Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([O:19][C@H:20]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33](OC)[CH:32]=4)=[CH:27][CH:26]=3)[C:21]([F:24])([F:23])[F:22])[N:16]=[C:15]([NH2:39])[N:14]=2)=[CH:9][CH:8]=1)[C:3]([O-:5])=[O:4].[CH3:40][C:41]1[CH:42]=[CH:43][C:44]([S:47]([OH:50])(=[O:49])=[O:48])=[CH:45][CH:46]=1.O.C(#N)C.O.C1C[O:59][CH2:58]C1>O.O.O.S(C1C=CC(C)=CC=1)(O)(=O)=O.N[C@@H](CC1C=CC(C2C=C(O[C@H](C3C=CC(C4C=CC=C(OC)C=4)=CC=3)C(F)(F)F)N=C(N)N=2)=CC=1)C(O)=O>[OH2:4].[OH2:48].[S:47]([C:44]1[CH:45]=[CH:46][C:41]([CH3:40])=[CH:42][CH:43]=1)([OH:50])(=[O:49])=[O:48].[NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([O:19][C@H:20]([C:25]3[CH:26]=[CH:27][C:28]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[CH:29][C:30]=3[O:59][CH3:58])[C:21]([F:22])([F:23])[F:24])[N:16]=[C:15]([NH2:39])[N:14]=2)=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4]
Reactant: C1CCOC1
Reactant: COc1cccc(-c2ccc([C@@H](Oc3cc(-c4ccc(C[C@H](N)C(=O)[O-])cc4)nc(N)n3)C(F)(F)F)cc2)c1
Agent: COc1cccc(-c2ccc([C@@H](Oc3cc(-c4ccc(C[C@H](N)C(=O)O)cc4)nc(N)n3)C(F)(F)F)cc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: COc1cc(-c2ccccc2)ccc1[C@@H](Oc1cc(-c2ccc(C[C@H](N)C(=O)O)cc2)nc(N)n1)C(F)(F)F
Temperature: 50 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
(S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxybiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoate (120.0 g, 88 w %, 105.6 g active, 196 mmol) was added to a solution of TsOH.H2O (39.8 g, 209 mmol) in a mixture of THF (240 mL) and water (48 mL). The mixture was heated to 50° C. to give a homogeneous solution. Approximately 120 mL of a mixture of ACN/water (1200/60 mL) was added and the mixture was seeded with (S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxybiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoate tosylate dihydrate (0.63 g). After aging for 1 hour at 40° C., a nice slurry was obtained. The remaining ACN/water mixture was added slowly over 3 hours at 40° C. and the slurry was aged at 40° C. for 2 hours then slowly cooled to 20° C. and aged overnight. The solid was collected by filtration and the filter cake was washed with 5/1 ACN/THF with ˜5 vol % water (500 mL). Air drying at room temperature overnight gave 138.5 g of the product as a white solid (99.5 A %, 93.4% yield corrected for purity). Loss in the mother liquor and wash was 6.5%. KF of solid was 4.4%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[F:17].Cl[C:19]1[CH:20]=[C:21]([CH2:25][N:26]2[CH:30]=[CH:29][N:28]=[C:27]2[CH3:31])[N:22]=[N:23][CH:24]=1>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:19]2[CH:20]=[C:21]([CH2:25][N:26]3[CH:30]=[CH:29][N:28]=[C:27]3[CH3:31])[N:22]=[N:23][CH:24]=2)=[CH:4][C:3]=1[F:17]
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: CC1(C)OB(c2ccc(Cl)c(F)c2)OC1(C)C
Product: Cc1nccn1Cc1cc(-c2ccc(Cl)c(F)c2)cnn1
Product: Cl

Procedure:
The title compound, MS: m/e=303.3 (M+H+), was prepared from 2-(4-chloro-3-fluoro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:16])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2O)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:19])=O.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:16])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2[Cl:19])=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cn2ncnc(O)c2c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn2ncnc(Cl)c2c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.7 %

