Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[O:14][N:15]=[C:16]([C:17]([OH:19])=O)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:20]1([CH2:23][NH2:24])[CH2:22][CH2:21]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[O:14][N:15]=[C:16]([C:17](=[O:19])[NH:24][CH2:23][CH:20]3[CH2:22][CH2:21]3)[C:10]=2[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCC1CC1
Reactant: CC(C)(C)OC(=O)N1CCc2onc(C(=O)O)c2C1
Product: CC(C)(C)OC(=O)N1CCc2onc(C(=O)NCC3CC3)c2C1
Yield: 78 %

Procedure:
In a manner similar to general method 1, 280 mg (1.0 mmol) of 6,7-dihydro-4H-isoxazolo[4,5-c]pyridine-3,5-dicarboxylic acid 5-tert-butyl ester were reacted with 90 μL of cyclopropylmethylamine to yield 260 mg (78% of theoretical) of 3-(cyclopropylmethyl-carbamoyl)-6,7-dihydro-4H-isoxazolo[4,5-c]pyridine-5-carboxylic acid tert-butyl ester, which were obtained in the form of a yellow oil.
Reaction SMILES: [NH2:1][C@H:2]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33](=[O:49])[N:34]([CH2:42][CH2:43][O:44][Si](C)(C)C)[CH2:35][CH2:36][O:37][Si](C)(C)C)=[CH:27][CH:26]=1)[C:3]([NH:5][C@H:6]([C:15]1[NH:19][C:18]2[CH:20]=[C:21]([I:24])[CH:22]=[CH:23][C:17]=2[N:16]=1)[C@H:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])=[O:4].[O:50]=[C:51](Cl)OC(Cl)(Cl)Cl>>[OH:37][CH2:36][CH2:35][N:34]([CH2:42][CH2:43][OH:44])[C:33](=[O:49])[CH2:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C@@H:2]2[C:3](=[O:4])[N:5]([C@H:6]([C:15]3[NH:19][C:18]4[CH:20]=[C:21]([I:24])[CH:22]=[CH:23][C:17]=4[N:16]=3)[C@H:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:8])[C:51](=[O:50])[NH:1]2)=[CH:26][CH:27]=1
Reactant: C[C@@H](c1ccccc1)[C@H](NC(=O)[C@H](N)c1ccc(OCC(=O)N(CCO[Si](C)(C)C)CCO[Si](C)(C)C)cc1)c1nc2ccc(I)cc2[nH]1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Product: C[C@@H](c1ccccc1)[C@@H](c1nc2ccc(I)cc2[nH]1)N1C(=O)N[C@H](c2ccc(OCC(=O)N(CCO)CCO)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 27.7 %

Procedure:
After cyclization of (R)-2-amino-2-(4-{[bis-(2-trimethylsilanyloxy-ethyl)-carbamoyl]-methoxy}-phenyl)-N-[(1S,2S)-1-(6-iodo-1H-benzoimidazol-2-yl)-2-phenyl-propyl]-acetamide with diphosgene was complete and the reaction mixture had been partitioned between ethyl acetate and ice/water (as described in example 1, step 1-G) 1N aqueous hydrochloric acid (20 mL) was added to the ethyl acetate extracts and the mixture was stirred at ambient temperature for 15 minutes. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL) and washed with brine (50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by gradient flash chromatography using silica gel eluted with from 0 to 10% v/v methanol in dichloromethane. The product containing fractions were combined and concentrated to give a solid which was triturated with a 1:1 v/v mixture of dichloromethane/ether (1 mL). The suspension was stirred for 1 hour then filtered and dried to give N,N-bis-(2-hydroxy-ethyl)-2-(4-{(R)-1-[(1S,2S)-1-(6-iodo-1H-benzoimidazol-2-yl)-2-phenyl-propyl]-2,5-dioxo-imidazolidin-4-yl}-phenoxy)-acetamide (30 mg, 27.7%).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[NH2:29][C:30]1[C:35]([OH:36])=[C:34]([F:37])[C:33]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[C:32]([CH3:44])[C:31]=1[C:45]#[N:46].[O:47]1[CH:51]=[CH:50][CH:49]=[C:48]1[CH2:52][C:53](O)=O>C(#N)C>[F:37][C:34]1[C:33]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[C:32]([CH3:44])[C:31]([C:45]#[N:46])=[C:30]2[C:35]=1[O:36][C:53]([CH2:52][C:48]1[O:47][CH:51]=[CH:50][CH:49]=1)=[N:29]2
Reactant: Cc1c(C#N)c(N)c(O)c(F)c1-c1ccccc1
Reactant: O=C(O)Cc1ccco1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)c(F)c2oc(Cc3ccco3)nc2c1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.5 %

