Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[S:5][C:6]=1[C:7](O)=[O:8].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:55][CH:56]([CH3:59])[CH2:57][OH:58]>CN(C=O)C>[OH:58][CH2:57][CH:56]([NH:55][C:7]([C:6]1[S:5][C:4]([CH2:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:3][C:2]=1[CH3:1])=[O:8])[CH3:59]
Reactant: CC(N)CO
Reactant: Cc1nc(CCc2c(-c3ccccc3)noc2C)sc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(CCc2c(-c3ccccc3)noc2C)sc1C(=O)NC(C)CO
Reaction time: 2 h
Yield: 49.4 %

Procedure:
To a solution of 4-methyl-2-[2-(5-methyl-3-phenyl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (100 mg, 0.31 mmol) in DMF (3 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (108 mg, 0.33 mmol), N,N-diisopropyl ethyl amine (197 μL, 1.67 mmol) and rac-2-amino-1-propanol (30 mg, 0.40 mmol). The resulting reaction mixture was stirred for 2 h. The reaction mixture was extracted with ethyl acetate. The combined organic layers were then dried over sodium sulfate, filtered and evaporated. Concentration and purification by chromatography (silica, 0 to 2.5% methanol in dichlormethane) afforded the title compound (59 mg, 50%) as a colourless oil. MS: m/e=386.2 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH:21][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1NC(=O)c1ccccc1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 90 %

Procedure:
By using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and benzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 90%. Melting point: 218-220° C. (Ethyl acetate-hexane).
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[CH:10][C:11]([F:23])=[C:12]([C:14]3[C:15]([C:21]#[N:22])=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[CH:13]=2)OC1.Br[C:26]1[N:30]2[N:31]=[CH:32][C:33]([C:35]([OH:38])([CH3:37])[CH3:36])=[N:34][C:29]2=[N:28][CH:27]=1>>[F:20][C:17]1[CH:16]=[C:15]([C:21]#[N:22])[C:14]([C:12]2[CH:13]=[C:8]([C:26]3[N:30]4[N:31]=[CH:32][C:33]([C:35]([OH:38])([CH3:36])[CH3:37])=[N:34][C:29]4=[N:28][CH:27]=3)[CH:9]=[CH:10][C:11]=2[F:23])=[CH:19][CH:18]=1
Reactant: CC1(C)COB(c2ccc(F)c(-c3ccc(F)cc3C#N)c2)OC1
Reactant: CC(C)(O)c1cnn2c(Br)cnc2n1
Product: CC(C)(O)c1cnn2c(-c3ccc(F)c(-c4ccc(F)cc4C#N)c3)cnc2n1
Yield: 54 %

Procedure:
5′-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-4,2′-difluorobiphenyl-2-carbonitrile (see Example 4) was coupled to 2-(7-bromoimidazo[1,2-b][1,2,4]triazin-3-yl)propan-2-ol in 54% yield using a similar procedure to that described in Example 3, step f, to give a yellow solid: mp 215° C.; 1H NMR (360 MHz, CDCl3) δ 1.71 (6H, s), 3.27 (1H, br s), 7.35-7.59 (4H, m), 8.09-8.15 (2H, m), 8.26 (1H, s), 8.78 (1H, s); MS (ES+) m/z 392 [M+H]+. Anal. Found: C, 64.38; H, 3.88; N, 17.66%. Required for C21H15F2N5O: C, 64.45; H, 3.86; N, 17.89%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([Sn](CCCC)(CCCC)CCCC)=[N:6][CH:7]=1.Cl[C:22]1[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([N:29]2[CH2:32][CH:31]([C:33]3[N:37]([CH3:38])[C:36]4[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=4[N:34]=3)[CH2:30]2)[CH:23]=1>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.CN(C=O)C>[CH3:38][N:37]1[C:36]2[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=2[N:34]=[C:33]1[CH:31]1[CH2:32][N:29]([C:24]2[CH:23]=[C:22]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=3)[N:27]=[C:26]([CH3:28])[N:25]=2)[CH2:30]1
Reactant: Cc1nc(Cl)cc(N2CC(c3nc4ccccc4n3C)C2)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(N3CC(c4nc5ccccc5n4C)C3)nc(C)n2)nc1
Temperature: 110 °C

Procedure:
