Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([C:13](O)=[O:14])[N:12]=2)=[C:4]([NH:17][CH:18]([CH3:20])[CH3:19])[CH:3]=1.S(Cl)(Cl)=O.[N-:25]=[N+:26]=[N-:27].[Na+]>O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([C:13]([N:25]=[N+:26]=[N-:27])=[O:14])[N:12]=2)=[C:4]([NH:17][CH:18]([CH3:20])[CH3:19])[CH:3]=1
Reactant: Cc1oc(-c2cnc(Cl)cc2NC(C)C)nc1C(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Product: Cc1oc(-c2cnc(Cl)cc2NC(C)C)nc1C(=O)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxylic acid (30a) (750 mg, 2.54 mmol) and thionyl chloride (12.68 mmol) were refluxed at 100° C. for 20 h. Thionyl chloride was removed under reduced pressure. The resulting solid acid chloride was dissolved in acetone (15 mL) and cooled to 0° C. Sodium azide (7.61 mmol) dissolved in water (3 mL) was added to the reaction mixture at 0° C. and stirred for 30 min. The reaction temperature was raised to room temperature and stirred for 5 h. The reaction mixture was concentrated to remove the solvent. The compound precipitated in the aqueous layer was filtered and dried under vacuum to obtain the desired compound 2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carbonyl azide. LC/MS: ZORBAX SB C18, 4.6×50 mm, 5 μm; Solvent A=10% MeOH: 90% H2O: 0.1% TFA; Solvent B=90% MeOH: 10% H2O: 0.1% TFA; gradient 0-100% B over 2 min (3 min run time); retention time: 2.363 min.
Reaction SMILES: [C:1]1([C:7]([S:9][CH2:10][C:11]([OH:13])=[O:12])=[S:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:18]O>>[C:1]1([C:7]([S:9][CH2:10][C:11]([O:13][CH3:18])=[O:12])=[S:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CO
Reactant: O=C(O)CSC(=S)c1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)CSC(=S)c1ccccc1
Yield: 98 %

Procedure:
2-((Phenylcarbonothioyl)thio)acetic acid (10 g, 47.1 mmol) was dissolved in 200 mL of methanol followed by the dropwise addition of thionylchloride (16 g, 120 mmol) at room temperature. The reaction mixture was refluxed for 4 hours. The reaction mixture was concentrated in vacuo and ethyl acetate was added. The mixture was washed with sat. aq. NaHCO3 and brine and dried over Na2SO4. The reaction mixture was concentrated in vacuo to afford Methyl 2-((phenylcarbonothioyl)thio)acetate 2 as brown oil (10.5 g, 98%).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][C:27]([C:34]([O:36][CH2:37][CH3:38])=[O:35])([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30])/[C:9]1=[O:39])=O)(C)(C)C.[Cl:40][C:41]1[CH:42]=[CH:43][C:44]([CH3:56])=[C:45]([CH:47]=[N:48][C:49]([O:51][Si](C)(C)C)=[CH2:50])[CH:46]=1>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:39])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][C:27]([C:34]([O:36][CH2:37][CH3:38])=[O:35])([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30])[CH2:51][C:49](=[O:50])[NH:48][CH:47]3[C:45]3[CH:46]=[C:41]([Cl:40])[CH:42]=[CH:43][C:44]=3[CH3:56])[C:11]2=[CH:12][CH:13]=1
Reactant: CCCC(CCC)(Oc1ccc(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21)C(=O)OCC
Reactant: C=C(N=Cc1cc(Cl)ccc1C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCCC(CCC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)OCC
Yield: 20.1 %

Procedure:
In a manner similar to the method described in Example 10d, E/Z-6-chloro-3-[5-chloro-2-(1-ethoxycarbonyl-1-propyl-butoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1.3 g, 2.3 mmol) was reacted with 1-(5-chloro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (10 mmol) prepared in Example 13b in toluene to give the title compound as a white solid (310 mg).
Reaction SMILES: [C:1]([O:4][CH:5]([CH:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:10][O:11][C:12](=[O:14])[CH3:13])[C:6](Cl)=[O:7])(=[O:3])[CH3:2].[Br-:19].[Li+]>C(Cl)Cl>[C:1]([O:4][CH:5]([CH:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:10][O:11][C:12](=[O:14])[CH3:13])[C:6]([Br:19])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(OC(C)=O)C(OC(C)=O)C(=O)Cl
Reactant: [Br-]
Agent: [Li+]
Solvent: ClCCl
Product: CC(=O)OCC(OC(C)=O)C(OC(C)=O)C(=O)Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.5 %

