Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[C:5]([C@@H:7]2[CH2:12][CH2:11][N:10](C(OC)=O)[C@H:9]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[CH2:8]2)[O:4][NH:3]1.Br>>[F:26][C:24]([F:25])([F:27])[C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][C@@H:9]1[CH2:8][C@H:7]([C:5]2[O:4][NH:3][C:2](=[O:1])[CH:6]=2)[CH2:12][CH2:11][NH:10]1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@H]1Cc1cccc(C(F)(F)F)c1
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@H](Cc3cccc(C(F)(F)F)c3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 41 h
Yield: 67.5 %

Procedure:
(2S,4R)-Methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(3-(trifluoromethyl)benzyl)piperidine-1-carboxylate (0.64 g, 1.67 mmol) (from example 107, step 3) was dissolved in hydrogen bromide (33% in acetic acid, 5 mL, 71.37 mmol) and stirred at room temperature for 41 h. Reaction mixture was evaporated and restarted under the same conditions. After 28 h solvents evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx I, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2S,4R)-2-(3-(trifluoromethyl)benzyl)piperidin-4-yl)isoxazol-3(2H)-one (368 mg, 68%). 1H NMR (600 MHz, DMSO) δ 1.07-1.15 (m, 1H), 1.36 (dq, 1H), 1.74-1.80 (m, 2H), 2.54-2.58 (m, 1H), 2.64-2.79 (m, 4H), 2.96-3.01 (m, 1H), 5.66 (s, 1H), 7.50-7.59 (m, 4H). HRMS Calculated for [C16H17F3N2O2+H]+: 327.1320. Found: 327.1333
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[C:15]([CH3:19])[CH:14]=[CH:13][C:12]=3[NH:11][C:10](=[O:20])[C:9]=2[CH:8]=[N:7]1)[CH3:2].CI.[C:24]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[C:15]([CH3:19])[CH:14]=[CH:13][C:12]=3[N:11]([CH3:24])[C:10](=[O:20])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c(=O)[nH]c3ccc(C)cc3c21
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1ncc2c(=O)n(C)c3ccc(C)cc3c21
Yield: 80 %

Procedure:
(8-Methyl-4-oxo-4,5-dihydro-pyrazolo[4,3-c]quinolin-1-yl)-acetic acid ethyl ester m (285 mg, 1 mmol), methyl iodide (142 mg, 1 mmol) and Cs2CO3 (650 mg, 2 mmol) were combined in dry DMF (4 mL) and the resultant mixture was heated at 40° C. for 8 h. The reaction mixture was cooled, diluted with water and extracted with ethyl acetate (2×20 mL) and the combined organic extract was dried over Na2SO4, and concentrated in vacuo. The crude residue was purified by column chromatography to provide the desired compound n (80% yield): LC MS (Method B): 300 (M+1).
Reaction SMILES: C([Li])CCC.O1CCCC1.[Br-].[CH2:12]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[CH:43]([C:45]1[CH:46]=[C:47]([C:50]([O:52][CH3:53])=[O:51])[NH:48][CH:49]=1)=O>CCCCCC.O>[CH:43](/[C:45]1[CH:46]=[C:47]([C:50]([O:52][CH3:53])=[O:51])[NH:48][CH:49]=1)=[CH:23]/[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCCCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cc(C=O)c[nH]1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCC/C=C\c1c[nH]c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
A ca. 15% solution (18.5 ml) of n-butyllithium in hexane was added dropwise at -50° C. to a tetrahydrofuran suspension (95 ml) of 16.0 g (31.4 mmol) of dodecyltriphenylphosphonium bromide described in Chemistry and Industry (London) p. 1086, 1958. The temperature was raised to room temperature and the mixture was stirred for 30 minutes. The temperature was again lowered to -50° C. To the mixture was added dropwise a tetrahydrofuran solution (50 ml) of 2.4 g (15.7 mmol) of methyl 4-formylpyrrole-2-carboxylate described in Bulletin de la Societe Chimique de France, p. 283, 1972. The mixture was stirred for 1 hour, diluted with water, extracted with ethyl acetate, washed with an aqueous saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, the residue was purified by subjecting it to column chromatography over silica gel (eluent: ethyl acetate/hexane=1/7) to obtain 3.11 g (65% yield) of methyl 4-(1-cis-tridecenyl)pyrrole-2-carboxylate, m.p. 51°-52° C.
Reaction SMILES: C(OC([N:8]([CH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[F:26])[C:20]([OH:22])=[O:21])C(OC(C)(C)C)=O)=O)(C)(C)C.[ClH:27].[C:28](OCC)(=O)[CH3:29]>C(OCC)(=O)C>[ClH:27].[NH2:8][CH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[F:26])[C:20]([O:22][CH2:28][CH3:29])=[O:21]
Reactant: CC(C)(C)OC(=O)N(Cc1cc(C(=O)O)ccc1F)C(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Product: CCOC(=O)c1ccc(F)c(CN)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.59 g of 3-{[bis(tert-butoxycarbonyl)amino]methyl}-4-fluorobenzoic acid was dissolved in 10.0 mL of ethyl acetate, and 10.0 mL of a 4 M hydrogen chloride/ethyl acetate solution was added thereto, followed by stirring at room temperature for 4 hours. The reaction liquid was concentrated under reduced pressure, and the obtained residue was crystallized by addition of ethyl acetate and hexane to obtain 2.59 g of ethyl 3-(aminomethyl)-4-fluorobenzoate hydrochloride.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:20])[C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[C:8]([C:15](=[O:19])[N:16]([OH:18])[CH3:17])[CH:7]=1)[CH:2]=[CH2:3].[CH2:21](Br)[CH:22]=[CH2:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:4][C:5](=[O:20])[C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[C:8]([C:15](=[O:19])[N:16]([O:18][CH2:23][CH:22]=[CH2:21])[CH3:17])[CH:7]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1cc(C(=O)N(C)O)cc([N+](=O)[O-])c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1cc(C(=O)N(C)OCC=C)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.3 %

