Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(C([C@@H:17]([CH2:48][CH:49]([CH3:51])[CH3:50])[C:18]([NH:20][N:21]([CH2:44][CH:45]([CH3:47])[CH3:46])[C:22](=[O:43])[C@@H:23]([CH3:42])[NH:24][C:25]([O:27][CH2:28][CH:29]1[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:26])=[O:19])C/C=C/C1SC=CC=1)=O)(C)(C)C.Br>ClCCl.C(O)(=O)C>[CH2:44]([N:21]([C:22](=[O:43])[C@@H:23]([CH3:42])[NH:24][C:25]([O:27][CH2:28][CH:29]1[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:26])[NH:20][C:18](=[O:19])[CH2:17][CH2:48][CH:49]([CH3:51])[CH3:50])[CH:45]([CH3:46])[CH3:47]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@@H](C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C/C=C/c1cccs1)C(=O)OC(C)(C)C
Agent: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)CCC(=O)NN(CC(C)C)C(=O)[C@@H](C)NC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 1.5 h

Procedure:
A solution of 1.04 g of (E)-2(R)-[1(RS)-[(tert.butyloxy)carbonyl]-4-(2-thienyl)-3-butenyl]-2′-isobutyl-2′-[N-(9-fluorenylmethyloxycarbonyl)-D-alanyl]-4-methylvalerohydrazide in 50 ml of dichloromethane was treated with 1.0 ml of a 33% solution of hydrogen bromide in acetic acid at −15° C. The mixture was stirred at this temperature for 1.5 hours and then washed with water and dried over anhydrous magnesium sulfate. Evaporation was followed by addition of hexane and filtration of the resulting precipitate. The precipitate was dried to give 0.665 g of (E)-2(R)-[1(RS)-(carboxy)]-4-(2-thienyl)-3-butenyl]-2′-isobutyl-2′-[N-(9-fluorenylmethyloxycarbonyl)-D-alanyl]-4-methylvalerohydrazide in the form of a light brown solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].[F:12][C:13]1[C:20]([F:21])=[CH:19][CH:18]=[C:17]([O:22][CH3:23])[C:14]=1[CH2:15]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH2:15][C:14]1[C:17]([O:22][CH3:23])=[CH:18][CH:19]=[C:20]([F:21])[C:13]=1[F:12]
Reactant: COc1ccc(F)c(F)c1CBr
Reactant: O=C(O)c1ccc(F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(F)c(F)c1COc1cc(C(=O)O)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
A suspension of 4-fluoro-3-hydroxybenzoic acid (0.19 g), 2,3-difluoro-6-methoxybenzyl bromide (0.6 g) and potassium carbonate (0.5 g) in N,N-dimethylformamide (3 mL) was stirred at room temperature for 8 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (6 mL). To the solution were added methanol (3 mL), water (3 mL) and lithium hydroxide-monohydrate (0.5 g), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 1 mol/L hydrochloric acid (15 mL), and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was suspended in a mixed solvent (n-hexane/ethyl acetate=4/1) and collected by filtration, and dried under reduced pressure to give 4-fluoro-3-(2,3-difluoro-6-methoxybenzyloxy)benzoic acid (0.31 g). This material was dissolved in 1,4-dioxane (4 mL). To the solution were added triethylamine (0.41 mL) and diphenylphosphoryl azide (0.21 mL), and the mixture was stirred at room temperature for 1 hour. Then the mixture was heated for reflux for 4 hours. To the reaction mixture was added 1 mol/L aqueous sodium hydroxide solution (4 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1−1/1) to give crude product. To the crude product was added methylene chloride, and the insoluble material was removed by filtration.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:6](O)=O.FC1C=[C:24](C=CC=1OCCN1CCCCC1)[CH2:25][NH:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=1>>[CH2:25]([N:26]([CH2:6][C:5]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:3]([F:2])[CH:4]=1)[C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=1)[CH3:24]
Reactant: COc1ccc(-c2ccc3ccccc3c2)c(NCc2ccc(OCCN3CCCCC3)c(F)c2)c1
Reactant: O=C(O)c1ccc(OCCN2CCCCC2)c(F)c1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(OC)ccc1-c1ccc2ccccc2c1