Procedure:
A mixture of 4-hydroxy-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid ethyl ester (60.0 g, 271.2 mmol, for preparation see WO 0071129), phosphorus oxychloride (30.3 mL, 325.4 mmol) and diisopropylethyl amine (37.7 mL, 217 mmol) in toluene (800 mL) was heated to reflux under argon for 18 h and then cooled to room temperature. The mixture was concentrated on rotovap and the residue was diluted with dichloromethane (1000 mL) and cold sodium bicarbonate solution (300 mL). The resulting mixture was stirred at room temperature for 10 min. The separated organic layer was washed with cold brine (300 mL), dried, and concentrated in vacuo. The crude material was purified by chromatography on silica gel eluting with dichloromethane to provide the desired compound (64.8 g, 99%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:16][CH2:17][CH3:18])[N:5]([C:7]2[N:8]=[CH:9][S:10][C:11]=2[NH:12][C:13](=O)[CH3:14])[CH:6]=1.[P].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O=P(Cl)(Cl)Cl>[CH3:14][C:13]1[C:6]2[N:5]([C:4]([CH2:16][CH2:17][CH3:18])=[N:3][C:2]=2[CH3:1])[C:7]2[N:8]=[CH:9][S:10][C:11]=2[N:12]=1
Reactant: CCCc1nc(C)cn1-c1ncsc1NC(C)=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [P]
Solvent: O=P(Cl)(Cl)Cl
Product: CCCc1nc(C)c2c(C)nc3scnc3n12
Temperature: 110 °C
Yield: 52.6 %

Procedure:
To a solution of N-(4-(4-methyl-2-propyl-1H-imidazol-1-yl)thiazol-5-yl)acetamide from example 1.7 (10 mg, 0.038 mmol) in POCl3 (3 mL) was quickly added phosphorus P2O5 (10.74 mg, 0.076 mmol). The reaction mixture was refluxed at 110° C. for 4 h. POCl3 was evaporated and the residue was carefully quenched with ice-water. The mixture was neutralized with saturated Na2CO3 solution and extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with brine and concentrated to give brown liquid and then purified by pre-HPLC to give the title compound (5 mg, 0.02 mmol, 53.7%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[H-].[Na+].Cl[CH2:16][C:17]1[N:21]([CH:22]([CH3:24])[CH3:23])[N:20]=[N:19][N:18]=1.O>CN(C)C=O.ClCCl>[CH:22]([N:21]1[C:17]([CH2:16][N:9]2[C:10]3[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=3)[CH:7]=[CH:8]2)=[N:18][N:19]=[N:20]1)([CH3:24])[CH3:23]
Reactant: CC(C)n1nnnc1CCl
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)n1nnnc1Cn1ccc2cc([N+](=O)[O-])ccc21
Temperature: 60 °C
Reaction time: 1 h