Procedure:
With cooling with ice, 1-hydroxybenzotriazole (134 mg, 0.991 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (174 mg, 0.908 mmol) and triethylamine (127 μl, 0.980 mmol) were added to an acetonitrile (8 ml) solution of 4-amino-6-fluoro-5-hydroxy-2-methylbiphenyl-3-carbonitrile (I-41) (200 mg, 0.826 mmol) and 2-furylacetic acid (115 mg, 0.908 mmol), followed by stirring at room temperature for 16 hours. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, then concentrated under reduced pressure, and the resulting residue was dissolved in xylene (20 ml), then pyridinium p-toluenesulfonate (50 mg) was added, followed by heating under reflux in an oil bath at 160° C. for 1 hour. The reaction liquid was concentrated under reduced pressure, then the residue was dissolved in ethyl acetate, washed with saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=4:1, v/v) to obtain the entitled compound (155 mg, 57%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[N:18][CH:19]=3)[NH:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:33][C:34]([CH3:37])([OH:36])[CH3:35]>C(O)C.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:25][CH2:24][N:23]([CH2:33][C:34]([CH3:37])([OH:36])[CH3:35])[CH2:22][CH2:21]4)=[N:18][CH:19]=3)[NH:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(-c2c[nH]c(-c3ccc(N4CCNCC4)nc3)n2)cc1Cl
Reactant: CC(C)(O)CCl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(O)CN1CCN(c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)c[nH]3)cn2)CC1
Yield: 54.6 %

Procedure:
(Reference: Ind. Acad. Sci. 1939, 49, 101-4.) A solution of 1-{5-[4-(3,4-dichloro-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-piperazine (155 mg, 0.41 mmol), sodium carbonate (66 mg, 0.62 mmol, 1.5 equiv) and 1-chloro-2-methyl-propan-2-ol (51 μl, 53 mg, 0.50 mmol, 1.2 equiv) in 50% aqueous ethanol (20 ml) under nitrogen atmosphere was heated at reflux overnight. The reaction mixture was then diluted with brine and extracted with ethyl acetate (3×25 ml). The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash column chromatography (50% THF/0.5% ammonium hydroxide/hexanes) provided the desired product (100 mg, 54%). MS m/z 446 (M++1).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([CH2:14][C:15]3[CH:34]=[CH:33][C:18]4[C:19](=[C:29]([CH3:32])[C:30]#[N:31])[C:20]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=5[O:22][CH2:23][C:17]=4[CH:16]=3)=[C:9]([CH:11]3[CH2:13][CH2:12]3)[N:10]=2)[CH:5]=[CH:6][N:7]=1.[CH3:35][O-:36].[Na+].O>CO>[CH:11]1([C:9]2[N:10]=[C:3]3[C:2]([O:36][CH3:35])=[N:7][CH:6]=[CH:5][N:4]3[C:8]=2[CH2:14][C:15]2[CH:34]=[CH:33][C:18]3/[C:19](=[C:29](/[CH3:32])\[C:30]#[N:31])/[C:20]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=4[O:22][CH2:23][C:17]=3[CH:16]=2)[CH2:13][CH2:12]1
Reactant: C[O-]
Reactant: CC(C#N)=C1c2ccc(Cc3c(C4CC4)nc4c(Cl)nccn34)cc2COc2cc(F)ccc21
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nccn2c(Cc3ccc4c(c3)COc3cc(F)ccc3/C4=C(\C)C#N)c(C3CC3)nc12
Temperature: 60 °C
Yield: 1 %

