Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]3[O:21][C:22]([NH:25][CH:26]([CH3:28])[CH3:27])=[N:23][N:24]=3)[CH:18]=2)[N:13]([S:29]([C:32]2[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:12]=1.Cl.[CH3:40][NH2:41].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:41][CH3:40])=[O:7])=[CH:4][C:3]=1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]3[O:21][C:22]([NH:25][CH:26]([CH3:27])[CH3:28])=[N:23][N:24]=3)[CH:18]=2)[N:13]([S:29]([C:32]2[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:12]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cc(C(=O)O)ccc3F)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CNC(=O)c1ccc(F)c(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccc(-c4nnc(NC(C)C)o4)cc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
To a solution of 4-fluoro-3-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1-tosyl-1H-indol-3-yl)benzoic acid (500 mg, 0.936 mmol) and methylamine hydrochloride (97 mg, 1.40 mmol) in pyridine (10 mL) was added POCl3 (0.13 mL, 1.40 mmol). The reaction was stirred at RT for 1 h, then quenched with ice cold water (20 mL) to get a precipitate. The precipitate was filtered, washed with water (2×100 mL) and dried. The crude product was purified with basic alumina chromatography (eluting with EtOAc) to give 4-fluoro-3-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1-tosyl-1H-indol-3-yl)-N-methylbenzamide (250 mg, 48%). MS (ESI, pos. ion) m/z: 548.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:19])([CH3:18])[CH2:9][NH:10][C:11]2[S:15][N:14]=[C:13]([C:16]#[N:17])[N:12]=2)=[CH:4][CH:3]=1.C([O-])([O-])=[O:21].[K+].[K+].OO>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:19])([CH3:18])[CH2:9][NH:10][C:11]2[S:15][N:14]=[C:13]([C:16]([NH2:17])=[O:21])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(CNc1nc(C#N)ns1)c1ccc(F)cc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(CNc1nc(C(N)=O)ns1)c1ccc(F)cc1
Reaction time: 0.25 h
Yield: 1.6 %

Procedure:
To a 0° C. mixture of 5-(2-(4-fluorophenyl)-2-methylpropylamino)-1,2,4-thiadiazole-3-carbonitrile (100 mg, 3.65 mmol, 1.0 equiv) and K2CO3 (202 mg, 14.6 mmol, 4.0 equiv) in DMSO (1.0 mL) was added hydrogen peroxide (30% in water, 1.1 mL, 36 mmol, 10 equiv) by syringe. After stirring for 15 min, the ice bath was removed, and the reaction mixture was stirred overnight. The reaction mixture was diluted with EtOAc and washed repeatedly with water and once with brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Preparatory thin layer chromatography (5% MeOH/DCM) provided the title compound (17 mg, 16%). m/z=295 [M+H]+.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:22](Cl)(=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCOCC>ClCCl>[C:1]1([N:7]2[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:14]=[C:22]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccccc1Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: c1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 69.9 %

Procedure:
40 ml of N-phenyl-1,2-phenylenediamine (7.36 g, 40 mmol) was charged in a 250 ml round bottle, 10 ml of triethylamine was then added, and the mixture was cooled to 0° C. Benzoyl chloride (5.6 g, 40 mmol) was dissolved in 40 ml of dichloromethane and then slowly added to the 250 ml round bottle. The reaction was conducted under a nitrogen atmosphere for 6 hours. After the reaction was complete, ether was added to form precipitation. The solid product was collected by filtration, washed with ether several times, and heated under reduced pressure to form 1,2-diphenyl-1H-benzoimidazole (yield=7.56 g, 70%).
