Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:5]([OH:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.Br[CH2:9][CH:10]1[CH2:12][CH2:11]1.C1(CC2(CO)CCC2)CC1.C1(CC2(C=O)CCC2)CC1.C1(CC2(C(O)C#C)CCC2)CC1.C([Si](OC(C1(CC2CC2)CCC1)C#C)(C)C)(C)(C)C.[Si](OC(C1(CC2CC2)CCC1)C#CCO)(C(C)(C)C)(C)C>CCOC(C)=O.CCCCCC>[CH:10]1([CH2:9][C:1]2([C:5]([OH:7])=[O:6])[CH2:4][CH2:3][CH2:2]2)[CH2:12][CH2:11]1
Reactant: O=C(O)C1CCC1
Reactant: BrCC1CC1
Agent: C#CC(O)C1(CC2CC2)CCC1
Agent: C#CC(O[Si](C)(C)C(C)(C)C)C1(CC2CC2)CCC1
Agent: CC(C)(C)[Si](C)(C)OC(C#CCO)C1(CC2CC2)CCC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(O)C1(CC2CC2)CCC1

Procedure:
The title compound was prepared according to the procedure described for Intermediate 15.1 from cyclobutanecarboxylic acid and (bromomethyl)cyclopropane. Intermediate 19.2: [1-(cyclopropylmethyl)cyclobutyl]methanol. The title compound was prepared according to the procedure described for Intermediate 15.2 from intermediate 19.1. Intermediate 19.3: 1-(cyclopropylmethyl)cyclobutanecarbaldehyde. The title compound was prepared according to the procedure described for Intermediate 15.3 from intermediate 19.2. Intermediate 19.4: 1-[1-(cyclopropylmethyl)cyclobutyl]prop-2-yn-1-ol. The title compound was prepared according to the procedure described for Intermediate 15.4 from intermediate 19.3. Intermediate 19.5: tert-butyl({1-[1-(cyclopropylmethyl)cyclobutyl]prop-2-ynyl}oxy) dimethylsilane. The title compound was prepared according to the procedure described for Intermediate 15.5 from intermediate 19.4. Rf 0.8 (EtOAc/hexanes 1/9). Intermediate 19.6: 4-{[tert-butyl(dimethyl)silyl]oxy}-4-[1-(cyclopropylmethyl) cyclobutyl]but-2-yn-1-ol.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[C:13]([CH:14]=[CH:15][C:16]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:17]=3)=[C:12]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[NH:11]2)=[CH:6][CH:5]=1)([O-])=O>C(O)(=O)C.[Zn]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[C:13]([CH:14]=[CH:15][C:16]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:17]=3)=[C:12]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[NH:11]2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)C1=C2C=CC(c3ccccc3)(c3ccccc3)C=C2N(c2ccc([N+](=O)[O-])cc2)N1
Agent: [Zn]
Solvent: CC(=O)O
Product: CCOC(=O)C1=C2C=CC(c3ccccc3)(c3ccccc3)C=C2N(c2ccc(N)cc2)N1
Temperature: 20 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
A solution of 0.6 g of ethyl 1-(4-nitrophenyl)-6,6-diphenyl-1H-indazole-3-carboxylate in 24 cm3 of acetic acid is cooled to the region of 0° C. 4.8 g of zinc are then added portionwise. After warming to a temperature in the region of 20° C., the suspension obtained is stirred for about 4 hours. The insoluble material is filtered off through Celite and washed with three times 10 cm3 of dichloromethane. The filtrate is concentrated to dryness under reduced pressure (13 kPa) and taken up in 50 cm3 of dichloromethane. The solution is washed with three times 20 cm3 of saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa). After flash chromatography on a column of silica [eluent: dichloromethane/ethyl acetate (98/2 by volume)], 0.41 g of ethyl 1-(4-aminophenyl)-6,6-diphenyl-1H-indazole-3-carboxylate is thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[O:30]=[C:31]1[NH:35][C:34](=[O:36])[C:33](=[CH:37][C:38]2[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=2)[S:32]1>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:42][C:41]3[CH:40]=[CH:39][C:38](/[CH:37]=[C:33]4/[C:34](=[O:36])[NH:35][C:31](=[O:30])[S:32]/4)=[CH:45][CH:44]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=Cc1ccc(C=C2SC(=O)NC2=O)cc1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C1NC(=O)/C(=C/c2ccc(CNc3cccc(-c4c(C(=O)c5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)cc2)S1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and 4-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-benzaldehyde according to the procedure of Example 66. MS (ES) m/z 607.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][CH2:8]2.C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21]>C(Cl)Cl>[C:20]([N:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[CH2:8]1)(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: COc1cccc2c1CCNC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc2c1CCN(C(C)=O)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.2 %

Procedure:
To a solution of the product of step (b) (6.26 g, 31.4 mmol) and triethylamine (9.6 ml, 69.0 mmol) in CH2Cl2 (150 ml) was added acetyl chloride (2.7 ml, 37.7 mmol) at 0° C. over a period of 15 min. The reaction mixture was stirred at room temperature for 18 h after which time the solution was washed sequentially with H2O and saturated aqueous sodium bicarbonate solution, dried over MgSO4 and evaporated under reduced pressure. The crude product was purified on silica gel eluting with EtOAc to afford the subtitle compound as an orange oil (6.07 g, 94%). Rf 0.65 (CH2Cl2/MeOH/0.88NH3 90/10/1, v/v). MS m/s 206 (MH+).
