Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:47])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4].[C:48]([NH:58][C@H:59]([C:64](O)=[O:65])[CH2:60][CH:61]([CH3:63])[CH3:62])([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49]>>[C:48]([NH:58][C@H:59]([C:64]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:47])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4])=[O:65])[CH2:60][CH:61]([CH3:62])[CH3:63])([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCCCCCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Product: CCCCCCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-octadecyl-dodecanamide and N-carbobenzoxy-L-leucine.
Reaction SMILES: [Cl:1][C:2]1(O)[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][NH:3]1.[F:10][C:11]1[CH:12]=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=[CH:15][C:16]=1F.C(=O)([O-])[O-:22].[Li+].[Li+].Cl>O.CO.CS(C)=O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:22][C:16]2[CH:15]=[CH:14][C:13]([N+:18]([O-:20])=[O:19])=[CH:12][C:11]=2[F:10])[CH:5]=[CH:4][N:3]=1
Reactant: OC1(Cl)NC=CC=C1Cl
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: Cl
Agent: [Li+]
Solvent: CS(C)=O
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2Cl)c(F)c1
Temperature: 115 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
To a 2-L Chem-Glass reactor was added 2,3-dichloropyridinol (90 g, 0.55 mol), 3,4-difluoronitrobenzene (100 g, 0.63 mol), lithium carbonate (59.4 g, 0.80 mol) and dimethyl sulfoxide (360 mL). The mixture was heated to 115° C. for 21 hrs, until the reaction was deemed complete by HPLC analysis. The mixture was cooled to 25° C. and methanol (180 mL) was added, followed by water (960 mL). The mixture was neutralized by addition of conc. HCl (60 g) and the resulting slurry was stirred at 35° C. for 1 h. After cooling to 28° C., the slurry was filtered on a Buechner funnel and the filter cake was washed with water (four times 250 mL). The crude cake was then suspended in methanol (20 mL) and water (250 mL), and the resulting mixture was stirred for 20 min at 45° C. After cooling to 25° C., the slurry was filtered. The resulting cake washed with heptane (two times 75 mL) and dried under vacuum to yield 164.68 g (99%) of 2,3-dichloro-4-(2-fluoro-4-nitrophenoxy)pyridine as yellow solid.
Reaction SMILES: Cl.[N:2]1([C:7]2[CH:18]=[CH:17][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:9][CH:8]=2)[CH:6]=[N:5][N:4]=[N:3]1.[OH-].[Na+].[Br:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>O.C(OCC)C>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:9]=[CH:8][C:7]([N:2]3[CH:6]=[N:5][N:4]=[N:3]3)=[CH:18][CH:17]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: NCCCCOc1ccc(-n2cnnn2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: O=S(=O)(NCCCCOc1ccc(-n2cnnn2)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 2.7 g of 4-[4-(1H-tetrazol-1-yl)phenoxy]butaneamine hydrochloride (Example 39) in 100 ml of water is treated successively with 3.5 ml of 10N NaOH and a solution of 2.7 g of 4-bromobenzenesulfonyl chloride in 100 ml of diethyl ether. The mixture is stirred at room temperature for 1.5 hours, the precipitate collected, washed with diethyl ether and water, and air dried. Recrystallization from ethanol gives the pure compound, m.p. 109°-110° C.; yield, 1.6 g.
Reaction SMILES: [NH2:1]C(N)=O.[F-].[Ce+3].[F-].[F-].[CH3:9][O:10][CH2:11][C@H:12]1[CH2:16][O:15][C:14](=O)[O:13]1>CS(C)=O>[CH3:9][O:10][CH2:11][C@@H:12]1[O:13][C:14](=[O:15])[NH:1][CH2:16]1
Reactant: COC[C@H]1COC(=O)O1
Reactant: NC(N)=O
Agent: [Ce+3]
Agent: [F-]
Solvent: CS(C)=O
Product: COC[C@H]1CNC(=O)O1
Temperature: 140 °C
Reaction time: 36 h
Yield: 82972.7 %

Procedure:
Urea (246 g, 4.09 mmol) was dissolved in dimethyl sulfoxide (2.27 L), and thereto were added cerium fluoride (69.0 g, 0.454 mol) and (S)-4-methoxymethyl-1,3-dioxolan-2-one (600 g, 4.54 mol, optical purity 98.9%ee), in order. The mixture was stirred for 36 hours at 140° C. under an atmosphere of argon. After filtering off the insoluble materials, the filtrate was condensed in vacuo, and the residue was purified by distillation to give the subject (R)-5-methoxymethyloxazolidin-2-one (445 g, yield 74.7%, optical purity 98.6%ee).