Procedure:
1.5 Grams of 5-nitroindole was dissolved in 70 ml of dimethylformamide, then 370 mg of sodium hydride (in oil) was added thereto, the mixture was stirred under nitrogen gas stream at 60° C. for 1 hour. Under cooling at 0° C., 1.63 g of 5-chloromethyl-1-isopropyl-1,2,3,4-tetrazole was added, the reaction mixture was stirred at room temperature for 4.5 hours. After the reaction was finished, water was added to the reaction mixture, then the separated crystals were collected by filtration and washed with water. The crystals were dissolved in dichloromethane, the solution was dried with anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue obtained was subjected to a silica gel column chromatography (eluent: dichloromethane→3% methanol/dichloromethane), there was obtained 2.3 g of 1-(1-isopropyl-1,2,3,4-tetrazol-5-ylmethyl)-5-nitroindole as in the form of yellow powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17](O)=[O:18])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:20]([F:23])([F:22])[F:21])([O-:3])=[O:2].F[P-](F)(F)(F)(F)F.[N:31]1(OC(N(C)C)=[N+](C)C)[C:35]2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN>O1CCCC1.CN(C)C=O>[CH3:35][NH:31][C:17]([C@H:14]1[CH2:15][CH2:16][C@H:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:20]([F:23])([F:21])[F:22])[CH:6]=2)[CH2:12][CH2:13]1)=[O:18]
Reactant: O=C(O)[C@H]1CC[C@H](Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)[C@H]1CC[C@H](Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanecarboxylic acid (500 mg, 1.50 mmol, prepared in accordance with Example 42), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (570 mg, 1.5 mmol), and diisopropylethylamine (600 μL, 3.30 mmol) were dissolved in dry tetrahydrofuran (10 mL). The resulting mixture was stirred at room temperature for 10 min, and then cooled to 0° C. A solution of methylamine in tetrahydrofuran (750 μL, 2M, 1.50 mmol) and dimethylformamide (1 mL) was added, and the resulting mixture was stirred at room temperature for 3 hr. The mixture was then concentrated under vacuum. The resulting residue was taken up in dichloromethane (25 mL), and the organic phase was washed with water (10 mL), and then with aqueous saturated hydrogencarbonate (3×10 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was diluted in dioxane (5 mL), and a concentrated solution of HCl in dioxane was added (10 mL, 4N). A precipitate formed, which was then washed with diethylether (10 mL) and dried under vacuum. The desired product was isolated as a yellow solid (498 mg, 87% yield).
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:13]1([C:19]#[CH:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(NCC)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:13]1([C:19]#[C:20][C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCOC(=O)c1ccc(C#Cc2ccccc2)cc1
Temperature: 60 °C
Yield: 173.2 %

Procedure:
To a solution of ethyl 4-iodobenzoate (5.0 g, 18.2 mmol) in DMF (8 mL) was added phenylacetylene (2.25 g, 22.1 mmol), Pd(Ph3P)4 (502 mg, 0.45 mmol), CuI (172 mg, 0.91 mmol) and diethylamine (2 mL). The reaction vessel was sealed and heated at 60° C. for 1 h in a microwave reactor. The reaction was cooled to room temperature, diluted with EtOAc:hexanes (2:1, 150 mL) and washed with water (2×100 mL) and brine (100 mL). The organic phase was dried over MgSO4, filtered and concentrated under vacuum. The crude product was purified by column chromatography (silica gel) using 0 to 10% EtOAc/hexanes to afford ethyl 4-(phenylethynyl)benzoate (7.89 g, 86%) as a pale yellow solid; 1H-nmr (400 MHz, CDCl3) δ 8.05 (d, J=8.0 Hz, 2H), 7.61 (d, J=8.0 Hz, 2H), 7.56 (dd, J=8.0, 2.0 Hz, 2H), 7.41-7.37 (m, 3H), 4.41 (q, J=7.0 Hz, 2H), 1.44 (t, J=7.0 Hz, 3H); LC (275 nM) 5.79 min (>98%); MS (ESI) m/z=250.9.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:31])[CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][CH2:14][C@H:13]([NH:22][C:23](OC(C)(C)C)=[O:24])[C:12]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN([CH:35]=[O:36])C.[C:37](Cl)(=O)[C:38](Cl)=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:31])[CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]([CH:35]=[O:36])[CH2:14][C@H:13]([NH:22][C:23]([C:1]2[C:37]3[C:38](=[CH:21][CH:16]=[CH:17][CH:18]=3)[CH:4]=[CH:3][CH:2]=2)=[O:24])[C:12]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Solvent: ClCCl
Product: O=CN1C[C@H](NC(=O)c2cccc3ccccc23)C(=O)N(CC(=O)OCc2ccccc2)c2ccccc21

