Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH3:10][O:11][C:12](=[O:16])[C:13]#[C:14][CH3:15].N12CCCN=C1CCCCC2>O1CCCC1>[CH3:10][O:11][C:12](=[O:16])/[CH:13]=[C:14](/[O:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1)\[CH3:15]
Reactant: CC#CC(=O)OC
Reactant: N#Cc1cccc(O)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COC(=O)/C=C(\C)Oc1cccc(C#N)c1
Yield: 75.6 %

Procedure:
To a stirred mixture of 3-hydroxy-benzonitrile (3.30 g, 0.028 mol) and methyl-2-butynoate (5.40 g, 0.055 mol) in tetrahydrofuran (50 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (4.20 g, 0.028 mol) slowly. After addition was complete the mixture was stirred at reflux for 6 h. Upon completion of the reaction the tetrahydrofuran was removed in vacuo and the residue was diluted in diethyl ether and washed first with 1N aqueous hydrochloric acid, then 10% aqueous sodium hydroxide solution, a saturated sodium chloride solution and dried over magnesium sulfate. The mixture was filtered and evaporated and the residue dried under high vacuum which afforded (E)-3-(3-cyano-phenoxy)-but-2-enoic acid methyl ester as an oil (4.60 g, 76%) and used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:42])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([I:30])[CH:27]=[CH:26][C:25]=3[O:31][CH:32]3[CH2:37][CH2:36][N:35]([CH2:38][C:39](O)=[O:40])[CH2:34][CH2:33]3)[C:5]2=[CH:4][CH:3]=1.CC[N:45]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[NH4+].[Cl-]>CN(C)C=O>[C:39]([CH2:38][N:35]1[CH2:36][CH2:37][CH:32]([O:31][C:25]2[CH:26]=[CH:27][C:28]([I:30])=[CH:29][C:24]=2[CH:11]2[C:10]3([C:5]4[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:9]3=[O:42])[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH2:14][C:13](=[O:23])[NH:12]2)[CH2:33][CH2:34]1)(=[O:40])[NH2:45]
Reactant: O=C(O)CN1CCC(Oc2ccc(I)cc2C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)CC1
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)CN1CCC(Oc2ccc(I)cc2C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)CC1
Temperature: 80 °C

Procedure:
To a solution of racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(1-hydroxycarbonylmethyl-4-piperidinyloxy)-5-iodo-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (50 mg, 0.069 mmol) in anhydrous N,N-dimethylformamide (2 mL) was added EDCI (26.5 mg, 0.139 mmol), HOBT (18.8 mg, 0.139 mmol), diisopropylethylamine (35.9 mg, 0.278 mmol), NH4Cl (7.4 mg, 0.278 mmol). The reaction mixture was heated at 80° C. for 1 h, then cooled to room temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (MeOH:EtOAc=8:92) to give racemic(2′R, 3R, 4′S)-2′-[2-(1-carbamoylmethyl-4-piperidinyloxy)-5-iodo-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off white solid (Yield 25.6 mg, 51%)
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[S:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1>CC(O)=O>[Br:1][C:5]1[CH:6]=[C:7]([C:9]([OH:11])=[O:10])[S:8][C:4]=1[Cl:3]
Reactant: BrBr
Reactant: O=C(O)c1ccc(Cl)s1
Solvent: CC(=O)O
Product: O=C(O)c1cc(Br)c(Cl)s1
Reaction time: 168 h