To a microwave vial was added 5-methyl-2-(tributylstannyl)pyridine (97 mg, 2.6 mmol), Intermediate 3 (40 mg, 0.13 mmol), tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol), and DMF (1 mL). The vial was sealed and heated in a heating block at 110° C. for 16 h. The reaction was cooled to room temperature, passed through a syringe filter, and purified by reverse-phase chromatography (5-55% acetonitrile/water/0.1% TFA). The product fractions were poured into aqueous NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated to give Example 94 as a white solid. 1H NMR: (400 MHz, CDCl3) δ 8.50 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 7.75 (d, J=7.3 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.29 (m, 3H), 7.15 (s, 1H), 4.66 (m, 4H), 4.29 (m, 1H), 3.74 (s, 3H), 2.60 (s, 3H), 2.40 (s, 3H) ppm. MS: m/z=371.5 (M+H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]([F:38])([F:37])[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([N:24]2[CH2:32][CH:31]3[C:26]([C:27]4[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=4[CH2:29][CH2:30]3)=[N:25]2)=[O:23])=[CH:17][CH:16]=1.Cl[C:40]([O:42][CH3:43])=[O:41]>C1COCC1.CCCCCC>[CH3:43][O:42][C:40]([C:31]12[CH2:30][CH2:29][C:28]3[CH:33]=[CH:34][CH:35]=[CH:36][C:27]=3[C:26]1=[N:25][N:24]([C:22]([NH:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:37])[F:38])=[CH:20][CH:19]=1)=[O:23])[CH2:32]2)=[O:41]
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)N1CC2CCc3ccccc3C2=N1
Reactant: COC(=O)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)C12CCc3ccccc3C1=NN(C(=O)Nc1ccc(C(F)(F)F)cc1)C2
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 0.9 ml of diisopropylamine in 10 ml of THF, at -78° C., was added 2.3 ml of 2.5M n-butyl lithium in hexane and the mixture was stirred for 5 mins. To this solution was added a solution of 1.0 g of the title compound of Step A in 5 ml of THF. The reaction was warmed to 0° C., recooled to -78° C. and then 0.75 ml of methyl chloroformate was added. The reaction mixture was then stirred for 24 h, with gradual warming to room temperature, quenched with 0.5 ml of glacial acetic acid, and poured into a 5% solution of aqueous NaHCO3. The mixture was extracted with chloroform, dried over magnesium sulfate and concentrated. Chromatography on silica gel with 30% ethyl acetate hexane afforded 0.25 g of the title compound, m.p. 177° to 180° C.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].CN([CH:9]=[O:10])C.O=[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C(OCC)(=O)C.CCCCCC>[Cl:3][C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14][C:13]=1[CH:9]=[O:10]
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=CC1=C(Cl)CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
POCl3 (26.35 g, 16.06 ml, 1.6 eq.) was added dropwise to DMF (16.4 ml, 2 eq.) at 0-5° C. To the mixture was added dichloromethane (50 ml) in a dropwise fashion and it was stirred for 2 h at room temperature. A solution of benzyl 4-oxopiperidine-1-carboxylate (25 g, 0.10 mol) in dichloromethane (200 ml) was added dropwise to the mixture and it was stirred for 2 h at room temperature. Progress of the reaction was monitored by TLC (30% ethyl acetate/hexane). Upon completion of the reaction the mixture was poured into crushed ice and basified to a pH˜8 with sodium carbonate. Then the dichloromethane layer was separated and the aqueous layer was extracted with dichloromethane (2×200 ml). The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure and the crude product obtained was purified by column chromatography (silica, 8% ethyl acetate/hexane). Yield: 14.5 g (48%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8](Cl)[C:9]=1[F:10])[C:5]#[N:6].[Cl:12][C:13]1[CH:14]=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:16]=[C:17](Cl)[C:18]=1[F:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:19])[C:9]=1[F:10])[C:5]#[N:6].[Cl:12][C:13]1[CH:14]=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:16]=[C:17]([F:10])[C:18]=1[F:19]
Reactant: N#Cc1cc(Cl)c(F)c(Cl)c1
Reactant: Fc1c(Cl)cc(C(F)(F)F)cc1Cl
Product: Fc1cc(C(F)(F)F)cc(Cl)c1F
Product: N#Cc1cc(F)c(F)c(Cl)c1

Procedure:
reacting the 3,5-dichloro-4-fluorobenzonitrile or 3,5-dichloro-4-fluorobenzotrifluoride compound prepared in step (B) with an alkali metal fluoride to form the corresponding 3-chloro-4,5-difluorobenzonitrile or 3-chloro-4,5-difluorobenzotrifluoride compound.