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:42]=[CH:41][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:29]4[CH:34]=[CH:33][C:32]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:31][CH:30]=4)[O:25][C:26]=3[CH2:27]C)=[C:18]([O:43][CH3:44])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.Cl.[Cl-].[CH2:47]([N:49]1[C:53]([CH2:54][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:52][N:51]=[CH:50]1)[CH3:48].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:47]([N:49]1[C:53](/[CH:54]=[CH:1]\[C:3]2[C:4]([O:14][CH2:15][C:16]3[CH:42]=[CH:41][C:19]([O:20][CH2:21][C:22]4[N:23]=[C:24]([C:29]5[CH:30]=[CH:31][C:32]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:33][CH:34]=5)[O:25][C:26]=4[CH3:27])=[C:18]([O:43][CH3:44])[CH:17]=3)=[N:5][N:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:7]=2)=[CH:52][N:51]=[CH:50]1)[CH3:48]
Reactant: CCn1cncc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(CC)o2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C\c4cncn4CC)cc3OC)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.3 %

Procedure:
A mixture of ethyl (4-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl)-2-methoxyphenoxy)methyl]-5-ethyl-1,3-oxazol-2-yl}phenyl)acetate (2.00 g), [(1-ethyl-1H-imidazol-5-yl)methyl](triphenyl)phosphonium chloride hydrochloride (2.29 g), anhydrous potassium carbonate (1.78 g) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 16 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (9:1 to 1:0, v/v) to give ethyl {4-[4-({4-[({4-[(Z)-2-(1-ethyl-1H-imidazol-5-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate as colorless crystals (0.459 g, yield 20%). The crystals were recrystallized from tetrahydrofuran-hexane. melting point: 85-86° C.
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.C([Li])CCC.[CH:13]1([C:19]([O:21][CH3:22])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(I)C=C>O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:22][O:21][C:19]([C:13]1([CH2:7][CH:5]=[CH2:6])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:20]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)C1CCCCC1
Agent: C=CCI
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCC1(C(=O)OC)CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.6 %

Procedure:
To a solution of diisopropylamine (10 mL, 72 mmol) in tetrahydrofuran (100 mL) pre-cooled to −69° C. was added a 2.5 M solution of n-butyllithium in hexanes (29 mL, 72 mmol) dropwise. Following addition, the reaction mixture was warmed to 0° C. for 30 min and then re-cooled to −70° C. To the mixture was added a solution of methyl cyclohexane carboxylate (8.9 mL, 60 mmol) in tetrahydrofuran (30 mL) dropwise. After stirring for 30 min, a solution of allyl iodide (7.2 mL, 78 mmol) in HMPA (5 mL) was added dropwise. The cooling bath was removed to allow the mixture to warm to 20° C. After 1.5 h, the reaction mixture was poured into H2O (200 mL). The two layers were separated and the aqueous layer was extracted with Et2O (100 mL). The organic solutions were combined and dried over K2CO3, filtered and concentrated to afford 11 g of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([O:21]C(OC4C=CC=CC=4)=O)[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([Cl:31])[CH:18]=4)[C:13]3=[O:32])=[N:9]2)=[CH:4][CH:3]=1.ClC1C=C2C(=O)OC(=O)C2=CC=1.NC1C=CC2C(=NC(O)=CC=2)N=1.OC1N=C2C(C=CC(C34C=CC(Cl)=CC3C(NC4=O)=O)=N2)=CC=1.ClC1N=C2C(C=CC(C34C=CC(Cl)=CC3C(NC4=O)=O)=N2)=CC=1.P(Cl)(Cl)(Cl)=O.[BH4-].[K+].ClC1N=C2C(C=CC(N3C(O)C4C(=CC(Cl)=CC=4)C3=O)=N2)=CC=1>C(O)(=O)C.CO.O1CCOCC1.CN(C)C=O>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([OH:21])[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([Cl:31])[CH:18]=4)[C:13]3=[O:32])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Oc1ccccc1)OC1c2cc(Cl)ccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Agent: Nc1ccc2ccc(O)nc2n1
