Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([C:10]([C:25]#[N:26])=[C:11](SC)[NH:12][CH2:13][CH2:14][S:15][CH2:16][C:17]2[NH:21][CH:20]=[N:19][C:18]=2[CH3:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:27]([NH2:30])[C:28]#[CH:29]>>[C:1]1([S:7]([C:10]([C:25]#[N:26])=[C:11]([NH:30][CH2:27][C:28]#[CH:29])[NH:12][CH2:13][CH2:14][S:15][CH2:16][C:17]2[NH:21][CH:20]=[N:19][C:18]=2[CH3:22])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CSC(NCCSCc1[nH]cnc1C)=C(C#N)S(=O)(=O)c1ccccc1
Reactant: C#CCN
Product: C#CCNC(NCCSCc1[nH]cnc1C)=C(C#N)S(=O)(=O)c1ccccc1

Procedure:
The product of Step A is reacted with a four-fold excess of propargylamine according to the general procedure of Example 2, and the title product is produced.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[OH:14].[CH3:15][C:16]([CH3:21])=[CH:17][CH:18](O)[CH3:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[O:14][CH:18]([CH:17]=[C:16]([CH3:21])[CH3:15])[CH3:19]
Reactant: Oc1cc(Nc2nccs2)ccc1Cl
Reactant: CC(C)=CC(C)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)=CC(C)Oc1cc(Nc2nccs2)ccc1Cl
Reaction time: 1 h
Yield: 24 %

Procedure:
Following the procedure general for O-alkylation, Method C, 2-chloro-5-(thiazol-2-ylamino)phenol (50 mg, 0.22 mmol), 4-Methylpent-3-en-2-ol (23 mg, 0.23 mmol), Ph3P (58 mg, 0.22 mmol) were suspended in THF (0.07 mL). The reaction flask was lowered into a sonication bath and sonicated for several minutes giving a clear and highly viscous solution. While sonication, DEAD (0.043 mL, 0.22 mmol) was added slowly. The reaction mixture was stirred for 1 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 4/1) in 24% yield (16 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([N:13]2[C:18](=[O:19])[NH:17][C:16](=[O:20])[C:15](C(O)=O)=[N:14]2)=[CH:8][C:7]=1[CH3:24].C(O)(=S)C>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[O:5][C:6]1[C:7]([CH3:24])=[CH:8][C:9]([N:13]2[C:18](=[O:19])[NH:17][C:16](=[O:20])[CH:15]=[N:14]2)=[CH:10][C:11]=1[CH3:12]
Reactant: COc1ccc(Oc2c(C)cc(-n3nc(C(=O)O)c(=O)[nH]c3=O)cc2C)cc1Br
Agent: CC(O)=S
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2c(C)cc(-n3ncc(=O)[nH]c3=O)cc2C)cc1Br
Temperature: 170 °C
Yield: 58.9 %

Procedure:
A mixture of 2-[4-(3-bromo-4-methoxy-phenoxy)-3,5-dimethyl-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic acid (0.3 g) of EXAMPLE 2 and thioacetic acid (0.6 ml) was heated at 170° C. for 4 h. The mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate, and dried with sodium sulfate to afford a crude brown oil (0.6 g). Chromatography on silica gel, eluting with ethyl acetate and hexanes, gave the title compound (160 mg) as a yellow foam.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][C:12]([F:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[NH:9][C:8]=1[C:19]([OH:21])=O)(=[O:3])[CH3:2].[CH:22]([N:25](C(C)C)CC)(C)C.Cl.CN.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[C:1]([NH:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][C:12]([F:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[NH:9][C:8]=1[C:19]([NH:25][CH3:22])=[O:21])(=[O:3])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc2c(CCNC(C)=O)c(C(=O)O)[nH]c2cc1F
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1[nH]c2cc(F)c(OC)cc2c1CCNC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(2-acetamidoethyl)-6-fluoro-5-methoxy-1H-indole-2-carboxylic acid (2.11 g), diisopropylethylamine (6.14 mL), methylamine hydrochloride (1.45 g), and N,N-dimethyl formamide (42.2 mL) was added 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (6.82 g), followed by stirring at room temperature overnight. To the mixture was added ice water, followed by extraction with ethyl acetate and further extraction with chloroform/methanol (10:1). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble materials were separated by filtration, the filtrate was concentrated under reduced pressure, and then the obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 10:1) to obtain 3-(2-acetamidoethyl)-6-fluoro-5-methoxy-N-methyl-1H-indole-2-carboxamide (1.64 g).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([NH:7][C:8](=[O:11])[CH2:9][Cl:10])[N:6]=1.C([O-])(=O)C.[Na+].[H][H]>CO.[Pd]>[Cl:10][CH2:9][C:8]([NH:7][C:5]1[N:6]=[CH:2][S:3][CH:4]=1)=[O:11]
Reactant: O=C(CCl)Nc1csc(Br)n1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(CCl)Nc1cscn1
Yield: 57.9 %