Reaction SMILES: C(N[C:7]1[S:8][C:9]2[CH:15]=[C:14]([O:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=2[N:11]=1)(=O)C(C)C.[NH2:27]C1SC2C=C(OS(C3C=CC(F)=CC=3)(=O)=O)C=CC=2N=1.[C:48]([OH:53])(=O)[CH:49]([CH3:51])[CH3:50]>>[C:48]([C:7]1[S:8][C:9]2[CH:15]=[C:14]([O:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:13]=[C:12]([NH2:27])[C:10]=2[N:11]=1)(=[O:53])[CH:49]([CH3:51])[CH3:50]
Reactant: CC(C)C(=O)O
Reactant: Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Reactant: CC(C)C(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Product: CC(C)C(=O)c1nc2c(N)cc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Yield: 86 %

Procedure:
According to the method of intermediate 46, 4-fluorobenzenesulfonic acid 2-isobutyrylaminobenzothiazol-6-yl ester is prepared via the action of 4-fluorobenzenesulfonic acid 2-aminobenzothiazol-6-yl ester (intermediate 16, brevetbenzothiazole_V2) with isobutyric acid. The crude reaction product is crystallized from ethyl ether and, after filtering off by suction, 0.17 g of colorless solid is isolated, i.e. an 86% yield.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>O1CCOCC1>[CH2:24]([O:23][C:21](=[O:22])[C:17]1[CH:18]=[C:19]([Cl:20])[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:15][CH:16]=1)[CH3:25]
Reactant: CCOC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(N2CCNCC2)c(Cl)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Dissolve a solution of 4-(3-chloro-5-ethoxycarbonyl-pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (7.78 g, 0.021 mol) in dioxane, and then add a solution of 4M HCl/dioxane (12 mL). Stir at 50° C. for 2 h, and then add additional 4M HCl/dioxane (5 mL) and stir for an additional 1 h. Cool the mixture in ice, collect the precipitate and wash with ether. Prepare the freebase by partitioning between EtOAc and 10% NaOH solution. Dry the organic layer (Na2SO4) and concentrate under reduced pressure to give the title compound.