Procedure:
A solution of bromine (634 uL, 12.3 mmol) in AcOH (2.5 mL) was added dropwise to 5-chloro-2-thiophenecarboxylic acid (2 g, 12.3 mmol) and FeCl3 (399 mg, 2.50 mmol) in AcOH (25 mL) at 25° C. The reaction mixture was warmed to reflux where additional bromine (634 uL, 12.3 mmol) and FeCl3 (399 mg, 2.50 mmol) were added. After 7 d, the solution was poured onto ice and the precipitate was filtered and washed with water affording the title compound (3 g, quant.) as a yellow powder: LCMS (ES) m/z 242 (M+H)+.
Reaction SMILES: [CH2:1]1N2CCN(CC2)C1.[CH3:9][C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:33]=3[NH:32][CH:31]=[C:30]4[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])[N:21]=2)[CH:13]=[N:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18]>C(=O)(OC)OC.CN(C=O)C>[CH3:1][N:32]1[C:33]2[C:29](=[CH:28][CH:27]=[CH:26][C:25]=2[C:22]2[N:21]=[C:20]([C:12]3[CH:13]=[N:14][C:15]([O:16][CH:17]([CH3:19])[CH3:18])=[C:10]([CH3:9])[CH:11]=3)[O:24][N:23]=2)[C:30]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:31]1
Reactant: C1CN2CCN1CC2
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4cnc(OC(C)C)c(C)c4)n3)cccc12
Solvent: COC(=O)OC
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc(-c3cccc4c(CCC(=O)O)cn(C)c34)no2)cnc1OC(C)C
Temperature: 70 °C
Yield: 25.3 %

Procedure:
DABCO (20 mg) was added to a solution of ethyl 3-[7-(5-{5-methyl-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D119) (188 mg) in dimethyl carbonate (2 mL) and DMF (0.2 mL). The resulting mixture was stirred at reflux for 1 day. After cooling, the reaction was quenched with water, and extracted with EtOAc for 3 times. The combined organic solution was washed with brine, dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was dissolved in iPrOH (8 mL) and water (8 mL). Sodium hydroxide (40 mg) was added to the mixture. The resulting mixture was heated at 70° C. for 30 mins. Then 0.5 M HCl solution was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[1-methyl-7-(5-{5-methyl-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E17) (19 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.35 (6H, d), 2.23 (3H, s), 2.60 (2H, t), 2.96 (2H, t), 3.62 (3H, s), 5.40 (1H, m), 7.16 (1H, d), 7.19 (1H, s), 7.43 (1H, d), 7.79 (1H, d), 8.29 (1H, s), 8.84 (1H, d), 12.12 (1H, br s). MS (ES): C23H24N4O4 requires 420; found 421.2 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH:4]=[C:3]1[CH:12]=O.[C:14]([CH2:16]C(O)=O)#[N:15]>N1C=CC=CC=1>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH:4]=[C:3]1/[CH:12]=[CH:16]/[C:14]#[N:15]
Reactant: N#CCC(=O)O
Reactant: O=Cc1coc2ccccc2c1=O
Solvent: c1ccncc1
Product: N#C/C=C/c1coc2ccccc2c1=O
Temperature: 110 °C

Procedure:
A mixture of 10.44 parts of 4-oxo-4H-1-benzopyran-3- carboxaldehyde and 5.4 parts of cyanoacetic acid are heated in an oil bath at 110° C., and to the mixture 25 volume parts of pyridine are added dropwise over about 30 seconds, after which time the whole mixture is further heated for 8 minutes. After cooling, the separated crystals are recovered by filtration, treated with activated carbon and recrystallized three times from ethanol. This procedure yields trans-3-(4-oxo-4H-1-benzopyran-3-yl)-acrylonitrile as pale-yellowish prisms. Melting point: 192°-194° C.
Reaction SMILES: [OH-:1].[Na+].ClC(Cl)(Cl)[C:5]1[CH:10]=[CH:9][N:8]2[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=[C:7]2[N:6]=1>C(#N)C>[N:6]1[C:7]2[N:8]([C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:9]=[CH:10][C:5]=1[OH:1]
Reactant: ClC(Cl)(Cl)c1ccn2c(n1)nc1ccccc12
Reactant: [OH-]
Agent: [Na+]
Solvent: CC#N
Product: Oc1ccn2c(n1)nc1ccccc12
Yield: 100 %