Procedure:
A solution of 2-bromo-4-chloroacetamidothiazole (4 g) and sodium acetate (1.15 g) in methanol (100 ml) was hydrogenated at atmospheric pressure over 10% Pd/C catalyst (1 g) until theoretical uptake of hydrogen had occurred. The catalyst was removed by filtration and washed with methanol and the extracts evaporated to dryness in vacuo. The residue was recrystallised twice from carbon tetrachloride to give the title compound (1.6 g) m.p. 115°-119° C. (Found: C, 33.7; H, 2.9; N, 15.5. C5H5ClN2OS requires C, 34.0; H, 2.9; N, 15.8%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][C@H:9]1[CH2:13][N:12]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][C@@H:10]1[NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:7].[H-].[Na+]>C1COCC1.CN(C=O)C>[CH2:14]([N:12]1[CH2:13][C@H:9]([N:8]2[CH2:2][CH2:3][CH2:4][CH2:5][C:6]2=[O:7])[C@@H:10]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:11]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(Cc2ccccc2)C[C@@H]1NC(=O)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CN(Cc2ccccc2)C[C@@H]1N1CCCCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a solution of the product of Step 7 (6.3 g, 13.9 mmol) in THF (60 mL) and DMF (30 mL) was added sodium hydride (611 mg, 60% in oil, 15.29 mmol). After stirring the reaction mixture overnight at RT, it was quenched with water and extracted with EtOAc (3×100 mL). The combined extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to furnish the crude product. The residue was purified by column chromatography on silica gel (90:10 petroleum ether/EtOAc) to obtain desired product (4.53 g, 87.4%). 1H NMR (300 MHz, CDCl3) δ 5.38 (1H, s), 4.60 (1H, m), 4.18 (1H, s), 3.50-3.20 (6H, m), 3.00 (1H, m), 2.80 (1H, m), 2.40 (4H, m), 1.80 (4H, m), 1.40 (9H, m). MS m/z 374 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[N:4][CH:5]=[CH:6][CH:7]=1.C([Mg]Cl)(C)C.[F:14][C:15]([F:49])([F:48])[C:16]1[CH:17]=[C:18]([C:26]([CH3:47])([CH3:46])[C:27]([N:29]([C:31]2[CH:32]=[N:33][C:34]([N:38]3[CH2:42][C@H:41]([OH:43])[CH2:40][C@H:39]3[CH2:44][OH:45])=[CH:35][C:36]=2I)[CH3:30])=[O:28])[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1.[OH-].[Na+]>O1CCCC1.[Cl-].[Zn+2].[Cl-].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:25][C:22]([F:23])([F:24])[C:20]1[CH:19]=[C:18]([C:26]([CH3:46])([CH3:47])[C:27]([N:29]([C:31]2[CH:32]=[N:33][C:34]([N:38]3[CH2:42][C@H:41]([OH:43])[CH2:40][C@H:39]3[CH2:44][OH:45])=[CH:35][C:36]=2[C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH3:30])=[O:28])[CH:17]=[C:16]([C:15]([F:49])([F:14])[F:48])[CH:21]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2C[C@H](O)C[C@H]2CO)cc1I
Reactant: Clc1cccnc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2C[C@H](O)C[C@H]2CO)cc1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.2 %

