Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:30][CH2:29][C:28]([CH3:42])([O:31][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[CH2:27][CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.CCOC(C)=O>[CH3:42][C:28]1([O:31][Si:32]([CH:33]([CH3:35])[CH3:34])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])[CH2:29][CH2:30][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26][CH2:27]1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CC(C)[Si](OC1(C)CCN(c2nnc3ccc(F)cn23)CC1)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)[Si](OC1(C)CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1)(C(C)C)C(C)C
Temperature: 60 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
To a solution of Intermediate A (111 mg, 0.680 mmol) in DMF (2 mL) was added NaH (60% in oil, 68 mg, 1.70 mmol) and the mixture stirred at RT for 20 min, before Intermediate 79d (230 mg, 0.566 mmol) was added. This mixture was stirred at 60° C. for 1 h. The cooled reaction mixture was diluted with EtOAc (100 mL), washed with water (2×), brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound (160 mg, 51%). LCMS (Method 1): Rt 3.06 min, m/z 550 [MH+].
Reaction SMILES: C(Cl)(=O)C.[C:5]1([S:11]([CH2:14][C:15]2[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([O:26][CH3:27])[C:18]([C:28]3[N:32](C4CCCCO4)[N:31]=[CH:30][CH:29]=3)=[CH:17][CH:16]=2)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO>[C:5]1([S:11]([CH2:14][C:15]2[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([O:26][CH3:27])[C:18]([C:28]3[CH:29]=[CH:30][NH:31][N:32]=3)=[CH:17][CH:16]=2)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccnn2C2CCCCO2)c1OC
Solvent: CC(=O)Cl
Solvent: CO
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2cc[nH]n2)c1OC
Yield: 99.2 %

Procedure:
Acetyl chloride (0.1 ml) was added to methanol (10 ml) cooled in ice and the resultant solution was added to ethyl 6-(benzenesulphonylmethyl)-2-methoxy-3-[1-(tetrahydropyran-2-yl)pyrazol-5-yl]benzoate (Intermediate 47, 0.05 g). The resultant mixture was stirred at room temperature for 1 hour then evaporated to dryness. The residue was treated with sodium bicarbonate (saturated aqueous solution) and extracted with DCM, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give ethyl 6-(benzenesulphonylmethyl)-2-methoxy-3-(3-pyrazolyl)benzoate (0.041 g) as a gum.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].N([O-])=O.[Na+].C(OCC)(=O)C.[BrH:25].O>O.[Cu]Br>[Br:25][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1cc([C@@H]2CNC(=O)C2)ccc1Cl
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1C[C@H](c2ccc(Cl)c(Br)c2)CN1
Reaction time: 0.17 h

Procedure:
(4R)-4-(3-Amino-4-chlorophenyl)pyrrolidin-2-one (12 g, 57.14 mmol) was added to a mixture of 75 mL of 48% HBr/water and 150 mL of water. The solution was cooled in ice. Sodium nitrite (4.33 g, 62.85 mmol) in 10 mL of water was added dropwise. The resulting mixture was stirred for 10 min. Copper(I) bromide (8.9 g, 62.85 mmol) was dissolved in a mixture of 75 mL of 48% HBr/water and 150 mL of water and added dropwise to the reaction mixture. The mixture was then stirred overnight at room temperature. Ethyl acetate (250 mL) was added to the reaction mixture and stirred for 10 min. The organic layer was separated and the aqueous layer was extracted with 200 mL of ethyl acetate. The combined ethyl acetate layers were washed with water (3 times), brine and then concentrated to give the desired product as a brownish yellow oil, which was purified by silica gel column chromatography eluting with methylene chloride/methanol to provide 7.2 g of the title compound (60% yield). 1H-NMR (400 MHz, CD3OD): δ 7.62-7.63 d, J=2.0 Hz, 1H), 7.45-7.47 (m, 1H), 7.26-7.30 (m, 1H), 3.69-3.79 (m, 2H), 3.33-3.37 (m, 1H) 2.67-2.74 (dd, J=16.4, 8.8 Hz, 1H), 2.40-2.47 (dd, J=16.4, 8.4 Hz, 1H); MS (ESI) m/z 275.89 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[N:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:16]=[N+:17]=[N-:18].[Na+].[Cl-].[NH4+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:18][N:17]=[N:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2nnn[nH]2)CC1
Temperature: 100 °C
Reaction time: 20 h
Yield: 59.6 %