Procedure:
2,3,4-Triacetoxybutanoyl chloride (39.9 g, 0.142 mol), prepared according to the literature procedure Glattfeld, J. and Kribben, B., J.Am. Chem. Soc. 61 (1939) 1720) was mixed with lithium bromide (30.9 g, 0.356 mol) in methylene chloride (400 ml) and stirred at ambient temperature for 24 h. The mixture was filtered, the solid was washed with additional methylene chloride (50 ml) and the filtrate was evaporated at ambient temperature to give 45 g (97%) of the crude product as an oil.
Reaction SMILES: [Na+].[N+:2]([C:5]1[CH:22]=[CH:21][C:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][S:17]([O-])(=[O:19])=[O:18])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([O-:4])=[O:3].P(Cl)(Cl)(Cl)(Cl)[Cl:24]>O>[Cl:24][S:17]([CH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][C:8]2[CH:21]=[CH:22][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][CH:7]=2)=[CH:11][CH:12]=1)(=[O:19])=[O:18]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(Cc2ccc(CS(=O)(=O)[O-])cc2)cc1
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(Cc2ccc(CS(=O)(=O)Cl)cc2)cc1
Temperature: 90 °C
Yield: 27.8 %

Procedure:
4-(4-Nitrobenzyl)-phenylmethanesulfonic acid sodium salt (2.29 g) was combined with phosphorus pentachloride (1.45 g). The mixture was heated to 90° C. for 5 minutes, poured into water, and extracted with dichloromethane (3×20 mL). Solvents were evaporated to give 4-(4-chlorosulfonylmethylbenzyl)-nitrobenzene as an impure yellow solid (0.63 g). This product was used directly in the next step.
Reaction SMILES: [C:1]([NH:4][NH2:5])([NH2:3])=[NH:2].Cl.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([O:18][C:19]1[CH:20]=[C:21]([CH:27]=[C:28]([CH3:30])[CH:29]=1)[O:22][CH2:23][CH2:24][CH:25]=[O:26])(=[O:17])=[O:16].[CH2:31]([OH:33])[CH3:32]>>[C:25]([OH:26])(=[O:33])[CH3:24].[C:31]([OH:8])(=[O:33])[CH3:32].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([O:18][C:19]1[CH:20]=[C:21]([CH:27]=[C:28]([CH3:30])[CH:29]=1)[O:22][CH2:23][CH2:24][CH2:25][NH:5][NH:4][C:1]([NH2:3])=[NH:2])(=[O:16])=[O:17]
Reactant: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCC=O)c1
Reactant: CCO
Reactant: N=C(N)NN
Agent: Cl
Product: CC(=O)O
Product: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCCNNC(=N)N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
2-[2-[3-(2-Methoxyphenylsulfonyloxy)-5-methylphenoxy]ethyl-1-methylene]hydrazinecarboximidamide acetate: A mixture of aminoguanidine hydrochloride (0.811 g, 7.33 mmol) and 3-[3-(2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propionaldehyde (1.28 g, 3.66 mmol, prepared in the preceding step) in ethanol (30 mL) was stirred overnight at ambient temperature. The mixture was concentrated in vacuo to approximately 15 mL, then dichloromethane (60 mL) was added to precipitate excess aminoguanidine hydrochloride. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane (30 mL) and extracted with aqueous NaOH (1.85 mL of 2N NaOH in 90 mL water). The aqueous layer was extracted with CH2Cl2 (2×30 mL). The combined organic extracts were washed with water (50 mL) and brine (2×50 mL), dried over K2CO3, filtered, and evaporated to give the free base of the title compound (1.38 g, 93%) as a gold foam.
Reaction SMILES: [C:1]([OH:10])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][C:6](O)=O.C(O)(=O)CCCC(O)=O>C1CCCCC1>[C:1]1(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1.[CH:1]1([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CCCCC(=O)O
Agent: O=C(O)CCCC(=O)O
Solvent: C1CCCCC1
Product: O=C1CCCCC1
Product: OC1CCCCC1

