Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]1([CH3:19])[C:16](=[O:17])[CH:15]=[C:14]([CH3:18])[O:13]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[CH:18][C:14]1[O:13][C:12]([CH3:19])([CH3:11])[C:16](=[O:17])[CH:15]=1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CC1=CC(=O)C(C)(C)O1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)OC(C=Cc2ccc(Cl)cc2Cl)=CC1=O
Temperature: 60 °C
Yield: 69.9 %

Procedure:
To a solution of 2,4-dichlorobenzaldehyde (2.3 g, 13.2 mM) and 2,2,5-trimethyl-3(2H)-furanone (2.0 g, 15.9 mM) in ethanol (100 mL), was added 1N aqueous sodium hydroxide (1.6 mL, 1.6 mM). The reaction solution was heated at 60° C. for 4 hours. After the reaction solution was cooled, saturated aqueous sodium chloride (400 mL) was added. The aqueous layer was extracted with diethyl ether (3×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a yellow solid. The crude product was triturated with 10% diethyl ether/pet. ether to afford a light yellow powder (2.6 g, 70% yield), m.p. 154°-156° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14].[OH-].[K+].Cl>CS(C)=O.O>[N+:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-:10])=[CH:6][C:5]=1[CH2:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1
Reactant: O=S(=O)(CCl)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc[n+]([O-])cc1CS(=O)(=O)c1ccccc1
Reaction time: 0.75 h
Yield: 41 %

Procedure:
Adapting the procedure of Makosza, et al, Liebigs Ann. Chem., 1984, 8–14, a stirred mixture of 4-nitro-pyridine-N-oxide (1.40 g, 10.0 mmol) and chloromethylphenylsulfone (1.92 g, 10.0 mmol) in DMSO (25 mL) in a cold water bath is treated with a solution of KOH (4.0 g, 71 mmol) in DMSO, stirred for 45 min, poured into 1.0 M hydrochloric acid and water and extracted with CH2Cl2. The aqueous phase is filtered and the filtercake is dried in vacuo to afford the title compound, 1.20 g (41% yield). The organic extracts are combined, dried over MgSO4 and concentrated in vacuo. The resultant wet solid is heated in boiling ethanol:water (4:1) and filtered. The filtrate is cooled, concentrated and filtered. This filtercake is dried in vacuo to afford an additional portion of the title compound, 0.967 g (74% total yield), mp 219–220° C., identified by mass spectral and HNMR analyses.
Reaction SMILES: [Br:1][C:2]([Br:12])=[CH:3][C@H:4]1[C@@H:6]([C:7]([O-:9])=[O:8])[C:5]1([CH3:11])[CH3:10].[Cl:13]/[CH:14]=[CH:15]\[CH2:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]O)=[CH:19][CH:18]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:1][C:2]([Br:12])=[CH:3][C@H:4]1[C@@H:6]([C:7]([O:9][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([CH2:16]/[CH:15]=[CH:14]\[Cl:13])=[CH:18][CH:19]=2)=[O:8])[C:5]1([CH3:10])[CH3:11]
Reactant: CC1(C)[C@H](C(=O)[O-])[C@@H]1C=C(Br)Br
Reactant: OCc1ccc(C/C=C\Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)[C@H](C(=O)OCc2ccc(C/C=C\Cl)cc2)[C@@H]1C=C(Br)Br
Reaction time: 0.5 h

Procedure:
To a solution of (1R)cis 3(2,2-dibromovinyl)-2,2-dimethylcyclopropane carboxylate (0.11 g) in CH2Cl2 (3 ml) cooled to 0° is added successively 4(Z-3-chloroallyl) benzyl alcohol (0.070 g) in CH2Cl2 (2 ml), N,N1 dicyclohexylcarbodiimide (0.076 g) in CH2Cl2 (2 ml), and 4-dimethylamino pyridine (0.010 g). This mixture is stirred for 30 minutes at 0°, then for 16 hours at 20°. The resulting precipitate is filtered off, the filtrate evaporated under reduced pressure and the residue chromatographed on florisil. The fraction eluted by 7% diethyl ether in petroleum ether bp 60°-80° C. ether in petrol is evaporated to a residue of 4(-3-chloroallyl)benzyl (1R)-3(2,2-dibromovinyl)-2,2-dimethylcyclopropane carboxylate (0.15 g) 91% nD20 1.5684.