Procedure:
A mixture of 2.10 g (10.0 mmol) of 1-(t-butoxycarbonyl)-4-cyanopiperidine (from Step A), 1.95 g (30.0 mmol) of sodium azide and 1.60 g (30.0 mmol) of ammonium chloride in 20 mL of DMF was stirred at 100° C. for 20 h. The mixture was cooled and partitioned between 200 mL of methylene chloride and 200 mL of 1.0 N HCl and the layers were separated. The organic layer was washed with 200 mL of water, dried over magnesium sulfate and concentrated. Flash chromatography on 50 g of silica gel using 4:1 v/v methylene chloride/ethyl acetate+1% acetic acid, then 2:1 v/v methylene chloride/ethyl acetate+1% acetic acid as the eluent afforded 1.51 g (60%) of the title compound:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].Cl[C:21]([O:23]CC)=[O:22].Cl>O1CCCC1.O>[C:9]([CH:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[C:21]([OH:23])=[O:22])([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: CCOC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(C(=O)O)c1ccc(O)cc1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
About 0.5 mole of 4-hydroxybenzeneacetic acid is dissolved in about 50 ml of anhydrous tetrahydrofuran at -40° C. To this solution is added 3 equivalents of lithium diisopropylamide. The temperature is maintained at about -40° C. for about 15 minutes. Then 1 equivalent of ethyl chloroformate is added and the temperature is raised from about -40° C. to about 20° C. and the reaction mixture stirred for about 60 minutes. The reaction mixture is poured into water and the monoester of α-carboxy-4-hydroxybenzeneacetic acid is recovered from the aqueous solution. Hydrolysis of the half-ester with sodium hydroxide followed by acidification with hydrochloric acid gives α-carboxy-4-hydroxybenzeneacetic acid.
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14](N)[N:15](C(OC(C)(C)C)=O)[CH2:16][C@H:17]([OH:39])[C@@H:18]([NH:26][C:27](=[O:38])[C@H:28]([C@H:34]([CH2:36][CH3:37])[CH3:35])[NH:29][C:30]([O:32][CH3:33])=[O:31])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:10][CH:9]=1.C[N:49](C=O)C>O1CCOCC1>[ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([NH2:49])[CH2:16][C@H:17]([OH:39])[C@@H:18]([NH:26][C:27](=[O:38])[C@H:28]([C@H:34]([CH2:36][CH3:37])[CH3:35])[NH:29][C:30]([O:32][CH3:33])=[O:31])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:10][CH:9]=1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(C(=O)OC(C)(C)C)C(N)c1ccc(-c2ccccn2)cc1
Reactant: CN(C)C=O
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2ccccn2)cc1
Reaction time: 2.5 h

Procedure:
Analogously to Example 40g, 40 ml of 4M HCl in dioxane are added to 1.9 g (3 mmol) of 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-2-N-Boc-amino-5(S)-N-(N-methoxycarbonyl-(L)-iso-leucyl)amino-6-phenyl-2-azahexane and the mixture is diluted with 3 ml of DMF. After 2.5 hours, the mixture is worked up. The title compound is obtained: TLC: Rf =0.55 (methylene chloride/methanol: 9/1); HPLC20-100 : tRet =8.74; FAB MS (M+H)+ =534.
Reaction SMILES: [CH2:1]([N:5]([CH2:14][CH2:15][CH2:16][CH3:17])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1)=[O:21]>>[CH2:1]([N:5]([CH2:14][CH2:15][CH2:16][CH3:17])[C:6]1[CH:13]=[CH:12][C:9]([CH2:10][N:32]2[CH2:33][CH2:34][CH:29]([C:25]3[CH:24]=[C:23]([NH:22][C:20](=[O:21])[CH:19]([CH3:18])[CH3:35])[CH:28]=[CH:27][CH:26]=3)[CH2:30][CH2:31]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: CCCCN(CCCC)c1ccc(C=O)cc1
Product: CCCCN(CCCC)c1ccc(CN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1