Procedure:
was synthesized from 600b by methods similar to those used to make 602n from 600b, using the reagent obtained from reacting DMF with 3 equiv. of oxalyl chloride in a CH2Cl2 solution as R3X, to afford 404 mg of 652.
Reaction SMILES: Br[C:2]1[C:3](=[O:32])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[CH3:59][O:60][C:61]1[N:66]=[C:65](B(O)O)[CH:64]=[CH:63][CH:62]=1>>[F:17][C:15]1[CH:16]=[C:11]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][CH:22]4[CH2:23][CH2:24][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:26][CH2:27]4)=[CH:7][CH:8]=3)[C:3](=[O:32])[C:2]=2[C:64]2[CH:65]=[N:66][C:61]([O:60][CH3:59])=[CH:62][CH:63]=2)[CH:12]=[C:13]([F:18])[CH:14]=1
Reactant: COc1cccc(B(O)O)n1
Reactant: CS(=O)(=O)N1CCC(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2cc(F)cc(F)c2)CC1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: COc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCC4CCN(S(C)(=O)=O)CC4)cc3C2=O)cn1
Yield: 59 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-{2-[1-(methylsulfonyl)piperidin-4-yl]ethoxy}-1H-inden-1-one obtained in Step 3 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 6-methoxypyridinylboronic acid instead of 3-pyridinylboronic acid, and being purified by silica gel column chromatography (EtOAc/CH2Cl2=1:1) to obtain the title compound (59%).
Reaction SMILES: [NH2:1][C@@:2]([C:7]1[CH:12]=[C:11]([Br:13])[C:10]([F:14])=[CH:9][C:8]=1[F:15])([CH3:6])[CH2:3][CH2:4][OH:5].C[Si](N([Si](C)(C)C)C(=O)C(F)(F)F)(C)C.[C:31]([N:39]=[C:40]=[S:41])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[C:31]([NH:39][C:40]([NH:1][C@@:2]([C:7]1[CH:12]=[C:11]([Br:13])[C:10]([F:14])=[CH:9][C:8]=1[F:15])([CH3:6])[CH2:3][CH2:4][OH:5])=[S:41])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: C[C@](N)(CCO)c1cc(Br)c(F)cc1F
Agent: C[Si](C)(C)N(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: C1CCOC1
Product: C[C@@](CCO)(NC(=S)NC(=O)c1ccccc1)c1cc(Br)c(F)cc1F
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of (S)-3-amino-3-(5-bromo-2,4-difluoro-phenyl)-butan-1-ol (9.5 g, 34 mmoles, 1 equiv) in THF (50 mL) is added bis(trimethylsilyl)trifluoroacetamide (8.7 g, 34 mmol, 1 equiv). After 2 h, benzoyl isothiocyanate (5.5 g, 34 mmoles, 1 equiv) is added dropwise. The reaction is stirred 18 h, quenched with water, and extracted with ethyl acetate. The combined organic phases are extracted with 1 N HCl and saturated aqueous NaCl. The organic phase is dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (>95% yield, 90% purity as determined by LCMS): MS (m/z): 443, 445 (M+1).
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1)#[N:2].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:28]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([C:3]1[N:8]=[CH:7][C:6]([CH2:9][Br:28])=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1ccc(C#N)nc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)cn1
Yield: 50.8 %