Procedure:
Synthesized from 5-methoxy-2-naphthalen-2-ylamine and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 114, [3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl](5-methoxy-2-naphthalen-2-ylphenyl)amine (290 mg) was used according to an analogous synthetic method to Example 36 to provide ethyl[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl](5-methoxy-2-naphthalen-2-ylphenyl)amine (252 mg). This compound (250 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (222 mg).
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]([F:24])[F:23])=[C:16]([Cl:25])[CH:15]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>>[Cl:25][C:16]1[CH:15]=[C:14]([CH:12]([N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:26]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:27])[C:7]=3[CH2:8]2)[CH3:13])[CH:19]=[CH:18][C:17]=1[O:20][CH2:21][CH:22]([F:24])[F:23]
Reactant: O=COc1ccccc1
Reactant: CC(c1ccc(OCC(F)F)c(Cl)c1)N1Cc2c(ccnc2Cl)C1=O
Product: CC(c1ccc(OCC(F)F)c(Cl)c1)N1Cc2c(ccnc2C(=O)Oc2ccccc2)C1=O
Yield: 70 %

Procedure:
The title compound is prepared in 70% yield (86 mg, yellow oil) from 4-chloro-2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (100 mg, 0.26 mmol, Intermediate-25, single enantiomer) and phenyl formate (63 mg, 0.52 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: C(OC([N:8]1[N:17](C(OC(C)(C)C)=O)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.O=S(Cl)Cl>CO>[CH2:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][NH:17][NH:8]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2CN1C(=O)OC(C)(C)C
Solvent: CO
Solvent: O=S(Cl)Cl
Product: c1ccc2c(c1)CNNC2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1,4-dihydrophthalazine-2,3-dicarboxylic acid di-tert-butyl ester, 4, (1.0 g, 3 mmol) is dissolved in MeOH (20 mL) and SOCl2 (0.5 mL) added dropwise. After stirring at room temp for 72 hours, the solvent is removed in vacuo to afford 0.6 g of the desired product as white solid.
Reaction SMILES: CN(C=O)C.[Br:6]N1C(=O)CCC1=O.[C:14]1([C:20]2[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=2[OH:30])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[Br:6][C:22]1[CH:23]=[C:24]([C:26]([CH3:27])([CH3:29])[CH3:28])[CH:25]=[C:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:21]=1[OH:30]
Reactant: CC(C)(C)c1ccc(O)c(-c2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cc(Br)c(O)c(-c2ccccc2)c1
Reaction time: 48 h

Procedure:
A 20 mL DMF solution of N-bromosuccinimide (4.07 g, 22.9 mmol) was slowly added to a DMF solution (100 mL) of 2-phenyl-4-tert-butyl-phenol (4.93 g, 21.8 mmol), forming a dark green solution. After stirring in the dark for 48 h, the resultant dark red solution was poured into 500 mL of water, forming a cloudy solution. This was extracted with 95:5 hexane/toluene (3×200 mL), dried over MgSO4, filtered and the solvent removed to give 7 as a thick red oil. Yield: 6.32 g (95%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[S:14][CH2:13][CH2:12][O:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1C=C(C=CC=1)C(OO)=[O:20].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[S:14](=[O:20])[CH2:13][CH2:12][O:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(C2COCCS2)cc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S1CCOCC1c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
A stirred solution of 3-(3,4-dichlorophenyl)-1,4-oxathiane (1 g, 4 mmol) in dichloromethane (10 ml) at 0° C. was treated with a solution of meta-chloroperoxybenzoic acid (85%, 860 mg, 4 mmol) in dichloromethane (10 ml) and stirred at 0° C. for 30 mins then at room temperature for 3 hrs. The mixture was shaken with aqueous sodium bicarbonate solution and the organic phase separated, dried (MgSO4) and evaporated to give a solid which was triturated with hexane/toluene (1:1) to give 3-(3,4-dichlorophenyl)-1,4-oxathiane 4-oxide (860 mg), as a colourless crystalline solid, m.p. 100°-103° C.;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[S:11]([OH:14])(=[O:13])=[O:12].C(Cl)(Cl)Cl.[N+:19]([O-])([OH:21])=[O:20]>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([N+:19]([O-:21])=[O:20])=[CH:5][C:4]=1[S:11]([OH:14])(=[O:13])=[O:12]
Reactant: COc1ccc(S(=O)(=O)O)c(OC)c1
Reactant: O=[N+]([O-])O
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: COc1cc(OC)c(S(=O)(=O)O)cc1[N+](=O)[O-]

