Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12](I)[CH:11]=2)=[O:8])=[C:5]([CH3:18])[O:4][N:3]=1.[Br-].C[C:21]1[C:22]([Zn+])=[N:23][CH:24]=[CH:25][CH:26]=1.[CH2:28]1COCC1>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:18])=[O:8])=[CH:11][C:12]=1[C:24]1[CH:25]=[CH:26][CH:21]=[C:22]([CH3:28])[N:23]=1
Reactant: Cc1cccnc1[Zn+]
Reactant: Cc1noc(C)c1C(=O)Nc1ccc(Cl)c(I)c1
Reactant: C1CCOC1
Agent: [Br-]
Product: Cc1cccc(-c2cc(NC(=O)c3c(C)noc3C)ccc2Cl)n1

Procedure:
Procedure B was performed with 3,5-dimethyl-N-(4-chloro-3-iodophenyl)isoxazole-4-carboxamide (190 mg, 0.5 mmol) and 3-methyl-2-pyridylzinc bromide (2.5 mL of a 0.5 M solution in THF). The crude reaction was purified by silica gel chromatography (5-100% Ethyl acetate/Hexanes) to yield N-(4-chloro-3-(6-methylpyridin-2-yl)phenyl)-3,5-dimethylisoxazole-4-carboxamide as a white solid: TLC Rf=0.43 (50% ethyl acetate/hexanes); 1H NMR (CDCl3, 400 MHz) δ 8.52 (bs, 1H), 7.68 (m, 2H), 7.48 (m, 3H), 2.70 (s, 3H), 2.49 (s, 3H), 2.21 (s, 3H); MS (Q1) 342.3 (M)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([OH:17])[CH:10]=1>CCO>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([NH:8][C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:10][C:11]=1[OH:17])#[N:14]
Reactant: N#Cc1ccc(N)cc1O
Reactant: Clc1ncccn1
Solvent: CCO
Product: N#Cc1ccc(Nc2ncccn2)cc1O
Temperature: 90 °C
Yield: 5 %

Procedure:
Following the general procedure for the synthesis of 2-R-5-(heteroaryl-2-ylamino)phenol, 2-chloropyrimidine (209 mg, 1.8 mmol) and 4-amino-2-hydroxybenzonitrile (123 mg, 0.9 mmol) in 10% aqueous EtOH (5 mL) was heated at 90° C. for 18 h. The title compound was obtained in 5% yield a (10 mg) and used for the next step without additional purification.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7](Cl)=[N:8][S:9](=[O:11])(=[O:10])[C:4]2=[CH:3][CH:2]=1.[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:13]([N:15]([CH2:16][CH3:17])[C:7]1[C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1)[CH3:14]
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Reactant: CCNCC
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCN(CC)C1=NS(=O)(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
10.0 g of pseudosaccharine chloride are initially introduced in 150 ml of toluene. 3.7 g of diethylamine diluted with 25 ml of toluene are added dropwise at room temperature over the course of 30 minutes. After a further 30 minutes, 50 ml of pyridine in 25 ml of toluene are added and the mixture is subsequently stirred at room temperature for 2.5 hours. The solvent is then removed in vacuo and the residue is stirred up with 350 ml of water. The colorless precipitate is filtered off to give 10.1 g (84%) of 3-diethylaminobenzoisothiazole 1,1-dioxide.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[C:12]([O:15][CH:16]([O:20][C:21](ON1C(=O)CCC1=O)=[O:22])[CH2:17][CH2:18][CH3:19])(=[O:14])[CH3:13]>CC(OC)(C)C.CC(C)=O.O>[C:12]([O:15][CH:16]([O:20][C:21]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:22])[CH2:17][CH2:18][CH3:19])(=[O:14])[CH3:13]
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCCC(OC(C)=O)OC(=O)ON1C(=O)CCC1=O
Solvent: O
Solvent: CC(C)=O
Solvent: COC(C)(C)C
Product: CCCC(OC(C)=O)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (472 mg, 3.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]butyl acetate (620 mg, 2.27 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 33 (174 mg, 24% yield) as a waxy white solid after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.82-0.94 (br. m, 5H), 1.17-1.38 (br. m, 5H), 1.63-1.73 (br. m, 4H), 1.83-1.91 (br. m, 2H), 2.05 (s, 3H), 2.10 (tt, J=11.6, 3.6 Hz, 1H), 2.74-2.88 (m, 2H), 6.58 (t, J=5.6 Hz, 1H), 7.42 (t, J=6.0 Hz, 1H), 11.97 (br. s, 1H). MS (ESI) m/z 338.16 (M+Na)+; 314.12 (M−H)−.
Reaction SMILES: [N:1]([CH:4]([OH:20])[C@H:5]1[O:9][C@@H:8]([N:10]2[CH:17]=[C:16]([Br:18])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[OH:19])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N>N1C=CC=CC=1>[Br:18][C:16]1[C:14](=[O:15])[NH:13][C:11](=[O:12])[N:10]([CH:17]=1)[C@@H:8]1[O:9][C@H:5]([CH2:4][OH:20])[C@@H:6]([OH:19])[CH2:7]1.[NH2:1][CH:4]([OH:20])[C@H:5]1[O:9][C@@H:8]([N:10]2[CH:17]=[C:16]([Br:18])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[OH:19]
Reactant: [N-]=[N+]=NC(O)[C@H]1O[C@@H](n2cc(Br)c(=O)[nH]c2=O)C[C@@H]1O
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: NC(O)[C@H]1O[C@@H](n2cc(Br)c(=O)[nH]c2=O)C[C@@H]1O
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1Br