Procedure:
Prepared by Procedure F and Scheme R using 4-(dibutylamino)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 464.6 (M+H)+.
Reaction SMILES: [CH2:1]([C@@:4]1([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].B.C1C[O:36]CC1>C1COCC1>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C@:4]2([CH2:1][CH2:2][CH2:3][OH:36])[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([F:23])([F:24])[F:22])=[CH:17][CH:18]=3)[CH3:12])[CH2:6][CH2:5]2)=[CH:26][CH:27]=1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(OCC(F)(F)F)cc2)C(=O)O1
Reactant: C1CCOC1
Agent: B
Product: C[C@@H](c1ccc(OCC(F)(F)F)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a solution of (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1,3-oxazinan-2-one (500 mg, 1.6 mmol) in THF (20 mL) was added BH3/THF (1 M, 3.2 mL) at 0° C. The mixture was stirred at rt for 2 h. The mixture was quenched with H2O (2.5 mL) at 0° C., then NaOH (3 M, 1.1 mL) and 30% H2O2 (2.5 mL) were added. After stirring at rt for another 2 h, 1N HCl was added to the mixture. The mixture was extracted with EtOAc. The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by preparative TLC to give (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1,3-oxazinan-2-one (320 mg, 62%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([O:13][C:14]([N:16]1[CH2:25][C:24]2[N:20]([CH:21]=[N:22][N:23]=2)[C:19]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:18]=2[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>O1CCCC1>[C:9]([O:13][C:14]([N:16]1[CH2:25][C:24]2[N:20]([C:21]([Br:1])=[N:22][N:23]=2)[C:19]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:18]=2[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)ccc2-n2cnnc2C1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1Cc2cc(Cl)ccc2-n2c(Br)nnc2C1
Yield: 84.8 %

Procedure:
N-Bromosuccinimide (4.50 g, 24.0 mmol) was added to 8-chloro-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-carboxylic acid tert-butyl ester (7.00 g, 21.8 mmol) in tetrahydrofuran (140 ml). The mixture was stirred in boiling tetrahydrofuran for 2 hours. The solvent was removed in vacuo and the residue was purified by chromatography (50 g silica gel, heptane: ethylacetate 1:9 to 1:0) to yield 7.39 g (85%) 1-bromo-8-chloro-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-carboxylic acid tert-butyl ester as white solid. MS m/e: 401 (M+H+).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([OH:10])=[C:8]([F:11])[C:7]([F:12])=[C:6]([F:13])[C:5]=1[F:14].Cl[C:16]1[CH:17]=[CH:18][C:19]([N+:31]([O-:33])=[O:32])=[C:20]([N:22](C)[C:23](=O)OC(C)(C)C)[CH:21]=1>CN(C)C=O>[CH3:23][NH:22][C:20]1[CH:21]=[C:16]([O:10][C:9]2[C:4]([F:3])=[C:5]([F:14])[C:6]([F:13])=[C:7]([F:12])[C:8]=2[F:11])[CH:17]=[CH:18][C:19]=1[N+:31]([O-:33])=[O:32]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1cc(Oc2c(F)c(F)c(F)c(F)c2F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 19 %