Procedure:
Using cyclopropanecarboxyaldehyde (0.586 mL, 7.74 mmol), 3-chloropyrazin-2-amine (739 mg, 5.7 mmol) and 2-(8-ethynyl-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (1.5 g, 5.18 mmol) obtained in Reference Example 9, and in the same manner as in Reference Example 8B, 2-{8-[(8-chloro-2-cyclopropylimidazo[1,2-a]pyrazin-3-yl)methyl]-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile was obtained. Successively, the obtained 2-{8-[(8-chloro-2-cyclopropylimidazo[1,2-a]pyrazin-3-yl)methyl]-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile was dissolved in methanol (1 mL), 28% sodium methoxide (0.3 mL, 0.425 mmol) was added, and the mixture was stirred with heating at 60° C. Water was added to the mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 v/v) to give the title compound (25 mg, 1%).
Reaction SMILES: C(O[CH:5]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)(=O)C.[CH3:19][N:20]([CH3:27])[CH:21]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]1>C1C=CC=CC=1>[CH:7]1[C:6]2[CH:5]([N:23]3[CH2:24][CH2:25][CH2:26][CH:21]([N:20]([CH3:27])[CH3:19])[CH2:22]3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)C1CCCNC1
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Solvent: c1ccccc1
Product: CN(C)C1CCCN(C2c3ccccc3Oc3ccccc32)C1

Procedure:
A solution of 9.92 g. (41.3 mmoles) of 9-acetoxyxanthene and 5.9 g. (46.1 mmoles) of 3-dimethylaminopiperidine in 200 ml. of benzene was refluxed for 18 hours. The mixture was then washed with aqueous sodium bicarbonate solution, dried, and evaporated. Chromatography on alumina (chloroform eluant) afforded 1-(9-xanthenyl)-3-dimethylaminopiperidine, as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[Ca+2].[Cl-]>C(O)C>[N:13]1([CH2:12][CH2:11][S:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: O=[N+]([O-])c1ccc(SCCn2ccnc2)cc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: Nc1ccc(SCCn2ccnc2)cc1
Temperature: 25 °C
Yield: 90.9 %

Procedure:
To 1-[2-[(4-nitrophenyl)sulfanyl]ethyl]imidazole (0.60 g) was added 85% ethanol solution (18 ml), and to this solution was added calcium chloride (0.13 g) and reduced iron (0.67 g), and the mixture was heated to reflux for 3 hours. After cooling to room temperature, the mixture was filtered with Celite, and washed with ethyl acetate. The solvent was removed under reduced pressure, and the obtained residue was dissolved in ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 4-[[2-(imidazol-1-yl)ethyl]sulfanyl]phenylamine (0.48 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[O:10](C(OC(C)(C)C)=O)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=O.C(N(CC)CC)C>CO>[C:11]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:10]
Reactant: NCCCCCC(=O)O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCCC(=O)O
Temperature: 60 °C
Reaction time: 12 h
Yield: 72 %

Procedure:
NH2—(CH2)5—COOH (5.00 g, 38.2 mmol), (BOC)2O (9.16 g, 42.0 mmol) and triethylamine (4.24 g, 42.0 mmol) were dissolved in 200 mL of methanol, and the mixture was stirred at 60° C. for 12 hours. After the reaction completed, methanol was removed under reduced pressure, and the obtained material was redissolved in 100 mL of ethyl acetate. Then, the solution was subjected to separation using 0.2 mol/l HCl (twice) and water (twice), and dehydrating was carried out with anhydrous sodium sulfate. After that, recrystallization with hexane at 4° C. and collection using a glass filter (G6) were performed, thereby obtaining Boc-NH—(CH2)5—COOH (6.35 g, 27.5 mmol, yield: 72%).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]([F:28])([F:27])[C:5]1[CH:6]=[C:7]([C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[CH:17]=2)[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1>CO.C(OCC)(=O)C>[F:3][C:4]([F:27])([F:28])[C:5]1[CH:6]=[C:7]([CH:15]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[CH:17]=2)[OH:26])[CH:8]=[C:9]([C:11]([F:13])([F:12])[F:14])[CH:10]=1
Reactant: Cc1cc(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(C(O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
Sodium borohydride (0.12 g) was added to a solution of 3′,5′-bis-trifluoromethyl-3-methyl-4-nitrobenzophenone (2.2 g) in methanol (10 ml) in an ice bath. After stirring at room temperature for 1 hour, and diluting with ethyl acetate, it was washed with water and a saturated salt solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off and the residue was purified by silica gel column chromatography to obtain (3,5-bis-trifluoromethylphenyl)(3-methyl-4-nitrophenyl)methanol (1.6 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([O:26][CH:23]1[CH2:24][CH2:25][N:20]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:21][CH2:22]1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1cccc([N+](=O)[O-])c1
Yield: 90.9 %

