Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[N+:5]([O-:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:3]=1.[F:18][B-:19]([F:22])([F:21])[F:20].[CH3:23][O+](C)C>ClCCl>[F:18][B-:19]([F:22])([F:21])[F:20].[CH3:23][O:7][N+:5]1[N:4]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:17])[F:16])=[CH:12][CH:13]=2)[N:3]=[C:2]([CH3:1])[CH:6]=1
Reactant: Cc1c[n+]([O-])n(-c2ccc(C(F)(F)F)cc2)n1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CO[n+]1cc(C)nn1-c1ccc(C(F)(F)F)cc1
Temperature: 23 °C
Reaction time: 65 h

Procedure:
To a stirred solution of 4-methyl-2-[4-(trifluoromethyl)phenyl]-2H-1,2,3-triazole 1-oxide (i.e. the product of Step A, 5.22 g, 21.5 mmol) in dichloromethane (100 mL) was added trimethyloxonium tetrafluoroborate (4.13 g, 27.9 mmol). The reaction mixture was stirred at 23° C. for 65 h, then concentrated under reduced pressure to afford a crude mixture of the title compound as a brown oil which was used directly in the next step without further purification.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1F.[NH2:15][CH2:16][CH:17]([NH2:19])[CH3:18].C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH3:18][CH:17]1[CH2:16][NH:15][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:4]=2[C:3](=[O:14])[NH:19]1
Reactant: COC(=O)c1c(F)cccc1[N+](=O)[O-]
Reactant: CC(N)CN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC1CNc2cccc([N+](=O)[O-])c2C(=O)N1
Yield: 66.6 %

Procedure:
A solution of 2-fluoro-6-nitrobenzoic acid methyl ester (500 mg, 2.51 mmol) in 1,4-dioxane (3 mL) was treated with 1,2-diaminopropane (0.186 mL, 2.51 mmol) and diisopropylethylamine (0.874 mL, 2.51 mmol). The reaction was irradiated at 140° C. for 20 minutes. The reaction mixture was then reduced en vacuo and purified by flash column chromatography (0% ethyl acetate/hexanes—100% ethyl acetate/hexanes) to afford 370 mg of 3-Methyl-6-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one and 2-Methyl-6-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (mixture of regioisomers) as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:21]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3C(C)=NO[N:16]=3)[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CC[C@H](OC(=O)C(F)(F)F)C2)C2N=NNC=2N=1)(C)(C)C.Cl[CH2:53][C:54]1[O:55]C(C)=N[N:58]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:21]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[O:55][C:54]([CH3:53])=[N:58][N:16]=3)[N:13]=2)[N:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1nnc(CCl)o1
Reactant: Cc1nonc1Cn1nc2nc(C(C)(C)C)nc(N3CC[C@H](O)C3)c2n1
Agent: CC(C)(C)c1nc(N2CC[C@H](OC(=O)C(F)(F)F)C2)c2nn[nH]c2n1
Product: Cc1nnc(Cn2nc3nc(C(C)(C)C)nc(N4CC[C@H](O)C4)c3n2)o1

Procedure:
In analogy to the procedure described for the synthesis of (S)-1-[5-tert-Butyl-2-(4-methyl-furazan-3-ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol (example 73), the title compound was prepared from Trifluoro-acetic acid (S)-1-(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-yl-ester and 2-(chloromethyl)-5-methyl-1,3,4-oxadiazole and isolated as light yellow gum. MS (m/e): 359.5 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][C:14](=[NH:18])OCC)=[CH:7][CH:6]=1)[CH3:3].[Cl-:19].[NH4+:20]>C(O)C>[ClH:19].[ClH:19].[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][C:14]([NH2:18])=[NH:20])=[CH:7][CH:6]=1)[CH3:1]
Reactant: [NH4+]
Reactant: [Cl-]
Reactant: CCOC(=N)CCSCc1ccc(CN(C)C)o1
Solvent: CCO
Product: CN(C)Cc1ccc(CSCCC(=N)N)o1
Product: Cl
Reaction time: 8 h
Yield: 97.2 %