Procedure:
A mixture of (8(a)) (0.60 g), allyl bromide (0.28 g), potassium carbonate (0.59 g) and DMF (20 ml) was stirred for 3 hours at ambient temperature under an argon atmosphere. The dimethyl formamide was then evaporated under reduced pressure and the residue dissolved in ethyl acetate (50 ml) and water (50 ml). The organic phase was separated, washed with brine (50 ml), dried over magnesium sulphate and evaporated under reduced pressure to dryness to give 3-(N-methyl-allyloxycarbamoyl)-5-nitro-benzoic acid allyl ester (8(b)) as a yellow oil (0.571 g).
Reaction SMILES: [N:1](C(OCC)=O)=NC(OCC)=O.[CH3:13][O:14][CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][OH:22])=[CH:19][CH:18]=1.ON1C(=O)C2=CC=CC=C2C1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:13][O:14][CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][O:22][NH2:1])=[CH:19][CH:18]=1
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: COCOc1ccc(CO)cc1
Agent: O=C1c2ccccc2C(=O)N1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCOc1ccc(CON)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
Diethyl azodicarboxylate (40% toluene solution, 142 g) was added dropwise to a solution of 4-methoxymethoxybenzylalcohol (50.0 g), N-hydroxyphthalimide (44.1 g) and triphenylphosphine (83.7 g) in tetrahydrofuran (900 ml) at room temperature and stirred for 1 hour. The reaction mixture was concentrated. In order to remove triphenylphosphine oxide, the residue was subjected to silica gel chromatography to obtain crystals from an ethyl acetate-hexane (1:5, v/v)-eluted fraction. The crystals were washed with ethyl acetate-hexane (1:5, v/v) and then dissolved in tetrahydrofuran (200 ml) and ethanol (50 ml). To this solution was added hydrazine monohydrate (33.7 ml) and heated under reflux for 3 hours. The reaction mixture was cooled to room temperature, an aqueous solution of potassium carbonate was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. Isopropyl ether was added to the residue and filtered to remove insolubles. The filtrate was concentrated to obtain 4-methoxymethoxybenzyloxyamine (28.9 g, yield 58%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](Cl)=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[C:2]1([NH:1][C:15](=[O:16])[C:12]2[CH:13]=[CH:14][C:9]([Br:8])=[CH:10][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccccc1)c1ccc(Br)cc1
Reaction time: 3 h
Yield: 39.8 %

Procedure:
Aniline (0.87 mL, 9.57 mmol) was added slowly to a mixture of 4-Bromo-1-benzenecarbonyl chloride (2.0 g, 9.11 mmol) and triethyl amine (1.9 mL, 13.67 mmol) in dichloromethane (95 mL). After 3 hours, solvent was removed under reduced pressure. Ethyl acetate was added and the mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was re-crystallized from ethyl acetate/heptane to give N1-phenyl-4-bromobenzamide (1.00 g, 40%). 1H NMR (DMSO-d6) δ 7.11 (m, 1H), 7.38 (m, 2H), 7.76 (m, 4H), 7.92 (m, 2H), 10.30 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[Cl:19][C:20]1[S:24][N:23]=[C:22]([C:25]2[S:29][C:28]([S:30](Cl)(=[O:32])=[O:31])=[CH:27][CH:26]=2)[N:21]=1>>[Cl:19][C:20]1[S:24][N:23]=[C:22]([C:25]2[S:29][C:28]([S:30]([NH:18][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[C:7]([F:8])[C:6]=3[NH:9][C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=3[F:17])(=[O:32])=[O:31])=[CH:27][CH:26]=2)[N:21]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2nsc(Cl)n2)s1
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: O=S(=O)(Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F)c1ccc(-c2nsc(Cl)n2)s1

