Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([CH:9]([CH3:29])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:24]([CH3:25])=[CH:23][N:22]=[CH:21][C:20]=2[CH3:26])=[C:15]([C:27]#[CH:28])[N:14]=1)=[O:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].I[C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[N:38]=[CH:37][CH:36]=[CH:35]2.C(N(CC)CC)C>CN1C(=O)CCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:30])[N:7]([CH:9]([CH3:29])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([CH3:26])=[CH:21][N:22]=[CH:23][C:24]=2[CH3:25])=[C:15]([C:27]#[C:28][C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[N:38]=[CH:37][CH:36]=[CH:35]3)[N:14]=1)=[O:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1nc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)ccc1-c1c(C)cncc1C
Reactant: Ic1ccc2ncccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1cncc(C)c1-c1ccc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)nc1C#Cc1ccc2ncccc2c1

Procedure:
A mixture of tert-butyl-N-[1-[[5-(3,5-dimethylpyridin-4-yl)-6-ethynylpyridin-2-yl]amino]-1-oxopropan-2-yl]-N-methylcarbamate (E1a desilylated according to the general method exemplified for F1a) (50 mg, 0.12 mmol), 6-iodoquinoline (89 mg, 0.35 mmol), copper(I) iodide (2.2 mg, 0.01 mmol), Dichlorobis(triphenylphosphine)palladium(II) (8.1 mg, 0.01 mmol) and triethylamine (64 μl, 0.47 mmol) is stirred under argon atmosphere in NMP (0.5 ml) for 1 h at 50° C. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 28 mg (45%). HPLC-MS: M+H=536; tR=1.79 min (*Method—3).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].IC.[C:19](=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][CH3:19])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(N)c2c1C
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: CCO
Product: CCOC(=O)c1oc2cccc(NC)c2c1C
Yield: 17 %

Procedure:
To 4-amino-3-methyl-benzofuran-2-carboxylic acid ethyl ester (500 mg, 2.28 mmol, 1 eq.) was added iodomethane (310 uL, 6.16 mmol, 2.7 eq.), sodium carbonate (314 mg, 2.96 mmol, 1.3 eq.), and ethanol (10 mL) and reaction was heated at reflux for 16 hours. 3-Methyl-4-methylamino-benzofuran-2-carboxylic acid ethyl ester was obtained in 17% yield after flash column chromatography, eluting with ethyl acetate/hexanes. (90 mg) 1H NMR (400 MHz, DMSO-d6) δ ppm 1.3 (t, J=7.1 Hz, 3 H) 2.7 (s, 3 H) 4.3 (q, J=7.1 Hz, 2 H) 6.5 (dd, J=7.8, 0.8 Hz, 1 H) 6.8 (d, J=8.3 Hz, 1 H) 7.2 (t, J=8.1 Hz, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]2[C:10](=[N:11][NH:12][C:13]=2[NH2:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O/[CH:18]=[C:19](\[CH3:23])/[C:20](=O)[CH3:21]>CC(O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]2=[C:13]3[N:12]([N:11]=[C:10]2[CH2:9]1)[C:20]([CH3:21])=[C:19]([CH3:23])[CH:18]=[N:16]3)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2n[nH]c(N)c2C1
Reactant: CC(=O)/C(C)=C/O
Solvent: CC(=O)O
Product: Cc1cnc2c3c(nn2c1C)CN(C(=O)OC(C)(C)C)C3
Temperature: 25 °C
Reaction time: 18 h
Yield: 10.9 %