Procedure:
0.388 g (0.0021 mol) of 3-nitro-benzoyl chloride were dissolved in 20 ml of toluene under argon and treated while stirring with 0.5 g (0.0026 mol) of 1-benzyl-4-hydroxy-piperidine and 0.643 ml (0.0046 mol) of triethylamine. After boiling at reflux for 2 hrs. the suspension was filtered and the filtrate was completely freed from solvent. The residue was chromatographed over silica gel with ethyl acetate/hexane 1:2 as the eluent. 0.65 g (92%) of 1-benzyl-piperidin-4-yl 3-nitro-benzoate was obtained as a yellow oil. MS: mele (% basic peak)=340 (C19H20 N2O4+, 27), 263 (25), 173 (36.5), 150 (14.5), 91 (100), 82 (100).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[CH:9][N:10]=2)[CH:7]=1.C([Mg]Br)(C)C.C1(C)C=CC(S([C:26]#[N:27])(=O)=O)=CC=1.O>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:26]#[N:27])=[CH:9][N:10]=2)[CH:7]=1
Reactant: Brc1ccc2ncc(I)n2c1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cnc2ccc(Br)cn12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
Method 2) 80 g of 6-bromo-3-iodoimidazo[1,2-a]pyridine (compound in Production Example 49) was dissolved in 500 mL tetrahydrofuran, and 273 mL of 1.0 M isopropyl magnesium bromide in tetrahydrofuran was slowly added dropwise thereto at 0° C. and stirred for 30 minutes, and 380 mL of 68 g 4-toluenesulfonyl cyanide in tetrahydrofuran was added dropwise slowly over 1 hour, and the mixture was stirred for additional 1.5 hours. The reaction solution was poured into iced water, diluted with ethyl acetate and filtered through Celite. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate, and the collected organic layer was washed with brine. The organic layer was dried over anhydrous sodium sulfate and filtered through NH silica gel. Solid obtained by removing the solvent was triturated with diethyl ether, collected by filtration and washed with hexane to give 39.4 g of the title compound (brown solid).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=O)[CH:3]=[CH:2]1.[CH3:12][CH:13]([CH3:29])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:18]=1)=[O:15]>CC(O)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:10][N:26]2[CH2:27][CH2:28][CH:23]([C:19]3[CH:18]=[C:17]([NH:16][C:14](=[O:15])[CH:13]([CH3:12])[CH3:29])[CH:22]=[CH:21][CH:20]=3)[CH2:24][CH2:25]2)[CH:3]=[CH:2]1
Reactant: O=Cc1cccc2cc[nH]c12
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Solvent: CC(=O)O
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4cc[nH]c34)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R, without HOAc, using 1H-indole-7-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 376.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:18]3[N:25]([CH2:26][CH2:27][NH:28]C(=O)OC(C)(C)C)[CH:24]=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1.[ClH:36]>O1CCCC1>[ClH:36].[ClH:36].[ClH:36].[NH2:28][CH2:27][CH2:26][N:25]1[C:18]2[C:17]([NH:16][C:4]3[CH:5]=[CH:6][C:7]([O:8][C:9]4[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=4)=[C:2]([CH3:1])[CH:3]=3)=[N:22][CH:21]=[N:20][C:19]=2[CH:23]=[CH:24]1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccn(CCNC(=O)OC(C)(C)C)c34)cc2C)cn1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccn(CCN)c34)cc2C)cn1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
tert-Butyl {2-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}carbamate (790 mg) was dissolved in tetrahydrofuran (24 mL)/2N hydrochloric acid (12 mL), and the mixture was stirred at 60° C. for 16 hrs. The reaction mixture was concentrated under reduced pressure, ethanol (30 mL) was added to the residue and the mixture was concentrated again under reduced pressure. Ethyl acetate was added to the residue and the solid was collected by filtration and dried under reduced pressure to give the title compound (701 mg) as a solid powder.
Reaction SMILES: [H-].[Na+].C(OP(OCC)([C:8]1[CH:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=[CH:10][C:9]=1[CH3:19])=O)C.[C:23]([C:26]1[CH:27]=[CH:28][C:29]2[CH2:35][CH2:34][C:33]([CH3:37])([CH3:36])[CH2:32][CH2:31][C:30]=2[CH:38]=1)(=O)[CH3:24]>CN(C)C=O>[CH3:36][C:33]1([CH3:37])[CH2:32][CH2:31][C:30]2[CH:38]=[C:26](/[C:23](/[CH3:24])=[CH:19]/[C:9]3[CH:8]=[CH:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:10]=3)[CH:27]=[CH:28][C:29]=2[CH2:35][CH2:34]1
Reactant: CCOC(=O)c1ccc(C)c(P(=O)(OCC)OCC)c1
Reactant: CC(=O)c1ccc2c(c1)CCC(C)(C)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)CCC(C)(C)CC3)cc1
Reaction time: 2 h
Yield: 79.6 %