Procedure:
The 5'-azido derivative of 5-bromo-2'-deoxy uridine is prepared via the method described above. The 5'-azido-5-bromo-2'-deoxyuridine (1 mmol) is treated with triphenyl phosphine (1.5 mmol) in pyridine at room temperature for 2 h. Concentrated ammonia (1 ml) is added to the reaction vessel. After 14 h the solvent is removed under vacuum. The residue is dissolved in THF and this solution is added to hexanes. The precipitate is collected and the solid triturated with the appropriate solvent to afford the 5'-amino-5-bromo-2'-deoxyuridine.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(Cl)Cl>[C:22]([O:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: OCCCSc1cccc2nccn12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCCCSc1cccc2nccn12
Temperature: 25 °C
Yield: 99.9 %

Procedure:
To a solution of 5-[3-(hydroxy)propylthio]imidazo[1,2-a]pyridine (2.00 g, 9.60 mmoles) and triethylamine (1.60 ml, 11.5 mmoles) in methylene chloride (50 ml) was added acetic anhydride (1.10 ml, 11.6 mmoles) with stirring at room temperature and the mixture was further stirred at room temperature for 7.5 hours. The reaction mixture was washed with an aqueous 1N sodium hydroxide solution and dried. After the solvent was distilled off, the residue was purified by column chromatography [eluent: hexane/acetone (1:1)] to obtain 2.40 g of the desired product (100%, brown oily product).
Reaction SMILES: Br[CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1.N1C(C)=CC=CC=1C.[CH3:25][OH:26]>[B-](F)(F)(F)F.[Ag+]>[CH3:25][O:26][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1
Reactant: CO
Reactant: O=C(O)CCCCCCC1=CC(Br)CC1=O
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: Cc1cccc(C)n1
Product: COC1C=C(CCCCCCC(=O)O)C(=O)C1
Reaction time: 0.03 h

Procedure:
To a stirred solution of 5.30 g. of crude 4-bromo-2-(6-carboxyhexyl)cyclopent-2-en-1-one (Example 93) in 85 ml. of methanol at 0°-3° C. is added 4.40 g. (22.6 mmole) of silver fluoborate in one portion. After 2 minutes, the mixture is treated with 2.66 g. (24.8 mmoles) of 2,6-lutidine. After stirring for 30 minutes at 0°-3° C. the mixture is stirred at ambient temperature for 45 minutes. Silver bromide is removed by filtration, and the filtrate is concentrated to a volume of 40 ml. The solution is treated with saturated sodium chloride solution and extracted with ether. The extract is washed successively with 0.5N hydrochloric acid solution, water, and saturated sodium chloride solution; dried over magnesium sulfate; and concentrated. Partition chromatography of the residue on Celite gives an oil, λ maxMeOH. = 220 mμ (7450); ν max - 1715 (carbonyl groups) and 1095 cm-1 (methoxy group).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:22][CH3:23])=[C:16]([N+:19]([O-])=O)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:24]#[N:25])[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH4+].CO>O.C(OCC)(=O)C.[Fe]>[NH2:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:22][CH3:23])[N:12]=[CH:11][C:10]([C:24]#[N:25])=[C:9]2[NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: COc1cc2ncc(C#N)c(Nc3cccc(Br)c3)c2cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2ncc(C#N)c(Nc3cccc(Br)c3)c2cc1N
Yield: 69 %