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]3[N:13]([CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC=CC=1.[C:22](Cl)(=[O:26])[C:23]([Cl:25])=[O:24]>C1COCC1>[CH:1]1([C:6]2[CH:7]=[C:8]3[N:13]([C:14]=2[C:22](=[O:26])[C:23]([Cl:25])=[O:24])[CH2:12][CH2:11][CH2:10][CH2:9]3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: c1c(C2CCCC2)cn2c1CCCC2
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(Cl)C(=O)c1c(C2CCCC2)cc2n1CCCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
2-Cyclopentyl-5,6,7,8-tetrahydro-indolizine (0.24 g, 1.27 mmol) was dissolved in THF (1 mL) and toluene (1.5 mL) and cooled to 0° C. Oxalyl chloride (0.14 mL, 1.52 mmol) was added dropwise and the mixture was stirred at 0° C. for 30 min, then at room temperature for 1 hour. Concentration in vacuo afforded (2-cyclopentyl-5,6,7,8-tetrahydro-indolizin-3-yl)-oxo-acetyl chloride (0.31 g, 88%) as a semi-solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C@H:17]([OH:30])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[C:21]=1[NH2:29])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O>[CH2:1]([N:8]([CH2:16][C@H:17]([OH:30])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[C:21]=1[NH2:29])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1c(OC[C@@H](O)CN(Cc2ccccc2)Cc2ccccc2)cccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cccc(OC[C@@H](O)CN(Cc2ccccc2)Cc2ccccc2)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
(S)-[3-(N,N-Dibenzylamino)-2-hydroxypropoxy]-2-amino-3-nitrobenzene (10.6 g, 26.0 mmol) was suspended in 1 L of 2:1 ethanol/water at ambient temperature and treated with excesses of sodium bicarbonate (26.22 g, 0.31 mol) and sodium hydrosulfite (54.34 g, 0.31 mol). The orange reaction mixture slowly became colorless over 1 hour, and the mixture was left to stir at ambient temperature for 16 hours. The suspension was filtered, and the filtrate concentrated in vacuo to a leave a white solid. This residue was partitioned between chloroform and water, and the organic layer washed twice with brine. The combined organic extracts were concentrated in vacuo to give 8.8 g of a brown oil. The compound was recrystallized rapidly from toluene to give 7.96 g (81%) of pale brown needles. NMR.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:26])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][N:19]=3)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4]>O1CCCC1>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:8]3[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[O:6][C:7]=3[CH3:26])=[CH:13][CH:14]=2)=[N:19][CH:20]=1
Reactant: COC(=O)c1cc(COc2ccc(-c3ccc(OC)cn3)cc2)c(C)o1
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(OCc3cc(C(=O)O)oc3C)cc2)nc1
Reaction time: 2 h
Yield: 53.6 %

Procedure:
A solution of 4-[4-(5-methoxy-pyridin-2-yl)-phenoxymethyl]-5-methyl-furan-2-carboxylic acid methyl ester (52) (118 mg, 0.33 mmoles) in dry tetrahydrofuran (10 ml) was treated with potassium trimethylsilanoate (260 mg, 2.0 mmoles) and the mixture stirred under an argon atmosphere for 2 hours. After evaporation of the solvent the residue was purified by HPLC (gradient: 18% acetonitrile/82% water containing 0.1% trifluoroacetic acid to 98% acetonitrile/2% water at a rate of 1%/min) to afford compound 53 (60 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[C:7]=1[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:5])[CH3:2].