.24 g (1.7 mmol) of 2-cyclohexylaminoethanol are added to a suspension of 130 mg (0.34 mmol) of (E)-N-(4′-chlorobiphenyl-4-yl)-3-(4-chloromethylphenyl)acrylamide in 10 mL of DMF and the mixture is stirred for 48 hours at 80° C. Then the reaction mixture is poured onto water and the precipitate formed is suction filtered and washed with water. The solid is dried in the circulating air dryer at 50° C. Yield: 20 mg (10% of theory); C30H33ClN2O2 (M=489.05); melting point: 178° C.-179° C.; calc.: molecular ion peak (M+H)+: 489/491 (Cl); found: molecular ion peak (M+H)+: 489/491 (Cl).
Reaction SMILES: [Br:1][C:2]1[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[C:17]([O:24][CH3:25])=[CH:16][C:3]=1[CH2:4][N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][C:8]([NH2:15])=[N:9][C:10]=2Cl.[NH3:26]>CO>[Br:1][C:2]1[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[C:17]([O:24][CH3:25])=[CH:16][C:3]=1[CH2:4][N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][C:8]([NH2:15])=[N:9][C:10]=2[NH2:26]
Reactant: COc1cc(Cn2cnc3c(Cl)nc(N)nc32)c(Br)c(OC)c1OC
Reactant: N
Solvent: CO
Product: COc1cc(Cn2cnc3c(N)nc(N)nc32)c(Br)c(OC)c1OC

Procedure:
A solution of 9-(2-bromo-3,4,5-trimethoxy-benzyl)-6-chloro-9H-purin-2-ylamine (see example 51) in MeOH was treated with NH3 (7N in MeOH) in a pressure vessel at 90° C. for 16 h. Work-up and purification by preparative TLC (EtOAc:hexane 3:1) gave the title compound. HPLC Rt: 4.884 min. 1H-NMR (DMSO-d6): δ 7.67 (s, 1H), 6.71 (s, 2H), 6.60 (s, 1H), 5.84 (s, 2H), 5.17 (s, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 3.66 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([NH:11]N=C2CCCNC2=O)[CH:3]=1.[CH:20]([OH:22])=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:2]3[CH2:3][CH2:4][NH:11][C:20](=[O:22])[C:10]=3[NH:11]2)=[C:6]2[CH2:7][CH2:8][O:9][C:10]=12
Reactant: O=C1NCCCC1=NNc1cc(Cl)c2c(c1)CCO2
Reactant: O=CO
Product: O=C1NCCc2c1[nH]c1cc(Cl)c3c(c21)CCO3
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 3-[(7-chloro-2,3-dihydro-1-benzofuran-5-yl)hydrazinylidene]piperidin-2-one (a mixture of E and Z isomers) (3.66 g) and formic acid (65.4 mL) was stirred at 100° C. for 1 hour. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 95:5) to obtain an orange solid. This solid was washed with ethyl acetate to obtain a mixture (1.74 g) of 4-chloro-1,2,6,8,9,10-hexahydro-7H-furo[3,2-e]pyrido[3,4-b]indol-7-one and 10-chloro-2,3,5,7,8,9-hexahydro-6H-furo[2,3-f]pyrido[3,4-b]indol-6-one as an orange solid.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([CH2:9]O)=[C:6]([CH3:8])[N:7]=1)[CH3:2].[CH2:11]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][CH2:23][CH:24]2[C:29]([NH:31][C:32]1[CH:33]=[N:34][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:36][CH:37]=1)=[O:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][CH2:23][CH:24]2[C:29]([N:31]([CH2:9][C:5]1[S:4][C:3]([CH2:1][CH3:2])=[N:7][C:6]=1[CH3:8])[C:32]1[CH:33]=[N:34][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:36][CH:37]=1)=[O:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCc1nc(C)c(CO)s1
Reactant: CC(C)c1ccc(NC(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Product: CCc1nc(C)c(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)s1
Yield: 60.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 142 using 2-ethyl-5-hydroxymethyl-4-methylthiazole (0.63 g) and 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.8 g) as starting materials, 5-benzyloxy-N-[(2-ethyl-4-methylthiazol-5-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.3 g) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[C:15]([C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])#[CH:16]>>[C:15]([C:17]1[CH:18]=[C:19]([NH:20][C:9](=[O:11])[C:8]2[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=2[O:2][CH3:1])[C:12]([NH2:14])=[O:13])[CH:21]=[CH:22][CH:23]=1)#[CH:16]
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: C#Cc1cccc(N)c1
Product: C#Cc1cccc(NC(=O)c2cc(C(N)=O)ccc2OC)c1