Reaction SMILES: ClCl.[H][H].F.B(F)(F)F.[C:10]([OH:21])(=O)[C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1.[CH3:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:24]=1[OH:30]>>[CH3:22][C:23]1[CH:28]=[C:27]([CH:26]=[C:25]([CH3:29])[C:24]=1[OH:30])[C:15]([C:14]1[CH:13]=[CH:12][C:11]([C:10](=[O:21])[C:27]2[CH:26]=[C:25]([CH3:29])[C:24]([OH:30])=[C:23]([CH3:22])[CH:28]=2)=[CH:19][CH:18]=1)=[O:17]
Reactant: Cc1cccc(C)c1O
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: [H][H]
Agent: ClCl
Agent: F
Agent: FB(F)F
Product: Cc1cc(C(=O)c2ccc(C(=O)c3cc(C)c(O)c(C)c3)cc2)cc(C)c1O
Temperature: 50 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
The diketodiols and diketodiesters of the formula ##STR8## where X is methyl or chlorine, Ar is m- or p-phenylene and R is hydrogen or hydrocarbyl of from 1-10 carbon atoms are prepared by reacting, under anhydrous conditions, a disubstituted monophenol, such as 2,6-dimethyl- or 2,6-dichlorophenol with terephthalic (for Ar=p-phenylene) or isophthalic (for Ar=m-phenylene) acid (or its diester) or hydrogen fluoride in the presence of boron trifluoride. The reaction is allowed to proceed to about 0° to about 100° C. For example, terephthalic acid (83 g) and 2,6-dimethylphenol (122 g) are charged to a 1 liter Hastalloy C® shaker tube. The tube was cooled and then charged with hydrogen fluoride (400 g) and boron trifluoride (150 g). It was warmed to 50° C., shaken at 50° C. for 4 hr, then cooled and vented. The contents, a dark red solid in a dark red solution, were allowed to evaporate in the hood to afford crude 1,4-bis(3,5-dimethyl-4-hydroxybenzoyl)benzene as a dark red solid. This material was stirred with 2 l. of water, warmed and isolated by filtration of the warm mixture. It was again stirred with 2 l. of water, warmed, neutralized with sodium bicarbonate, and isolated by filtration of the warm mixture. After being washed with water and air dried, the product was obtained as a tan powder in a yield of 79%.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][N:7]([CH3:13])[C:8]([CH3:12])([CH3:11])[C:9]#[N:10].[OH-:14].[Ba+2].[OH-]>>[CH3:6][N:7]([CH3:13])[C:8]([CH3:12])([CH3:11])[C:9]([NH2:10])=[O:14]
Reactant: CN(C)C(C)(C)C#N
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Ba+2]
Product: CN(C)C(C)(C)C(N)=O
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 43.1 %

Procedure:
Conc. Sulphuric acid (8 ml.) was added to 2-dimethylamino-2-methyl-propionitrile (2 g.), and was heated to 90° C. and allowed to stand for five mins. The reaction mixture was added to ice cold water (100 ml.), barium hydroxide (32 g.) was added to neutralise the acid and the mixture was filtered (hyflo). The filtrate was evaporated under reduced pressure to give a solid residue which was crystallised from light petroleum (80°-100° C.) to give 2-dimethylamino-2-methylpropionamide (1 g. 45%) m.p. 109°-111° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.[C:15]([O:18][CH2:19][CH2:20][C@@H:21]([NH:25][C:26]1[C:31]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][CH2:42][OH:43])=[CH:35][C:34]=2[O:44][CH3:45])=[C:30]([CH3:46])[N:29]=[C:28]([NH2:47])[N:27]=1)[CH2:22][CH2:23][CH3:24])(=[O:17])[CH3:16]>C1COCC1.O.C(OC([O-])=O)(O)=O.[Na+]>[C:15]([O:18][CH2:19][CH2:20][C@@H:21]([NH:25][C:26]1[C:31]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][CH2:42][O:43][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:35][C:34]=2[O:44][CH3:45])=[C:30]([CH3:46])[N:29]=[C:28]([NH2:47])[N:27]=1)[CH2:22][CH2:23][CH3:24])(=[O:17])[CH3:16]
Reactant: CS(=O)(=O)Cl