Procedure:
Sodium hydroxide (36.5 ml, 36.5 mmol) was added to a solution containing 2-(trichloromethyl)-benzo[4,5]imidazo[1,2-a]pyrimidine (8.04 g, 28.1 mmol) in Acetonitrile (Volume: 122 ml). Heated the reaction to 90 C for 30 minutes. Cooled the reaction to room temperature and concentrated. Added ice to the resulting residue, followed by 35 mL of 1M HCl. Filtered the solid and dried under vacuum to afford crude benzo[4,5]imidazo[1,2-a]pyrimidin-2-ol (5.2 g, 28.1 mmol, 100% yield).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.[N+:11]([C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([N+]([O-])=O)[C:15]=1[C:16]#[N:17])([O-:13])=[O:12]>>[C:16]([C:15]1[C:14]([N+:11]([O-:13])=[O:12])=[CH:21][CH:20]=[CH:19][C:18]=1[O:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1)#[N:17]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: O=C(O)C1CCC(O)CC1
Product: N#Cc1c(OC2CCC(C(=O)O)CC2)cccc1[N+](=O)[O-]

Procedure:
Prepared as in Example Ed from 4-hydroxycyclohexanecarboxylic acid and 2,6-dinitrobenzonitrile as a brown solid (50%). MS 291 (MH+).
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:22]=[CH:23][CH:24]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=3)=[O:31])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(Cn2ncc(N)n2)o1
Reactant: COc1cccc(-c2ocnc2C(=O)O)c1
Product: COc1cccc(-c2ocnc2C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)n2)c1

Procedure:
Following general procedure Z2, starting from 2-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-methoxy-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][C:10]3[C:17]4([CH3:20])[CH2:18][CH2:19][CH:14]([C:15]([CH3:22])([CH3:21])[O:16]4)[C:11]=3[N+:12]=2[O-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCCCC=1>[Pd].C(O)C>[C:1]1([C:7]2[N:8]=[N:9][C:10]3[C:17]4([CH3:20])[CH2:18][CH2:19][CH:14]([C:15]([CH3:22])([CH3:21])[O:16]4)[C:11]=3[N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC12CCC(c3c1nnc(-c1ccccc1)[n+]3[O-])C(C)(C)O2
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CC12CCC(c3nc(-c4ccccc4)nnc31)C(C)(C)O2

Procedure:
To a solution of 1.80 g. (0.006 mole) 3-phenyl-5,8-dihydro-6,6,8-trimethyl-5,8-ethano-6H-pyrano[4,3-e]-as-triazine-4-oxide and 1.50 g. (0.018 mole) cyclohexene in 30 ml. absolute ethanol there is added 60 mg. 10% palladium on charcoal. The resulting mixture is refluxed under a nitrogen atmosphere for 18 hours. The catalyst is then removed by filtration and the filtrate evaporated to give 3-phenyl-5,8-dihydro-6,6,8-trimethyl-5,8-ethano-6H-pyrano[4,3-e]-as-triazine; m.p. 180° to 189° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:14](Cl)([Cl:17])(=[O:16])=[O:15]>C(#N)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([Cl:17])(=[O:16])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: CC#N
Product: O=S(=O)(Cl)N1CCN(Cc2ccccc2)CC1
Yield: 88.8 %

Procedure:
A solution of 1-benzylpiperazine (20.0 g, 0.114 mol) in acetonitrile (45 ml) was added to a solution of sulphuryl chloride (28 ml, 0.346 mol) in acetonitrile (50 ml) and the mixture heated under reflux for 17 hours, then cooled. The solvent was removed by evaporation under vacuum, then the residue triturated with either (20×50 ml) to yield the title compound (27.8 g, 89%), which was used without further purification.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=3)[N:22]=[C:21]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:37][CH:36]=3)[N:20]=2)=[CH:15][CH:14]=1.Br[C:46]1[CH:47]=[CH:48][C:49]([C:52]2[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=2)=[N:50][CH:51]=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.O1CCCC1>[C:31]([C:28]1[CH:27]=[CH:26][C:25]([C:23]2[N:22]=[C:21]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([CH3:43])([CH3:44])[CH3:42])=[CH:37][CH:36]=3)[N:20]=[C:19]([C:16]3[CH:15]=[CH:14][C:13]([C:46]4[CH:47]=[CH:48][C:49]([C:52]5[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=5)=[N:50][CH:51]=4)=[CH:18][CH:17]=3)[N:24]=2)=[CH:30][CH:29]=1)([CH3:32])([CH3:33])[CH3:34]
Reactant: CC(C)(C)c1ccc(-c2nc(-c3ccc(Br)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Reactant: Brc1ccc(-c2ccncc2)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)c1ccc(-c2nc(-c3ccc(-c4ccc(-c5ccncc5)nc4)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 56.2 %