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[N:10]2[C:11](=[O:28])[C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[N:13][C:14]([Cl:15])=[C:9]2[C@@:8]([NH:30][C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])([CH3:29])[CH2:7]1)=[O:5])C.[OH-].[Li+]>C1COCC1.CO.O.CCOC(C)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:34]([O:33][C:31]([NH:30][C@@:8]1([CH3:29])[C:9]2=[C:14]([Cl:15])[N:13]=[C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=3)[C:11](=[O:28])[N:10]2[C@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1)=[O:32])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCOC(=O)[C@@H]1C[C@@](C)(NC(=O)OCc2ccccc2)c2c(Cl)nc(OCc3cccc(C(F)(F)F)c3)c(=O)n21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@]1(NC(=O)OCc2ccccc2)C[C@@H](C(=O)O)n2c1c(Cl)nc(OCc1cccc(C(F)(F)F)c1)c2=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
In a flask (6S,8R)-8-benzyloxycarbonylamino-1-chloro-8-methyl-4-oxo-3-(3-trifluoromethyl-benzyloxy)-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrazine-6-carboxylic acid ethyl ester (50 mg, 0.0862 mmol) was dissolved in THF (800 μL) and 2 drops MeOH and cooled to 0° C. Lithium hydroxide (260 μL, 0.259 mmol) 1.0 M in water was added and the mixture allowed to stir for approximately 2 h at 0° C. TLC indicated complete reaction. The mixture was diluted with EtOAc and 5% citric acid was added. The mixture was separated and the aqueous layer extracted 1× with EtOAc. The organics were dried with Na2SO4 filtered and concentrated to give the product as a white solid (47 mg, 99% yield). 1HNMR (300 MHz, CD3OD) δ 1.6(s, 3H) 2.25 (m, 1H) 2.95(m, 1H) 4.63 (s, 2H) 5.05 (m, 2H) 7.25–7.8 (m, 9H)
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12]([NH2:14])[C:11]([NH2:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](O)=O.[OH-].[Na+]>P(Cl)(Cl)(Cl)=O>[O:1]([C:8]1[N:13]=[C:12]2[N:14]=[C:21]([C:20]3[CH:24]=[CH:25][CH:26]=[C:18]([O:17][CH3:16])[CH:19]=3)[NH:15][C:11]2=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(C(=O)O)c1
Reactant: Nc1ccc(Oc2ccccc2)nc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc(-c2nc3nc(Oc4ccccc4)ccc3[nH]2)c1
Temperature: 140 °C
Reaction time: 4 h
Yield: 24 %

Procedure:
6-Phenoxy-2,3-pyridine diamine (Compound of Reference Example 115) (0.2 g) and 3-methoxybenzoic acid (0.08 g) were dissolved in phosphorus oxychloride (5 ml) and the solution was stirred at 140° C. for 4 hours. The reaction mixture was poured onto ice, neutralized with 8 N sodium hydroxide solution and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with water and dried over MgSO4. The solvent was distilled off under reduced pressure, and the resulting crystals were collected by filtration to obtain 5-phenoxy-2-(3-methoxyphenyl)-1H-imidazo[4,5-b]pyridine (0.04 g, 23%).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:9]=[C:10]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[C:23]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:22]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70].CO>C(Cl)Cl>[Br:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][C:58]1[C:59]([O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])=[CH:60][C:61]2[C:26]3[C:21](=[CH:22][C:23]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:25]=3)[C:10]3[C:11](=[CH:12][C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:9]=3)[C:62]=2[CH:63]=1
Reactant: CCCCCCOc1ccccc1CCCCCCCCCCCCCCCCBr
Reactant: CCCCCCOc1ccc(-c2ccc(OCCCCCC)c(OCCCCCC)c2)cc1OCCCCCC
Solvent: CO
Solvent: ClCCl
Product: CCCCCCOc1cc2c(cc1CCCCCCCCCCCCCCCCBr)c1cc(OCCCCCC)c(OCCCCCC)cc1c1cc(OCCCCCC)c(OCCCCCC)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 988 %

Procedure:
In 40 mL of methylene chloride, 5.70 g (10 mmol) of 3,3′,4,4′-tetrakishexyloxybiphenyl and 15.3 g (31 mmol) of 1-(16-bromohexadecyl)-2-hexyloxybenzene were dissolved. Under argon, 10.0 g (62 mmol) of FeCl3 was added to the solution, and the solution was stirred at ambient temperature for three hours. The resulting reaction mixture was put into 800 mL of methanol and filtered to obtain 102 g of a solid. The solid was purified by silica-gel column chromatography to obtain a yellow solid. The yellow solid was recrystallized from ethanol and 8.2 g of a white solid was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH:4]=[C:5]([C:7]1[CH:31]=[CH:30][C:10]2[S:11][CH:12]=[C:13]([C:14]3[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:17]=[C:16]([CH:23]([CH3:25])[CH3:24])[C:15]=3[O:26]COC)[C:9]=2[CH:8]=1)[CH3:6]>CO.Cl>[CH3:1][O:2][C:3](=[O:32])[CH:4]=[C:5]([C:7]1[CH:31]=[CH:30][C:10]2[S:11][CH:12]=[C:13]([C:14]3[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:17]=[C:16]([CH:23]([CH3:24])[CH3:25])[C:15]=3[OH:26])[C:9]=2[CH:8]=1)[CH3:6]
Reactant: COCOc1c(-c2csc3ccc(C(C)=CC(=O)OC)cc23)cc(C(C)C)cc1C(C)C
Agent: Cl
Solvent: CO
Product: COC(=O)C=C(C)c1ccc2scc(-c3cc(C(C)C)cc(C(C)C)c3O)c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-[3-(3,5-Di-iso-propyl-2-methoxymethoxy-phenyl)-benzo[b]thien-5-yl]-but-2-enoic acid methyl ester (15 mg, 0.033 mmol) was dissolved in methanol (5 ml) and 2 drops of concentrated HCl was added. This mixture was stirred at ambient temperature for 4 h then concentrated in vacuo. The residue was passed over a silica gel plug (50% ethyl acetate in hexane) to yield a quatitative amount of 3-[3-(2-hydroxy-3,5-di-iso-propylphenyl)-benzo[b]thien-5-yl]-but-2-enoic acid methyl ester as a white solid which was used without further purification. 1H NMR (250 MHz, CDCl3): δ 7.96 (d, 1H, J=11.2), 7.77 (d, 1H, J=0.6), 7.75-7.61 (m, 2H), 7.18 (d, 1H, J=3.1), 7.05 (d, 1H, J=3.1), 6.20 (d, 1H, J=1.2), 5.05 (bs, 1H), 3.77 (s, 3H), 3.38 (m, 1H), 2.94 (m, 1H), 2.62 (d, 3H, J=1.2), 1.36 (s, 3H), 1.34 (s, 3H), 1.33 (s, 3H), 1.31 (s 3H). MS [EI+] 426 (M+H2O)+, [EI−] 407 (M−1)−.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]([F:46])([F:45])[C:9]1[CH:10]=[C:11]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:12][NH:13][CH2:14][C:15]1[C:16]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[CH2:27][CH2:26]2)=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2.Cl[C:48]([O:50][CH2:51][CH3:52])=[O:49].O>C1COCC1>[CH2:51]([O:50][C:48](=[O:49])[N:13]([CH2:12][C:11]1[CH:38]=[C:39]([C:41]([F:44])([F:42])[F:43])[CH:40]=[C:9]([C:8]([F:7])([F:45])[F:46])[CH:10]=1)[CH2:14][C:15]1[C:16]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]3)[CH2:27][CH2:26]2)=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:52]
Reactant: FC(F)(F)c1cc(CNCc2cc3ccccc3nc2N2CCN(CC3CCCCC3)CC2)cc(C(F)(F)F)c1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc2ccccc2nc1N1CCN(CC2CCCCC2)CC1
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
Anhydrous potassium carbonate (0.17 g, 1.23 mmol) was added to a solution of (3,5-bis-trifluoromethyl-benzyl)-[2-(4-cyclohexylmethyl-piperazin-1-yl)-quinolin-3-ylmethyl]-amine (0.23 g, 0.4 mmol) in anhydrous THF (5 mL). After stirring 0.5 h, ethyl chloroformate (0.06 mL, 0.6 mmol) was added slowly under a nitrogen atmosphere. After stirring at RT for overnight, water (25 mL) was added, and the mixture was extracted with ethyl acetate (3×25 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give a colorless liquid. Purification by silica gel chromatography and eluting with 10-30% ethyl acetate/hexane afforded the desired final product as a viscous liquid (0.206 g, yield: 81%).