Procedure:
A mixture of 3-amino-2,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester (1 g; 4.46 mmol; 1 eq.) and (3E)-4-hydroxy-3-methylbut-3-en-2-one (prepared according to J. Het. Chem. 1980, 17(1), 33-37) (0.6 g; 4.91 mmol; 1.1 eq.) in AcOH (5 mL) was stirred at room temperature for 18 hours then concentrated in vacuo. The residue was partitioned between 1M NaOH and DCM, the organic layer was dried over magnesium sulfate and concentrated in vacuo. The resulting oil was triturated in Et2O, the precipitate filtered off and the solution concentrated in vacuo. The residue was purified by SFC (column: Chiralpak IC, eluent 25% MeOH) to afford successively the title compound (140 mg, 11%) as a white solid and Intermediate C2. 1H NMR (CDCl3) δ 8.33 (s, 1H), 4.72-4.62 (m, 4H), 2.54 (d, J=3.1 Hz, 3H), 2.29 (d, J=0.7 Hz, 3H), 1.52 (d, J=3.3 Hz, 9H). HPLC (max plot) 87.3%; Rt 3.27 min. UPLC/MS: (MS+) 289.1 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([C:16](=[O:18])[CH3:17])[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)=[O:7])(C)(C)[CH3:2].C(OCC)(=O)CC(C)=O>>[CH2:1]([O:5][C:6]([C:8]1([C:16](=[O:18])[CH3:17])[CH2:9][O:10][C:11]([CH3:14])([CH3:15])[O:12][CH2:13]1)=[O:7])[CH3:2]
Reactant: CC(=O)C1(C(=O)OC(C)(C)C)COC(C)(C)OC1
Solvent: CCOC(=O)CC(C)=O
Product: CCOC(=O)C1(C(C)=O)COC(C)(C)OC1
Yield: 31 %

Procedure:
Compound 99a was prepared in the same manner as 5-acetyl-2,2-dimethyl-[1,3]dioxane-5-carboxylic acid tert-butyl ester using ethyl acetoacetate instead of 3-oxo-butyric acid tert-butyl ester in 31% yield over 2 steps. 1H NMR (300 MHz, CDCl3) δ 1.29 (t, J=7.1 Hz, 3H), 1.40 (s, 3H), 1.44 (s, 3H), 2.33 (s, 3H), 4.23 (q, J=7.1 Hz, 2H), 4.30 (ABq, ΔδAB=0.04, JAB=11.9 Hz, 4H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:26][C:27]1[C:32]([OH:33])=[C:31]([F:34])[C:30]([F:35])=[C:29]([F:36])[C:28]=1[F:37].Cl>ClCCl>[C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([O:33][C:32]3[C:27]([F:26])=[C:28]([F:37])[C:29]([F:36])=[C:30]([F:35])[C:31]=3[F:34])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc(OCc2ccccc2)cc1
Temperature: -15 °C
Reaction time: 1.75 h

Procedure:
To a stirred solution of 4-[(phenyhnethyl)oxy]benzenesulfonyl chloride (D48) (13.77 g, 48.70 mmol) in dichloromethane (265 ml) was added triethylamine (9.16 ml, 65.75 mmol) under argon and the mixture cooled to −15° C. A solution of pentafluorophenol (9.86 g, 53.57 mmol) in dichloromethane (20 ml+20 ml wash) was then added quickly and the reaction allowed to wami slowly to room temperature over 1.75 h. Hydrochloric acid (2M, 250 ml) was then added and the mixture stirred for 20-30 min and the layers separated. The aqueous layer was then re-extracted with dichloromethane (100 ml) and the combined organic fractions washed with saturated aqueous sodium hydrogen carbonate (200 ml). The layers were separated and the aqueous re-extracted with dichloromethane (100 ml). All the dichloromethane layers were combined and dried over sodium sulfate, filtered and evaporated. The resulting solid was then dissolved in dichloromethane (40 ml) with warming, and allowed to cool and then purified by chromatography on silica gel eluting with 10-15% diethyl ether/hexane to afford the title compound (D49). 1H-NMR (d6-DMSO) d 7.97-7.94 (2H, m), 7.50-7.31 (7H, m), 5.29 (2H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[CH:9]1[C:21]2[NH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>[Cu](I)I>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:20]2[C:21]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]3[C:19]2=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:3][CH:4]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Brc1ccc(Br)cc1
Agent: I[Cu]I
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Product: Brc1ccc(-n2c3ccccc3c3ccccc32)cc1
Temperature: 180 °C
Reaction time: 6 h
Yield: 35 %