Reactant: CCC[C@@H](CCOC(C)=O)Nc1nc(N)nc(C)c1Cc1ccc(OCCCO)cc1OC
Agent: O=C([O-])OC(=O)O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCC[C@@H](CCOC(C)=O)Nc1nc(N)nc(C)c1Cc1ccc(OCCCOS(C)(=O)=O)cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methanesulfonyl chloride (0.083 mL) was added to a solution of diisopropylethylamine (0.279 mL) and the product from step (iv) (0.246 g) in THF (10 mL). The mixture was stirred at RT for 3 h and additional diisopropylethylamine (0.14 mL) and methanesulfonyl chloride (0.042 mL) was added. The mixture was stirred at RT for 2 h, diluted with water and sat. sodium hydrogen dicarbonate and extracted with EtOAc. The combined organic layer was dried and concentrated under reduced pressure to afford the crude product (300 mg) as a pale yellow oil, which was used for the next reaction without further purification; LC-MS: m/z 539.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:17]([OH:19])=[O:18])[N:13]3[CH:14]=[N:15][CH:16]=[C:12]3[CH2:11][CH2:10]2)=[C:5]([F:20])[CH:4]=1)#[N:2].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH3:32][CH:33](O)[CH3:34]>C(Cl)Cl.CCN(CC)CC>[CH:33]([O:18][C:17]([C:9]1([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[F:20])[N:13]2[CH:14]=[N:15][CH:16]=[C:12]2[CH2:11][CH2:10]1)=[O:19])([CH3:34])[CH3:32]
Reactant: CC(C)O
Reactant: N#Cc1ccc(C2(C(=O)O)CCc3cncn32)c(F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)C1(c2ccc(C#N)cc2F)CCc2cncn21

Procedure:
5-(4-Cyano-2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid (0.15 g, 0.279 mmol) is suspended in CH2Cl2 (3 mL) and DMF (0.01 ml) and cooled to 0° C. A solution of oxalyl chloride (0.31 mL, 2 M) in CH2Cl2 is added dropwise. After 1 h i-PrOH (3 mL) is added. After 2 h Et3N is added until basic and the solution is concentrated. The resulting slurry is dissolved in CH2Cl2, washed with aqueous saturated NaHCO3/H2O (1:1) and brine, then dried over Na2SO4. After concentration, the residue is purified by HPLC (2-38% MeCN/H2O containing 0.1% TFA) to give 5-(4-cyano-2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid isopropyl ester as solid. MS (ESI) m/z 314.0 (M+H); 1H NMR (400 MHz, CD3CN) (TFA salt) δ ppm 1.22 (d, J=6.06 Hz, 3 H), 1.23 (d, J=6.06 Hz, 3 H), 3.01-3.18 (m, 3 H), 3.38-3.45 (m, 1 H), 5.08-5.18 (m, 1 H), 7.20 (s, 1 H), 7.34 (app t, J=8.08 Hz, 1 H), 7.62-7.68 (m, 2 H) 8.52 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][OH:18])=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:22]([O:26][C:27]1(OCC(C)C)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH:23]([CH3:25])[CH3:24]>>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][O:18][C:27]3([O:26][CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(C)COC1(OCC(C)C)CCCCCC1
Reactant: CC(C)c1nc(CCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Product: CC(C)COC1(OCCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2C)CCCCCC1
Yield: 45.6 %

Procedure:
The compound 22 (345 mg, 1 mmol) was converted to the acetal with 1,1-diisobutoxycycloheptane (2.42 g, 10 mmol) in the same manner as the example 20 to give the compound 28 (234 mg, 46%). Rf 0.31 (Al2O3 type E, hexane-EtOAc (10:1)) PMR (CDCl3 -0.1% d5 -Py): δH0.87 (6 H, d, J 6.6 Hz, CH3) 1.24 (6 H, d, J 6.6 Hz, (CH3)2C), 1.30-1.75 (13 H, m, --CH2 --), 3.00 (2 H, t, J 6.2 Hz, CH2 -Im), 3.10 (1 H, sep, J 6.6 Hz, (CH3)2CH), 3.17 (2 H, t, J 6.6 Hz), 3.51 (3 H, s, NCH3), 3.70 (2 H, t, J 6.2 Hz, OCH2), 6.81 (2 H, d, J 1.6 Hz, arom-H), 7.12 (1 H, t, J 1.6 Hz, arom-H) Elementary analysis (for C26H38N2O2Cl2S) Cacld.: C, 60.81% H, 7.46% N, 5.45% S, 6.24% Cl, 13.81% Found: C, 61.34% H, 7.69% N, 5.33% S, 6.10% Cl, 13.42%