Procedure:
A mixture of 2.05 g (5.1 mmol) of 4-[(3-bromophenyl)amino]-7-methoxy-6-nitro-quinoline-3-carbonitrile, 1.37 g (25.7 mmol) of ammonium chloride, and 0.86 g (15.4 mmol) of powdered iron was stirred at reflux in 26 ml water and 26 ml methanol for 2 hours. The mixture was diluted with ethyl acetate and the hot mixture was filtered. The organic layer was separated from the filtrate and dried over magnesium sulfate. The solvent was removed and the residue was chromatographed on silica gel eluting with mixtures of chloroform and ethyl acetate. Product fractions were combined to give 1.3 g of 6-amino-4-[(3-bromophenyl)amino]-7-methoxy-quinoline-3-carbonitrile as a yellow solid: mass spectrum (electrospray, m/e): M+H 369.1, 371.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[C:4]([CH:11]=O)[CH:3]=1.Br[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[CH2:21][C:22]#[N:23].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:14]3[C:15](=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[C:21]([C:22]#[N:23])=[CH:11][C:4]=2[CH:3]=1
Reactant: N#CCc1cc(Cl)ccc1Br
Reactant: O=Cc1cc(Cl)ccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#Cc1cc2cc(Cl)ccc2c2ccc(Cl)cc12
Temperature: 25 °C
Yield: 20.2 %

Procedure:
To a microwave vial was added 4-chloro-2-formylphenylboronic acid (480 mg, 2.6 mmol), 2-(2-bromo-5-chlorophenyl)acetonitrile (500 mg, 2 mmol), tetrakis(triphenyl phosphine)palladium (0) (100 mg, 0.085 mmol) and cesium carbonate (2.12 g, 6.5 mmol) sequentially. The mixture was suspended in toluene (10 mL) and methanol (5 mL). Then the reaction vial was sealed and place in a microwave reactor and irradiated at 150° C. for 10 minutes. The reaction was cooled to room temperature, diluted with ethyl acetate, and filtered through a short celite pad. The solution was concentrated. The crude residue was purified by flash chromatography to yield 2,7-dichlorophenanthrene-9-carbonitrile (110 mg, 19%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:11])[CH:9]=O)=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[C:15]([NH:18][CH:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:17])[CH3:16].C[O-].[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1C=CC=CC=1>[CH2:23]([O:22][C:20]([C:19]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[N+:12]([O-:14])=[O:13])=[CH:11][N:18]1[C:15](=[O:17])[CH3:16])=[O:21])[CH3:24]
Reactant: C=C(C=O)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C1(C(=O)OCC)CC(c2ccc(Cl)cc2[N+](=O)[O-])=CN1C(C)=O
Reaction time: 0.5 h

Procedure:
A solution of 143.0 g (0.676 mol) of 2-(4-chloro-2-nitrophenyl) acrolein in 600 ml. of benzene was added over 1.5 hour to a stirred suspension of 148.5 g (0.684 mol) of diethyl acetamidomalonate and 0.80 g of sodium methoxide in 600 ml. of benzene. The Michael addition was complete after 30 minutes. 3.8 g of p-toluenesulfonic acid monohydrate was added and the mixture was heated at reflux for 40 minutes with constant removal of the water formed. The reaction mixture was washed with saturated sodium bicarbonate and brine. After drying with anhydrous NaSO4, the orange solution was concentrated to yield 278.5 g, m.p. 90°-95°. Crystallization from ethanol (500 ml) gave 264.6 g (95%) of deep yellow crystals, m.p. 96°-98°. A sample was recrystallized again from ethanol: m.p. 96.5°-98°.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[CH:20]([C:22]1[NH:26][C:25]([CH3:27])=[C:24]([C:28]([OH:30])=O)[C:23]=1[CH3:31])=[O:21].ON1C2C=CC=CC=2N=N1.[CH3:42][N:43]([CH3:51])[C:44]1[CH:49]=[CH:48][C:47]([NH2:50])=[CH:46][CH:45]=1>O.CN(C=O)C>[CH3:42][N:43]([CH3:51])[C:44]1[CH:49]=[CH:48][C:47]([NH:50][C:28]([C:24]2[C:23]([CH3:31])=[C:22]([CH:20]=[O:21])[NH:26][C:25]=2[CH3:27])=[O:30])=[CH:46][CH:45]=1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Reactant: CN(C)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1[nH]c(C=O)c(C)c1C(=O)Nc1ccc(N(C)C)cc1
Temperature: 0 °C
Yield: 60 %