Procedure:
56 g (240 mmol) of p-dibromobenzene, 31 g (180 mmol) of carbazole, 4.6 g (24 mmol) of copper iodide, 66 g (480 mmol) of potassium carbonate, and 2.1 g (8 mmol) of 18-crown-6-ether were put into a 300 mL three-necked flask, and nitrogen was substituted for the content of the flask. Then, 8 mL of N—N′-dimetylpropyleneurea was added thereto, and this mixture was stirred for 6 hours at 180° C. to be reacted. After the reaction, cooling of the reaction mixture to the room temperature was performed, and the precipitated object was removed by suction filtration. The filtrate was washed with dilute hydrochloric acid, a saturated sodium hydrogen carbonate solution, and a saturated saline solution, in this order, and then dried with magnesium sulfate. After drying, filtration was performed, and an oily substance that was obtained by concentrating the filtrate was purified by silica column chromatography. For the column purification, a mixed solvent of hexane:ethyl acetate=9:1 was used as a developing solvent. After the column purification, an obtained solution was re-crystallized with chloroform and hexane, whereby 21 g of a light brown solid of 9-(4-bromophenyl)carbazole was obtained in the yield of 35% (Synthesis Scheme (k-1)).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>Cl>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:22][CH2:23][O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: BrCCOc1ccccc1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(CCOc3ccccc3)C2=O)cn1
Temperature: 25 °C
Yield: 54.2 %

Procedure:
3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) (200 mg, 0.7 mmol), (2-bromoethoxy)benzene (200 mg, 1 mmol), and cesium carbonate (325 mg, 1 mmol) were irradiated in the microwave reactor at 85° C. for 20 minutes. The reaction was cooled to room temperature, diluted with aqueous 1N HCl (100 mL) and extracted with ethyl acetate (3×, 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was taken up in methanol (10 mL) and purified by reversed phase HPLC (5 to 95% acetonitrile in H2O: 25 minute gradient). The pure fractions were pooled, concentrated then re-dissolved in absolute ethanol and concentrated on the rotovap (4×) to afford 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-(2-phenoxyethyl)imidazolidine-2,4-dione (150 mg, 54%) as a white solid. 1H NMR (CDCl32.18, 400 MHz): δ (s, 3H), 2.41 (s, 3H), 3.86 (t, J=5.2 Hz, 2H), 4.19 (t, J=4.4 Hz, 2H), 4.25 (s, 2H), 5.05 (s, 2H), 6.88 (dd, J=9.2, 1.2 Hz, 2H), 7.00 (dt, J=7.6, 1.2 Hz, 1H), 7.27-7.32 (m, 2H), 7.89 (s, 1H), 8.05 (s, 1H). MS M+H calculated 396.17; found 396.1. Melting point: 117-118° C. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.06 μM.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].CO[CH:24]1[CH2:28][CH2:27][CH:26](OC)O1>C(O)(=O)C.C(OCC)C>[N+:12]([C:11]1[CH:10]=[C:9]2[C:4]([C:5](=[O:21])[N:6]([NH:16][S:17]([CH3:20])(=[O:18])=[O:19])[C:7](=[O:15])[NH:8]2)=[CH:3][C:2]=1[N:1]1[CH:24]=[CH:28][CH:27]=[CH:26]1)([O-:14])=[O:13]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(N)cc2c1=O
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Solvent: CCOCC
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(-n3cccc3)cc2c1=O