Procedure:
To a solution of 0.500 g (2.09 mmol) 3-chloro-2-iodo-pyridine in 6 ml tetrahydrofuran 1.04 ml (2.09 mmol) of a 2 M solution of isopropylmagnesium chloride in tetrahydrofuran was added dropwise at −40° C. under an atmosphere of argon. After 30 min. 2.3 ml (4.2 mmol) of an anhydrous 1.8 M solution of zinc chloride in tetrahydrofuran was added slowly. The cooling bath was removed after completed addition, and the reaction mixture was stirred at room temperature for 90 min. A portion of 1.6 ml of this solution was added to a solution of 0.15 g (0.24 mmol) (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-N-methyl-isobutyramide and 14 mg (0.012 mmol) tetrakis(triphenylphosphine)palladium(0) in 1 ml tetrahydrofuran. The mixture was heated at 100° C. under microwave irradiation for 30 min. After cooling to room temperature a 0.5 M solution of sodium hydroxide was added, and the mixture was extracted with three portions of dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 58 mg (40%) of the title compound as a light yellow solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[S:16](Cl)(=[O:18])=[O:17])([CH3:3])[CH3:2].CS(C)=[O:22].O>CS(C)=O.O>[CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[S:16]([OH:18])(=[O:22])=[O:17])([CH3:3])[CH3:2]
Reactant: CS(C)=O
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Solvent: O
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)O)c(C(C)C)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To 30.2 g (0.1 mol) of commercially available 2,4,6-triisopropylbenzenesulfonyl chloride were added 30 g of dimethyl sulfoxide and 30 g of water. The mixture was heated and stirred on an oil bath at 80° C. for 3 hours. The dimethyl sulfoxide/water solution was ready for use in the subsequent step of anion exchange reaction.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH3:25]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH:31]=[CH:30][C:29]([S:26]([CH2:24][CH3:25])(=[O:28])=[O:27])=[CH:34][CH:33]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Product: CCS(=O)(=O)c1ccc(-c2cc3c(cn2)OC(C2CCN(C(=O)OC(C)(C)C)CC2)C3)cc1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-(ethylsulfonyl)phenylboronic acid following a procedure analogous to that described in Example 28. LC (method 7): tR=1.39 min; Mass spectrum (ESI+): m/z=473 [M+H]+.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][O:40][C:41]1[CH:42]=[C:43]([CH:54]=[CH:55][CH:56]=1)[CH2:44]B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:39][O:40][C:41]1[CH:42]=[C:43]([CH:54]=[CH:55][CH:56]=1)[CH2:44][C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1
Reactant: COc1cccc(CB2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1cccc(Cc2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Yield: 50.9 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (140 mg, 0.17 mmol) was treated with 2-(3-methoxybenzyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (100 mg, 0.17 mmol), cesium carbonate (164 mg, 0.50 mmols) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (14 mg, 0.02 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 50%, hexane-ethyl acetate) to obtain 55 mg of the title compound. Purity 50%.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[Na+].[Na+].[C:27]1([CH3:36])[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>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.C1(C)C=CC=CC=1>[CH3:17][C:16]([CH3:19])([CH3:18])[C:15]([NH:14][C:3]1[CH:4]=[N:5][C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:7][C:2]=1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH3:36])=[O:20]
Reactant: CC(C)(C)C(=O)Nc1cnc(N2CCOCC2)cc1I
Reactant: Cc1ccccc1B(O)O
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: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1cc(N2CCOCC2)ncc1NC(=O)C(C)(C)C
Temperature: 80 °C

Procedure:
A mixture of 3.50 g (9.0 mmol) N-(4-iodo-6-morpholin-4-yl-pyridin-3-yl)-2,2-dimethyl-propionamide, 35 ml toluene, 18 ml 2 N sodium carbonate solution, 312 mg (0.27 mmol) tetrakis(triphenylphosphine)palladium(0) and 1.34 g (9.9 mmol) o-tolylboronic acid was heated under argon at 80° C. for 12 h. After cooling to room temperature, the aqueous phase was separated and washed twice with ethyl acetate. The combined organic layers were washed with 50 ml brine, dried (sodium sulfate) and evaporated. Purification by flash-chromatography gave 3.23 g (quantitative) of the title compound as a white foam.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[C:1]1([C:7]([C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25]([N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[O:26])=[CH:21][CH:22]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)N(CC)CC)cc1)c1ccccc1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCC(=C(c1ccccc1)c1ccc(CCC(=O)N(CC)CC)cc1)c1ccccc1
Temperature: 25 °C
Yield: 97.2 %