Reaction SMILES: C[O:2][C:3]([C@@:5]12[CH2:23][C@H:22]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH3:24])[C:14](=[O:25])[N:13]1[C@@H:8]([CH2:9][C@H:10]([O:26][C:27]3[C:36]4[C:31](=[C:32]([CH3:39])[C:33]([O:37][CH3:38])=[CH:34][CH:35]=4)[N:30]=[C:29]([C:40]4[S:41][CH:42]=[C:43]([C:45]#[CH:46])[N:44]=4)[CH:28]=3)[CH2:11][CH2:12]1)[C:7](=[O:47])[NH:6]2)=[O:4].[Li+].[OH-].Cl>O1CCCC1.O>[C:45]([C:43]1[N:44]=[C:40]([C:29]2[CH:28]=[C:27]([O:26][C@H:10]3[CH2:9][C@@H:8]4[N:13]([C:14](=[O:25])[N:15]([CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH:21][C@H:22]5[C@:5]([C:3]([OH:4])=[O:2])([NH:6][C:7]4=[O:47])[CH2:23]5)[CH2:12][CH2:11]3)[C:36]3[C:31](=[C:32]([CH3:39])[C:33]([O:37][CH3:38])=[CH:34][CH:35]=3)[N:30]=2)[S:41][CH:42]=1)#[CH:46]
Reactant: C#Cc1csc(-c2cc(O[C@@H]3CCN4C(=O)N(C)CCCCC=C[C@@H]5C[C@@]5(C(=O)OC)NC(=O)[C@@H]4C3)c3ccc(OC)c(C)c3n2)n1
Agent: C#Cc1csc(-c2cc(O[C@@H]3CCN4C(=O)N(C)CCCC/C=C\[C@@H]5C[C@@]5(C(=O)O)NC(=O)[C@@H]4C3)c3ccc(OC)c(C)c3n2)n1
Agent: C#Cc1csc(-c2cc(O[C@@H]3CCN4C(=O)N(C)CCCC/C=C\[C@@H]5C[C@@]5(C(=O)OC)NC(=O)[C@@H]4C3)c3ccc(OC)c(C)c3n2)n1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1csc(-c2cc(O[C@@H]3CCN4C(=O)N(C)CCCCC=C[C@@H]5C[C@@]5(C(=O)O)NC(=O)[C@@H]4C3)c3ccc(OC)c(C)c3n2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of compound 37 (0.11 g, 1 eq.) and LiOH (0.022 g, 5 eq.) in a mixture of tetrahydrofuran (5 mL) and water (5 mL) was stirred at room temperature overnight. HCl (1N) was added and the mixture was extracted with dichloromethane. Dried organics were evaporated in vacuo. The crude residue was purified by chromatography on silica gel to give compound 38 in 46% yield. MS (ESI, EI+) m/z=644 (MH+).
Reaction SMILES: [Cl:1]N(Cl)S(C1C=CC(C)=CC=1)(=O)=O.Cl.[CH2:15]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([OH:38])=[O:37])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(O)(=O)C>[Cl:1][C:25]1[CH:26]=[C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([OH:38])=[O:37])=[CH:32][CH:31]=2)[CH:28]=[CH:29][C:24]=1[O:23][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)N(Cl)Cl)cc1
Agent: Cl
Solvent: CC(=O)O
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1Cl
Reaction time: 8 h
Yield: 128.2 %

Procedure:
N,N-dichloro-p-toluenesulfonamide (hereinafter abbreviated to "dichloramine T") (7.5 g, 0.032 mol) was dissolved in acetic acid (100 ml), followed by adding to the solution, hydrochloric acid (0.4 ml), dropwise adding to the acetic acid solution of dichloramine T, a solution of 4'-octyloxy-4-biphenylcarboxylic acid (20 g, 0.063 mol) dissolved in acetic acid (100 ml), refluxing the mixture, allowing it to stand overnight, distilling off acetic acid and filtering off deposited crystals to obtain 3'-chloro-4'-octyloxy-4-biphenylcarboxylic acid (14.8 g) (C-Sc 146° C., Sc '-N' 224° C. and N'-I 232° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:20](=[O:29])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:6]([N:8]([C:15](=[O:19])[C:16](Cl)=[O:17])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[CH3:30][O:31][CH2:32][CH2:33][OH:34].CCN(CC)CC>C1COCC1>[CH3:30][O:31][CH2:32][CH2:33][O:34][C:16](=[O:17])[C:15]([N:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[C:20](=[O:29])[CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:19]