[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:36]3[CH:37]=[CH:38][C:33]([C:32]([F:43])([F:42])[F:31])=[CH:34][CH:35]=3)[CH:13]=2)[N:8]([C:16]2[CH:17]=[CH:18][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=2)[C:7]=1[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(C(C)C)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2n1-c1ccc(C(C)C)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-1-(4-isopropylphenyl)-5-hydroxyindole-3-carboxylic acid ethyl ester (143 mg, 0.35 mmol, see step (b) Example 10) and 4-trifluoromethylphenylboronic acid (100 mg, 0.53 mmol). Yield 110 mg (57%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[NH:18][C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([C:9]2[NH:18][C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2nc3ccccc3c(=O)[nH]2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1[nH]c(-c2cccc(O)c2)nc2ccccc12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To 2-(3-methoxyphenyl)quinazolin-4(3H)-one (11.6 g, 45.98 mmole) was added of CH2Cl2 (120 mL) and the mixture was cooled to −78° C. Then, a 1 M solution of BBr3 in CH2Cl2 (60 mL, 60.0 mmol) was added drop wise and the reaction was stirred at −78° C. for 1 h and then ambient temperature for 3 h. The reaction was re-cooled to −78° C. and cautiously quenched with MeOH (20 mL). The ice bath was removed and the system allowed to stir at ambient temperature for 0.5 h. The pH was adjusted to 7 with 10% w/w NaHCO3 solution. The solid was filtered, washed with ether, dried and then azeotroped from toluene (3 X) and dried under high vacuum overnight to give 2-(3-hydroxyphenyl)quinazolin-4(3H)-one. (11.0 g, mmol, 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([Li])CCC.[Li]C1C=CN=CC=1.[Br:20][C:21]1[CH:22]=[CH:23][C:24]2[O:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[CH2:27][C:26](=[O:35])[C:25]=2[CH:36]=1>CCOCC.CCCCCC>[Br:20][C:21]1[CH:22]=[CH:23][C:24]2[O:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[CH2:27][C:26]([C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)([OH:35])[C:25]=2[CH:36]=1
Reactant: O=C1Cc2ccccc2Oc2ccc(Br)cc21
Reactant: Brc1ccncc1
Agent: [Li]CCCC
Agent: [Li]c1ccncc1
Solvent: CCOCC
Solvent: CCCCCC
Product: OC1(c2ccncc2)Cc2ccccc2Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 26.2 %

Procedure:
Under an argon atmosphere, a solution of 4-bromopyridine (16.6 g) in anhydrous ether (90 ml) previously cooled to -40°, was transferred slowly via a cannular to a stirred solution of n-butyl lithium in hexane (1.55M; 68 ml) cooled to -78°. The mixture was stirred at -78° for 20 minutes and the resulting 4-lithiopyridine was transferred to a chilled (-78°) stirred suspension of 8-bromodibenz[b,f]oxepin-10(11H)-one (15 g) in anhydrous ether (100 ml). The reaction was stirred at -78° for 30 minutes, then the cooling bath was removed and the mixture was treated with 100 ml of water and allowed to warm to room temperature. The solids were filtered off, washed with water and dried to give 5.0 g of 8-bromo-10,11-dihydro-10-(4-pyridinyl)dibenz[b,f]oxepin-10-ol. The mother liquor was worked up and a total of 9.4 grams of the starting ketone 8-bromodibenz[b,f]oxepin-10(11H)-one were recovered.