Procedure:
Conventionally, 1,6-hexanediol is produced from an organic acid mixture containing adipic acid, hydroxycapronic acid and glutaric acid, wherein the organic acid mixture is by-produced during the production of cyclohexanone and/or cyclohexanol by oxidation of cyclohexane with air. For producing 1,6-hexanediol, the organic acid mixture is subjected to esterification and then to hydrogenation in the presence of a copper catalyst to thereby obtain 1,6-hexanediol, and the obtained 1,6-hexanediol is purified by distillation. 1,6-Hexanediol which is conventionally produced in the above-mentioned manner contains 1,4-cyclohexanediol, and such 1,6-hexanediol is not suitable as a raw material for producing the polycarbonate diol of the present invention. The boiling point of 1,4-cyclohexanediol and the boiling point of 1,6-hexanediol are very close to each other and, therefore, it is difficult to decrease the amount of 1,4-cyclohexanediol in 1,6-hexanediol to the above-mentioned preferred level (i.e., 0.5% by weight or less) by distillation.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21](O)=[O:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.O[NH:25][C:26]([C:28]1[S:29][C:30]([S:33](=[O:36])(=[O:35])[NH2:34])=[CH:31][CH:32]=1)=[NH:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:16])([F:15])[F:17])[N:11]3[N:18]=[CH:19][C:20]([C:21]4[O:22][N:27]=[C:26]([C:28]5[S:29][C:30]([S:33]([NH2:34])(=[O:36])=[O:35])=[CH:31][CH:32]=5)[N:25]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)s1
Product: NS(=O)(=O)c1ccc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(Cl)cc5)nc34)n2)s1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.4) (171 mg, 0.5 mmol) and N-hydroxy-5-sulfamoyl-thiophene-2-carboxamidine (example B.2) (166 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (dichloromethane) as a yellow solid (180 mg, 68%). MS (ISN) 525.0 [(M−H)−]; mp 294° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:7]([OH:9])=[O:8].[N+:18]([C:21]1[C:22]([S:27]Cl)=[N:23][CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19].C(N(CC)CC)C>ClCCl>[C:14]([O:13][C:11]([NH:10][C@@H:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:27][C:22]1[C:21]([N+:18]([O-:20])=[O:19])=[CH:26][CH:25]=[CH:24][N:23]=1)[C:7]([OH:9])=[O:8])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: O=[N+]([O-])c1cccnc1SCl
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNSc1ncccc1[N+](=O)[O-])C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 14.1 %

Procedure:
(S)-6-Amino-2-((tert-butoxycarbonyl)amino)hexanoic acid (Compound tk86) (270 mg, 1.096 mmol) was added to a solution of nitro-2-pyridinesulfenyl chloride (313 mg, 1.644 mmol) in dichloromethane (30 ml), and triethylamine (1.53 ml, 10.96 mmol) was added dropwise to the suspension over 3 minutes. The reaction solution was stirred at room temperature for 3 hours and then concentrated under reduced pressure using an evaporator, and the resulting residue was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (S)-2-((tert-butoxycarbonyl)amino)-6-(((3-nitropyridin-2-yl)thio)amino)hexanoic acid (Compound tk87) (62 mg, 14%).
Reaction SMILES: [CH:1]1[C:13]2[N:12]([CH2:14][C:15]#[C:16][C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1C2[N:35]([CH2:37]C#C)[C:34]3C(=CC=CC=3)C=2C=CC=1.C([OH:46])CCCC#C.Br[O-].[Na+]>>[CH3:34][NH:35][C:37]([O:23][CH2:22][CH3:21])=[O:46].[CH:10]1[C:11]2[N:12]([CH2:14][C:15]#[C:16][C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: C#CCCCCO
Reactant: C#CCn1c2ccccc2c2ccccc21
Agent: OCCCCC#CC#CCn1c2ccccc2c2ccccc21
Agent: [Na+]
Agent: [O-]Br
Product: CCOC(=O)NC