Procedure:
A solution of N-(6-amino-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (90 mg, 0.285 mmol) and 2,5-dimethoxytetrahydrofuran (0.038 ml, 0.291 mmol) in acetic acid (0.5 ml) is refluxed for 80 minutes. The resulting suspension is filtered and the residue washed with ethyl acetate. The filtrate is concentrated in vacuo to give a brown solid which is suspended in diethyl ether and filtered to give a brown-orange solid as the desired pure product, m.p. 243-250° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:20](/[CH:21]=[CH:22]/[CH:23]=[CH:24]/[C:25](/[CH3:32])=[CH:26]/[C:27]([O:29]CC)=[O:28])=[CH:19][C:9]2[C:10]3([CH3:18])[CH:15]([OH:16])[C:14]([CH3:17])([C:8]=2[CH:7]=1)[CH2:13][CH2:12][CH2:11]3)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C(O)C.C1COCC1>[CH2:1]([O:5][C:6]1[C:20](/[CH:21]=[CH:22]/[CH:23]=[CH:24]/[C:25](/[CH3:32])=[CH:26]/[C:27]([OH:29])=[O:28])=[CH:19][C:9]2[C:10]3([CH3:18])[CH:15]([OH:16])[C:14]([CH3:17])([C:8]=2[CH:7]=1)[CH2:13][CH2:12][CH2:11]3)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc2c(cc1/C=C/C=C/C(C)=C/C(=O)OCC)C1(C)CCCC2(C)C1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCOc1cc2c(cc1/C=C/C=C/C(C)=C/C(=O)O)C1(C)CCCC2(C)C1O

Procedure:
This ester was dissolved in 7 ml of ethanol/THF=1/1 and treated under argon with 2.1 ml of 2N NaOH. The mixture was left to react at room temperature for 64 h. and then poured into ice/HCl/ethyl acetate. The organic phase was washed twice with water, dried and evaporated. Recrystallization from hexane/ethyl acetate=7/3 yielded 153 mg of (2E,4E,6E)-(5RS,9SR,10RS)-7-(3-butoxy-10-hydroxy-5,9-dimethyl-6,7,8,9-tetrahydro-5,9-methano-5H-benzocyclohepten-2-yl)-3-methyl-hepta-2,4,6-trienoic acid as yellow crystals of m.p. 176°-178°.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[N+:9]([C:12]1[CH:24]=[C:16]2[C:17](O[C:20](=O)[N:21](C)[C:15]2=[CH:14][CH:13]=1)=O)([O-:11])=[O:10].B>O1CCCC1>[CH3:20][N:21]1[C:15]2[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:24][C:16]=2[CH2:17][N:1]2[CH2:8][CH2:7][CH2:6][CH:2]2[C:3]1=[O:5]
Reactant: Cn1c(=O)oc(=O)c2cc([N+](=O)[O-])ccc21
Reactant: O=C(O)[C@@H]1CCCN1
Agent: B
Solvent: C1CCOC1
Product: CN1C(=O)C2CCCN2Cc2cc([N+](=O)[O-])ccc21

Procedure:
This compound is obtained when 1,2,3,11a-tetrahydro- 10-methyl-7-nitro-11H-pyrrolo[2,1-c] [1,4]benzodiazepin-5,11- (10H]-dione (prepared from proline and 5-nitro-N-methylisatoic anhydride by the procedure of Example 1) is treated with 1 M borane in tetrahydrofuran by the procedure of Example 1.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Reactant: CCCCCCCC=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCCCCCC=C1SC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.61 g (5.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 0.641 g (5.0 mmol) of 1-octanal in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 1.5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=4/1) to yield 1.54 g (71.4%, yellow oily substance) of the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:12][OH:13])=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>ClCCl>[CH3:21][S:22]([O:13][CH2:12][CH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:11]=2)[CH2:7][CH2:8]1)(=[O:24])=[O:23]
Reactant: N#Cc1ccc2c(c1)C(CO)CC2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-cyano-1-indanylmethanol 2a (3 g) and triethylamine (2.8 ml) in dichloromethane (50 ml) was added dropwise a solution of methansulfonylchloride (1.5 ml) in dichloromethane (25 ml) at 0° C. The mixture was stirred at room temperature for 1 hour. Water was added (200 ml) and the organic phase was subsequently separated and worked-up according to the standard procedure above. The remaining crystalline product was stirred with diethyl ether and filtered off. Yield 2.7 g. Mp 62-63° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[OH:20])[N:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:29][CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32].O>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:29][CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32])[N:7]=1
Reactant: CCC(CC)CCl
Reactant: COC(=O)CCc1cc(C)n(Cc2cc(Cl)ccc2O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)COc1ccc(Cl)cc1Cn1nc(CCC(=O)OC)cc1C
Temperature: 150 °C
Yield: 84 %