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 3-ethynylaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: Cl.[CH3:2][C@H:3]1[C:11]2[C:10]([N:12]3[C:25]4[C:20](=[C:21]([C@H:26]5[CH2:30][CH2:29][CH2:28][N:27]5C(OC(C)(C)C)=O)[CH:22]=[CH:23][CH:24]=4)[C:14]4([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH2:13]3)=[N:9][CH:8]=[N:7][C:6]=2[CH2:5][CH2:4]1>O1CCOCC1.C(Cl)Cl>[CH3:2][C@H:3]1[C:11]2[C:10]([N:12]3[C:25]4[C:20](=[C:21]([C@H:26]5[CH2:30][CH2:29][CH2:28][NH:27]5)[CH:22]=[CH:23][CH:24]=4)[C:14]4([CH2:15][CH2:16][NH:17][CH2:18][CH2:19]4)[CH2:13]3)=[N:9][CH:8]=[N:7][C:6]=2[CH2:5][CH2:4]1
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCNCC4)c4c([C@H]5CCCN5C(=O)OC(C)(C)C)cccc43)c21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H]1CCc2ncnc(N3CC4(CCNCC4)c4c([C@H]5CCCN5)cccc43)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
4M HCl in dioxane (2 mL) was added into a solution of (R)-tert-butyl 2-(1-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)pyrrolidine-1-carboxylate (8 mg, 0.02 mmol) in CH2Cl2 (5 mL). The reaction was stirred at room temperature for 1 hour. The solvent was evaporated, and the crude material was recovered to afford the product 1-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-4-((R)-pyrrolidin-2-yl)spiro[indoline-3,4′-piperidine] (3 mg, 47% yield) as a solid. 1H NMR (d6-DMSO, 400 MHz) δ 8.80 (s, 1H), 8.00-8.10 (m, 1H), 7.52 (t, 1H), 7.40 (d, 1H), 5.35-5.45 (m, 1H), 4.60-4.70 (m, 1H), 4.20-4.30 (m, 1H), 3.85-4.00 (m, 1H), 3.70-3.80 (m, 1H), 3.60-3.70 (m, 3H), 3.50-3.60 (m, 2H), 3.20-3.30 (m, 2H), 3.10-3.20 (m, 1H), 2.80-2.90 (m, 1H), 2.50-2.70 (m, 2H), 2.40-2.50 (m, 1H), 2.30-2.40 (m, 1H), 2.10-2.20 (m, 2H), 1.90-2.05 (m, 2H), 1.10 (d, 311). MS (APCI+) [M+H]+ 390.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:16]=[CH:15][C:14]([CH:17]([CH2:21][CH:22]=C)[CH2:18][CH:19]=C)=[C:13]2[C:9]=1[C:10](=[O:25])[N:11]([CH3:24])[CH2:12]2)([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:21][CH:22]=[CH:19][CH2:18]2)=[C:13]2[C:9]=1[C:10](=[O:25])[N:11]([CH3:24])[CH2:12]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCC(CC=C)c1ccc(NC(=O)OC(C)(C)C)c2c1CN(C)C2=O
Solvent: ClCCl
Product: CN1Cc2c(C3CC=CC3)ccc(NC(=O)OC(C)(C)C)c2C1=O
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of tert-butyl[7-(hepta-1,6-dien-4-yl)-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl]carbamate (Compound 243D, 180 mg, 0.50 mmol) in DCM (10 mL) was added (benzylidene)bis(tricyclohexylphosphine)ruthenium(IV)dichloride (21 mg, 0.025 mmol). The resulting mixture was stirred at rt under nitrogen. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (ISCO Combi-flash system, eluting with 10-30% EtOAc/Heptane) to give the title compound as a white solid, 150 mg, 90% yield. 1H NMR (CDCl3): 1.54 (s, 9H), 2.43-2.48 (m, 2H), 2.81-2.86 (m, 2H), 3.18 (s, 3H), 3.45 (m, 1H), 4.32 (s, 2H), 5.80-5.84 (m, 2H), 7.35 (d, J=8.6 Hz, 1H), 8.12 (d, J=8.6 Hz, 1H), 9.53 (br s, 1H). MS (ES+): m/z=329.13 [MH+]. HPLC: tR=4.65 min (ZQ3, polar—5 min).
Reaction SMILES: C([Mg]Cl)(C)C.[Cl-].[Li+].Br[C:9]1[N:13]([CH3:14])[CH:12]=[N:11][CH:10]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]=[O:22]>C1COCC1>[CH3:14][N:13]1[C:9]([CH:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=2)[OH:22])=[CH:10][N:11]=[CH:12]1
Reactant: O=Cc1ccccn1
Reactant: Cn1cncc1Br
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1cncc1C(O)c1ccccn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of isopropylmagnesium chloride/lithium chloride complex (1.3 M in THF, 19.5 mL, 25.35 mmol) was added dropwise by syringe to a solution of 5-bromo-1-methyl-1H-imidazole (4.12 g, 25.58 mmol) in dry THF (130 mL) at 0° C. After 15 minutes, the Grignard solution was added via cannulation to a solution of picolinaldehyde (2.0 mL, 20.93 mmol) in dry THF (55 mL) at 0° C. The reaction mixture was stirred for 5 minutes at 0° C., then warmed to room temperature for 1 hour. The reaction mixture was then cooled in an ice bath and quenched with saturated aqueous ammonium chloride. The mixture was partitioned between brine and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-5% MeOH-DCM) to provide the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([CH:12]2[CH2:14][CH2:13]2)O)=[CH:4][CH:3]=1.P(Br)(Br)[Br:16].[Br-].[Li+]>[Br-].[Zn+2].[Br-]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]=[CH:12][CH2:13][CH2:14][Br:16])=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: OC(CCc1ccc(Cl)cc1)C1CC1
Agent: [Br-]
Agent: [Li+]
Agent: [Zn+2]
Product: Clc1ccc(CCC=CCCBr)cc1