Procedure:
To a suspension of sodium hydride (55 wt. %, 1.66 g) in anhydrous N,N-dimethylformamide (50 ml) was added pentafluorophenol (6.38 g). The mixture was stirred at ambient temperature for several minutes. To this mixture was added t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (10 g) in small portions and the mixture was stirred at 150° C. for 15 hours. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and water. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane/toluene=4/1 as the eluant to give the title compound (2.2 g).
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][C:5]([CH2:8][CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[CH:6][N:7]=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>ClCCl.CCOC(C)=O>[C:25]1([O:24][C:22](=[O:23])[NH:2][C:3]2[S:4][C:5]([CH2:8][CH2:9][N:10]3[C:18](=[O:19])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]3=[O:20])=[CH:6][N:7]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ncc(CCN2C(=O)c3ccccc3C2=O)s1
Agent: Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1ncc(CCN2C(=O)c3ccccc3C2=O)s1)Oc1ccccc1
Reaction time: 2 h

Procedure:
To a suspension of a HBr salt of 2-[2-(2-amino-thiazol-5-yl)-ethyl]-isoindole-1,3-dione (compound 58.1; 1.42 mmol) in dichloromethane was added TEA (4.30 mmol) followed by the addition of phenyl chloroformate (1.43 mmol) at room temperature. After 2 hours, the reaction was concentrated to dryness to give a solid that was suspended in EtOAc, filtered, washed with additional EtOAc and dried under vacuum to provide {5-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-thiazol-2-yl}-carbamic acid phenyl ester (compound 58.2, which is contaminated with triethyl amine salts) which was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[N:17]=[C:16]2[NH2:24])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:26][CH:27]=O.O>CC(N(C)C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[N:17]3[CH:26]=[CH:27][N:24]=[C:16]23)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCCl
Reactant: Nc1nc2cccnc2n1-c1ccc(OCc2ccccc2)cc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: c1ccc(COc2ccc(-n3c4ncccc4n4ccnc34)cc2)cc1

Procedure:
A solution of 3-[4-(benzyloxy)phenyl]-3H-imidazo[4,5-b]pyridin-2-amine (1.58 g) and 6.1 M aqueous chloroacetoaldehyde solution (1.64 mL) in DMA (20 mL) was stirred at 90° C. for 1.5 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate) and recrystallized from hexane/THF to give the title compound (0.665 g).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1.[C:21](Cl)(=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24]>>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][C:21](=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24])=[C:3]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[NH:4]2)=[CH:9][CH:8]=1
Reactant: Cc1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Reactant: CC(C)CC(=O)Cl
Product: Cc1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2NC(=O)CC(C)C)c1

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(3-methylbenzoyl)indole (Example 21) and isovaleryl chloride. m.p.: 182-185° C. 1H-NMR (CDCl3) δ: 10.05 (1H, br s), 8.42-8.17 (2H, m), 7.62-7.53 (2H, m), 7.48-7.40 (2H, m), 7.30-7.25 (1H, m), 7.12-7.03 (1H, m), 2.45 (3H, s), 2.39-2.17 (3H, m), 1.04 (6H, dd, J=6.6 Hz)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[N:19]O)[C:10]=2[CH:9]=[CH:8][CH:7]=1>C(O)C.O1CCCC1.[Ni]>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([NH2:19])[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1ncc[nH]1
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: NC1c2ccccc2-c2c(-c3ncc[nH]3)cccc21
Reaction time: 3 h