Reactant: COCCO
Reactant: O=C(Cl)C(=O)N(c1ccccc1)c1cc(F)ccc1C(=O)CCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCOC(=O)C(=O)N(c1ccccc1)c1cc(F)ccc1C(=O)CCc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of {[5-fluoro-2-(3-phenyl-propionyl)-phenyl]-phenyl-amino}-oxo-acetyl chloride (540 mg) in THF (3 mL) was added 2-methoxyethanol (0.12 mL), followed by Et3N (0.22 mL). The reaction mixture became a pale yellow slurry: additional THF (2 mL) was added, and the mixture allowed to stand for 1 h. The mixture was then quenched with NH4Cl (sat'd aq), extracted with EtOAc, washed with brine, and concentrated to yield N-[5-fluoro-2-(3-phenyl-propionyl)-phenyl]-N-phenyl-oxalamic acid 2-methoxy-ethyl ester (504 mg) as an oil.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][N:33]([CH3:37])[C:34](Cl)=[O:35]>>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=4)[CH:18]=[C:19]([CH:27]3[CH2:31][CH2:30][N:29]([C:34]([N:33]([CH3:37])[CH3:32])=[O:35])[CH2:28]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: CN(C)C(=O)Cl
Reactant: Nc1ncnn2c(C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Product: CN(C)C(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Yield: 34.1 %

Procedure:
(5-(2-benzyl-2H-indazol-6-yl)-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (75 mg, 0.183 mmol) was reacted with dimethylcarbamoyl chloride (14 uL, 0.192 mmol), according to the procedure of Example 126. The crude product was triturated with 1:1 ether-hexanes to yield (30 mg, 34%) desired product. 1H NMR (300 MHz, DMSO-d6) δ 8.53 (s, 1 H), 7.91 (s, 1 H), 7.81 (d, 1 H), 7.59 (s, 1H), 7.45-7.32 (m, 6 H), 7.13 (d, 1 H), 6.65 (s, 1 H), 5.64 (s, 2 H), 3.76 (m, 2 H), 3.42 (m, 3 H), 3.29 (m, 1 H), 2.73 (s, 6 H), 2.31-1.95 (m, 2 H); ES-MS m/z 481.2 [M+H]+, HPLC RT (min) 2.57.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8].[OH-].[Na+]>O1CCCC1>[NH2:1][C:2]1[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1ccccc1Oc1ccc(C(F)(F)F)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1cc(C(F)(F)F)ccc1Oc1ccccc1C(=O)O

Procedure:
Methyl 2-(2-amino-4-trifluoromethylphenoxy)benzoate (11.68 g, 0.0375 mol) was mixed in tetrahydrofuran (175 ml) and sodium hydroxide (77 ml) at 40° C. for sixteen hours. The solvents were evaporated and water added to the residue. 3N hydrochloric acid was then added to the mixture until the maximum precipitate was given. The aqueous mixture was extracted with ethyl acetate (3×) and the organic phase dried over MgSO4 and evaporated. The residue was flash chromatographed (silica gel, methylene chloride/ethanol/ammonium hydroxide) to give the title compound. 1H NMR (250 MHz, CD3OD) δ7.90 (dd, 1H), 7.5 (tt, 1H), 7.2 (tt, 1H), 7.09 (d, 1H), 6.95 (dd, 1H), 6.85 (dd, 1H), 6.75 (d, 1H).