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine (0.182 mmol) was reacted with 5-(5-chloro-1,2,4-thiadiazol-3-yl)thiophene-2-sulfonyl chloride (0.5 mmol) to obtain 5-(5-chloro-1,2,4-thiadiazol-3-yl)-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)thiophene-2-sulfonamide. 1H NMR (300 MHz, CDCl3)) δ 5.8 (dt, 1H), 5.95 (s, 1H), 6.95 (d, 1H), 7.4 (m, 2H), 7.6 (d, 1H), 7.8 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]1.[CH3:15][C:16]1[O:17][C:18]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:19]([C:21](O)=[O:22])[N:20]=1>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH:12][C:21]([C:19]2[N:20]=[C:16]([CH3:15])[O:17][C:18]=2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:22])=[N:8]1
Reactant: CC(F)(F)CCCCn1ccc(N)n1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)o1
Product: Cc1nc(C(=O)Nc2ccn(CCCCC(C)(F)F)n2)c(-c2ccccc2)o1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-3-ylamine and 2-methyl-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.19 min; [M+H]+=389.29.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]([N+:23]([O-])=O)=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]>P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]2[C:13]3[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=[CH:21][C:22]=3[NH:23][C:5]=2[CH:6]=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=12
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1-c1ccc2ccccc2c1OC
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Product: COC(=O)c1cccc2[nH]c3cc4ccccc4c(OC)c3c12
Temperature: 25 °C
Yield: 26.9 %

Procedure:
A solution of 2-(1-methoxynaphthalen-2-yl)-3-nitrobenzoic acid, methyl ester, (1.52 g, 4.5 mM) in triphenyl phosphite (7.19 g, 6.1 mL, 22.5 mM) was heated at 160° C. for 19 h under a nitrogen atmosphere. The mixture was cooled to room temperature and dried azeotropically in vacuo with toluene, then purified by column chromatography on silica gel (elution with gradient hexane/ethyl acetate) to afford 0.37 g (27%) of the title compound 11-methoxy-5H-benzo[b]carbazole-1-carboxylic acid, methyl ester as a yellow solid (MP 190–196° C., MW 305.34).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)=[C:6]([CH2:14]Cl)[C:5]=1[OH:16])(=[O:3])[CH3:2].[OH-:17].[K+].Cl>C(O)C.O>[C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)=[C:6]([CH2:14][OH:17])[C:5]=1[OH:16])(=[O:3])[CH3:2]
Reactant: [OH-]
Reactant: CC(=O)c1cc2c(c(CCl)c1O)CCCC2
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(=O)c1cc2c(c(CO)c1O)CCCC2

Procedure:
To a solution of the product of step (a) (23.8 g) in ethanol (500 ml) was added a solution of potassium hydroxide (11.2 g) in ethanol (250 ml) and water (100 ml). The resulting mixture was heated on a steam bath for 30 minutes, poured into water (2 l) and the mixture was made acid with concentrated hydrochloric acid. It was then extracted with ethyl acetate and the extracts were dried (MgSO4), filtered and the filtrate was evaporated to dryness leaving 7-acetyl-1,2,3,4-tetrahydro-6-hydroxy-5-hydroxymethylnaphthalene as an oil, 21 g (95%).
Reaction SMILES: [C:1]1([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20]Br)[CH3:17]>CCCC[N+](CCCC)(CCCC)CCCC.[OH-].CC[N+](CC1C=CC=CC=1)(CC)CC.[Cl-]>[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20][CH:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:8])[CH3:17]
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: CCOC(CBr)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Product: CCOC(CC(C(=O)c1ccccc1)c1ccccc1)OCC

Procedure:
The compound is prepared from 19.6 g of desoxybenzoin and 19.7 g of bromacetaldehyde diethyl acetal according to the procedure in Example 1(a). The reaction is performed however at 90° C. and using TBAH as catalyst instead of TEBAC.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>ClCCl>[C:1]([O:5][C:6]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][O:16][S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=2)(=[O:32])=[O:31])=[CH:12][CH:13]=1)=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCO)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1
Reaction time: 0.75 h
Yield: 97.8 %