Procedure:
To a solution of 3-[1-(5-Chloro-2-hydroxy-benzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid methyl ester, 15. (0.2 g, 0.63 mmol) in DMF (5 mL) were added potassium carbonate 0.15 g (1.26 mmol), tetrabutylammonium iodide 0.03 g and 3-chloromethylpentane 0.15 g (1.26 mmol). The resulting mixture was heated at 150° C. in a microwave reactor. The mixture was poured into water and extracted with EtOAc. The organic layers were combined, washed with brine (30 mL), dried (MgSO4) and the volatiles were removed in vacuo to give 0.21 g (84%) of the methyl ester 16 as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1.Br[C:25]1C=C(C=C[CH:32]=1)C#N>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[CH:32][CH:25]=[C:21]([C:20]#[N:19])[CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccn(C)n2)n1
Reactant: N#Cc1cccc(Br)c1
Product: Cc1ccc(Nc2cccc(C#N)c2)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (example 16) in accordance with the general method of example 20 using 3-Bromobenzonitrile instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow solid, MS (ISP): m/e=333.3 (M+H+).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:11])=O)[CH2:5][CH2:4]1)#[CH:2].CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[F:46][C:47]([F:77])([F:76])[C:48]1[CH:49]=[C:50]([C:58]([CH3:75])([CH3:74])[C:59]([N:61]([CH3:73])[C@H:62]2[C@H:66]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)[CH2:65][NH:64][CH2:63]2)=[O:60])[CH:51]=[C:52]([C:54]([F:57])([F:56])[F:55])[CH:53]=1>C1COCC1>[F:76][C:47]([F:46])([F:77])[C:48]1[CH:49]=[C:50]([C:58]([CH3:74])([CH3:75])[C:59]([N:61]([C@H:62]2[C@H:66]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)[CH2:65][N:64]([C:9]([CH:6]3[CH2:5][CH2:4][CH:3]([C:1]#[CH:2])[CH2:8][CH2:7]3)=[O:11])[CH2:63]2)[CH3:73])=[O:60])[CH:51]=[C:52]([C:54]([F:55])([F:56])[F:57])[CH:53]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CNC[C@H]1c1ccccc1
Reactant: C#CC1CCC(C(=O)O)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CC1CCC(C(=O)N2C[C@@H](N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](c3ccccc3)C2)CC1
Reaction time: 48 h
Yield: 54 %

Procedure:
To a stirred solution of 4-ethynyl-cyclohexanecarboxylic acid (commercially available) (6.5 mg, 0.043 mmol) in THF (2 ml) at RT were added Et3N (12 μl, 0.086 mmol), BOP (25 mg, 0.057 mmol) and rac-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-((3S,4R)-4-phenyl-pyrrolidin-3-yl)-isobutyramide (Intermediate VII-1) (20 mg, 0.043 mmol). Stirring was continued at 40° C. for 48 hours. Concentration and purification by preparative HPLC afforded 13.7 mg (54%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[NH:13][C:12](=[O:14])[O:11][C:9](=O)[C:8]=12.[NH:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1C(O)=O>CS(C)=O>[F:15][C:2]([F:1])([F:16])[C:3]1[C:8]2[C:9](=[O:11])[N:17]3[CH2:24][CH2:23][CH2:22][C@H:18]3[C:12](=[O:14])[NH:13][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=c1[nH]c2cccc(C(F)(F)F)c2c(=O)o1
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CS(C)=O
Product: O=C1Nc2cccc(C(F)(F)F)c2C(=O)N2CCC[C@@H]12