Reaction SMILES: [CH:1]([N:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[C:7](Cl)[C:6]1=[O:13])([CH2:3][CH3:4])[CH3:2].Cl.[Cl:15][C:16]1[CH:17]=[C:18]([O:25][CH3:26])[CH:19]=[C:20]2[C:24]=1[NH:23][CH2:22][CH2:21]2>>[Cl:11][C:9]1[N:8]=[C:7]([N:23]2[C:24]3[C:20](=[CH:19][C:18]([O:25][CH3:26])=[CH:17][C:16]=3[Cl:15])[CH2:21][CH2:22]2)[C:6](=[O:13])[N:5]([CH:1]([CH3:2])[CH2:3][CH3:4])[CH:10]=1
Reactant: CCC(C)n1cc(Cl)nc(Cl)c1=O
Reactant: COc1cc(Cl)c2c(c1)CCN2
Agent: Cl
Product: CCC(C)n1cc(Cl)nc(N2CCc3cc(OC)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 1-sec-butyl-3,5-dichloro-2(1H)-pyrazinone and 7-chloro-5-methoxyindoline hydrochloride as the starting materials. mp 143–145° C.; 1H NMR (300 MHz, CDCl3): δ 6.89 (s, 1 H), 6.77–6.72 (m, 2 H), 4.96–4.89 (m, 1 H), 4.34 (t, J=7.9 Hz, 2 H), 3.76 (s, 3 H), 3.07 (t, J=7.7 Hz, 2 H), 1.74–1.64 (m, 2 H), 1.33 (d, J=7.0 Hz, 3 H), 0.89 (t, J=7.6 Hz, 3 H); HRMS (ESI) calcd for C17H20N3O2Cl2 (M+H)+: 368.0933; found m/z 368.0927.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:12])=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:6]=1.[Cl:13][C:14]1[C:15]([CH3:24])=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>>[Cl:13][C:14]1[C:15]([CH3:24])=[C:16]([S:20]([NH:1][C:2]2[S:3][C:4]([CH3:12])=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:6]=2)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)Cc1nc(N)sc1C
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: COC(=O)Cc1nc(NS(=O)(=O)c2cccc(Cl)c2C)sc1C

Procedure:
The title compound was prepared from methyl 2-(2-amino-5-methyl-1,3-thiazol-4-yl)acetate and 3-chloro-2-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (23.2 mg) with purity >90%. LCMS (pos) m/z 375.2.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2].C(N(C(C)C)CC)(C)C.[N+:64]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=1[S:73](Cl)(=[O:75])=[O:74])([O-:66])=[O:65]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][S:73]([C:68]3[CH:69]=[CH:70][CH:71]=[CH:72][C:67]=3[N+:64]([O-:66])=[O:65])(=[O:74])=[O:75])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OS(=O)(=O)c4ccccc4[N+](=O)[O-])C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 24.1 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (200 mg, Example 38) in dry methylene chloride (20 ml) was added diisopropylethylamine (150 μl) followed by 2-nitrobenzenesulonyl chloride (60 mg), then 4-dimethylaminopyridine (27 mg). The yellow solution was stirred at room temperature under nitrogen atmosphere for 4 h, then quenched with sat'd aqueous sodium bicarbonate solution. The organic layer was washed (water, sat'd NaHCO3, sat'd NaCl), dried (anhydrous Na2SO4) and the solvent was removed in vacuo. Chromatography on silica gel (2:1 ethyl acetate/hexane) gave 70 mg of the title compound A and 60 mg of the title compound B (Mass, 1H and 13C NMR data were consistent with the structures).