Procedure:
6-(4-Chlorophenyl)-3-hexenyl bromide [V; Ar is 4-ClC6H4, R is H] was prepared from 21 g. of 2-(4-chlorophenyl)ethyl cyclopropyl carbinol (Preparation B7), 23 g. of phosphorus tribromide, 18.85 g. of lithium bromide and 22.5 g. of zinc bromide according to the procedure given above in Preparation C1, affording 25.5 g. of product as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1>CN(C)C=O>[N:12]1([C:2]2[C:7]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1
Reactant: NS(=O)(=O)c1cccnc1Cl
Reactant: C1CSCCN1
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cccnc1N1CCSCC1

Procedure:
In a dry flask under an inert nitrogen atmosphere was mixed 2.5 g of 2-chloro-3-pyridinesulfonamide, 100 mL of dry N,N-dimethylformamide (DMF), and 2.7 mL of thiomorpholine. The mixture was heated at 80° C. overnight at which time an additional 0.3 mL of thiomorpholine was added and the heating was continued. After 24 hours the mixture was concentrated and the residue was taken up in THF. The solids were filtered and the filtrate was concentrated and chromatographed on silica gel using 1:1 ethyl acetate/hexane as eluent. The pure subject compound was isolated as a solid, which melted at 176°-177° C.; NMR (200 MHz, CDCl3): δ 2.89 (m, CH2S, 4H), 3.45 (m, CH2N, 4H), 5.52 (s, NH2, 2H), 7.26 (t, ArH, 1H), 8.2-8.6 (m, ArH, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([C:8]([CH3:12])=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=O.[Cl:14][C:15]1[CH:21]=[C:20]([S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23])[CH:19]=[CH:18][C:16]=1[NH2:17]>>[Br:1][C:2]1[C:3]([OH:13])=[C:4]([C:8]([CH3:12])=[C:9]([Cl:11])[CH:10]=1)[C:5]([NH:17][C:16]1[CH:18]=[CH:19][C:20]([S:22]([C:25]([F:28])([F:26])[F:27])(=[O:24])=[O:23])=[CH:21][C:15]=1[Cl:14])=[O:7]
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1Cl
Reactant: Cc1c(Cl)cc(Br)c(O)c1C(=O)O
Product: Cc1c(Cl)cc(Br)c(O)c1C(=O)Nc1ccc(S(=O)(=O)C(F)(F)F)cc1Cl