Procedure:
For example, 9-(N-carbazolyl)-5, 7-nonadiyn -1-ol (5) is synthesized in about 80% yield by cross coupling of 3-(N-carbazolyl)-1-propyne (3) with 6-bromo-5-hexyn-1-ol (6), which, in turn, is synthesized from 5-hexyn-1-ol with sodium hypobromite. Reaction of (5) with methylisocyanate (7) gives 9-(N-carbazolyl)- 5,7-nonadiyn-1-ol methylurethane (8) in almost quantitative yield. ##STR12##
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[Br:13][C:14]1[C:18]2[CH:19]=[C:20]([CH2:23][N:24]3[C:28]([C:29]([OH:31])=O)=[C:27]([CH:32]4[CH2:34][CH2:33]4)[N:26]=[C:25]3[CH2:35][CH3:36])[CH:21]=[CH:22][C:17]=2[O:16][C:15]=1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[NH:43][S:44]([C:47]([F:50])([F:49])[F:48])(=[O:46])=[O:45]>C1COCC1>[Br:13][C:14]1[C:18]2[CH:19]=[C:20]([CH2:23][N:24]3[C:28]([C:29]([NH2:3])=[O:31])=[C:27]([CH:32]4[CH2:33][CH2:34]4)[N:26]=[C:25]3[CH2:35][CH3:36])[CH:21]=[CH:22][C:17]=2[O:16][C:15]=1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[NH:43][S:44]([C:47]([F:49])([F:48])[F:50])(=[O:45])=[O:46]
Reactant: CCc1nc(C2CC2)c(C(=O)O)n1Cc1ccc2oc(-c3ccccc3NS(=O)(=O)C(F)(F)F)c(Br)c2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCc1nc(C2CC2)c(C(N)=O)n1Cc1ccc2oc(-c3ccccc3NS(=O)(=O)C(F)(F)F)c(Br)c2c1
Reaction time: 16 h
Yield: 100.2 %

Procedure:
1,1'-Carbonyldiimidazole (14.3 g) was added in one portion to a solution of the product of Example 5 (18 g) in dry THF (600 ml) at room temperature under nitrogen. The mixture was stirred for 16 h, then ammonia was bubbled through the solution for 30 mins, and the mixture then stirred for 5 h. Ammonia was again bubbled through the reaction mixture for 30 mins, and the solution stirred for a further 16 h. The reaction mixture was diluted with ethyl acetate (1 liter) and cooled in an ice-bath. Cold dilute hydrochloric acid (0.25M ca. 1 liter) was added dropwise to the vigorously stirred reaction mixture until pH6 was achieved. The aqueous phase was separated and extracted further with ethyl acetate (3×500 ml). The combined organic extracts were washed with brine (2×800 ml) and dried. The solvent was evaporated to give a colourless foam (18 g) which was triturated under ether (250 ml) and filtered to give a colourless amorphous solid (13.8 g), m.p. 155.6°-159.2°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:26])[C:3]=1[OH:27].Br[CH2:29][C:30]([O:32][CH3:33])=[O:31].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:26][C:4]1[CH:5]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=[C:2]([Br:1])[C:3]=1[O:27][CH2:29][C:30]([O:32][CH3:33])=[O:31]
Reactant: COC(=O)CBr
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Reaction time: 8 h
Yield: 98.2 %