Reaction SMILES: [C:1]([CH:5]1CC2O[CH:6]1C=C2)(OC)=[O:2].[CH2:12]([NH2:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(Cl)(Cl)Cl.Cl>O>[CH2:12]([NH:30][C:1](=[O:2])[CH:5]=[CH2:6])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: COC(=O)C1CC2C=CC1O2
Reactant: CCCCCCCCCCCCCCCCCCN
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=CC(=O)NCCCCCCCCCCCCCCCCCC
Temperature: 60 °C
Reaction time: 15 h

Procedure:
7.2 parts 30% methanolic Na-methylate solution and 77 parts 2-carbomethoxy-7-oxabicyclo(2,2,1)hept-5-ene are added to 134.8 parts stearylamine. The reaction medium is heated to 60° C. and stirred for 15 hours at this temperature. 300 parts of chloroform are next added and the mixture neutralised with 4 parts concentrated hydrochloric acid. 100 parts of water are added, the organic phase is separated off, and the aqueous phase extracted with 50 parts chloroform. The combined organic phases are reduced in a rotary evaporator at a bath temperature of 90° C. under a vacuum of 20 Torr. The residue is heated in a vacuum to 110° to 120° C. (bath temperature 140° C.). At the conclusion of the furane separation, the sedimentation temperature increases to 140° C. The mixture is cooled down, the product is dissolved in hot acetone, filtered, and allowed to recrystallise. 117 parts N-stearylacrylamide having a melting point of 75° to 77° C. are obtained.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:42](O)[C:43]([CH3:46])([CH3:45])[CH3:44]>C1COCC1>[CH3:42][C:43]([CH3:46])([CH3:45])[CH2:44][O:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=1
Reactant: CC(C)(C)CO
Reactant: Cc1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(OCC(C)(C)C)cc1
Temperature: 60 °C

Procedure:
To a solution of p-cresol (526 mg, 4.87 mmol) in THF (50 mL), add with stirring diisopropyl azodicarboxylate (2.16 mL, 10.7 mmol) followed by triphenylphosphine (306 mg, 11.7 mmol) and neopentyl alcohol (5.15 g, 58.4 mmol). Heat at 60° C. for 3 h, cool to ambient temperature and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc to give the desired intermediate as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:15]C(=O)C(F)(F)F)=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[BH4-].[Na+].O>C(O)C>[NH2:15][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:14][C:6]=1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: Cc1ccc(NC(=O)C(F)(F)F)c(C(=O)OC(C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(N)c(C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a suspension of tert-butyl 5-methyl-2-(2,2,2-trifluoroacetamido)benzoate (19.78 mmol, 6.0 g) in ethanol (19 ml) was cooled with a water-iced bath. NaBH4 (39.57 mmol, 1.50 g) was added in portions and the mixture was stirred at room temperature for 3 hours. Water (40 ml) was added slowly and evaporated. The solid was dissolved with CHCl3 and washed with water and brine. The organic phase was evaporated affording 3.73 g (yield 91%) of the expected product.