Procedure:
Ethyl 3-(5-dimethylaminomethyl-2-furanylmethylthio)propionimidate (27.72 g), ammonium chloride (5.48 g) and ethanol (170 ml) were stirred at room temperature for one hour and then allowed to stand overnight. The ethanol was evaporated at reduced pressure and the residue purified by chromatography on silica gel at medium pressure using chloroform-methanol as eluant. The fractions containing the major product were combined, evaporated to dryness at reduced pressure and treated with ethanol containing anhydrous hydrogen chloride. The solvent was evaporated at reduced pressure to give 3-(5-dimethylaminomethyl-2-furanylmethylthio)propionamidine dihydrochloride (15.65 g).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([CH3:7])=[C:4]([C:8]([N:10]([CH3:12])[CH3:11])=O)[NH:3]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:14]>N1C=CC=CC=1.O>[O:1]=[C:2]1[NH:6][C:5]([CH3:7])=[C:4]([C:8](=[S:14])[N:10]([CH3:12])[CH3:11])[NH:3]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cc1[nH]c(=O)[nH]c1C(=O)N(C)C
Solvent: O
Solvent: c1ccncc1
Product: Cc1[nH]c(=O)[nH]c1C(=S)N(C)C

Procedure:
A suspension of 3.4 g (20 mmol) of 2,3-dihydro--N,N,5-trimethyl-2-oxo-1H-imidazole-4-carboxamide (prepared in example 3) and 4.4 g cf phosphorus pentasulfide in 100 ml of dry pyridine is stirred at reflux temperature for 6 hours. The mixture is allowed to cool overnight and is diluted with water. The precipitate is collected and recrystallized from 50% aqueous ethanol to give the title compound.
Reaction SMILES: [OH:1][C:2]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[C:5]([CH3:14])([CH3:13])[CH2:4][CH2:3]1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(Cl)Cl.CCOC(C)=O>[C:21]([O:1][C:2]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[C:5]([CH3:13])([CH3:14])[CH2:4][CH2:3]1)(=[O:23])[CH3:22]
Reactant: CCOC(=O)CC1(O)CCC(C)(C)c2ccc(Br)cc21
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(OC(C)=O)CCC(C)(C)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (+/-) ethyl 2-(1-hydroxy-1,2,3,4-tetrahydro-4,4-dimethyl-7-bromo-naphthalen-1-yl)acetate (Compound E47, 200.0 mg, 0.586 mmol) and 4-N,N-dimethylaminopyridine (86.0 mg, 0.703 mmol) in 4.0 mL CH2Cl2 at 0° C. was added acetic anhydride (239.3 mg, 2.344 mmol). The resulting solution was warmed to room temperature and stirred overnight. The reaction was warmed to 50° C. for 3 h, cooled to room temperature, and diluted with EtOAc (70 mL). The solution was washed with H2O, saturated aqueous NaHCO3, 10% aqueous HCl, and saturated aqueous NaCl, before being dried over MgSO4. Removal of the solvents under reduced pressure followed by column chromatography afforded the title compound as a colorless oil. 1H NMR (CDCl3): δ 1.23 (t, J=7.1 Hz, 3H), 1.30 (s, 3H), 1.31 (s, 3H), 1.76 (t, J=6.9 Hz, 2H), 2.05 (s, 3H), 2.48 (m, 1H), 2.67 (m, 1H), 3.03 (s, 2H), 4.12 (q, J=7.1 Hz, 2H), 7.19 (d, J=8.5 Hz, 1H), 7.33 (dd, J=2.1, 8.5 Hz, 1H), 7.45 (d, J=2.1 Hz, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[C:7]=1[CH2:25][C:26]([O:28]CC)=[O:27])=[O:5])C.[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[Cl:38]>>[C:4]([CH2:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:23])[CH3:24])=[CH:18][CH:17]=2)[C:9]2[C:10]([C:25]=1[C:26]([OH:28])=[O:27])=[CH:11][C:12]([O:15][C:35]1[CH:34]=[CH:33][C:32]([Cl:31])=[C:37]([Cl:38])[CH:36]=1)=[CH:13][CH:14]=2)([OH:3])=[O:5]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(C(C)C)cc1
Product: CC(C)c1ccc(-n2c(CC(=O)O)c(C(=O)O)c3cc(Oc4ccc(Cl)c(Cl)c4)ccc32)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-isopropylphenyl)indole-3-carboxylic acid ethyl ester (150 mg, 0.37 mmol, see step (b) Example 10) and 3,4-dichlorophenylboronic acid (140 mg, 0.74 mmol). Yield 110 mg (55%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:4][CH2:3]1.C1C(=O)N([Br:24])C(=O)C1>CC#N.CO.C(OCC)(=O)C>[Br:24][C:13]1[CH:14]=[C:15]2[C:5]3([CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[C:8](=[O:16])[NH:9][C:10]2=[CH:11][CH:12]=1
Reactant: CN1CCC2(CC1)C(=O)Nc1ccccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN1CCC2(CC1)C(=O)Nc1ccc(Br)cc12
Yield: 48.9 %