Agent: O=C1NC(=O)C2(c3ccc4ccc(Cl)nc4n3)C=CC(Cl)=CC12
Agent: O=C1NC(=O)C2(c3ccc4ccc(O)nc4n3)C=CC(Cl)=CC12
Solvent: CO
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: O=C1c2ccc(Cl)cc2C(O)N1c1ccc2ccc(Cl)nc2n1

Procedure:
2-(7-Chloro-1,8-naphthyridin-2-yl)-3-phenoxycarbonyloxy-5-chloro-isoindolin-1-one can be prepared in the following way: Preparation of 4-chlorophthalic anhydride, m.p. 96° C., according to E. E. Ayling, J. Chem. Soc., 1929, 253. Preparation of 2-amino-7-hydroxy-1,8-naphthyridine, m.p. 300°-305° C., according to S. Carboni et al, Ann. Chim. (Roma), 54, 883 (1964). Preparation of 2-(7-hydroxy-1,8-naphthyridin-2-yl)-5-chlorophthalimide (7 g.), m.p. 320° C., by reacting 2-amino-7-hydroxy-1,8-naphthyridine (9.5 g.) with 4-chlorophthalic anhydride (21.5 g.) in acetic acid (450 cc.) for 1 hour at 116° C. Preparation of 2-(7-chloro-1,8-naphthyridin-2-yl)-5-chlorophthalimide (6.4 g.), m.p. 280° C., by reacting phosphorus oxychloride (70 cc.) with 2-(7-hydroxy-1,8-naphthyridin-2-yl)-5-chlorophthalimide (7 g.) in the presence of dimethylformamide (0.7 cc.). By reacting potassium borohydride (0.75 g.) with 2-(7-chloro-1,8-naphthyridin-2-yl)-5-chlorophthalimide (6.4 g.) in a mixture (300 cc.) of dioxan and methanol (50--50 by volume), a mixture (5.2 g.) of 2-(7-chloro-1,8-naphthyridin-2-yl)-5-chloro-3-hydroxy-isoindolin-1-one and 2-(7-chloro-1,8-naphthyridin-2-yl)-6-chloro-3-hydroxy-isoindolin-1-one is obtained. This mixture is recrystallised firstly from dichloroethane (700 cc.) and then a second time from the same solvent (315 cc.). A product (1.51 g.) is thus obtained and is recrystallised successively from bromoform (38 cc.) and then from a mixture (104.5 cc.) of dichloroethane and ethanol (91-9 by volume). 2-(7-Chloro-1,8-naphthyridin-2-yl)-5-chloro-3-hydroxy-isoindolin-1-one (0.65 g.) is thus obtained. Preparation of 2-(7-chloro-1,8-naphthyridin-2-yl)-5-chloro-3-phenoxycarbonyloxy-isoindolin-1-one (1.6 g.), m.p. 220°-230° C., from 2-(7-chloro-1,8-naphthyridin-2-yl)-5-chloro-3-hydroxy-isoindolin-1-one (1 g.) and phenyl chloroformate (1.36 g.) in anhydrous pyridine (15 cc.).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:12](=[O:17])[NH:13][CH:14]=[CH:15][CH:16]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.Br[C:19]1[S:20][C:21]2[C:27]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[C:26]([C@H:35]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:36]([O:38][CH3:39])=[O:37])[C:25]([CH3:45])=[CH:24][C:22]=2[N:23]=1.CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu]I>[C:41]([O:40][C@@H:35]([C:26]1[C:25]([CH3:45])=[CH:24][C:22]2[N:23]=[C:19]([N:13]3[CH:14]=[CH:15][CH:16]=[C:11]([C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:2]([CH3:1])[N:3]=[CH:4]5)[C:12]3=[O:17])[S:20][C:21]=2[C:27]=1[C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C:36]([O:38][CH3:39])=[O:37])([CH3:44])([CH3:42])[CH3:43]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: Cn1ncc2cc(-c3ccc[nH]c3=O)ccc21