Reaction SMILES: [Li]CCCC.CCCCCC.[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=2)[C:15]2[C:24]3[C:29]([CH2:30][C:14]1=2)=[CH:28][CH:27]=[CH:26][CH:25]=3.N1C2C(C=CC3C=2C=C2C=3C=CC=C2)=CC=1.[Cl:47][Si:48](Cl)([CH3:50])[CH3:49]>C1COCC1>[Cl:47][Si:48]([CH3:50])([CH3:49])[CH:30]1[C:14]2[N:13]([CH3:12])[C:21]3[C:16]([C:15]=2[C:24]2[C:29]1=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=3
Reactant: COc1ccc2c(c1)c1c(n2C)Cc2ccccc2-1
Reactant: C[Si](C)(Cl)Cl
Agent: C1=Nc2c3c(ccc2=C1)=c1ccccc1=C3
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c1c(n2C)C([Si](C)(C)Cl)c2ccccc2-1
Temperature: -78 °C
Reaction time: 5 h

Procedure:
3.4 mL of a 2.5 M solution of n-BuLi in hexane (8.50 mmol) were added dropwise to a solution of 2.22 g of N-methyl-2-methoxy-5,6-dihydroindeno[2,1-b]indole, obtained as reported above, (Mw=249.32, purity 85.8%, 7.64 mmol; indenoindole: n-BuLi=1:1.1) in 50 mL of THF, previously cooled to −78° C. At the end of the addition, the brown solution was allowed to warm up to room temperature and stirred for 5 hours. Then it was cooled again to −78° C. and added dropwise to a solution of dichlorodimethylsilane (Mw=129.06, d=1.064, 0.92 mL, 7.64 mmol; indenoindole: Me2SiCl2=1:1) in 20 mL of THF, previously cooled to −78° C. At the end of the addition, the dark brown solution was allowed to warm up to room temperature and stirred overnight. The solvents were evaporated under reduced pressure to give the desired product, containing few by-products, in the form of a brown sticky solid; this product was used in the following step without further purification.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][CH:8]2[N:13]3[C:14](=[O:30])[CH:15]([NH2:29])[CH2:16][N:17]([S:18]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])(=[O:20])=[O:19])[CH:12]3[CH2:11][N:10]([CH:31]([CH3:33])[CH3:32])[C:9]2=[O:34])=[CH:5][CH:4]=1.[CH2:37](O)[CH2:38][CH2:39][CH3:40].C(=O)([O-])[O-].[K+].[K+].BrCCCCBr>O>[Cl:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][CH:8]2[N:13]3[C:14](=[O:30])[CH:15]([N:29]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[CH2:16][N:17]([S:18]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])(=[O:20])=[O:19])[CH:12]3[CH2:11][N:10]([CH:31]([CH3:33])[CH3:32])[C:9]2=[O:34])=[CH:5][CH:4]=1
Reactant: CCCCO
Reactant: CC(C)N1CC2N(C(=O)C(N)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: BrCCCCBr
Solvent: O
Product: CC(C)N1CC2N(C(=O)C(N3CCCC3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Temperature: 90 °C
Reaction time: 16 h

Procedure:
32 mg of 6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-3-amino-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione hydrobromide (Example 2) were suspended in 1 ml of water, and 2 ml of 1-butanol were added. 1 mmol of potassium carbonate and 200 μl of 1,4-dibromobutane were added to this mixture. The reaction mixture was stirred at 90° C. for 16 hours and evaporated. The residue was suspended in 5% Et3N/ethyl acetate, filtered and evaporated. The pure title compound was removed after purification by HPLC. The system and process described under “general processes” was used for this. MW=612.11 (calculated, monoisotopic); measured value (M+H)+: 613.4.