Procedure:
A solution of 1′-(methyl)spiro[indole-3,4′-piperidin]-2(1H)-one (6.3 g, 29.1 mmol) in CH3CN (100 ml) and MeOH (5 ml) was cooled to −5° C. and NBS (7.8 g, 44 mmol) was slowly added with stirring. The reaction mixture was stirred for 3.5 h at 0° C. Solvent was removed by vacuo. The residue was purified by silica gel chromatography (2-20% MeOH/CH2Cl2) to give 6 g as a solid. The solid compound was dissolved in ethyl acetate (600 ml) and washed with saturated aqueous NaHCO3 solution, dried (Na2SO4). Evaporation of the solvent in vacuo gave 4.2 g (47%) of 11. 1HNMR (CD3OD, 400 MHz) δ 7.51 (d, J=1.8 Hz, 1H), 7.35 (dd, J=1.9 and 8.2 Hz, 1H), 6.81 (d, J=8.2 Hz, 1H), 2.93 (m, 2H), 2.67 (m, 2H), 2.41 (s, 3H), 1.86 (m, 4H).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[OH:16])[CH2:11][CH2:10]1)C.C(=O)(O)[O-].[Na+]>C(O)C.O>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:15]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)([OH:16])[CH:12]2[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:31])=[O:3])[CH2:14][CH2:13]2)=[CH:22][CH:21]=1
Reactant: CCOC(=O)CCCCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)CCCCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reaction time: 16 h
Yield: 52 %

Procedure:
To a stirred solution of 9.0 g (0.020 mole) of 4-[bis(4-fluorophenyl)hydroxymethyl]-1-piperidinepentanoic acid ethyl ester in 300 ml of 95% ethanol was added a solution of 21.0 g (0.250 mole) of sodium bicarbonate in 250 ml of water, and the mixture was heated at reflux for 6 h under a nitrogen atmosphere. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl ether and water (300 ml each). The layers were separated, and the aqueous layer was further extracted with three 300 ml portions of ethyl ether. The aqueous layer pH was adjusted to 6 with glacial acetic acid, whereupon a soid precipitate began to form. After standing for 16 h the crystals were collected by filtration, washed with water and recrystallized from benzene to yield 4.2 g (52%) of the title compound as a white solid, mp 105°-107° C.
Reaction SMILES: [Li][CH2:2]CCC.[Br:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([F:15])[CH:8]=1.CI>C1COCC1>[Br:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([F:15])[C:8]=1[CH3:2]
Reactant: N#Cc1ccc(Br)cc1F
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(Br)ccc(C#N)c1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of DIPA (12.1 g, 0.120 mmol) in 20 mL of dry THF was added 2.5M of n-BuLi (44 mL, 0.11 mmol) dropwise under Ar at −78° C., and then the reaction was allowed to warm to 0° C. After stirring for 1 hour, the solution was added to a solution of 4-bromo-2-fluorobenzonitrile (20 g, 0.1 mmol) in 200 mL of dry THF dropwise at −78° C. under Ar and the mixture was stirred for 3 hours, then MeI (15.6 g, 0.110 mmol) was added at one portion and the mixture was stirred for another 30 minutes. Then the reaction was quenched with aq. NH4Cl and extracted with EtOAc (200 mL×3). The combined organic layers were washed with water, brine, dried and concentrated to brown oil, which was purified by silica gel column to give 4-bromo-2-fluoro-3-methylbenzonitrile.
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][Br:13])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Br-:13].[C:27]1([P+:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)C(=O)OCCCCCBr
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)OCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Reaction time: 72 h