Procedure:
A solution of 50 mg (0.12 mmol) of 3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-N,N-diethyl acrylamide (see Example 2) and 3 mg of tris(triphenylphosphine)-rhodium(I) chloride (Wilkinson's catalyst) in 1 mL dry toluene was stirred over an atmosphere of H2 gas at 50° C. for 16 h. The solution was cooled to RT and the toluene removed in vacuo. Purification of the residue by silica gel flash chromatography using hexane/ethyl acetate 2/1 as eluent afforded 48 mg (95%) of the desired compound named above of the desired compound named above as a clear, colorless oil: 1H NMR (CDCl3, 300 MHz) s 7.37-7.11 (m, 10H), 6.85 (d, 2H, J=8.3), 6.78 (d, 2H, J=8.3), 3.31 (q, 2H, J=7.1), 3.08 (q, 2H, J=7.3), 2.81 (t, 2H, J=8.3), 2.44 (m, 4H), 1.03 (m, 6H), 0.91 (t, 3H, J=7.3); low resolution MS m/e 412 (MH+); Anal. (C29H33NO) C, H, N. [see, for example (i), Scheme C, supra].
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[CH:22])=[CH:17][CH:16]=1.Cl>CN(C=O)C.N1CCCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]2[O:12][C:21]([C:18]3[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=3)=[CH:22][C:2]=2[CH:3]=1)=[O:6]
Reactant: C#Cc1ccc(OC)cc1
Reactant: COC(=O)c1ccc(O)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2oc(-c3ccc(OC)cc3)cc2c1
Temperature: 6 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
A mixture of Methyl 3-Iodo-4-hydroxybenzoate (0.7 g, 2.5 mmol), 4-Methoxyphenylacetylene (0.33 g, 2.5 mmol), Pd(Cl)2(PPh3)2 (0.05 g) and Cul (0.03 g) in DMF/Piperidine (20 ml) was heated at 6° C. After 2 hr, the reaction was cooled and poured into 2N HCl. The aqueous layer was extracted with EtOAc and then separated, dried, concentrated to give a solid. The solid was triturated with MeOH, filtered to give 142 (0.5 g, 71%): Mp=157–159° C.; 1H NMR (CDCl3) δ 8.28 (d, 1 H, J=1.3 Hz), 7.97 (dd, 1 H, J=8.5 Hz, 1.7 Hz), 7.82–7.79 (m, 2 H), 7.51 (d, 1 H, 8.5 Hz), 6.99 (d, 2 H, J=8.3 Hz), 6.93 (d, 1 H, J=9 Hz), 3.94 (s, 3 H), 3.87 (s, 3 H); MS 283 (M+H)+
Reaction SMILES: C1(O)C=CC=CC=1.[CH2:8]([C:17]1C=CC=C[C:18]=1O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]CC.[OH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2([C:46]3[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=3)[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:38](=[O:45])[C:37]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]2=3)=[CH:27][CH:26]=1>>[OH:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2([C:46]3[CH:47]=[CH:48][C:49]([OH:52])=[CH:50][C:51]=3[CH2:18][CH2:17][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:38](=[O:45])[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:44]2=3)=[CH:29][CH:30]=1
Reactant: O=C1c2ccccc2C(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Reactant: CCCCCCCCCc1ccccc1O
Solvent: Oc1ccccc1
Product: CCCCCCCCCc1cc(O)ccc1C1(c2ccc(O)cc2)c2ccccc2C(=O)c2ccccc21

Procedure:
A 1:1 weight ratio of phenol and a 2-n-nonyl-phenol should be substituted for the phenol of Example 12 in this Example and the procedure of Example 12 should be followed in this Example to obtain the product herein.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([N:17](C(OC(C)(C)C)=O)[NH:18][C:19](OC(C)(C)C)=O)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:33][O:34][Si](C(C)(C)C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:44]C(O)=O>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][C:13]3[N:12]([C:19]([CH3:44])=[N:18][N:17]=3)[C:11]=2[CH:10]=[C:9]1[CH2:33][OH:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(CO[Si](C)(C)C(C)(C)C)n2Cc2ccccc2)n1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nnc2ccc3c(cc(CO)n3Cc3ccccc3)n12