Procedure:
4-(2-Hydroxyethyl)phenylcarbamic tert-butyl ester (described in Example 38b) (170 g; 0.716 mole) was suspended in dichloromethane (1.7 l) and placed in an ice bath. Pyridine (113 g; 1.43 mole) was added giving a clear yellow solution. p-Toluenesulfonyl chloride (205 g; 1.07 mole) was dissolved in dichloromethane (850 ml) and added slowly with stirring to the reaction mixture during 45 minutes. The reaction mixture was allowed to reach room temperature over night. The solution was then washed with water (4×1 L) and dried with magnesium sulfate. The solvent was evaporated under reduced pressure until the weight was 440 g. The remaining brownish oil was slowly poured into heptane (1.6 L) with vigorous stirring. After approx. 20 seconds the oil started to crystallize. The heavy precipitate was filtered off, washed with heptane (200 ml) and dried in vacuo at 40° C. over night. This procedure gave 274 g (97.8% yield) of crude 2-[4-(tert-butoxycarbonylamino)phenyl]ethyl-4-methylbenzenesulfonate.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:15][CH2:14][C@@H:13]([O:16][C:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])[CH2:12][NH:11][C:10]1=[O:25])=O)(C)(C)C.Cl>C(OCC)(=O)C>[NH2:8][C@H:9]1[CH2:15][CH2:14][C@@H:13]([O:16][C:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])[CH2:12][NH:11][C:10]1=[O:25]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](OC(=O)C2CCCCC2)CNC1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@H]1CC[C@@H](OC(=O)C2CCCCC2)CNC1=O
Reaction time: 6 h
Yield: 114.3 %

Procedure:
(3S, 6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-(cyclohexanecarbonyl)oxy-2H-azepin-2-one (300 g, 846 mmol) is added portionwise to a stirred solution of ethyl acetate (3 L) and HCl gas (225 g, 6.2 mol) at room temp. The reaction is stirred at room temp. for 6 h. The resulting precipitate is filtered and the solid is washed with ethyl acetate (1.2 L). The solid is dried to give 246 g (98%) of (3S, 6R)-3-aminohexahydro-6-(cyclohexanecarbonyl)oxy-2H-azepin-2-one.HCl which is used directly in the next step. A soln consisting of (6E)-6,7,8,9-tetradeoxy-8,8-dimethyl-2-O-methyl-3,5-O-(1-methylethylidene)-gulo-non-6-enoic acid lactone (100 g, 352 mmol), (3S, 6R)-3-aminohexahydro-6-(cyclohexanecarbonyl)oxy-2H-azepin-2-one.HCl (112.5 g, 387 mmol), sodium 2-ethylhexanoate (116 g, 700 mmol), and tetrahydrofuran (1.75 L) is stirred at room temp for 20 h. Water (350 mL) is then added to the mixture. After stirring for an additional 30 min, heptane (3.5 L) is added. The mixture is then stirred for 3 h, then cooled to 2° C. and then stirred for an additional 2 h. The mixture is filtered through a polypropylene filter. The solid that remains is washed with water (200 mL) and heptane (800 mL). The solid is then dried to give 166 g (88%) of the desired compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([C:10](=[O:21])[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)=[CH:6][N:7](C)C)[CH3:2].C(OC(=O)C(C(=O)C1C=CC(Cl)=CC=1Cl)=CN(C)C)C>>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[N:7][O:21][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)=[O:22])[CH3:2]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccc(C(F)(F)F)cc1
Agent: CCOC(=O)C(=CN(C)C)C(=O)c1ccc(Cl)cc1Cl
Product: CCOC(=O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Yield: 47 %

Procedure:
The procedure of Example 12 was employed utilizing ethyl-2-(4'-trifluoromethylbenzoyl)-3-dimethylaminopropenoate in lieu of ethyl-2-(2',4'-dichlorobenzoyl)-3-dimethylaminopropenoate to yield ethyl-5-(4'-trifluoromethylphenyl)-4-isoxazolecarboxylate (2.03 g.; 47% yield) as yellow crystals having a melting point of 42°-44° C. and the following analysis:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][C:16]=1[O:30][CH3:31])=[O:13])[NH:7]2.Br[C:33]1[N:34]=[C:35]([C@H:43]2[CH2:48][CH2:47][C@H:46]([N:49]3[CH2:54][CH2:53][N:52]([CH3:55])[CH2:51][CH2:50]3)[CH2:45][CH2:44]2)[N:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[C:37]=12>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:33]3[N:34]=[C:35]([C@H:43]4[CH2:48][CH2:47][C@H:46]([N:49]5[CH2:54][CH2:53][N:52]([CH3:55])[CH2:51][CH2:50]5)[CH2:45][CH2:44]4)[N:36]4[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[C:37]=34)=[CH:17][C:16]=1[O:30][CH3:31])=[O:13])[NH:7]2
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2c(OC)cccc2[nH]1
Reactant: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](N2CCN(C)CC2)CC1
Product: COc1cc(-c2nc([C@H]3CC[C@H](N4CCN(C)CC4)CC3)n3ccnc(C)c23)ccc1NC(=O)c1cc2c(OC)cccc2[nH]1