Procedure:
Work in an autoclave as in Stage 3 in Example 5, starting from 449 mg of equimolecular mixture of the Z and E isomers of 4-(1H-imidazol-2-yl)-fluoren-9-one oxime, obtained in the preceding stage, in a mixture of 25 mL of ethanol and 25 mL of tetrahydrofuran, in the presence of Raney nickel, under an initial hydrogen pressure of 1 bar, at 60° C. for 3 hours. After filtration of the catalyst on Celite, concentration of the filtrate at reduced pressure and purification by making into a paste with diisopropyl oxide, we obtain 367 mg of 4-(1H-imidazol-2-yl)-9H-fluorene-9(R,S)-amine, in the form of a white powder, with the following characteristics:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:19][CH3:20])[C:9]2([C:12]([O:14]C(C)(C)C)=[O:13])[CH2:11][CH2:10]2)=[CH:4][C:3]=1[NH:21][C:22](=[O:37])[C@H:23]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C@@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26].C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:19][CH3:20])[C:9]2([C:12]([OH:14])=[O:13])[CH2:10][CH2:11]2)=[CH:4][C:3]=1[NH:21][C:22](=[O:37])[C@H:23]([C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1)[C@@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26]
Reactant: COC(c1ccc(Cl)c(NC(=O)[C@H](c2ccc(Cl)cc2)[C@@H](C)C(F)(F)F)c1)C1(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(c1ccc(Cl)c(NC(=O)[C@H](c2ccc(Cl)cc2)[C@@H](C)C(F)(F)F)c1)C1(C(=O)O)CC1
Reaction time: 0.5 h

Procedure:
151 mg (0.269 mmol) of tert-butyl 1-[(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)(methoxy)methyl]cyclopropanecarboxylate (as diastereomer mixture) were dissolved in 2.9 ml of dichloromethane, and 1.0 ml of TFA was added at RT. After 30 min at RT, the reaction mixture was concentrated under reduced pressure and the residue was concentrated under reduced pressure. The crude product obtained in this manner was purified by RP-HPLC (mobile phase acetonitrile/water). This gave 87 mg (64% of theory) of the target compound.
Reaction SMILES: [S:1]([C:5]1[S:13][C:12]2[C:7](=[N+:8]([O-:14])[CH:9]=[CH:10][CH:11]=2)[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>C(#N)C>[CH3:17][N:18]([CH3:20])[CH:19]=[N:2][S:1]([C:5]1[S:13][C:12]2[C:7](=[N+:8]([O-:14])[CH:9]=[CH:10][CH:11]=2)[CH:6]=1)(=[O:3])=[O:4]
Reactant: NS(=O)(=O)c1cc2c(ccc[n+]2[O-])s1
Reactant: COC(OC)N(C)C
Solvent: CC#N
Product: CN(C)C=NS(=O)(=O)c1cc2c(ccc[n+]2[O-])s1
Reaction time: 18 h
Yield: 93.8 %

Procedure:
To a partial suspension of 2-sulfamoylthieno[3,2-b]pyridine-4-oxide (1.64 g, 7.1 mmol) in acetonitrile (45 ml), under a nitrogen atmosphere at room temperature was added dimethylformamide dimethyl acetal (1.5 ml, 11 mmol). The product began to precipitate after initial complete solution. After stirring for 18 hours, the reaction mixture was diluted with chloroform to dissolve the product. The solution was washed with water, dried over anhydrous sodium sulfate, filtered through charcoal and evaporated to give nearly pure product (1.9 g, 94% yield). Recrystallization from hot chloroform gave pure product (1.6 g), m.p. 224°-225.5° C.
Reaction SMILES: [F:1][C:2]([F:12])=[CH:3][C@H:4]1[C@H:6]([C:7](O)=[O:8])[C:5]1([CH3:11])[CH3:10].CN(C)C=O.C(Cl)(=O)C([Cl:21])=O>C(OCC)C>[F:1][C:2]([F:12])=[CH:3][C@H:4]1[C@H:6]([C:7]([Cl:21])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: CC1(C)[C@@H](C=C(F)F)[C@@H]1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC1(C)[C@@H](C=C(F)F)[C@@H]1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of 2.0 g (0.0114 mole) of trans-3-(2,2-difluoroethenyl)-2,2-dimethylcyclopropanecarboxylic acid and 0.08 g of N,N-dimethylformamide in 20 ml of dry diethyl ether was cooled to 0° C. A solution of 2.17 g (0.017 mole) of oxalyl chloride in 2 ml of dry diethyl ether was added to the reaction mixture during a 20 minute period. Upon complete addition the mixture was allowed to warm to room temperature and stirred for two hours. The mixture was concentrated under reduced pressure to give a yellow oil. The oil was dissolved in 5 ml of dry diethyl ether and the solvent removed under reduced pressure to yield trans-3-(2,2-difluoroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride as an oil.
Reaction SMILES: [OH:1][CH:2]([CH2:15][S:16][C:17]1[S:18][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:20][CH:21]=1)[CH2:3][N:4]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[OH:1][CH:2]([CH2:15][S:16][C:17]1[S:18][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:20][CH:21]=1)[CH2:3][NH2:4]
Reactant: O=C1c2ccccc2C(=O)N1CC(O)CSc1ccc(CN2CCCCC2)s1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCC(O)CSc1ccc(CN2CCCCC2)s1