Reaction SMILES: C(N1CCC(CO)CC1)(OC(C)(C)C)=O.OC1C=C(C(OC)=O)ON=1.[N].[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C([N:43](C(OCC1C=CC=CC=1)=O)[C:44](=[NH:47])SC)(OCC1C=CC=CC=1)=O>>[C:44]([N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)(=[NH:43])[NH2:47]
Reactant: CSC(=N)N(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: C1CCNCC1
Agent: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: COC(=O)c1cc(O)no1
Agent: [N]
Product: N=C(N)N1CCCCC1

Procedure:
Scheme XIXb outlines the synthesis of the analogous compounds where R1 is 4-(1-amidinopiperidinyl) instead of 4-amidinophenyl. After initial condensation of N-BOC-4-piperidinylcarbinol with methyl 3-hydroxyisoxazole-5-carboxylate under Mitsunobu conditions, the intermediate ester is saponified and condensed with a 1,3-diaminpropionate using conditions described above. The piperidine nitrogen is deprotected and treated with N,N,-diCBz-S-methylisothiourea to give a protected amidinopiperdine. Hydrogenation gives the amidinopiperidine compounds as the methyl esters. ##STR76##
Reaction SMILES: [NH4+:1].[Cl-].C[Al](C)C.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([CH2:19][C:20]#[N:21])[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2([CH2:19][C:20]([NH2:1])=[NH:21])[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:12][CH:13]=1
Reactant: [NH4+]
Reactant: N#CCC1(c2ccc(Br)cc2)CCCC1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: N=C(N)CC1(c2ccc(Br)cc2)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
To a suspension of NH4Cl (1.21 g, 43.65 mmol) in toluene (30 mL) was added dropwise a solution of trimethyl aluminium (1.64 g, 43.65 mmol, 2M in toluene) at 0° C. and stirred for 2 h at room temperature prior to the addition of a solution of [1-(4-bromophenyl)-cyclopentyl]-acetonitrile (228) (2.0 g, 7.57 mmol) in toluene (10 mL). The resulting solution was heated to 80° C. for 16 h. The cooled reaction mixture was poured into a slurry of silica gel (10 g) in CHCl3 (20 mL), followed by vigorous stirring for 30 min. The silica gel was filtered off and the cake was rinsed in turn with methanol. The solvent was evaporated and the crude product was taken up in 10% methanol in dichloromethane (200 mL) and stirred for 30 min. The solid suspension was removed by filtration and the filtrate was evaporated. The crude product was triturated in diethyl ether and the solid was collected by filtration and dried under vacuum to afford HCl-salt of 2-[1-(4-bromophenyl)-cyclopentyl]-acetamidine (229) (1.78 g, 74%) as a white solid.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:9]1[CH:14]=[N+:13]([C@@H:15]2[O:19][C@H:18]([CH2:20][O:21][P:22]([O:25][P:26]([O:29][CH2:30][C@H:31]3[O:35][C@@H:34]([N:36]4[C:40]5[N:41]=[CH:42][N:43]=[C:44]([NH2:45])[C:39]=5[N:38]=[CH:37]4)[C@H:33]([OH:46])[C@@H:32]3[OH:47])([OH:28])=[O:27])([O-:24])=[O:23])[C@@H:17]([OH:48])[C@H:16]2[OH:49])[CH:12]=[C:11]([C:50]([NH2:52])=[O:51])[CH:10]=1.[CH:53]([C:55]1[NH:56][CH:57]=[CH:58][N:59]=1)=[CH2:54].[CH2:60]([Cl:67])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>CN(C=O)C>[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:9]1[CH:14]=[N+:13]([C@@H:15]2[O:19][C@H:18]([CH2:20][O:21][P:22]([O:25][P:26]([O:29][CH2:30][C@H:31]3[O:35][C@@H:34]([N:36]4[C:40]5[N:41]=[CH:42][N:43]=[C:44]([NH2:45])[C:39]=5[N:38]=[CH:37]4)[C@H:33]([OH:46])[C@@H:32]3[OH:47])([OH:28])=[O:27])([O-:24])=[O:23])[C@@H:17]([OH:48])[C@H:16]2[OH:49])[CH:12]=[C:11]([C:50]([NH2:52])=[O:51])[CH:10]=1.[CH:53]([C:55]1[NH:56][CH:57]=[CH:58][N:59]=1)=[CH2:54].[CH:9]1[CH:14]=[N+:13]([C@@H:15]2[O:19][C@H:18]([CH2:20][O:21][P:22]([O:25][P:26]([O:29][CH2:30][C@H:31]3[O:35][C@@H:34]([N:36]4[C:40]5[N:41]=[CH:42][N:43]=[C:44]([NH2:45])[C:39]=5[N:38]=[CH:37]4)[C@H:33]([OH:46])[C@@H:32]3[OH:47])([OH:28])=[O:27])([O-:24])=[O:23])[C@@H:17]([OH:48])[C@H:16]2[OH:49])[CH:12]=[C:11]([C:50]([NH2:52])=[O:51])[CH:10]=1.[Cl-:67].[CH:34]([N+:36]1[CH:40]=[CH:39][N:38]([CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH:37]=1)=[CH2:33]