Procedure:
An equivalent of 5-bromopentyl pivalate and an equivalent of triphenylphosphine in toluene at 110° C. are placed in a flask. After 72 hours of agitation in these conditions, and once returned to ambient temperature, the toluene is evaporated and the triphenyl(5-(pivaloyloxy)pentyl)phosphonium bromide formed is used directly for the following step.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([O:10][Si](C(C)(C)C)(C)C)[CH2:4][C:5](=[CH2:9])[C:6]=1[CH2:7][CH3:8].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.C(O)(=O)C(O)=O>O1CCCC1>[CH3:1][C:2]1[CH:3]([OH:10])[CH2:4][C:5](=[CH2:9])[C:6]=1[CH2:7][CH3:8]
Reactant: C=C1CC(O[Si](C)(C)C(C)(C)C)C(C)=C1CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)C(=O)O
Agent: [F-]
Solvent: C1CCOC1
Product: C=C1CC(O)C(C)=C1CC
Temperature: 0 °C
Yield: 91.3 %

Procedure:
After 4.0 g of (RS)-2-methyl-4-methylidene-3-ethyl-1-t-butyldimethylsilyloxy-2-cyclopentene was dissolved in 35 ml of dry tetrahydrofuran, 17.5 ml of a 1M tetrabutylammonium fluoride/tetrahydrofuran solution was added under cooling and stirred at ambient temperatures for twelve hours. The reaction solution was then added to 100 ml of an ice-cooled 5% aqueous oxalic acid, and extracted with diethyl ether (300 ml×3 times). The combined ether layer was washed successively with a saturated sodium hydrogencarbonate solution and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the residue was treated by silica gel column chromatography (eluent: n-hexane:ethyl acetate=3:1 (v/v)) to yield 2.0 g of (RS)-2-methyl-4-methylidene-3-ethylcyclopent-2-en-1-ol.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][C:8]2[C:9](=[O:15])[NH:10][C:11](=[S:14])[NH:12][CH:13]=2)[CH:4]=[N:3][CH:2]=1.[CH3:16]CN(C(C)C)C(C)C.Cl[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[C:38]([C:43]([F:46])([F:45])[F:44])[CH:37]=2)=[C:31]([CH:34]=1)[C:32]#[N:33].CI>C(Cl)Cl.[Zn+2].[Br-].[Br-].CN1C(=O)CCC1>[F:42][C:39]1[CH:40]=[CH:41][C:36]([O:35][C:30]2[CH:29]=[CH:28][C:27]([CH2:26][S:14][C:11]3[N:12]([CH3:16])[CH:13]=[C:8]([CH2:7][C:5]4[CH:6]=[N:1][CH:2]=[N:3][CH:4]=4)[C:9](=[O:15])[N:10]=3)=[CH:34][C:31]=2[C:32]#[N:33])=[CH:37][C:38]=1[C:43]([F:46])([F:45])[F:44]
Reactant: O=c1[nH]c(=S)[nH]cc1Cc1cncnc1
Reactant: CCN(C(C)C)C(C)C
Reactant: N#Cc1cc(CCl)ccc1Oc1ccc(F)c(C(F)(F)F)c1
Agent: [Br-]
Agent: [Zn+2]
Solvent: CI
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: Cn1cc(Cc2cncnc2)c(=O)nc1SCc1ccc(Oc2ccc(F)c(C(F)(F)F)c2)c(C#N)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 14.9 %