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-n3cccc(-c4ccc5c(cnn5C)c4)c3=O)sc2c1-c1ccc(Cl)cc1
Temperature: 110 °C

Procedure:
To a solution of 3-(1-methyl-1H-indazol-5-yl)pyridin-2(1H)-one (13.0 mg, 0.055 mmol), (S)-methyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (22 mg, 0.046 mmol), trans-N1,N2-dimethylcyclohexane-1,2-diamine (9 μL, 0.055 mmol) and potassium carbonate (13 mg, 0.091 mmol) in DMF (0.5 mL) was added copper(I) iodide (5.0 mg, 0.026 mmol). The mixture was degassed with N2 for 5 minutes and then heated at 110° C. for 3 h. The mixture was then diluted with EtOAc, extracted with H2O, brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give the product. LCMS-ESI+ (m/z): [M+H]+ calcd for C34H32ClN4O4S: 627.18; Found: 627.2.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:34])[C:10]2[CH:15]=[C:14]([CH2:16][C:17]3[C:18](=[O:29])[C:19]([O:27][CH3:28])=[C:20]([O:25][CH3:26])[C:21](=[O:24])[C:22]=3[CH3:23])[CH:13]=[CH:12][C:11]=2[O:30]C(=O)C)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])O.[Na+]>CO.O>[Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:34])[C:10]2[CH:15]=[C:14]([CH2:16][C:17]3[C:18](=[O:29])[C:19]([O:27][CH3:28])=[C:20]([O:25][CH3:26])[C:21](=[O:24])[C:22]=3[CH3:23])[CH:13]=[CH:12][C:11]=2[OH:30])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cccnc3Cl)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3cccnc3Cl)c2)=C(C)C1=O
Yield: 62.7 %

Procedure:
N-(2-Chloropyridin-3-yl)-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide (0.070 g, 0.144 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (1.5 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (ethyl acetate:hexane=1:1) and then recrystallized from ether to obtain the titled compound (0.040 g, 0.0903 mmol, 63%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=1)[CH2:12]OS(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:21]([O-:24])([O-:23])=[O:22].[Na+:25].[Na+].C(OCC)(=O)C>O>[Na+:25].[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:12][S:21]([O-:24])(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S([O-])[O-]
Reactant: CS(=O)(=O)OCc1cccc(OCc2ccccc2)c1
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=S(=O)([O-])Cc1cccc(OCc2ccccc2)c1
Temperature: 90 °C
Reaction time: 5 h
Yield: 39.8 %

Procedure:
5.80 g of methanesulfonic acid 3-benzyloxybenzyl ester and 5.21 g of sodium sulfite were dissolved in 50 ml of water and stirred at 90° C. for 5 hours. The mixture was allowed to cool to room temperature overnight, then 30 ml of ethyl acetate were added and the mixture was stirred in an ice bath for 1 hour. The precipitate was filtered off with suction, washed twice with 10 ml of ice-water and twice with 10 ml of ice-cold ethyl acetate, and dried in a vacuum drying cabinet at 40° C. overnight. This gave the product (2.37 g) with a molecular weight of 300.3 g/mol (C14H13O4S.Na); MS (ESI): m/e=296 (M−Na++H2O+H+).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:36])([F:35])[C:21]1[CH:22]=[C:23]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:36])([F:19])[F:35])[CH:22]=3)=[O:33])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1cccc(C(F)(F)F)c1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(C(F)(F)F)c3)n2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-trifluoromethyl-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 01b: tR=1.02 min; [M+H]+=445.14.