Reaction SMILES: C(OC(=O)CCCOC1C=CC=C(CCCCCCOC2C=C([C:33]3[CH:38]=[CH:37][C:36](F)=[C:35]([F:40])[CH:34]=3)C=C(C(=O)N(C)C)C=2)C=1CCC(OCC)=O)C.[CH2:49]([O:51][C:52](=[O:98])[CH2:53][CH2:54][CH2:55][O:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][O:69][C:70]2[CH:75]=[C:74]([C:76](=[O:89])[NH:77][CH2:78][C:79]3[CH:84]=[CH:83][CH:82]=[CH:81][C:80]=3[O:85][CH:86]([F:88])[F:87])[CH:73]=[C:72](Br)[CH:71]=2)[C:58]=1[CH2:91][CH2:92][C:93]([O:95][CH2:96][CH3:97])=[O:94])[CH3:50].FC1C=CC=CC=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:49]([O:51][C:52](=[O:98])[CH2:53][CH2:54][CH2:55][O:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][O:69][C:70]2[CH:71]=[C:72]([C:36]3[CH:37]=[CH:38][CH:33]=[CH:34][C:35]=3[F:40])[CH:73]=[C:74]([C:76](=[O:89])[NH:77][CH2:78][C:79]3[CH:84]=[CH:83][CH:82]=[CH:81][C:80]=3[O:85][CH:86]([F:88])[F:87])[CH:75]=2)[C:58]=1[CH2:91][CH2:92][C:93]([O:95][CH2:96][CH3:97])=[O:94])[CH3:50]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N(C)C)cc(-c3ccc(F)c(F)c3)c2)c1CCC(=O)OCC
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)NCc3ccccc3OC(F)F)c2)c1CCC(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)NCc3ccccc3OC(F)F)cc(-c3ccccc3F)c2)c1CCC(=O)OCC
Yield: 84 %

Procedure:
The title compound was prepared by the same method as 4-{3-[6-(5-dimethylcarbamoyl-3′,4′-difluoro-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester starting from 4-[3-{6-[3-bromo-5-(2-difluoromethoxy-benzylcarbamoyl)-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (150 mg, 0.196 mmol), 2-fluoro-phenylboronic acid (55 mg, 0.392 mmol), PdCl2(dppf) (29 mg, 0.04 mmol) and cesium carbonate (128 mg, 0.392 mmol) in 1,2-dimethoxyethane (5.0 mL) to obtain 4-[3-{6-[5-(2-difluoromethoxy-benzylcarbamoyl)-2′-fluoro-biphenyl-3-yloxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (128 mg, 84%) as a colorless oil.
Reaction SMILES: [OH-].[Na+].OO.[CH3:5][C:6]1([CH3:34])[CH2:11][O:10][CH:9]([CH:12]([C@@H:14]2[C@:31]3([CH3:32])[C@H:17]([C@H:18]4[C@H:28]([CH2:29][CH2:30]3)[C@:26]3([CH3:27])[C:21](=[CH:22][C:23](=[O:33])[CH:24]=[CH:25]3)[CH:20]=[CH:19]4)[CH2:16][CH2:15]2)[CH3:13])[O:8][CH2:7]1.C(OCC)(=[O:37])C.CCCCCC>CO.O>[CH3:34][C:6]1([CH3:5])[CH2:7][O:8][CH:9]([CH:12]([C@@H:14]2[C@:31]3([CH3:32])[C@H:17]([C@H:18]4[C@H:28]([CH2:29][CH2:30]3)[C@:26]3([CH3:27])[C:21](=[CH:22][C:23](=[O:33])[C@@H:24]5[O:37][C@@H:25]53)[CH:20]=[CH:19]4)[CH2:16][CH2:15]2)[CH3:13])[O:10][CH2:11]1
Reactant: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCOC(C)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCCCCC
Product: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
A 10 weight % solution of sodium hydroxide in methanol (1.16 ml) and 6.36 ml of a 30 weight % solution of hydrogen peroxide in water (containing 62.3 mmoles of hydrogen peroxide) were added to a solution of 4.66 g (11.3 mmoles) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)pregna-1,4,6-trien-3-one in 150 ml of methanol and the mixture was stirred at room temperature for 16 hours. The reaction mixture thus obtained was diluted with water and after the methanol was partially distilled off under reduced pressure at room temperature, the residue was extracted with ether. The extract was washed successively with aqueous potassium iodide solution and aqueous sodium chloride solution and the organic layer was dried over magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: ethyl acetate/hexane=1:10, v/v) to recover 3.72 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-4,6-dien-3-one (yield: 77%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16](O)=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Br-].[K+].Cl[O-].[Na+].C(=O)(O)[O-].[Na+]>ClCCl.CC1(C)N([O])C(C)(C)CCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH:16]=[O:17])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(-c2ccc(F)cc2)cc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: ClCCl
Product: O=CCCc1ccc(-c2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of the compound obtained from step d above (0.7 g) in dichloromethane (10 mL), 2,2,6,6,-tetramethylpiperidine N-oxyl (4.74 mg) and potassium bromide (36.05 mg) were added at 0° C. under nitrogen atmosphere. Sodium hypochlorite (0.28 g, 4% solution) was added at pH 8-9 (maintained by adding aqueous sodium bicarbonate solution). The reaction mixture was stirred for 20 minutes at 0° C. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with saturated aqueous sodium bicarbonate solution, water, and brine. The organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford the title compound (0.55 g).