Procedure:
770 mg of sodium hydride (50% in mineral oil) are treated at room temperature under an argon atmosphere with 5.30 g of ethyl o-(diethoxyphosphinyl)-p-toluate. After stirring for 2 hours 2.55 g of 2-acetyl-6,7,8,9-tetra-hydro-7 7-dimethyl-5H benzocycloheptene, dissolved in small amount of dimethylformamide, are added dropwise. After 2 hours, the reaction mixture is poured on to ice and extracted with diethyl ether. The ethereal extract is washed with water, dried and evaporated. After chromatography on silica gel with petroleum ether (low-boiling)/ ethyl acetate (9:1), there are obtained 3.40 g of ethyl p-[(E)-2-(6,7,8,9-tetrahydro-7,7-dimethyl-5H-benzocyclo-hepten-2-yl)propenyl]benzoate of m.p. 87-°88° (from hexane).
Reaction SMILES: [Br:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]([CH3:29])([CH3:28])[C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH:21](C(O)=O)[C:22]([OH:24])=[O:23])[C:18]#[C:19][CH3:20])=[CH:13][CH:12]=2)=[O:9])=[C:4]([Cl:32])[CH:3]=1>O1CCOCC1>[Br:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]([CH3:28])([CH3:29])[C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([CH:17]([C:18]#[C:19][CH3:20])[CH2:21][C:22]([OH:24])=[O:23])=[CH:15][CH:16]=2)=[O:9])=[C:4]([Cl:32])[CH:3]=1
Reactant: CC#CC(c1ccc(NC(=O)C(C)(C)Oc2ccc(Br)cc2Cl)cc1)C(C(=O)O)C(=O)O
Solvent: C1COCCO1
Product: CC#CC(CC(=O)O)c1ccc(NC(=O)C(C)(C)Oc2ccc(Br)cc2Cl)cc1
Reaction time: 0.25 h
Yield: 54.3 %

Procedure:
A solution of 171 mg of 2-(1-{4-[2-(4-bromo-2-chlorophenoxy)-2-methylpropionylamino]phenyl}but-2-ynyl)malonic acid in 5 ml of dioxane was boiled at 120° C. for 17 h. The reaction mixture was concentrated and separated by means of preparative HPLC (Merck Hibar Purospher Star RP-18e 10 μm 25×250 mm; A: H2O+0.05% TFA; B: ACN+0.05% TFA; flow rate: 50 ml/min; in 15 minutes 10% B→90% B). The product fractions were freeze-dried to obtain 85 mg (54%) of 3-{4-[2-(4-bromo-2-chlorophenoxy)-2-methylpropionylamino]phenyl}hex-4-ynoic acid. C22H21BrClNO4 (478.77), LCMS (ESI-pos): 478/480/482 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:19]([Cl:20])=[CH:18][C:10]3[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[O:13][C:9]=3[C:8]=2[Cl:21])[N:5]=[C:4]([C:22]#[N:23])[CH:3]=1.[F:24][C:25]([F:30])([F:29])[S:26]([O-])=O.[Na+].S(C1C=CC(C)=CC=1)(O)(=O)=O.CNC.S(Cl)(Cl)=O>C1(C)C=CC=CC=1.O>[NH2:1][C:2]1[N:6]([C:7]2[C:19]([Cl:20])=[CH:18][C:10]3[C:11]([F:16])([F:17])[C:12]([F:14])([F:15])[O:13][C:9]=3[C:8]=2[Cl:21])[N:5]=[C:4]([C:22]#[N:23])[C:3]=1[S:26][C:25]([F:30])([F:29])[F:24]
Reactant: N#Cc1cc(N)n(-c2c(Cl)cc3c(c2Cl)OC(F)(F)C3(F)F)n1
Reactant: O=S([O-])C(F)(F)F
Agent: CNC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: O
Product: N#Cc1nn(-c2c(Cl)cc3c(c2Cl)OC(F)(F)C3(F)F)c(N)c1SC(F)(F)F
Temperature: 55 °C
Reaction time: 10 h
Yield: 24.6 %