Reaction SMILES: CC1N(S(O)(=O)=[O:7])C(=O)C1.C(N(CCCC)CCCC)CCC.ON1C2C=CC=CC=2N=N1.[CH:34]1([N:40]=[C:41]=[N:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:41]([NH:40][CH:34]1[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1)([NH:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)=[O:7]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC1CC(=O)N1S(=O)(=O)O
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
[3S-[3α(Z),4β]]-3-[[(2-Amino-4-thiazolyl)-](1-carboxy-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid (2.18 g), 0.93 g of tributylamine, 0.1 g of N-hydroxybenzotriazole and 0.05 g of 4-dimethylaminopyridine were dissolved in 20 ml of dimethylformamide and a solution of 1.06 g of dicyclohexylcarbodiimide in 5 ml of dimethylformamide was added. After stirring for 15 minutes at room temperature, a solution of 0.94 g Girard Reagent P in 20 ml of dimethylformamide was added. After 3 hours of stirring, formed dicyclohexylurea was filtered off and the dimethylformamide of the filtrate was distilled off. Addition of 50 ml of tetrahydrofuran to the residue yielded 1.8 g of crude product, which was purified by column chromatography on HP-20 using water as an eluent, yielding 0.63 g of product, melting point 235° C.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:12]2[CH2:13][N:14]3[C:19](=[O:20])[C:18]4[CH2:21][O:22][C:23]([C@:25]([OH:28])([CH2:26][CH3:27])[C:17]=4[CH:16]=[C:15]3[C:11]=2[N:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[CH2:34][CH2:33]1)=[O:31])[CH:7]=[CH:8]2)=[O:24].C([O-])(=[O:46])C.C([OH:50])C.[ClH:51].CCCCCCC>C(OCC)(=O)C>[CH3:1][CH2:2][C:3]1[C:12]2[CH2:13][N:14]3[C:19](=[O:20])[C:18]4[CH2:21][O:22][C:23]([C@:25]([OH:28])([CH2:26][CH3:27])[C:17]=4[CH:16]=[C:15]3[C:11]=2[N:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([O:29][C:30]([N:32]1[CH2:33][CH2:34][CH:35]([N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[CH2:36][CH2:37]1)=[O:31])[CH:7]=[CH:8]2)=[O:24].[OH2:46].[OH2:50].[OH2:20].[ClH:51]
Reactant: CC(=O)[O-]
Reactant: CCO
Agent: CCc1c2c(nc3ccc(OC(=O)N4CCC(N5CCCCC5)CC4)cc13)-c1cc3c(c(=O)n1C2)COC(=O)[C@]3(O)CC
Agent: Cl
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a suitable vessel were charged amorphous irinotecan acetate (6.35 g) and ethanol (45 mL). The resulting mixture was heated to reflux (about 70° C.) and remained as a suspension. 2N HCl (5.4 mL) was added to the reaction mixture to adjust the pH to less than 4. N-heptane (25 mL) and ethanol (30 mL) were added to the resulting mixture. The solution was then cooled to 0˜10° C. and stirred at this temperature for 1 hour, and then charged with 200 mL of ethyl acetate in order to perform a solvent swap. The solution was then filtrated and washed with ethyl acetate (50 mL). The solid was dried in vacuum. Due to a lower than expected water content, the solid was heated under high humidity for one hour and then cooled to give irinotecan hydrochloride trihydrate Form I (6.6 g).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[CH:11][S:10]/[C:9]/1=[N:13]\[C:14]([C:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2)=[O:15])(=O)=O.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(Cl)Cl>[N:26]1([CH2:6][CH2:7][N:8]2[CH:12]=[CH:11][S:10]/[C:9]/2=[N:13]\[C:14]([C:16]23[CH2:23][CH:22]4[CH2:21][CH:20]([CH2:19][CH:18]([CH2:24]4)[CH2:17]2)[CH2:25]3)=[O:15])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: CS(=O)(=O)OCCn1ccs/c1=N\C(=O)C12CC3CC(CC(C3)C1)C2
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: O=C(/N=c1\sccn1CCN1CCOCC1)C12CC3CC(CC(C3)C1)C2
Reaction time: 16 h
Yield: 28 %

Procedure:
To a solution of Example 79A (0.22 g, 0.57 mmol) in 3 mL of acetonitrile was added morpholine (50 μL, 0.63 mmol), potassium iodide (0.11 g, 0.63 mmol), and potassium carbonate (0.17 g, 1.3 mmol). The mixture stirred for 16 hours and then diluted with methylene chloride and was washed with water, saturated aqueous potassium carbonate and brine. The organic phase was dried over anhydrous potassium carbonate, filtered and concentrated tinder reduced pressure. Purification by preparative HPLC afforded 60 mg (28%) of the title compound. 1H NMR (CDCl3, 400 MHz) δ ppm 1.69-1.79 (m, 6 H), 1.96 (d, J=2.8 Hz, 6 H), 2.03 (s, 3 H), 2.48-2.58 (m, 4 H), 2.75 (t, J=6.3 Hz, 2 H), 3.64-3.72 (m, 4 H), 4.28 (t, J=6.3 Hz, 2 H), 6.55 (d, J=4.6 Hz, 1 H), 6.99 (d, J=4.6 Hz, 1 H); MS (DCI/NH3) m/z 376 (M+H)+. Anal. Calculated for C20H29N3O2S: C, 63.97; H, 7.78; N, 11.19. Found: C, 63.85; H, 7.42; N, 10.91.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH:5]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.COCCO[AlH2-]OCCOC.[Na+].[H-].COCCO[Al+]OCCOC.[Na+].[H-].Cl>C1(C)C=CC=CC=1.O>[CH2:20]([O:19][C:13]1[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=1[CH:5]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH2:4][CH2:3][OH:2])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)CC(c1ccccc1)c1cc(C)ccc1OCc1ccccc1
Agent: COCCO[Al+]OCCOC
Agent: COCCO[AlH2-]OCCOC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(OCc2ccccc2)c(C(CCO)c2ccccc2)c1
Temperature: 22.5 °C
Reaction time: 0.38 h
Yield: 91 %

Procedure:
810 g of methyl-3 -(2-benzyloxy-5-methylphenyl)-3 -phenylpropionate and 3240 ml of toluene were stirred at 25-30° C. for about 20 minutes. 842.5 ml of VITRIDE® (sodium bis(2-methoxyethoxy)aluminum hydride, 65% w/w in toluene) was added slowly to the reaction mass below 40° C. under a nitrogen atmosphere, and stirred for about 20-25 minutes. A solution of 1620 ml of concentrated hydrochloric acid and 1620 ml of water was added slowly to the reaction mass and stirred for 15-20 minutes. The aqueous layer was separated and extracted with toluene (810 ml). Combined organic layers were washed with 4050 ml of water and then with 10% aqueous sodium carbonate solution (4050 ml). Organic layer was further washed with water (2×2430 ml) and the solvent was distilled under vacuum (about 600 mm Hg) below 100° C. 3240 ml of hexane was added to the residue at 30-40° C. and stirred for 2-3 hours. It was further cooled to 20-25° C. and stirred for 2-3 hours. Filtered the solid and washed with hexane (810 ml). Dried the solid at 25-30° C. under vacuum (about 600 mm Hg) for 2-3 hours to get 680 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1B(O)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCO.O.COCCOC>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1
Reactant: O=[N+]([O-])c1cccc(Br)c1
Reactant: COc1cccc(OC)c1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: COc1cccc(OC)c1-c1cccc([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To 1-bromo-3-nitrobenzene (2.02 g, 10.0 mmol), 2,6-dimethoxyphenylboronic acid (2.70 g, 15.0 mmol), triphenylphosphine (0.52 g, 2.0 mmol), K2CO3 (4.14 g, 30.0 mmol) and palladium(II) acetate (0.009 g, 0.04 mmol) was added DME (80 mL) and EtOH/H2O (1:1, 20 mL). Argon gas was bubbled through the stirred reaction for 5 min. The reaction was stirred at 80° C. under argon for 20 h. The reaction was cooled to room temperature, concentrated, and H2O (60 mL) and dichloromethane (80 mL) were added. The layers were separated and the aqueous was extracted with dichloromethane (2×40 mL). The combined organic extracts were dried with Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using 10% ethyl acetate/hexanes as eluent to afford 1.69 g (65%) of I-81 as a white solid.