Reactant: ClCc1ccccc1
Agent: C=Cc1ncc[nH]1
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)([O-])OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Solvent: C=Cc1ccccc1
Solvent: CN(C)C=O
Product: C=C[n+]1ccn(Cc2ccccc2)c1
Product: [Cl-]
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A solution of 625 g of a 20.0 wt. % solution of styrene-co-1-vinylimidazole (50/50) in DMF was quaternized with benzyl chloride as described for the preparation of compound F-4, except that 15.9 g of benzyl chloride was used. Following heating and stirring at 100° C. for 18 hr the reaction mixture was cooled and the polymer precipitated into diethyl ether with rapid stirring. The flaky precipitate was washed well with diethyl ether and dried in a vacuum oven.
Reaction SMILES: [Br:1][C:2]1[CH:10]=C2[C:5]([CH:6]=[CH:7]N2)=[CH:4][CH:3]=1.[CH3:11][N+:12]([CH3:15])=CCl.[Cl-].[OH2:17].[OH-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:15]2[C:5]([C:6]([CH:7]=[O:17])=[CH:11][NH:12]2)=[CH:4][CH:3]=1
Reactant: O
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: C[N+](C)=CCl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=Cc1c[nH]c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-bromo-1H-indole (4 g, 20.4 mmol) in DMF (20 mL) was added Vilsmeier reagent (3.929 g, 30.6 mmol) portion-wise and the resulting mixture was stirred at rt overnight. After 45 minutes, water (100 mL) was added and the mixture was stirred at rt overnight. Water (50 mL) and 10M aqueous NaOH (10 mL) was added and the reaction was stirred at rt until a precipitate formed. The resulting solid was filtered and dried under high vacuum to give 6-bromo-1H-indole-3-carbaldehyde and used as crude for the next step. Mass Spectrum (ESI) m/e=225 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]([OH:13])=[O:12])[C:8]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].CI.[C:24](=O)([O-])O.[Na+].O>CN(C=O)C>[C:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]([O:13][CH3:24])=[O:12])[C:8]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(OCc2ccccc2)c(C(=O)O)n1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(NC(C)=O)ccc1OCc1ccccc1
Yield: 90 %

Procedure:
1.5 g (5.2 mmol) of the obtained 6-acetylamino-3-benzyloxypicolinic acid and 1.0 g (7 mmol) of methyl iodide were dissolved in 100 ml of DMF, and 20 ml of an aqueous solution of 0.53 g (6.3 mmol) of sodium hydrogen carbonate was added thereto. The mixture was reacted at 60° C. for 3 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The crystals thereby obtained was washed with diisopropyl ether to obtain methyl 6-acetylamino-3-benzyloxypicolinate.
Reaction SMILES: [Br:1][C@H:2]([CH2:6][OH:7])[C:3]([OH:5])=[O:4].[C:8](OC(=N)N(C(C)C)C(C)C)([CH3:11])([CH3:10])[CH3:9]>C(Cl)(Cl)Cl>[Br:1][C@H:2]([CH2:6][OH:7])[C:3]([O:5][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:4]
Reactant: O=C(O)[C@H](Br)CO
Reactant: CC(C)N(C(=N)OC(C)(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)[C@H](Br)CO
Temperature: 25 °C
Reaction time: 15 h
Yield: 61 %

Procedure:
18.1 g of (2R)-2-bromo-3-hydroxypropionic acid and 200 ml of chloroform were mixed, and 53.6 g of O-tert-butyl-N,N-diisopropylisourea was added under cooling with ice, followed by stirring at room temperature for 15 hours. Insoluble matters were filtered off, and then, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1→5/1) to obtain 14.7 g (yield: 61%) of the above identified compound as a colorless oily substance.