Procedure:
1-Ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.074 g, 5.6 mmol), triethylamine (1.12 mL, 8 mmol), 5-formyl-2,4-dimethyl-1H-pyrrole-3-formic acid (0.668 g, 4 mmol) and 1-hydroxybenzotriazole (0.756 g, 5.6 mmol) were added to DMF (10 mL) with stirring at about 0° C. and stirred for 1.5 hrs, then N,N-dimethyl-p-phenylenediamine (1.09 g, 8 mmol) was added. The reaction was stirred at room temperature until completion was indicated by thin layer chromatography (TLC). 1.2 mL of water and 1 mL of saturated salt water were added, and the mixture was extracted with 10% methanol/dichloromethane (25 mL×3), the combined organic phase was washed with saturated salt water (30 mL×3), dried over anhydrous Na2SO4, and the solvent was distilled off under reduced pressure. The residue was then chromatographed (silica gel column chromatography, eluent: methanol:ethyl acetate=1:2) to give 0.682 g (2.4 mmol) of N-[4-(dimethylamino) phenyl]-5-formyl-2,4-dimethyl-1H-pyrrole-3-formamide. Yield 59.9%. 1HNMR (DMSO-d6) δ 10.92 (s, br, 1H, NH), 9.64 (s, 9.34 (s, br, 1H, NH), 7.54-7.52 (d, 2H), 6.77-6.74 (d, 2H), 3.38-2.58 (s, 6H), 2.58-2.56 (m, 3H), 2.55-2.41), (m, 3H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[C:4]([CH3:10])[CH:3]=1.O.O[N:13]1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.[CH2:32]([O:34][C:35](=[O:45])[C@H:36]([CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[NH2:37])[CH3:33].Cl.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH2:32]([O:34][C:35](=[O:45])[C@:36]([NH:13][C:7]([C:5]1[S:6][C:2]([Br:1])=[CH:3][C:4]=1[CH3:10])=[O:9])([CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[NH2:37])[CH3:33]
Reactant: Cc1cc(Br)sc1C(=O)O
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)CC[C@@](N)(NC(=O)c1sc(Br)cc1C)C(=O)OCC
Reaction time: 18 h
Yield: 95.2 %

Procedure:
To a stirred solution of 10.86 g (49.1 mmol) of 5-Bromo-3-methyl-thiophene-2-carboxylic acid (prepared according to D. Spinelli, JCS Perkin Trans. II, 1972, 1866), 6.97 g (51.6 mmol) of 1-Hydroxybenzotriazole hydrate, 9.0 mL (51.7 mmol) of diisopropylethylamine and 12.36 g (51.6 mmol) of L-glutamic acid diethyl ester hydrochloride in 70 mL of DMF was added 9.89 g (51.6 mmol) of 1-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride. The reaction mixture was stirred under Argon for 18 hours, poured into H2O and extracted with ethyl acetate. The organic layer was washed sequentially with 0.5N HCl, saturated NaHCO3 soln and saturated NaCl soln, dried over MgSO4, then concentrated under reduced pressure. This residue was purified by flash chromatography on silica gel eluting methylene chloride-ethyl acetate (20:1). In this manner, there was obtained 19.70 g (99%) of the desired product as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([F:18])[C:12]=2[Cl:19])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22].[CH2:26](N(CC)CC)C.O>CN(C)C=O.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.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:20][Si:21]([C:24]#[C:25][C:2]1[CH:3]=[C:4]([O:9][CH:10]([C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([F:18])[C:12]=2[Cl:19])[CH3:26])[C:5]([NH2:8])=[N:6][CH:7]=1)([CH3:23])[CH3:22]
Reactant: C#C[Si](C)(C)C
Reactant: CCN(CC)CC
Reactant: Nc1ncc(Br)cc1OCc1c(Cl)ccc(F)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(Oc1cc(C#C[Si](C)(C)C)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 90 °C
Reaction time: 4.5 h
Yield: 62.9 %