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:9]([O:11]/[C:12](=[CH:18]\[C:19]1[CH:20]=[N:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N:31]([CH3:44])[C:32]([O:34]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH:26]=2)=[CH:23][CH:24]=1)/[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:10].O.C(OCC)(=O)C>CN(C)C=O>[CH2:9]([O:11]/[C:12](=[CH:18]\[C:19]1[CH:20]=[N:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N:31]([CH3:44])[C:32]([NH:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:34])[CH:26]=2)=[CH:23][CH:24]=1)/[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:10]
Reactant: CCCCCCCN
Reactant: CCOC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)Oc3ccc([N+](=O)[O-])cc3)c2)nc1)OCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OCC)C(=O)OCC)cn2)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
0.16 mL (1.1 mmol) of n-heptylamine is added to a solution of 0.32 g (0.55 mmol) of ethyl (Z)-2-ethoxy-3-(6-{3-[methyl-(4-nitrophenoxycarbonyl)amino]phenyl}pyrid-3-yl)acrylate in 10 mL of dimethylformamide. The tube is sealed and rapidly placed in an oil bath preheated to 80° C. The reaction mixture is stirred at 80° C. for 1 hour 30 minutes. After cooling, the reaction is worked up by addition of 10 mL of water and extraction with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and then dried over magnesium sulfate. The solvents are evaporated off. The crude product obtained is purified by chromatography on a column of silica eluted with a 70/30 heptane/ethyl acetate mixture to give 0.14 g (54%) of ethyl (Z)-2-ethoxy-3-{6-[3-(3-heptyl-1-methylureido)phenyl]pyrid-3-yl}acrylate in the form of a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5](/[CH:6]=[CH:7]/[S:8]([N:11]([CH2:18][CH:19](OCC)[O:20]CC)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:6]=[CH:7]/[S:8]([N:11]([CH2:18][CH:19]=[O:20])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:9])=[O:10])=[CH:26][CH:27]=1
Reactant: CCOC(=O)CN(CC(OCC)OCC)S(=O)(=O)/C=C/c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CN(CC=O)S(=O)(=O)/C=C/c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.1 %

Procedure:
To a mixed solution of the compound obtained in Step 1 (2.00 g), chloroform (9.5 ml) and water (9.5 ml) was added trifluoroacetic acid (13.5 ml) under cooling with ice water. The reaction mixture was stirred at room temperature for 4 hours, adjusted to pH 8 with saturated aqueous solution of sodium hydrogencarbonate and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and thereafter the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=2:1) to obtain the title compound (1.27 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2Cl)[C:7]=1[CH3:25])[CH3:2].C(OC(=O)CC1C2C(=CC=C(OC)C=2)NC=1C)C.[H-].[Na+].[Cl:47]C1C=C(C=CC=1)CCl>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:47])[CH:19]=2)[C:7]=1[CH3:25])[CH3:2]
Reactant: ClCc1cccc(Cl)c1
Reactant: CCOC(=O)Cc1c(C)n(Cc2ccccc2Cl)c2ccc(OC)cc12
Agent: CCOC(=O)Cc1c(C)[nH]c2ccc(OC)cc12
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)Cc1c(C)n(Cc2cccc(Cl)c2)c2ccc(OC)cc12
Yield: 55 %

Procedure:
1-(2-Chlorophenylmethyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid ethyl ester. Using the procedure described in Example 1, Part F, 494 mg (2 mmol) of 5-methoxy-2-methyl-1H-indole-3-acetic acid ethyl ester was reacted with 80 mg (2 mmol) of 60% NaH/mineral oil and 0.25 mL (2 mmol) of meta-chlorobenzylchloride and after chromatography on silica (eluting with 33% EtOAc/hexane) and crystallizing from MeOH there was obtained 409 mg (55%) of 1-(3-chlorophenylmethyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid ethyl ester, mp, 79°-81° C.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.CN(C)CCN(C)C.[CH2:23]([Li])[CH2:24][CH2:25][CH3:26].[OH-].[K+]>C1COCC1.C(#N)C.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[CH2:23]([C:13]1[C:14]2[C:5]([N:6]=[C:7]3[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]3)=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH2:24][CH2:25][CH3:26]
Reactant: c1ccc2nc3ccccc3cc2c1
Reactant: [Li]CCCC
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: CN(C)CCN(C)C
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CCCCc1c2ccccc2nc2ccccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To an ice-cooled solution of acridine (24.8 g, 0.139 mol) and TMEDA (N,N,N′,N′-tetramethylethylenediamine) (5.0 ml, 0.034 mol) in THF (160 mL), was slowly added 2.5 M n-butyllithium in hexanes (162 mL, 0.405 mol). The resulting solution was stirred at 0° C. for 2 hours and quenched with water. After stirring for an additional 0.5 hour, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with water several times and dried over MgSO4. Removal of solvent afforded a residue. This residue was taken up in acetonitrile (700 mL) and treated with potassium ferricyanide (198.0 g, 0.601 mol) aqueous solution (1110 mL) containing potassium hydroxide (99.0 g, 1.764 mol) for about 42 hours at room temperature. The mixture was extracted with ethyl acetate and dried over MgSO4. After evaporation of the solvent, the crude product was purified by chromatography on silica gel (hexanes:ethyl acetate=10:1 as eluent) to afford 27.0 g (83%) of yellow powder.