Procedure:
2,6-Dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen- 11 -yl)-phenol (1.0 g, 1.78 mmol), methyl bromoacetate (0.35 mL, 3.70 mmol), potassium carbonate (0.50 g, 3.62 mmol) and N,N-dimethylformamide (5 mL) were combined and stirred at ambient temperatures overnight. The reaction mixture was added to water and filtered. The solid was washed with water and dried in vacuo to provide the title compound as a white solid (1.11 g, 98%): mp 183-184° C.: NMR (CDCl3); δ8.36 (ddd, J=8, 1, 1 Hz, 1 H), 7.84 (ddd, J=8, 1, 1 Hz, 1 H), 7.68 (ddd, J=8, 7, 1 Hz, 1 H), 7.62 (s, 2 H), 7.57 (ddd, J=8, 1, 1 Hz, 1 H), 7.51 (ddd, J=8, 7, 1 Hz, 1 H), 7.42 (ddd, J=8, 7, 1 Hz, 1 H), 7.18 (ddd, J=8, 7, 1 Hz, 1 H), 6.72 (ddd, J=8, 1, 1 Hz, 1 H), 4.88 (s, 2 H), 3.94 (s, 3 H); MS (EI): [M+], 3 bromine isotope pattern, 632 (30%), 634 (90%) 636 (100%) 638 (35%); Anal. Calc. for C25H15Br3O3S: C, 47.27, H, 2.38, N, 0.00. Found: C, 47.17, H, 2.19, N, 0.09.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[CH:34]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH:16]2[CH2:17][CH2:18]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[CH:34]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC2CC2)c(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Product: CC(C)(C)OC(=O)Nc1cc(OCC2CC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1

Procedure:
The title compound was prepared from (2-amino-5-cyclopropylmethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J29) (260 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (311 mg, 73%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](O)[C:5]2[N:13]3[C:8]([C:9]([C:14]4[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=4[CH3:22])=[CH:10][CH:11]=[CH:12]3)=[CH:7][C:6]=2[N:23]=1.OC1C2N3C(C=CC=C3)=C(C3C(C)=CC(C)=CC=3C)C=2N=C(C)C=1.P(Cl)(Cl)([Cl:51])=O>>[Cl:51][C:4]1[C:5]2[N:13]3[C:8]([C:9]([C:14]4[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=4[CH3:22])=[CH:10][CH:11]=[CH:12]3)=[CH:7][C:6]=2[N:23]=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(C)c(-c2cccn3c2cc2nc(C)cc(O)c23)c(C)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cc1cc(C)c(-c2c3nc(C)cc(O)c3n3ccccc23)c(C)c1
Product: Cc1cc(C)c(-c2cccn3c2cc2nc(C)cc(Cl)c23)c(C)c1
Temperature: 25 °C

Procedure:
Heat at 100° C. for 1 h a solution of 4-hydroxy-2-methyl-10-(2,4,6-trimethylphenyl)pyridino-[2,3-b]indolizine 2-methyl-9-(2,4,6-trimethylphenyl)pyrido[2,3-b]-indolizin-4-ol (10.1 g; 32 mmol) in phosphorus oxychloride (60 mL), cool to ambient temperature, and concentrate in vacuo. Partition the residue into ice water and CH2Cl2. Separate the aqueous phase, extract twice with CH2Cl2, and wash the combined organic extracts with a 1 N aqueous sodium hydroxide solution and then with water. Dry the solution over Na2SO4, filter, and concentrate in vacuo. Filter the dark residue through a short pad of silica gel and wash with 25% EtOAc in hexane. Concentrate the filtrate in vacuo to obtain the title compound as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 2.00 (s, 6 H), 2.37 (s, 3 H), 2.64 (s, 3 H), 6,58 (t, 1 H), 6.95 (dd, 1 H), 7,00 (s, 2 H), 7.07 (s, 1 H), 7.08 (d, 1 H), 9.26 (d, 1H).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:23]([O:27][C:28]([N:30]1[CH2:37][C@@H:36]([NH:38][C:39](=[O:49])[CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:35][C@@H:31]1[C:32](O)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24].[N:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:53]=[C:52]([NH:60][C:61](=[O:80])[C@@H:62]2[CH2:66][C@@H:65]([NH:67][C:68](=[O:79])[C@H:69]([OH:78])[CH2:70][CH2:71][C:72]3[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=3)[CH2:64][NH:63]2)[CH:51]=1>ClCCl.C(N(CC)CC)C>[N:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:53]=[C:52]([NH:60][C:61](=[O:80])[C@@H:62]2[CH2:66][C@@H:65]([NH:67][C:68](=[O:79])[C@H:69]([OH:78])[CH2:70][CH2:71][C:72]3[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=3)[CH2:64][N:63]2[C:32](=[O:33])[C@H:31]2[CH2:35][C@H:36]([NH:38][C:39](=[O:49])[CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37][N:30]2[C:28]([O:27][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:29])[CH:51]=1
Reactant: O=C(N[C@H]1CN[C@H](C(=O)Nc2cnc3ccccc3c2)C1)[C@H](O)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@H]1C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)N[C@H]1C[C@H](C(=O)N2C[C@H](NC(=O)[C@H](O)CCc3ccccc3)C[C@H]2C(=O)Nc2cnc3ccccc3c2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.9 %