Procedure:
To a suspension wherein 5-amino-3-cyano-1-(5,7-dichloro-2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran-6-yl)pyrazole (734 mg, 2.00 mmol), sodium trifluoromethanesulfinate (624 mg, 4.00 mmol) and dimethylamine tosylate (1.086 g, 5.00 mmol) are in toluene (5 ml), thionyl chloride (476 mg, 2.00 ml) was added dropwise under ice cooling over a period of about 10 minutes and then stirred at 50 to 60° C. for 10 hours. After allowing time to cool, the reaction solution was poured into water, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography to give 230 mg of 5-amino-3-cyano-1-(5,7-dichloro-2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran-6-yl)-4-trifluoromethylsulfenylpyrazole.
Reaction SMILES: [F:1][C:2]([F:44])([CH:41]([F:43])[F:42])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:31][C:32]3[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=3)([CH3:30])[C:25]([O:27]CC)=[O:26])=[CH:19][CH:18]=2)=[O:12])=[CH:7][N:6]=1.[OH-].[Na+]>>[F:44][C:2]([F:1])([CH:41]([F:42])[F:43])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][C:24]([O:31][C:32]3[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=3)([CH3:30])[C:25]([OH:27])=[O:26])=[CH:21][CH:22]=2)=[O:12])=[CH:7][N:6]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCNC(=O)c2ccc(OCC(F)(F)C(F)F)nc2)cc1)Oc1ccc(C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1ccc(OC(C)(Cc2ccc(OCCNC(=O)c3ccc(OCC(F)(F)C(F)F)nc3)cc2)C(=O)O)cc1
Yield: 69.8 %

Procedure:
In a similar manner to that described in Example 2, ethyl 3-[4-[2-[2-(2,2,3,3-tetrafluoropropoxy)pyridine-5-carbonylamino]ethoxy]phenyl]-2-(4-isopropylphenoxy)-2-methylpropionate (210 mg), which is the product of Example 150, was reacted with aqueous sodium hydroxide solution (1N, 0.51 ml) and the reaction mixture was treated to give the title compound (140 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH3:13])[N:12]=1)[C:5]([N:7](C)[CH3:8])=O.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[N-:29]=[N+:30]=[N-:31].[Na+].C([O-])(O)=O.[Na+]>C(#N)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:7]([CH3:8])[N:31]=[N:30][N:29]=2)[CH:10]=[C:11]([CH3:13])[N:12]=1
Reactant: Cc1cc(C(=O)N(C)C)cc(Cl)n1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cc(-c2nnnn2C)cc(Cl)n1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 10.7 %

Procedure:
To a solution of 2-Chloro-6,N,N-trimethyl-isonicotinamide (2.3 g) in acetonitrile (30 ml) at −15° C. was added DCM (20 ml) pre-cooled triflic anhydride (3 mL) dropwise. This was stirred for 10 min at −10° C. and then sodium azide (4.6 g) was added. This was allowed to warm to room temperature and after 2 h, the reaction was neutralised with a cold 5% NaHCO3(aq) solution and extracted with EtOAc. The organic layer was separated, dried and concentrated in vacuum. Flash chromatography (100:0 to 40:60 gradient cyclohexane:EtOAc) afforded the title compound (260 mg). Rt=1.21 min (method D).