Procedure:
To a solution prepared by adding 90 g of 2,4-dimethoxybenzenesulfonic acid obtained in Step (1) above to 200 ml of chloroform, was added 225 ml of nitric acid (d=1.42) with stirring. The reaction mixture was stirred at 25° to 30° C. for 2 hours and 300 ml of acetonitrile was added thereto. The crystals thus-precipitated were collected by filtration and washed with 100 ml of acetonitrile.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][C:29]1[C:30]([CH:36]=O)=[N:31][CH:32]=[C:33]([CH3:35])[CH:34]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH2:36][C:30]2[C:29]([CH3:28])=[CH:34][C:33]([CH3:35])=[CH:32][N:31]=2)[CH2:15][C:16]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cnc(C=O)c(C)c1
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ncccc2-c2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CN(Cc2ncccc2-c2ccccc2)C2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1

Procedure:
Using General Procedure B: Reaction of the amine from above and 3,5-dimethyl-2-pyridinecarboxaldehyde in CH2Cl2 with NaBH(OAc)3 gave 4-[(3,5-dimethyl-pyridin-2-ylmethyl)-(3-phenyl-pyridin-2-ylmethyl)amino]-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[C:33][C:34]3[CH:35]=[CH:36][C:37]([CH2:40][CH2:41][CH:42]=O)=[N:38][CH:39]=3)=[N:30][CH:31]=2)=[CH:22][CH:21]=1.[CH3:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[C:33][C:34]3[CH:35]=[CH:36][C:37]([CH2:40][CH2:41][CH2:42][N:48]4[CH2:49][CH2:50][CH:45]([CH3:44])[CH2:46][CH2:47]4)=[N:38][CH:39]=3)=[N:30][CH:31]=2)=[CH:22][CH:21]=1
Reactant: CC1CCNCC1
Reactant: O=CCCc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC1CCN(CCCc2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
74 mg (0.35 mmol) of sodium triacetoxyborohydride and 41 μL (0.73 mmol) of HOAc were added to a solution of 100 mg (0.288 mmol) of 3-{5-[5-(4-chlorophenyl)pyridin-2-ylethynyl]pyridin-2-yl}propionaldehyde and 34 μL (0.288 mmol) of 4-methylpiperidine in 6 mL of THF and the mixture was stirred for 16 hours at RT. Saturated aqueous sodium bicarbonate solution was added and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried over magnesium sulfate and evaporated down in vacuo. Yield: 44 mg (35% of theoretical); C27H28ClN3 (M=429.984); calc.: molpeak (M+H)+: 430/432 (Cl); found: molpeak (M+H)+: 430/432 (Cl); HPLC-MS: 7.65 minutes (method A).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH3:13][CH2:14][O:15][C:16](/[CH:18]=[CH:19]/[CH2:20]P(OCC)(OCC)=O)=[O:17].[H-].[Na+].Cl>CN(C)C=O>[CH:1]([O:4][C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[CH:20]/[CH:19]=[CH:18]/[C:16]([O:15][CH2:14][CH3:13])=[O:17])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Reactant: CC(C)Oc1ccc(C=O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/C=C/c1ccc(OC(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.6 %