Procedure:
di-tert-Butyl 1-[1-benzyl-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]hydrazine-1,2-dicarboxylate (0.20 g, 0.34 mmol, from Step 4) in AcOH (2.7 mL) was heated in the microwave to a temperature of 180° C. for 5 minutes. Acetic acid was removed in vacuo and the residue was then stirred with NaOH (69 mg, 1.7 mmol) in THF (2.0 mL) and water (2 mL) for 20 minutes. The product was purified by preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (38 mg, 38%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([CH3:15])[CH:11]=3)[NH:6][C:5]=2[CH2:4][CH2:3]1.C(OCC)(=O)C>[Pd].C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([CH3:15])=[CH:9][CH:8]=3
Reactant: Cc1ccc2[nH]c3c(c2c1)CC(C)CC3
Agent: [Pd]
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: Cc1ccc2[nH]c3ccc(C)cc3c2c1
Temperature: 150 °C
Yield: 93.4 %

Procedure:
A mixture of 12.0 g (60.3 mmol) of 3,6-dimethyl-1,2,3,4,-tetrahydrocarbazole and 3.6 g of 10% palladium on charcoal (46-190, Strem Chemicals, Danvers, Mass.) in 120 ml xylene was refluxed vigorously (150° C) overnight. Addition of 200 ml of ethyl acetate, filtration of the cooled mixture through Celite 545 and evaporation of solvents gave 11.0 g (94%) of 3,6-dimethylcarbazole, mp 218°-21° C (lit. mp 217°-18° C).
Reaction SMILES: N1C=CN=CC=1N=C=O.[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH2:15])=[O:14].[F:20][C:21]([F:32])([F:31])[C:22]1[N:23]=[CH:24][C:25]([N:28]=[C:29]=[O:30])=[N:26][CH:27]=1>>[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH:15][C:29]([NH:28][C:25]1[CH:24]=[N:23][C:22]([C:21]([F:32])([F:20])[F:31])=[CH:27][N:26]=1)=[O:30])=[O:14]
Reactant: NC(=O)c1ccccc1Cl
Reactant: O=C=Nc1cnc(C(F)(F)F)cn1
Agent: O=C=Nc1cnccn1
Product: O=C(NC(=O)c1ccccc1Cl)Nc1cnc(C(F)(F)F)cn1

Procedure:
A compound of formula I may also be prepared by allowing a 2-substituted benzamide to react with a 2-pyrazinylisocyanate utilizing the appropriate solvents, times of reaction and general reaction conditions hereinabove described. For example, 2-chlorobenzamide is allowed to react with 5-trifluoromethylpyrazin-2-ylisocyanate to yield 1-(2-chlorobenzoyl)-3-(5-trifluoromethyl-2-pyrazinyl)urea, having a melting point of about 219°-220° C.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH2:16])=[O:15])=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].[H-].[Na+].[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:16][C:33](=[O:40])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:15])=[CH:11][CH:12]=2)[CH:7]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)=[CH:22][CH:23]=2)[CH2:6][CH:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(C(N)=O)cc2[C@H](Nc2ccc(N3CCOCC3)cc2)C[C@@H]1C
Reactant: O=C(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N1c2ccc(C(=O)NC(=O)c3ccccc3)cc2C(Nc2ccc(N3CCOCC3)cc2)CC1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
[Step 2] 33.2 mg of (2S,4R)-1-acetyl-2-methyl-4-[(4-morpholinophenyl)amino]-1,2,3,4-tetrahydroquinoline-6-carboxamide was dissolved in 1 mL of tetrahydrofuran, and 10.3 mg of sodium hydride was added to the solution at 0° C. The mixture was stirred for 30 minutes at room temperature. Subsequently, 10.3 μL of benzoyl chloride was added dropwise to the mixture, and the mixture was stirred for 12 hours at room temperature. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted three times with chloroform. The extraction product was washed with saturated brine, dehydrated over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (chloroform:methanol=10:1), and then was recrystallized from ethyl acetate-hexane. Thus, 23.6 mg (56.8%, cis:trans=20:1) of the title compound was obtained as a pale yellow crystalline powder.