Procedure:
Under a stream of argon, 2.1 ml of a hexane solution containing 3.2 mmol of butyl lithium was slowly added to 50 ml of tetrahydrofuran cooled to −78° C. in which 1.50 g of 2-(4-bromophenyl)-4,6-bis(4-tert-butylphenyl)-1,3,5-triazine obtained in Reference Example 1 had been dissolved. After stirring at −78° C. for 15 minutes, 0.83 g of dichloro(tetramethylethylenediamine)zinc(II) was added thereto and stirred at −78° C. for 10 minutes and then at room temperature for 2 hours. A 30 ml portion of tetrahydrofuran prepared by dissolving 0.74 g of 5-bromo-2,4′-bipyridyl and 0.14 g of tetrakis(triphenylphosphine)palladium(0) therein was added to this solution and stirred under heating reflux for 13 hours. The reaction solution was concentrated under a reduced pressure and the thus obtained solid was purified by a silica gel column chromatography (eluting solution hexane:chloroform=2:1 to chloroform) and an alumina gel column chromatography (eluting solution hexane:chloroform=1:1) and then recrystallized from dichloromethane-methanol to obtain a white solid of the intended 5-{4-[4,6-bis(4-tert-butylphenyl)-1,3,5-triazin-2-yl]phenyl}-2,4′-bipyridyl (0.97 g, yield 56%). Its melting point is shown in Table 4. In this case, a distinct point of glass transition was not observed.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:12])[N:6]=[CH:7]2.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]=[C:22]=[O:23])=[CH:16][C:15]=1[Cl:24]>C1(C)C=CC=CC=1>[Cl:24][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:14]=1[Cl:13])[CH2:20][NH:21][C:22]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:12])[N:6]=[CH:7]2)=[O:23]
Reactant: O=C=NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1cc2c(N)cccc2cn1
Solvent: Cc1ccccc1
Product: Cc1cc2c(NC(=O)NCc3ccc(Cl)c(Cl)c3)cccc2cn1
Temperature: 25 °C

Procedure:
5-Amino-3-methylisoquinoline (390 mg, 2.47 mmol) and the product from Example 194A (0.36 mL, 2.45 mmol) were heated in toluene (10 mL) at 80° for 2.5 hours. Upon cooling to room temperature, a precipitate formed, which was collected by filtration, washed with toluene, and air-dried. Remaining impurities were removed by slurrying the solid in 9:1 CH2Cl2:CH3OH and then filtering the mixture to provide the title compound. The corresponding hydrochloride salt was formed by treatment of the free base with methanolic HCl. 1HNMR (300 MHz, DMSO-d6) 69.17 (s, 1H), 8.27 (s, 1H), 8.17 (dd, 1H, J=7.8 Hz, 1.0 Hz), 7.74 (s, 1H), 7.71 (d, 1H, J=8.1 Hz), 7.61 (m, 2H), 7.50 (t, 1H, J=8.0 Hz), 7.35 (dd, 1H, J=8.3 Hz, 2.2 Hz), 7.12 (t, 1H, 5.9 Hz), 4.37 (d, 2H, J=6.1 Hz), 2.65 (s, 3H); MS (ESI+) m/z 360/362 (M+H, 35Cl/37Cl).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].Br[C:14]1[CH:15]=[C:16]([O:20][CH3:21])[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[C:2]2[C:10]([OH:12])=[O:11])[CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: COc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(-n2c(C(=O)O)cc3ccccc32)c1
Temperature: 170 °C
Yield: 45.7 %