Procedure:
To a mixture of 4-isopropoxybenzaldehyde (15.0 g), triethyl 4-phosphonocrotonate (27.3 g) and N,N-dimethylformamide (DMF) (100 ml) was added oily sodium hydride (60%, 4.38 g), and the mixture was stirred for 16 hours at room temperature. The reaction mixture was poured into ice-water, and neutralized with 2N-HCl. The mixture was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate (MgSO4). The solvent was distilled off and the residue was subjected to column chromatography. From the fractions eluted with ether-hexane, ethyl (E,E)-5-(4-isopropoxyphenyl)-2,4-pentadienoate (13.7 g, 58%) was obtained. Recrystallization from ether-hexane gave colorless prisms. Melting point 64°-65° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]#[CH:12])=[CH:9][S:8][C:7]=1[NH2:13])=[O:5])[CH3:2].I[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(NC(C)C)(C)C>CC#N.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]#[C:12][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][S:8][C:7]=1[NH2:13])=[O:5])[CH3:2]
Reactant: C#Cc1csc(N)c1C(=O)OCC
Reactant: Ic1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC#N
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1c(C#Cc2ccccc2)csc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
2-Amino-4-ethynyl-thiophene-3-carboxylic acid ethyl ester (0.075 g, 0.385 mmol) was dissolved in anhydrous CH3CN (2.0 mL). This was treated with iodobenzene (0.129 mL, 1.15 mmol) followed by diisopropylamine (0.272 mL, 1.92 mmol). The solution was then degassed and treated with copper iodide (0.0018 g, 0.010 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.014 g, 0.019 mmol). The reaction was then stirred at room temperature for 30 min. The reaction was concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 15 EtOAc/85 hexanes) to afford the title compound (0.081 g, 78%). MS m/e (CI) 272.0 (M+H)+.
Reaction SMILES: [ClH:1].[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[NH2:11].Cl.[N:13]1([C:18](=N)[NH2:19])C=CC=N1.C(N(C(C)C)CC)(C)C>C(#N)C>[ClH:1].[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[NH:11][C:18]([NH2:19])=[NH:13]
Reactant: N=C(N)n1cccn1
Reactant: NC1Cc2ccccc2C1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)NC1Cc2ccccc2C1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
Stir a solution of 2,3-dihydro-1H-inden-2-amine hydrochloride (197 g; 1.08 equiv; 1.16 moles), 1H-pyrazole-1-carboximidamide hydrochloride (158 g; 1.00 equiv; 1.08 moles) and diisopropylethylamine (400 g; 2.87 equiv; 3.09 moles; 539.74 mL) in acetonitrile (2 L) at 62° C. for 2 hours, during which time a white solid precipitates. Cool the mixture to 25° C., then filter and wash with 300 mL acetonitrile and 300 mL methyltert-butyl ether. Dry the product in air at 25° C. for 1 h to afford the title compound (200 g, 87%) as a white solid. MS (m/z): 176 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]([C:19](O)=[O:20])=[CH:17][C:12]3[C:13]([CH3:16])=[N:14][O:15][C:11]=3[C:10]=2[F:22])=[C:4]([Cl:23])[CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[CH:41]1([CH2:44][O:45][NH2:46])[CH2:43][CH2:42]1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.CCOC(C)=O>[CH:41]1([CH2:44][O:45][NH:46][C:19]([C:18]2[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[Cl:23])=[C:10]([F:22])[C:11]3[O:15][N:14]=[C:13]([CH3:16])[C:12]=3[CH:17]=2)=[O:20])[CH2:43][CH2:42]1
Reactant: Cc1noc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(=O)O)cc12
Reactant: NOCC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1noc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(=O)NOCC3CC3)cc12
Reaction time: 144 h
Yield: 47.1 %