Procedure:
Reaction of 4-methoxy-N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-indole-2-carboxamide (32 mg) and 1-bromo-8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazine (30 mg) according to the procedure described in example 4 step 4c and purification by column chromatography (silica gel; dichloromethane with gradient 0 to 20% of methanol) gave 4-methoxy-N-(2-methoxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1H-indole-2-carboxamide (11 mg)
Reaction SMILES: [C:1]1(=[O:7])[O:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:8].[Na+:9]>>[OH:8][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O-:6])=[O:7].[Na+:9]
Reactant: [OH-]
Reactant: O=C1CCCCO1
Agent: [Na+]
Product: O=C([O-])CCCCO
Temperature: 65 °C

Procedure:
A suspension of 800 mg (8.0 mmol) of δ-valerolactone in 8 mL (8.0 mmol, 1.0 equiv) of 1N aqueous sodium hydroxide was heated at 65° C. overnight. The clear solution was cooled and concentrated. Toluene was added and the resultant slurry was concentrated to give a white solid: IR (nujol mull) 1550 cm-1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].O(C(C)(C)C)[K].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:2]2[CH:7]=[N:6][C:5]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: Brc1ccc(N2CCOCC2)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [Pd]
Agent: CC(C)(C)O[K]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(N3CCOCC3)nc2)CC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 24 %

Procedure:
To a degassed solution of 4-(5-bromo-pyridin-2-yl)-morpholine (4.47 g, 18.39 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (4.42 g, 22.07 mmol, 1.2 equiv; commercially available) in toluene (40 mL) was added KOtert-Bu (5.16 g, 46.00 mmol, 2.5 equiv), dicyclohexyl-(2′,4′,6′-triisopropyl-biphenyl-2-yl)-phosphane (0.18 g, 0.37 mmol, 0.02 equiv; X-Phos ligand [CAS RN 564483-18-7]; commercially available from Strem Chemicals, USA) and tris(dibenzylideneacetone)dipalladium(0) (1.52 g, 1.47 mmol, 0.08 equiv). The reaction mixture was stirred under nitrogen at 100° C. for 16 h, cooled to rt, filtered and the filtrate concentrated by evaporation under reduced pressure. The crude material was purified with silica column chromatography eluting with dichloromethane/methanol (20:1+0.5% triethylamine) to provide 1.60 g (24%) of the title compound in 90% purity according to 1H NMR. 1H NMR (400 MHz, CH3OD): δ 1.20-1.37 (m, 2H), 1.46 (s, 9H), 1.95 (dd, J=13.0 Hz, J=2.7 Hz, 2H), 2.94 (br s, 2H), 3.21-3.28 (m, 4H), 3.32-3.41 (m, 1H), 3.73-3.84 (m, 4H), 4.01 (d, J=13.4 Hz, 2H), 6.74 (d, J=9.0 Hz, 1H), 7.12 (dd, J=9.0 Hz, J=2.9 Hz, 1H), 7.68 (d, J=2.7 Hz, 1H). MS (ISP): 363.3 [M+H]+.
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][C:13]([C:16](=O)[CH2:17][CH2:18][C:19]([OH:21])=O)=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.O.[NH2:24][NH2:25]>>[N:1]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:17][CH2:18][C:19](=[O:21])[NH:24][N:25]=3)=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)CCC(=O)c1ccc(-n2cnc3ccccc32)cc1
Reactant: NN
Solvent: O
Product: O=C1CCC(c2ccc(-n3cnc4ccccc43)cc2)=NN1

Procedure:
Similarly, the reaction of 4-(1H-benzimidazol-1-yl)-γ-oxobenzenebutanoic acid with hydrazine hydrate according to the procedure of this Example gives 4,5-dihydro-6-[4-(1H-benzimidazol-1-yl)phenyl]-3(2H)-pyridazinone (3i), mp 262°-264° C.