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]([N:16]([CH3:29])[CH2:17][CH2:18][CH2:19][N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:15])=[C:11]([CH3:30])[CH:10]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(N(CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(Cl)Cl>[NH2:8][C:9]1[S:13][C:12]([C:14]([N:16]([CH3:29])[CH2:17][CH2:18][CH2:19][N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:15])=[C:11]([CH3:30])[CH:10]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)sc1C(=O)N(C)CCCN(C)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N)sc1C(=O)N(C)CCCN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
The compound (129 mg, 0.292 mmol) obtained in Example 30c was dissolved in methylene chloride (3 mL), trifluoroacetic acid (1.5 mL) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, toluene (×2) was added to the resulting residue, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in methylene chloride (3 mL), triethylamine (0.318 mL, 2.29 mmol) and di-tert-butyl dicarbonate (244 mg, 1.75 mmol) were added, and the mixture was stirred at room temperature for 15 hours. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:2→0:100, v/v) to give the title compound (78 mg; yield, 78%) as a yellow oily substance.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CCC3C=CC=CC=3)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: ClCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: CC(C)(C)OC(=O)N1CCc2nn(CCc3ccccc3)c(-c3ccc(Cl)cc3)c2CC1
Product: Clc1ccc(-c2nn(CCc3ccccc3)c3c2CCNCC3)cc1

Procedure:
The title compound (0.048 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.1 g) using (2-chloroethyl)benzene (0.045 mL) in place of benzyl chloride. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-phenethyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C21H22ClN3, 351.15; found, m/z 352.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.52-7.47 (m, 4H), 7.28-7.21 (m, 3H), 7.03-7.01 (m, 2H), 4.39 (t, J=6.4 Hz, 2H), 3.20-3.18 (m, 2H), 3.13-3.10 (m, 2H), 2.95-2.93 (m, 2H), 2.91-2.89 (m, 2H), 2.69-2.67 (m, 2H).
Reaction SMILES: C(OC1C=C2C(=CC=1)C=C(C(O)=O)C=C2)(=O)C=C.CS(Cl)(=O)=O.C(N(CC)CC)C.[CH2:31]([O:38][C:39]1[CH:44]=[CH:43][C:42](O)=[C:41]([CH2:46][CH2:47]C)C=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1.CN(C)C1C=CN=CC=1>[CH2:39]([O:38][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:44]1[CH:43]=[CH:42][CH:41]=[CH:46][CH:47]=1
Reactant: CCCc1cc(OCc2ccccc2)ccc1O
Agent: C=CC(=O)Oc1ccc2cc(C(=O)O)ccc2c1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Specifically, 1.90 g (7.86 mmol) of 6-acryloyloxy-2-naphthoic acid was dissolved in 10 g of THF, to which 0.99 g (8.65 mmol) of methanesulfonyl chloride was added with ice-water bath cooling, and further 1.91 g (18.87 mmol) of triethylamine (TEA) was added dropwise. After stirring for 1 hour, 10 mg (0.08 mmol) of 4-dimethylaminopyridine (DMAP) was added, to which a solution of 2.00 g (8.25 mmol) of 4-benzyloxy-2-n-propylphenol dissolved in 7 g of THF was added dropwise. After stirring for 1 hour, the reaction mixture was allowed to warm to room temperature, the precipitates were removed by filtration, and the filtrate was washed with water. After removing the solvent by evaporation, the residue was purified by column chromatography (developing solvent: dichloromethane, SiO2) and recrystallized from acetone. Thus the target benzyl ether was obtained as a white solid (2.27 g, 61.9% yield).