Procedure:
To a solution of 5-(5-pyrimidinylmethyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (70 mg, 0.318 mmol) and DIPEA (0.083 ml, 0.477 mmol) in DCM (2 mL) was added 5-(chloromethyl)-2-{[4-fluoro-3-(trifluoromethyl)phenyl]oxy}benzonitrile (105 mg, 0.318 mmol). The reaction mixture was heated at 60° C. overnight. After removing the solvent by nitrogen, the residue was dissolved in MeCN (4 ml), and NMP (1.5 mL), and ZnBr2 (107 mg, 0.477 mmol) and DIPEA (0.083 mL, 0.477 mmol) were added. The mixture was then stirred at 60° C. for 10 min. And MeI (0.020 mL, 0.318 mmol) was added dropwise, then stirred at 60° C. for 1.5 h. Purification via MDAP then afforded the title compound (25 mg, 12.28% yield). LCMS: rt=3.07 min, [M+H+]=528
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:14]([N:15]=1)=[CH:13][C:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=1[C:5]=2[CH3:16].[Cl:17][CH2:18][CH2:19][CH2:20][S:21][C:22]1[N:23]([CH3:38])[C:24]([C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[CH:29]=[CH:30][C:31]([CH3:37])=[N:32]3)=[N:25][N:26]=1>>[ClH:17].[CH3:1][C:2]1[O:3][C:4]2[C:14]([N:15]=1)=[CH:13][C:7]1[CH2:8][CH2:9][N:10]([CH2:18][CH2:19][CH2:20][S:21][C:22]3[N:23]([CH3:38])[C:24]([C:27]4[CH:36]=[CH:35][CH:34]=[C:33]5[C:28]=4[CH:29]=[CH:30][C:31]([CH3:37])=[N:32]5)=[N:25][N:26]=3)[CH2:11][CH2:12][C:6]=1[C:5]=2[CH3:16]
Reactant: Cc1nc2cc3c(c(C)c2o1)CCNCC3
Reactant: Cc1ccc2c(-c3nnc(SCCCCl)n3C)cccc2n1
Product: Cc1ccc2c(-c3nnc(SCCCN4CCc5cc6nc(C)oc6c(C)c5CC4)n3C)cccc2n1
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 2,10-dimethyl-6,7,8,9-tetrahydro-5H-[1,3]oxazolo[4,5-h][3]benzazepine (80 mg) and 5-{5-[(3-chloropropyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylquinoline (147 mg) and was obtained as a colourless slightly hygroscopic solid (175 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:24]([OH:26])=O)[CH2:14][CH2:13][N:12]([C:15]2[C:16]3[CH:23]=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[NH2:36][CH:37]([C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1)[CH2:38][C:39]([NH2:41])=[O:40]>CN(C=O)C>[NH2:41][C:39](=[O:40])[CH2:38][CH:37]([NH:36][C:24]([C:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[CH2:10][CH2:11][N:12]([C:15]2[C:16]3[CH:23]=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:13][CH2:14]1)=[O:26])[C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: NC(=O)CC(N)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(CC(N)=O)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 79.4 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluoro-phosphate (129 mg, 0.34 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (82 mg, 0.23 mmol) and N,N-diisopropylethylamine (0.112 mL, 0.68 mmol) in DMF (4 mL) at 20° C. under nitrogen. The resulting solution was stirred at 20° C. for 5 minutes. 3-amino-3-(4-chlorophenyl)propanamide (Intermediate 107) (45 mg, 0.23 mmol) was then added to the reaction and stirred for 3 hours. The reaction mixture was concentrated and diluted with EtOAc (20 mL) and washed with water (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford tert-butyl 4-(3-amino-1-(4-chlorophenyl)-3-oxopropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (99 mg, 100%).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH2:11][C:12]([OH:14])=[O:13]>C(O)(=O)C.CC1CCCCC1>[Br:1][C:7]1[C:6]([CH3:10])=[C:5]([CH2:11][C:12]([OH:14])=[O:13])[C:4]([CH3:3])=[CH:9][CH:8]=1
Reactant: BrBr
Reactant: Cc1cccc(C)c1CC(=O)O
Solvent: CC1CCCCC1
Solvent: CC(=O)O
Product: Cc1ccc(Br)c(C)c1CC(=O)O
Temperature: 45 °C
Reaction time: 16 h