Procedure:
11.55 g (0.05 mol) of 6-(trifluoromethyl)-isatoic acid anhydride and 5.75 g (0.05 mol) of L-proline in 100 ml of dimethyl sulphoxide are heated to 70° for 1 hour, the solvent is removed in a high vacuum and the oil obtained is heated to 170° for 15 minutes. The crude product is purified by chromatography on silica gel using methylene chloride and mixtures of methylene chloride and ethyl acetate (5%, 10%, 15%) for the elution. After recrystallization of the crude product from ethyl acetate/diethyl ether there is obtained pure (S)-1,2,3,11a-tetrahydro-6-(trifluoromethyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H)-dione of melting point 176-178°.
Reaction SMILES: C[C:2]1[CH:3]=[C:4]2[C:9](=[C:10](C)[CH:11]=1)[O:8][CH2:7][C:6]([C:13](=[O:15])[CH3:14])=[CH:5]2.C(C1COC2C(C=1)=CC=CC=2)(=O)C>>[OH:15][CH:13]([C:6]1[CH2:7][O:8][C:9]2[C:4]([CH:5]=1)=[CH:3][CH:2]=[CH:11][CH:10]=2)[CH3:14]
Reactant: CC(=O)C1=Cc2cc(C)cc(C)c2OC1
Agent: CC(=O)C1=Cc2ccccc2OC1
Product: CC(O)C1=Cc2ccccc2OC1

Procedure:
The procedure is as in Example 1, stage B, 6,8-dimethyl-3-acetyl-2H-chromene being replaced by 3-acetyl-2H-chromene, obtained in the preceding stage.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[CH3:23])[CH:19]=[CH:18][C:17]=2[O:26][C:27]([F:30])([F:29])[F:28])[C@@H:9]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=O)(C)(C)C.Cl.[OH-].[Na+]>C(OCC)(=O)C>[F:25][C:22]([C:20]1[CH:19]=[CH:18][C:17]([O:26][C:27]([F:28])([F:29])[F:30])=[C:16]([CH:21]=1)[CH2:15][NH:14][C@H:10]1[CH2:11][CH2:12][CH2:13][NH:8][C@H:9]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([F:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NCc2cc(C(C)(F)F)ccc2OC(F)(F)F)[C@@H]1c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(F)(F)c1ccc(OC(F)(F)F)c(CN[C@H]2CCCN[C@H]2c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 69.5 %

Procedure:
To a stirred solution of Compound 26 (660 mg, 1.25 mmol) in ethyl acetate (6 ml) was added c. HCl aq. (2 ml) with ice-cooling. The reaction mixture was stirred at room temperature for 50 min. The mixture was basified to pH10-11 with 10% NaOH aq. with ice-cooling. The organic layer was separated and the aqueous layer was extracted with AcOEt. The combined solution was washed with brine, dried (MgSO4), and concentrated in vacuo to give crude product as a pale yellow oil. The crude product was purified by column chromatography on silica gel with dichloromethane-methanol (20:1) to give Compound 27 (360 mg, 70%) as a yellow oil.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:26])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C@@H:13]([C:15](=[O:25])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)[CH3:14])[CH:7]=1.O.Cl>CO>[C:23]([C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:15]([C@H:13]([O:12][C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[C:5]([OH:26])=[O:4])[CH3:14])=[O:25])=[CH:22][CH:21]=1)#[N:24]
Reactant: COC(=O)c1cccc(O[C@H](C)C(=O)Nc2ccc(C#N)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@@H](Oc1cccc(C(=O)O)c1)C(=O)Nc1ccc(C#N)cc1
Temperature: 50 °C
Yield: 218.8 %

Procedure:
Add 10% aqueous solution of sodium hydroxide (2.5 mL, 6.2 mmol) to a suspension of 3-[(R)-1-(4-cyano-phenylcarbamoyl)-ethoxy]-benzoic acid methyl ester (0.59 g, 0.81 mmol) in a 1:1 mixture of water: MeOH (20 mL). Heat the mixture at 50° C. for 1 h then cool to room temperature and adjust the pH of the mixture to approximately pH 5 by the addition of a 2 N solution of hydrochloric acid. Extract the mixture with EtOAc and wash the combined organic phase with brine, dry over anhydrous sodium sulfate and concentrate under reduced pressure to provide 0.55 g of 3-[(R)-1-(4-cyano-phenylcarbamoyl)-ethoxy]-benzoic acid as a foam.