Procedure:
5-bromo-3-(2,6-dichloro-3-fluoro-benzyloxy)-pyridine-2-amine (3.8 g, 10 mmol), trimethylsilylethyne (3.87 mL, 28 mmol), triethylamine (Et3N, 4.15 mL, 30 mmol), triphenylphosphine (PPh3, 52 mg, 0.2 mmol) and bis(triphenylphosphine)palladium dichloride (PdCl2(PPh3)2, 140.3 mg, 0.2 mmol) was dissolved in N,N-dimethyl formamide (DMF, 10 mL), to which argon gas was bubbled for 10 min, then CuI (19 mg, 0.1 mmol) was added, the resultant reaction liquid was stirred under heating at 90° C. After 4.5 h, the reaction liquid was cooled to room temperature, water (10 mL) was added to quench the reaction. The resultant mixture was extracted with ethyl acetate (3×20 mL), the organic phases were combined, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and then concentrated, the resultant residue was purified via silica gel column chromatography (PE/EA=3:1) to yield 2.5 g of the target product as brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[CH2:13][CH2:12][C:11]2=[O:16])=[CH:4][CH:3]=1.C[O:18][C:19]([C:21]1[C:26]([C:27](OC)=[O:28])=[CH:25][CH:24]=[CH:23][N:22]=1)=O.[H-].[Na+].Cl>O1CCCC1.C(OCC)C.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[C:13]3[C:19]([OH:18])=[C:21]4[C:26]([CH:25]=[CH:24][CH:23]=[N:22]4)=[C:27]([OH:28])[C:12]=3[C:11]2=[O:16])=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccnc1C(=O)OC
Reactant: O=C1CCC(=O)N1CCc1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: C1CCOC1
Product: O=C1c2c(c(O)c3ncccc3c2O)C(=O)N1CCc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To 1-[2-(4-Fluoro-phenyl)-ethyl]-pyrrolidine-2,5-dione 309 (270 mg, 1.22 mmol and pyridine-2,3-dicarboxylic acid dimethyl ester (261.6 mg, 1.34 mmol) dissolved in tetrahydrofuran (12.0 ml) and methanol (1.4 ml) was added a 60% dispersion of sodium hydride in mineral oil (108 mg, 2.7 mmol). The reaction mixture was warmed to 80° C. and kept at 80° C. with stirring overnight. The reaction mixture was then placed in an ice bath and titrated to a pH of 4 with 1 M HCl. Two hundred (200) ml of diethylether was then added and the resulting yellow solid was collected by filtration. The solid was washed twice with ether, twice with water, and dried under high vacuum with heating to provide 7-[2-(4-fluoro-phenyl)-ethyl]-5,9-dihydroxy-pyrrolo[3,4-g]quinoline-6,8-dione 310 (250 mg, 0.71 mmol, 58%). 1H NMR (d-DMSO) δ 10.7 (broad, 1H), 8.98 (dd, 1H), 8.66 (dd, 1H), 7.73 (m, 1H), 7.18 (m, 2H), 7.04 (t, 2H), 3.72 (t, 2H), 2.86 (t, 2H). MS: 353.1 (M+1).
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH2:34][C@@H:35]([OH:37])[CH3:36])[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:21][C:22]4[CH:23]=[C:24]([N:28]5[CH2:29][CH2:30][N:31]([CH2:34][C@@H:35]([OH:37])[CH3:36])[CH2:32][CH2:33]5)[CH:25]=[CH:26][CH:27]=4)[N:20]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Reactant: C[C@H](O)CN1CCN(c2cccc(N)c2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: C[C@H](O)CN1CCN(c2cccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)c2)CC1