Procedure:
3-Bromo-5-chloro-N-(2-chloro-4-trifluoromethanesulfonylphenyl)-2-hydroxy-6-methylbenzamide is synthesized from 3-bromo-5-chloro-2-hydroxy-6-methylbenzoic acid and 2-chloro-4-(trifluoromethanesulfonyl)aniline by General Procedure F.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[N:21]=[C:20]([C:22]5[C:23]([O:29]C)=[N:24][CH:25]=[C:26]([CH3:28])[CH:27]=5)[C:19]([CH3:31])=[CH:18][CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.I[Si](C)(C)C>C(#N)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([CH3:31])=[C:20]([C:22]5[C:23](=[O:29])[NH:24][CH:25]=[C:26]([CH3:28])[CH:27]=5)[N:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: COc1ncc(C)cc1-c1nc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)ccc1C
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: Cc1c[nH]c(=O)c(-c2nc(NC(=O)C3(c4ccc5c(c4)CCO5)CC3)ccc2C)c1
Yield: 61 %

Procedure:
To 1-(2,3-dihydrobenzofuran-5-yl)-N-(2′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (90 mg, 0.2 mmol) in acetonitrile (4 mL) at 50° C. was added iodotrimethylsilane (87 mg, 0.4 mmol). The reaction was heated for one hour before being quenched with methanol (1 mL). The reaction was diluted with dichloromethane (15 mL) and washed with an aqueous saturated sodium bisulfite solution (2×15 mL). The organics were dried over sodium sulfate and evaporated to dryness. The resulting white solid was purified by silica gel chromatography (eluting with 0-10% methanol in ethyl acetate) to yield the product (49 mg, 55%) as a white solid. ESI-MS m/z calc. 401.46. found 402.5 (M+1)+. Retention time 1.32 minutes.
Reaction SMILES: [C:1]([N:4]1[C:16]2[C:11](=[CH:12][C:13](Br)=[C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]3=2)[C:10]2[C:5]1=[CH:6][CH:7]=[C:8]1[CH:25]=[CH:24][CH:23]=[CH:22][C:9]1=2)(=[O:3])[CH3:2].[C:26]1([N:32]2[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[N:34]=[C:33]2[C:41]2[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1(C)C=CC=CC=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>[C:1]([N:4]1[C:16]2[C:11](=[CH:12][C:13]([C:44]3[CH:45]=[CH:46][C:41]([C:33]4[N:32]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=4)=[CH:42][CH:43]=3)=[C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]3=2)[C:10]2[C:5]1=[CH:6][CH:7]=[C:8]1[CH:25]=[CH:24][CH:23]=[CH:22][C:9]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)n1c2ccc3ccccc3c2c2cc(Br)c3ccccc3c21
Reactant: OB(O)c1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
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: CCO
Solvent: Cc1ccccc1
Product: CC(=O)n1c2ccc3ccccc3c2c2cc(-c3ccc(-c4nc5ccccc5n4-c4ccccc4)cc3)c3ccccc3c21
Yield: 90.9 %

Procedure:
Following the above procedure, Suzuki coupling of 3.4 g of 7-acetyl-12-bromo-7H-dibenzo [a,g]carbazole and 3.8 g of 4-(1-phenyl-1H-benzo [d]imidazol-2-yl) phenylboronic acid were stirred together in 30 ml of toluene. To this was added 0.01 g of tetrakis(triphenylphosphine)palladium, 2.7 g of potassium carbonate and 10 ml of aqueous ethanol were added and refluxed under nitrogen for 6 h. The reaction was quenched with water and the toluene layer was removed and passed through a celite column. The organic layers were combined and then evaporated in a rotary evaporator under vacuum to yield 4.6 g of 7-acetyl-12-[4-(1-phenyl-1H-benzo[d]imidazol-2-yl)phenyl]-7H-dibenzo [a,g]carbazole as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1([CH2:20][CH3:21])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19].ClC1C(=O)C(C#N)=C(C#N)C(=[O:31])C=1Cl>C1COCC1.O.C1COCC1>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1([CH2:20][CH3:21])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8](=[O:31])[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19]
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: C1CCOC1
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3=O
Reaction time: 8 h

Procedure:
The ester produced in step A (0.5g, 1.66 mmol) was dissolved in 5 ml of a 90% THF/water solution, and to this was added 2,3-dichloro-5,6-dicyano-1,4 -benzoquinone (0.75 g, 3.3 mmol., previously dissolved in 5 ml THF). This mixture was stirred overnight. The solvent was evaporated and 50 ml of ethyl acetate was added. The organic phase was extracted sequentially with 2.5N NaOH, distilled water and brine. The organic layer was separated, dried (MgSO4) and evaporated to produce 0.56 g of crude oil. The oil was flash chromatographed using CH2Cl2 --EtOAc 98-2 as eluant to yield 0.15 g of the desired product as a solid, m.p. 187°-189° C.