Procedure:
At 45° C., a solution of 62.5 g [391 mmol] of bromine in 120 ml of glacial acetic acid is added dropwise over a period of 1 hour to a solution of 47.6 g [290 mmol] of 2,6-dimethylphenylacetic acid in 300 ml of glacial acetic acid. The reaction mixture is then stirred at 45° C. for another 16 hours and concentrated on a rotary evaporator. The solid obtained is stirred in 180 ml of methylcyclohexane at room temperature for 4 hours. After filtration, the residue is washed twice with in each case 60 ml of methylcyclohexane and then dried. This gives 64.9 g of a solid. GC(sil.) analysis: 97.7% pure (89.9% of theory).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[CH:15]([C:20]([C:22]1[N:26]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[N:25]=[C:24]([C:35]([F:38])([F:37])[F:36])[CH:23]=1)=[O:21])C(OC)=O.S(O)(O)(=O)=O>CO>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[CH2:15][C:20]([C:22]1[N:26]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[N:25]=[C:24]([C:35]([F:38])([F:37])[F:36])[CH:23]=1)=[O:21]
Reactant: COC(=O)C(C(=O)c1cc(C(F)(F)F)nn1-c1ccc(OC)cc1)c1ccc(-n2ccccc2=O)cc1F
Agent: O=S(=O)(O)O
Solvent: CO
Product: COc1ccc(-n2nc(C(F)(F)F)cc2C(=O)Cc2ccc(-n3ccccc3=O)cc2F)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 51.9 %

Procedure:
Part A. To methyl 2-[2-fluoro-4-(2-oxo-1(2H)-pyridinyl)phenyl]-3-[1-(4-methoxyphenyl)-3-(trifluoro-methyl)-1H-pyrazol-5-yl]-3-oxopropanoate (Part H, Example 71) (24 mg, 0.045 mmol) was added methyl alcohol (2.3 mL) and concentrated aqueous dihydrogen sulfate (0.048 mL). The reaction was then warmed to reflux. After 48 h, monitoring by LC/MS (C18 reverse phase, eluted with 0.05% TFA in acetonitrile/water) showed 90% of starting material remaining. An additional 0.80 mL-portion of 4M aqueous dihydrogen sulfate was added, and the reaction was maintained under reflux conditions for 6 h. The reaction was cooled to 0° C., and the resulting white precipitate was filtered to afford 1-(3-fluoro-4-{2-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-yl]-2-oxoethyl}phenyl)-2(1H)-pyridinone (11 mg, 52%) as a white solid. LC/MS (ESI+): 472.1 (M+H)+. 1H NMR (enol form) (CD3OD) δ 7.70 (s, 1H), 7.60 (m, 2H), 7.43 (t, 1H), 7.28 (m, 3H), 7.20 (m, 1H), 6.98 (m, 2H), 6.62 (d, 1H), 6.44 (t, 1H), 4.42 (s 0.5H), 4.39 (br s, 0.5H), 3.81 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[NH:6][C:7](=[O:19])[C:8]3[CH:18]=[CH:17][CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[CH2:26][OH:27]>>[CH2:13]([N:10]1[C:9]2[N:15]=[CH:16][CH:17]=[CH:18][C:8]=2[C:7](=[O:19])[NH:6][C:5]2[C:4]([CH3:20])=[CH:3][C:2]([N:21]3[CH2:25][CH2:24][CH2:23][C@H:22]3[CH2:26][OH:27])=[N:12][C:11]1=2)[CH3:14]
Reactant: OC[C@@H]1CCCN1
Reactant: CCN1c2ncccc2C(=O)Nc2c(C)cc(Cl)nc21
Product: CCN1c2ncccc2C(=O)Nc2c(C)cc(N3CCC[C@H]3CO)nc21

Procedure:
The title compound, m.p. 238°-240° C., was synthesized from 2-chloro-5,11-dihydro-11-ethyl-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and (S)-(+)-2-pyrrolidinemethanol using procedures analogous to those described above, except that the mixture was heated in a pressure bottle at 170° C. for 3 hrs, and the product was crystallized from chloroform/hexane.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)C(C)C)(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:43]([NH:51][NH2:52])(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]([NH:52][NH:51][C:43](=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:19])([CH3:5])([CH3:6])[CH3:7]
Reactant: NNC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 mg (754 μmol) of N-Boc-L-phenylalanine were dissolved in 8 ml of DMF mixed with 131 μl (754 μmol) of N,N-diisopropylethylamine, 346 mg (2261 μmol) of HOBt, 434 mg (2261 μmol) of EDC, and 411 mg (3015 μmol) of benzoyl hydrazine. The reaction composition was stirred at RT overnight, then evaporated, and the residue purified over preparative HPLC. The yield was 313 mg (95% purity, 100% o. th.) of the title compound.