Procedure:
(S)-1-(4-{3-[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperazin-1-yl)-propan-2-ol was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (100.0 mg, 0.3249 mmol) and (S)-1-[4-(3-Amino-phenyl)-piperazin-1-yl]-propan-2-ol (84.0 mg, 0.357 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (36.0 mg, 0.0658 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.085 g, 51%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49 (d, J=6.6 Hz, 1H), 8.25 (d, J=8.4 Hz, 2H), 8.08 (d, J=8.4 Hz, 2H), 7.66 (d, J=7.3 Hz, 1H), 7.40 (s, 1H), 7.23 (t, J=8.2 Hz, 1H), 7.02 (t, J=7.1 Hz, 1H), 6.98-6.95 (m, 1H), 6.87 (s, 1H), 6.61-6.57 (m, 1H), 3.97-3.87 (m, 1H), 3.33-3.21 (m, 5H), 3.10 (s, 3H), 2.90-2.82 (m, 2H), 2.62-2.55 (m 2H), 2.43-2.30 (m, 2H), 1.17 (d, J=6.1 Hz, 3H). MS=507 (MH)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:22][CH2:23][CH:24]([CH2:27][O:28][C:29]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:25][OH:26])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>N1C=CC=CC=1>[CH2:6]([O:22][CH2:23][CH:24]([CH2:25][O:26][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:27][O:28][C:29]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCCCCCCCCCOCC(CO)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)COS(C)(=O)=O
Temperature: 0 °C
Yield: 99.3 %

Procedure:
Methanesulfonylchloride (0.752 g, 6.57 mmol) was added to a solution of 4 (3.00 g, 5.26 mmol) in dry pyridine (15 ml). After 3 hours the solution was poured into ice water and the product was extracted 3 times with hexane. The hexane extracts were washed with cold 1M H saturated NaHCO3 and water, and dried over Na2SO4 and concentrated. Chromatography on silica gel using hexane-CH2Cl2 (1:1 v/v) afforded 3.40 g (99%) the title compound (9) as a waxy solid, m.p. 39°. NMR (CDCl3, (CH3)4Si); δ0.90 (t, 3H, J=6 Hz, --CH3), 1.25 (s, 26H, --CH2 --), 1.52 (m, 2H, OCH2CH2R), 2.28 (m, 1H, CH), 2.84 (s, 3H, --CH3), 3.19, 3.21 (ABX, 2H, JAB = 10 Hz, /JAX +JBX /=8 Hz, CH2OTr, 3.35 (t, 2H, J=6.5 Hz, --OCH2R), 3.48 (d, 2H, J=6 Hz, CH2OR), 4.39 (d, 2H, J=6 Hz, CH2OMs).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1.FC(F)(F)[C:14]([O-])=[O:15].FC(F)(F)C(O)=O.[O-2].[Mg+2]>[Pd](Cl)Cl.CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:14](=[O:15])[O:9][CH2:8][C:4]=2[C:3]=1[O:10][CH3:11]
Reactant: O=C([O-])C(F)(F)F
Reactant: COc1c(Br)cccc1CO
Agent: Cl[Pd]Cl
Agent: [Mg+2]
Agent: [O-2]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1c(Br)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a flask charged with (3-bromo-2-methoxyphenyl)methanol (3.0 g, 14 mmol, 1.0 eq) was added thallic trifluoroacetate (10.0 g, 18.4 mmol, 1.3 eq). To above mixture was added trifluoroacetic acid (25 mL). The reaction was stirred at r.t. for 16 hr, then concentrated. The excess TFA was removed using high vacuum pump. To the residue was added palladium chloride (245 mg, 1.38 mmol, 0.1 eq), magnesium oxide (1.10 g, 27.6 mmol, 2.0 eq) and methanol (35 mL). The reaction was flushed with carbon monoxide three times and stirred under CO at r.t. for 2 hr. To this solution was added ethyl acetate. The mixture was filtered through a pad of celite and washed with EtOAc. The filtrate was concentrated and loaded on silica gel column. The fractions containing 5-bromo-4-methoxy-2-benzofuran-1(3H)-one were concentrated. 1H NMR (500 MHz, CDCl3, δ in ppm): 7.72 (1H, aromatic, d, J=8.0 Hz), 7.49 (1H, aromatic, d, J=8.0 Hz), 5.44 (2H, s, CH2 lactone), 4.00 (3H, s, Me). LC-MS (IE, m/z): 244.88 [M+1]+; tR=2.67 min.