Procedure:
The starting ester is prepared in the following manner: A mixture of indole-2-carboxylic acid (8.06 g), m-bromoanisole (9.35 g), anhydrous potassium carbonate (7 g) and cupric oxide (0.25 g) in dimethylformamide (10 ml) is heated at 170° C. under nitrogen for 18 hrs., diluted with a further 20 ml of solvent and heated 6 hours longer. It is cooled, diluted with water (500 ml) and extracted with methylene chloride (3×100 ml). The filtered aqueous layer is acidified with cold concentrated hydrochloric acid, refrigerated overnight and the precipitated product recrystallized from methanol to afford pure 1-(3-methoxypheny)indole-2-carboxylic acid (6.1 g), mp. 194°-196°. This acid (3.3 g) absolute ethanol (100 ml) and concentrated sulphuric acid (1.1 ml) are refluxed overnight, cooled, treated with water (50 ml) and the ethyl ester crystallizes. The crude ester (34 g) in trifluoroacetic acid (280 ml) is reduced with sodium borohydride (17.3 g) as described in Example 5 to afford ethyl 2,3-dihydro-1-(3-methoxyphenyl)indole-2-carboxylate as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[OH:37][CH2:38][CH2:39][N:40]1C2=C3C(=CC=C2[CH:42]=[N:41]1)C(=O)C(I)=C(C1C=CC=CC=1)O3.OCCN1N=C2C3OC(C4C=CC=CC=4)=C(I)C(=O)C=3C=CC2=C1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21]([O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:22]3[N:40]([CH2:39][CH2:38][OH:37])[N:41]=[CH:42][C:23]3=[CH:24][CH:25]=4)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: O=c1c(I)c(-c2ccccc2)oc2c1ccc1cnn(CCO)c12
Agent: O=c1c(I)c(-c2ccccc2)oc2c1ccc1cn(CCO)nc12
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5cnn(CCO)c54)c3=O)cc2)CCC1
Yield: 37 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, the crude mixture of 1-(2-hydroxy-ethyl)-7-iodo-8-phenyl-1H-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-6-one and 2-(2-hydroxy-ethyl)-7-iodo-8-phenyl-2H-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-6-one was reacted to give (1-{4-[1-(2-hydroxy-ethyl)-6-oxo-8-phenyl-1,6-dihydro-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-7-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester (53.3 mg, 37%), LCMS (Method H): RT=3.86 min, [M+H]+=552, as the earlier eluted compound and (1-{4-[2-(2-hydroxy-ethyl)-6-oxo-8-phenyl-2,6-dihydro-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-7-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester (57.1 mg, 40%), LCMS (Method H): RT=3.68 min, [M+H]+=552, as the later eluted compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.C([Li])CCC.[O:20]1[CH2:24][CH2:23]OS1(=O)=O.Cl>C1COCC1>[Cl:8][C:6]1[C:7]([CH2:23][CH2:24][OH:20])=[C:2]([Cl:1])[N:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:5]=1
Reactant: Clc1cc(Cl)nc(N2CCOCC2)n1
Reactant: O=S1(=O)OCCO1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OCCc1c(Cl)nc(N2CCOCC2)nc1Cl
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
To a solution of 4-(4,6-dichloropyrimidin-2-yl)morpholine (468 mg, 2.0 mmol) in THF (20 mL) was added n-butyllithium (1.56 mL, 1.6 M) dropwise at −78° C. After stirring for 30 min, 1,3,2-dioxathiolane 2,2-dioxide (336 mg, 2.71 mmol) was added, and after stirring for an additional 40 min, 6 N HCl (6.67 mL) was added. The reaction was stirred at room temperature for 18 h and then at 40° C. for 4 h. The reaction mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried with MgSO4, filtered and concentrated by rotary evaporation. The resulting residue was purified by silica gel chromatography using a gradient of EtOAc/heptane (25-75%) to give the title compound (231 mg, 42%). 1H NMR (400 MHz, CDCl3) δ 3.84 (t, J=7.0 Hz, 2 H), 3.80-3.76 (m, 4 H), 3.76-3.72 (m, 4 H), 3.04 (t, J=7.0 Hz, 2 H). m/z (APCI+) for C10H13Cl2N3O2 277.9 (M+H)+.