Procedure:
To a solution of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxylic acid (9a) (50.0 mg, 0.125 mmol) in DMF (1 mL) was added HOBt (24.6 mg, 0.161 mmol), Et3N (0.060 mL, 0.43 mmol), O-cyclopropylmethyl-hydroxylamine (15.5 mg, 0.178 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (32.2 mg, 0.168 mmol) at room temperature. After 6 days, the reaction mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl, brine, saturated aqueous NaHCO3, and brine. The organic layer was dried over MgSO4, filtered, concentrated in vacuo, and purified by flash column chromatography using the Biotage system (0.5% MeOH in CH2Cl2) to give 27.6 mg (47% yield) of the desired product (10a). MS APCI (−) m/z 466, 468 (M+, Br, Cl pattern) detected. 1H NMR (400 MHz, CD3OD) δ 7.82 (s, 1H), 7.57 (d, 1H), 7.31 (dd, 1H), 6.74 (dd, 1H), 3.73 (d, 2H), 2.60 (s, 3H), 1.16 (m, 1H), 0.55 (m, 2H), 0.28 (m, 2H). 19F NMR (376 MHz, CD3OD)−140.96 (s, 1F).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][C@@:9]12[C@@H:25]([OH:26])[CH2:24][CH2:23][C@H:22]1[C@H:21]1[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([OH:27])=[CH:17][C:18]=3[CH2:19][CH2:20]1)[CH2:11][CH2:10]2.[CH3:28][C:29](C)=[O:30].C(Cl)Cl>N1C=CC=CC=1>[CH3:2][C:1]([O:26][CH:25]1[C:9]2([CH3:8])[CH2:10][CH2:11][CH:12]3[C:13]4[CH:14]=[CH:15][C:16]([O:27][C:29]([CH3:28])=[O:30])=[CH:17][C:18]=4[CH2:19][CH2:20][CH:21]3[CH:22]2[CH2:23][CH2:24]1)=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)=O
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1ccc2c(c1)CCC1C2CCC2(C)C(OC(C)=O)CCC12
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
Under nitrogen, acetic anhydride (50 mL, 264.5 mmol) was added to a solution of estradiol (1a) (20.0 g, 73.43 mmol) in dry pyridine (200 mL). The reaction mixture was stirred at room temperature overnight (16 h). The next morning, analysis by tlc (5% acetone/CH2Cl2) indicated a complete reaction. The mixture was cooled in an ice bath and the excess acetic anhydride quenched by addition of methanol (25 mL). The mixture was stirred at 0° C. for one hour and then allowed to warm to room temperature. The solvents were removed in vacuo and the solid residue crystallized from hot methanol to give the pure diacetate (2a) (24.87 g, 95%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C@:13]([F:15])([CH3:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[C:21]([C:27](O)=[O:28])=[N:22][CH:23]=[C:24]([Cl:26])[CH:25]=1>>[NH2:16][C:10]1[O:11][CH2:12][C@@:13]([F:15])([CH3:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:21]3[C:20]([Cl:19])=[CH:25][C:24]([Cl:26])=[CH:23][N:22]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1ncc(Cl)cc1Cl
Reactant: C[C@]1(F)COC(N)=N[C@]1(C)c1cc(N)ccc1F
Product: C[C@]1(F)COC(N)=N[C@]1(C)c1cc(NC(=O)c2ncc(Cl)cc2Cl)ccc1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (A8.3) and 3,5-dichloro-pyridine-2-carboxylic acid following procedure I yielded the title compound as a colorless solid. MS (ISP): m/z=429.2[M+H]+ and 431.1 [M+2+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-:15].[Na+]>[C].[Pd].[Pd].CO>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([OH:15])=[CH:3][CH:4]=4)=[CH:9][CH:10]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: [OH-]
Agent: [Pd]
Agent: [Na+]
Solvent: CO
Product: Oc1ccc(-c2ccc(-c3ccc(-c4ccc(O)cc4)cc3)cc2)cc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Into an 1-liter stainless steel autoclave were added 60.0 g of 4-hydroxy-4'-bromobiphenyl, 100 g of methanol, 300 g of a 10% (by weight) aqueous solution of sodium hydroxide, and 13 g of a palladiumcarbon containing 5% by weight of palladium and a reaction was carried out at 120° C. for 4 hours under 5 atmospheric pressures. The precipitated disodium salt of 4,4'''-dihydroxy-p-quaterphenyl was filtered and dissolved into N,N-dimethyl-formamide. The catalyst was removed by filtration with heating at 60° C. An addition of dilute sulfuric acid to the filtrate gave white crystalline powder of 4,4'''-dihydroxy-p-quaterphenyl (DHQ), which was purified by washing with methanol. The liquid-crystal transition temperature of the DHQ was 336° C. ##STR24##
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(O)C=CC=CC=1.[C:15]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)([CH3:17])=[CH2:16]>Cl.OC1C=CC(C(C2C=CC(O)=CC=2)(C)C)=CC=1>[OH:24][C:21]1[CH:22]=[CH:23][C:18]([C:15]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)([CH3:17])[CH3:16])=[CH:19][CH:20]=1
Reactant: Nc1ccccc1
Reactant: C=C(C)c1ccc(O)cc1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: Cl
Solvent: Oc1ccccc1
Product: CC(C)(c1ccc(N)cc1)c1ccc(O)cc1
Temperature: 180 °C
Reaction time: 2 h
Yield: 378.5 %

Procedure:
Ten grams of aniline was added to a mixture consisting of 13.0 g of phenol, 3.4 g of p-isopropenyl phenol monomer, 8.5 g of a linear dimer of p-isopropenyl phenol, 1.1 g of a linear trimer of p-isopropenyl phenol and 0.8 g of a linear tetramer and higher polymers of p-isopropenyl phenol (1.05 mole of aniline per mole of the p-isopropenyl phenol monomeric unit). The mixture was stirred at 180° C. Then, 0.2 g of 10% hydrochloric acid (0.0053 mole per mole of the p-isopropenyl phenol monomeric unit) was added, and the reaction was performed for 2 hours. Gas-chromatographic analysis of the reaction mixture showed that 0.38 g of bisphenol A and 21.8 g (yield 93%) of 2-(4'-hydroxyphenyl)-2-(4'-aminophenyl)-propane were formed.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH:2]=1.ClN1C(=[O:22])CCC1=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C:8]2=[O:22])[CH:2]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: c1cncc(-n2ccc3ccccc32)c1
Product: O=C1Cc2ccccc2N1c1cccnc1
Yield: 59 %

Procedure:
1-(pyridin-3-yl)-1H-indole is reacted with N-chlorosuccinimide as described in Example 12 to give 1-(pyridin-3-yl)-1,3-dihydroindol-2-one (59% yield) as a light brown solid.