Reaction SMILES: [CH:1]([Si:4]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[O:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)([CH3:3])[CH3:2].[C:22](C1C2C(=CC=C(OC(F)(F)F)C=2)N(CC(O)=O)C=1)(=[O:24])[CH3:23]>>[CH:19]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:16]([CH3:18])[CH3:17])[O:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[C:22](=[O:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(=O)c1cn(CC(=O)O)c2ccc(OC(F)(F)F)cc12
Reactant: CC(C)[Si](OCc1ccc2[nH]ccc2c1)(C(C)C)C(C)C
Product: CC(=O)c1c[nH]c2ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cc12

Procedure:
The title compound was prepared from 5-triisopropylsilanyloxymethyl-1H-indole in a similar manner as described in step A of Scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl)-acetic acid. Brown solid. MS: 346 [M+H]+; tR (HPLC conditions c): 6.86 min.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].CCOCC.[C:10]([N:14]1[C:19](=[O:20])[C:18](Cl)=[C:17]([Cl:22])[CH:16]=[N:15]1)([CH3:13])([CH3:12])[CH3:11].ClC1C=NNC(=O)C=1Cl>C1(C)C=CC=CC=1>[CH2:1]([C:18]1[C:19](=[O:20])[N:14]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:15]=[CH:16][C:17]=1[Cl:22])[CH3:2]
Reactant: CC[Mg]Br
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Agent: O=c1[nH]ncc(Cl)c1Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCc1c(Cl)cnn(C(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
Into a four-necked flask of 1 liter, 43 g of ethylmagnesium bromide (3 mol/liter of an ether solution) and 200 ml of dehydrated toluene were charged. While thoroughly stirring the mixture at room temperature, 22.1 g (0.1 mol) of 2-t-butyl-4,5-dichloro-3(2H)pyridazinone was added in three portions. The reaction temperature was raised to a level of about 60° C., and the stirring was continued for about 30 minutes. The disappearance of the starting dichloropyridazinone was confirmed by thin layer chromatography (developer; hexane:acetone =20:1, v/v), whereupon the reaction was terminated. After the addition of about 300 ml of chilled water, the mixture was stirred vigorously, and transferred to a separating funnel, and then the aqueous layer was removed. The organic layer was washed with about 200 ml of water, and dried over anhydrous sodium sulfate, and then the solvent was distilled off. The pale brown oily substance thereby obtained was purified by silica gel column chromatography (developer; benzene) to obtain pale yellow crystals. 1.45 g (yield: 67.6%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](Cl)=[O:14])=[CH:8][CH:7]=1.[CH2:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[C:10]2[C:9](=[CH:8][CH:7]=1)[CH2:12][C:13](=[O:14])[CH2:16][CH:17]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C=Cc1ccccc1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1Cc2ccc(Cl)cc2C(c2ccccc2)C1
Temperature: 25 °C

Procedure:
8.00 g (0.06 mol) of aluminum chloride are suspended in 600 ml of methylene chloride, treated at 0° with 7.56 g (0.04 mol) of 4-chlorophenylacetyl chloride in 250 ml of methylene chloride and a solution of 4.17 g (0.04 mol) of styrene in 400 ml of methylene chloride is added dropwise thereto at -40° to -50°. After warming to room temperature, the mixture is poured on to ice, extracted with methylene chloride, dried with magnesium sulfate, filtered over Dicalit and the solvent is distilled in a vacuum. Chromatography on silica gel with ethyl acetate-hexane (1:4) and recrystallization from ether/hexane gives 6-chloro-3,4-dihydro-4-phenyl-2(1H)-naphthalenone as beige crystals with melting point 61°-62°.