Procedure:
A mixture of 6-cyano-3-picoline (1.32 g, 11.19 mmol), benzoylperoxide (0.54 g, 2.24 mmol), and N-bromosuccinimide (2.8 g, 15.7 mmol) in carbontetrachloride (30 mL) was heated at reflux for 2 h. The resulting suspension was filtered and the filtrate diluted with dichloromethane (400 mL), washed with a saturated sodium bicarbonate solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc:n-hexane, 1:9) to give the title compound as a yellow oil (1.12 g, 51%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:40]=[CH:39][C:18]([CH2:19][O:20][C:21]2[CH:25]=[C:24]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])[N:23]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:22]=2)=[CH:17][CH:16]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:40]=[CH:39][C:18]([CH2:19][O:20][C:21]2[CH:25]=[C:24]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[N:23]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:22]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)CCc1cc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nn1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2cc(CCC(=O)O)n(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
A mixture of ethyl 3-[3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-phenyl-1H-pyrazol-5-yl]propionate (950 mg), 1N aqueous sodium hydroxide solution (4 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 1 hr. 1N Hydrochloric acid (4 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give 3-[3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-phenyl-1H-pyrazol-5-yl]propionic acid (770 mg, yield 81%), which was then recrystallized from acetone-hexane. melting point: 154–155° C.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[N:29]1[CH2:36][C@H:35]2[NH:37][CH2:38][C@@H:30]1[CH2:31][CH:32]=[CH:33][CH2:34]2.CCN(C(C)C)C(C)C>C(O)C>[CH:9]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[C:6]([O:5][CH2:4][CH:2]([OH:1])[CH2:3][N:37]2[CH2:38][CH:30]3[N:29]([C:20]4[CH:21]=[CH:22][C:23]5[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:19]=4)[CH2:36][CH:35]2[CH2:34][CH:33]=[CH:32][CH2:31]3)=[CH:7][CH:8]=1
Reactant: C1=CC[C@H]2CN[C@@H](C1)CN2c1ccc2ccccc2c1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Agent: C1=C\C[C@H]2CN[C@@H](C/1)CN2c1ccc2ccccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: OC(COc1cccc2[nH]c3ccccc3c12)CN1CC2CC=CCC1CN2c1ccc2ccccc2c1
Temperature: 95 °C

Procedure:
(S)-4-Oxiranylmethoxy-9H-carbazole (18.5 mg, 0.077 mmol) and Z-(1S,6S)-7-naphthalen-2-yl-7,9-diaza-bicyclo[4.2.2]dec-3-ene (20 mg, 0.189 mmol) were placed in a μW tube with ethanol (3 ml), DIPEA (15 μL, 0.086 mmol) and heated to 95° C. for 900 sec. The solvent was evaporated from the reaction mixture and the residue was purified via silica chromatography (30% Ethyl acetate/heptane) to yield the title compound as a residue.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([OH:12])[CH:5]=1)[CH3:2].[H-].[Na+].Br[CH2:18][CH2:19][OH:20]>CN(C)C=O>[CH2:13]([N:3]([CH2:1][CH3:2])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([O:12][CH2:18][CH2:19][OH:20])[CH:5]=1)[CH3:14]
Reactant: OCCBr
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(C=O)c(OCCO)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
To a solution of 4-diethylamino-2-hydroxybenzaldehyde (1.00 g, 5.17 mmol) in 10 mL of dry N,N-dimethylformamide was added sodium hydride (250 mg, 55%, 5.7 mmol) under nitrogen at 0° C. After the reaction mixture was stirred at room temperature for 30 min, 2-bromoethanol (1.1 mL, 15 mmol) was added with additional stirring at 50° C. overnight. After quench with NH4Cl aqueous solution at 0° C., the solution was extracted with ethyl acetate three times. The extracts were washed with saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=75/25 to 25/75) to obtain the title compound as a brown gum (566 mg, 46%).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].CC(=C)C[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19].[C:23]1([CH3:33])[C:24](S(O)(=O)=O)=CC=C[CH:28]=1>CCOCC>[C:23]([C:9]1[C:10]([OH:12])=[CH:11][C:5]([C:1]([CH3:4])([CH3:2])[CH2:3][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:6]([OH:7])[CH:8]=1)([CH3:33])([CH3:24])[CH3:28]
Reactant: CC(C)(C)c1cc(O)ccc1O
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: C=C(C)CCCC(=O)OC
Solvent: CCOCC
Product: COC(=O)CCCC(C)(C)c1cc(O)c(C(C)(C)C)cc1O