Reaction SMILES: C([N:3](CC)CC)C.[C:8](Cl)(=[O:18])[C:9]1[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:11](Cl)=[O:12]>CN(C1C=CN=CC=1)C.ClCCl.C(OCC)(=O)C>[C:8]1(=[O:18])[NH:3][C:11](=[O:12])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1NC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of MCH17-1 (520 mg), triethyl amine (0.82 mL) and DMAP (24 mg) in 10 mL dichloromethane at 0° C. was added phthaloyl chloride (0.36 mL). The mixture was stirred overnight at rt, diluted with ethyl acetate and washed with 1N HCl, aq. NaHCO3 and brine. It was dried over anhydrous MgSO4, filtered, concentrated and purified by chromatography eluting with 0% to 50% ethyl acetate in hexane to provide 338 mg of phthalimide protected intermediate which was stirred with 5 mL of trifluoroacetic acid at rt for 40 min. The reaction mixture was evaporated to dryness, the residue was suspended in aq. NaHCO3 and extracted 3× with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated to dryness to obtain 220 mg MCH 17-2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:25][O:26]S(C)(=O)=O)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O[C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:25][O:26][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)CCCCCNC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c1ccc(Cl)cc1
Reactant: Oc1cccnc1
Product: COC(=O)CCCCCNC(=O)C(COc1cccnc1)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The procedure described in Example 105 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(5-methoxycarbonylpentyl)propanamide (95.4 mg) was reacted with 3-hydroxypyridine to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(5-methoxycarbonylpentyl)-3-(pyridin-3-yloxy)propanamide (91.3 mg).
Reaction SMILES: C(=N[C@H](C)C(C1C=CC=CC=1)(C1C=CC=CC=1)O)C1C(=CC=CC=1)O.[CH3:26][C:27](=[CH:29][CH:30]=[C:31]([CH3:33])[CH3:32])[CH3:28].C1(NN)C=CC=CC=1.[N+](=[CH:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])=[N-]>O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:49][CH2:48][O:47][C:45]([CH:44]1[C:31]([CH3:33])([CH3:32])[CH:30]1[CH:29]=[C:27]([CH3:28])[CH3:26])=[O:46]
Reactant: CC(C)=CC=C(C)C
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: C[C@@H](N=Cc1ccccc1O)C(O)(c1ccccc1)c1ccccc1
Solvent: NNc1ccccc1
Solvent: O
Product: CCOC(=O)C1C(C=C(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
19.64 mg (0.05 mmol) of a copper complex prepared from 9.98 mg (0.05 mmol) of copper acetate monohydrate and 18.23 mg (0.055 mmol) of (R)-N-salicylidene-2-amino-1,1-diphenylpropanol, and 6.09 (55 mmol) of 2,5-dimethyl-2,4-hexadiene were charged in a 50 ml Schlenk's tube wherein the atmosphere is substituted with nitrogen. After 5.4 mg of phenylhydrazine was further added, 1.14 g (10 mmol) of ethyl diazoacetate was added dropwise at 50° C. over 2 hours. After the completion of the dropwise addition of ethyl diazoacetate, the mixture was further stirred at 25° C. for 1 hour. The amount of chrysanthemic acid ethyl ester formed was determined by gas chromatography. As a result, it was 1.52 g and the yield was 77.7% based on ethyl diazoacetate and, furthermore, the trans/cis ratio was 61/39. After 2,5dimethyl-2,4-hexadiene (boiling point: 51° C./30 mmHg) was distilled off from the reaction mixture, 1 g of the concentrated solution was taken out. Then, 10 ml of an aqueous 1N sodium hydroxide solution and 5 ml of ethanol were added and alkali hydrolysis was performed by stirring at 100° C. for 1 hour. The resulting chrysanthemic acid was reacted with 1-menthol and the formed diastereomer ester was analyzed by gas chromatography. As a result, the optical purity of the (+)-trans isomer was 69% e.e., whereas, the optical purity of the (+)-cis isomer was 68% e.e.