Procedure:
8.60 g (20 mmol) of 2-[2-hydroxy-3-[5-(1-piperidylmethyl)-2-thienylthio]propyl]-1H-isoindole-1,3-dione and 3,3 ml of hydrazine hydrate (80%) are boiled in 80 ml of ethanol for 3 hours. The residue obtained after concentration of the mixture by evaporation is taken up in 50 ml of water; 8 ml of conc. hydrochloric acid are added and the reaction mixture is filtered. The filtrate is adjusted to pH 12 with conc. sodium hydroxide solution and extracted with 3×40 ml methylene chloride. The organic phase is dehydrated with Na2SO4 and concentrated by evaporation under vacuum. 4.9 g (82% of theoretical) of the title compound are obtained as a light green oil. ##STR7##
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12]2[CH2:17][CH2:16][CH2:15][NH:14][N:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH3:18][C:19]1[N:20]=[C:21]([C:27]2[CH:32]=[N:31][CH:30]=[CH:29][N:28]=2)[S:22][C:23]=1[C:24](Cl)=[O:25]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:24]([C:23]3[S:22][C:21]([C:27]4[CH:32]=[N:31][CH:30]=[CH:29][N:28]=4)=[N:20][C:19]=3[CH3:18])=[O:25])[N:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: Cc1nc(-c2cnccn2)sc1C(=O)Cl
Reactant: CCOc1cc(C2=NNCCC2)ccc1OC
Product: CCOc1cc(C2=NN(C(=O)c3sc(-c4cnccn4)nc3C)CCC2)ccc1OC
Yield: 86.4 %

Procedure:
Analogously to Example 2, reaction of 300 mg of 3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazine with 307 mg of 4-methyl-2-pyrazin-2-yl-thiazole-5-carbonyl chloride (“BC”) gives the compound 1-[3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-yl]-1-(4-methyl-2-pyrazin-2-yl-thiazol-5-yl)methanone (484 mg, HPLC-MS m/e 438).
Reaction SMILES: C([O:3][C:4](=[O:14])[CH2:5][S:6](=[O:13])(=[O:12])[NH:7][C:8]([CH3:11])([CH3:10])[CH3:9])C.[OH-].[Na+].Cl>CCO.O>[C:8]([NH:7][S:6]([CH2:5][C:4]([OH:14])=[O:3])(=[O:13])=[O:12])([CH3:11])([CH3:9])[CH3:10]
Reactant: CCOC(=O)CS(=O)(=O)NC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)NS(=O)(=O)CC(=O)O
Reaction time: 8 h
Yield: 68.7 %

Procedure:
To a solution of ethyl-2-(N-tert-butylsulfamoyl)acetate (4 g, 17.9 mmol.) in 65 mL of EtOH and 13 mL of H2O at 0° C. was slowly added NaOH (3.6 g, 89.5 mmol.). The reaction was allowed to room temperature and stirred overnight. TLC analysis showed the reaction complete. The mixture was acidified to pH=5 with aq. HCl (1M). The resulting mixture was extracted with EtOAc (30 mL×3). The combined organic layer was dried over Na2SO4, concentrated to afford crude 2-(N-tert-butylsulfamoyl)acetic acid (2.4 g, 69%), which was used directly without purification.