Procedure:
16.6 Parts of 2-t-butylhydroquinone, 14.2 parts of methyl 5-methyl-hex-5-enoate and 0.5 part of p.toluene sulphonic acid are heated on a steam-bath for 24 hours. The reaction mixture is then taken up in ether, washed with dilute sodium hydroxide solution, and then with water. After removing ether and lower boilers, distillation gave methyl 5-(4-t-butyl-2,5-dihydroxy-phenyl)-5-methyl-hexanoate, [formula (124)], b0.3 186°-210° C. This fraction after crystallisation from petroleum ether, had a m.p. 136°-139° C. and the following percentage composition by weight:
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[C:8]([Br:18])[CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.Cl[CH2:20][CH2:21][O:22][CH2:23][CH2:24]Cl.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Br:18][C:8]1[CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]2[NH:12][C:13]3[C:5]([C:6]=2[CH:7]=1)=[CH:4][CH:3]=[C:2]([N:1]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH:14]=3
Reactant: NC(=O)c1cc(Br)cc2c1[nH]c1cc(N)ccc12
Reactant: ClCCOCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Br)cc2c1[nH]c1cc(N3CCOCC3)ccc12
Temperature: 200 °C

Procedure:
7-Amino-3-bromo-9H-carbazole-1-carboxamide (250 mg, 0.822 mmol), 1-chloro-2-(2-chloroethoxy)ethane (0.387 mL, 3.29 mmol), sodium carbonate (697 mg, 6.58 mmol) were mixed in DMF (4 mL) in a sealed microwave vial. The vial was degassed and filled with N2. The mixture was heated in microwave at 200° C. for 2 hrs. The mixture was purified using preparative HPLC to give titled product. MS (ESI) m/z 374.01 (M+H)+.
Reaction SMILES: OO.[N:3]1([CH2:9][CH2:10][NH:11][C:12]2[N:13]=[N+:14]([O-:25])[C:15]3[CH:24]=[C:23]4[C:19]([CH2:20][CH2:21][CH2:22]4)=[CH:18][C:16]=3[N:17]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.C([O-])([O-])=[O:27].[Na+].[Na+]>C(O)(C(F)(F)F)=O.O>[N:3]1([CH2:9][CH2:10][NH:11][C:12]2[N:13]=[N+:14]([O-:25])[C:15]3[CH:24]=[C:23]4[C:19]([CH2:20][CH2:21][CH2:22]4)=[CH:18][C:16]=3[N+:17]=2[O-:27])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: [O-][n+]1nc(NCCN2CCOCC2)nc2cc3c(cc21)CCC3
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: [O-][n+]1nc(NCCN2CCOCC2)[n+]([O-])c2cc3c(cc21)CCC3
Temperature: 20 °C
Reaction time: 26 h
Yield: 36 %

Procedure:
H2O2 (70%, 0.50 mL, ca. 10.0 mmol) was added to a stirred solution of 1-oxide 44 (3.00 g, 9.52 mmol) in a mixture of TFA (30 mL) and water (2 mL) at 20° C. Ten more aliquots of 70% H2O2 (0.5 mL) were added in 30 min intervals and the reaction mixture was stirred at 20° C. for 26 h. Water (100 mL) was added and the mixture made basic with Na2CO3. The mixture was extracted with DCM (4×200 mL) and the combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give 1,4-dioxide 45 (1.13 g, 36%) as a red solid: 1H NMR δ 8.13 (s, 1H, H-9), 8.10 (s, 1H, H-5), 7.38 (br s, 1H, NH), 3.73 (t, J=4.5 Hz, 4H, CH2O), 3.67 (m, 2H, CH2N), 3.03-3.15 (m, 4H, H-6, H-8), 2.68 (t, J=6.0 Hz, 2H, CH2N), 2.53 (t, J=4.5 Hz, 4H, CH2N), 2.17-2.25 (m, 2H, H-7); 13C NMR δ 155.7, 149.4, 145.9, 137.9, 129.7, 115.8, 111.6, 65.9 (2), 56.8, 53.4 (2), 37.7, 33.4, 32.4, 25.6. The hydrochloride salt was crystallised as a red solid: mp (MeOH/DCM) 184-185° C. Anal. calcd for C16H21N5O3.¾HCl: C, 53.5; H, 6.2; N, 19.5. Found: C, 53.9; H, 6.3; N, 19.6%.