Procedure:
Triethylamine (40 μL), 1-hydroxybenzotriazole (36 mg), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (55 mg) were added to a solution of N-tert-butoxycarbonyl-trans-4-(N-tert-butoxycarbonylglycylamino)-D-proline (F, 112 mg) and trans-4-((R)-2-hydroxy-4-phenylbutyrylamino)-L-proline 3-quinolylamide (Compound D101 (H), 100 mg) in dichloromethane (10 mL) at 0° C. The mixture was stirred at room temperature for 18 hr and evaporated in vacuo. The residue was diluted with ethyl acetate and washed with 1 N hydrochloric acid, water, saturated sodium hydrogen carbonate, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (methanol:chloroform=1:50 to 1:20, v/v) to give the title compound (124 mg) as a colorless solid: 1H NMR (400 MHz, CDCl3) δ 1.34-1.44 (m, 18H), 1.86-1.92 (m, 1H), 2.03-2.14 (m, 1H), 2.21-2.64 (m, 3H), 2.71-2.75 (m, 2H), 3.33-3.75 (m, 4H), 3.94-4.10 (m, 2H), 4.21-4.78 (m, 3H), 7.14-7.27 (m, 5H), 7.51-7.71 (m, 2H), 7.83-7.99 (m, 2H), 8.70-8.72 (m, 1H), and 8.96-9.05 (m, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:2].[OH:9][N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2C1=O.[N]=[O:22]>C(O)(=O)C>[N+:10]([CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:2])([O-:9])=[O:22].[OH:15][CH:14]([C:13]1[CH:12]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:1]
Reactant: [N]=O
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CCc1ccccc1
Solvent: CC(=O)O
Product: CC(O)c1ccccc1
Product: CC(c1ccccc1)[N+](=O)[O-]
Yield: 18 %
Yield: 14 %

Procedure:
Into a flask, 1 mmole of ethylbenzene, 0.05 mmole of N-hydroxyphthalimide and 5 ml of acetic acid were added to mix and the flask was equipped with a gas bag (about 1L)of nitrogen monoxide NO. The mixture was reacted for 8 hours at 100° C. with stirring. The reaction products were analyzed by gas chromatography, and, as a result, the conversion of ethylbenzene was 85%, and 1-nitroethylbenzene (yield 14%), 1-hydroxyethylbenzene (yield 18%) and 1-acetyloxyethylbenzene (yield 30%) were formed.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[S:11][CH:12]=1.F[C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[C:32]([C:29]1[CH:30]=[CH:31][C:26]([O:19][C:16]2[CH:17]=[CH:18][C:13]([C:10]3[S:11][CH:12]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[C:9]=3[CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:14][CH:15]=2)=[CH:27][CH:28]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)c1ccc(F)cc1
Reactant: COC(=O)Cc1c(-c2ccccc2Cl)csc1-c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COC(=O)Cc1c(-c2ccccc2Cl)csc1-c1ccc(Oc2ccc(C(C)=O)cc2)cc1
Yield: 61.4 %

Procedure:
To a solution containing methyl [4-(2-chlorophenyl)-2-(4-hydroxyphenyl)thien-3-yl]acetate (0.50 g, 1.40 mmol) and 4′-fluoroacetophenone (0.195 g, 1.40 mmol) in DMA (5 mL) was added K2CO3 (0.211 g, 1.53 mmol). The solution was heated to reflux overnight. The solvent was removed and the resulting solid was partitioned between CHCl3 and H2O. The CHCl3 was dried (MgSO4) and the solvent removed to yield methyl [2-[4-(4-acetylphenoxy)phenyl]-4-(2-chlorophenyl)thien-3-yl]acetate (0.41 g) as a white solid.