Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=2)=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:3]=1.Cl.[CH3:32][N:33]([CH3:39])[CH2:34][CH2:35][C:36](O)=[O:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH2:10][CH2:11][N:12]([CH2:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=2)[C:36](=[O:37])[CH2:35][CH2:34][N:33]([CH3:39])[CH3:32])=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:3]=1
Reactant: CN(C)CCC(=O)O
Reactant: CCCCCNc1nc(N)nc(C)c1CCCNCc1cccc(CC(=O)OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCCCCNc1nc(N)nc(C)c1CCCN(Cc1cccc(CC(=O)OC)c1)C(=O)CCN(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.3 %

Procedure:
The product from Example 1 (80 mg) and 3-(dimethylamino)propanoic acid hydrochloride (45 mg) were combined in DCM (5 mL) then TEA (73 mg) and HATU (101 mg) were added. The reaction mixture was stirred at rt for 16 h. The solvents were evaporated, the residue dissolved in MeOH and purified by RPHPLC to give the title compound 32 mg.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:5]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=1)=O.Cl.[NH2:24][NH:25]C(N)=O.N1C=CC=CC=1>CO>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:4]2[C:3](=[O:2])[NH:24][NH:25][C:5]=2[C:7]2[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=2)=[CH:16][CH:17]=1
Reactant: NNC(N)=O
Reactant: COC(=O)C(C(=O)c1ccnc(SC)n1)c1ccc(F)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CSc1nccc(-c2[nH][nH]c(=O)c2-c2ccc(F)cc2)n1

Procedure:
A solution of 2-(4-fluorophenyl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-3-oxo-propionic acid methyl ester, 3, (1 g, 3.7 mmol), semicarbazide HCl (0.653 g, 5.8 mmol) and pyridine (10 mL) is heated at 90° C. for 12 hours. The solution is then concentrated in vacuo to afford a semi-solid residue which is taken up in methanol and the resulting solid removed by filtration. The filtrate is concentrated in vacuo to afford the desired compound as a white solid, which is used without further purification.
Reaction SMILES: [Li+].[OH-].[CH2:3]([NH:5][C:6](=[O:48])[NH:7][C:8]1[N:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][N:23]=2)[N:20]([CH2:24][C:25]2[N:26]=[CH:27][N:28]([CH3:30])[CH:29]=2)[CH:19]=[C:18]([C:31]([O:33]CC)=[O:32])[C:17]3=[O:36])=[C:10]([C:37]2[S:38][CH:39]=[C:40]([C:42]3[CH:43]=[N:44][N:45]([CH3:47])[CH:46]=3)[N:41]=2)[CH:9]=1)[CH3:4].C1COCC1>CO>[CH2:3]([NH:5][C:6](=[O:48])[NH:7][C:8]1[N:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][N:23]=2)[N:20]([CH2:24][C:25]2[N:26]=[CH:27][N:28]([CH3:30])[CH:29]=2)[CH:19]=[C:18]([C:31]([OH:33])=[O:32])[C:17]3=[O:36])=[C:10]([C:37]2[S:38][CH:39]=[C:40]([C:42]3[CH:43]=[N:44][N:45]([CH3:47])[CH:46]=3)[N:41]=2)[CH:9]=1)[CH3:4]
Reactant: CCNC(=O)Nc1cc(-c2nc(-c3cnn(C)c3)cs2)c(-c2cc3c(=O)c(C(=O)OCC)cn(Cc4cn(C)cn4)c3cn2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cc(-c2nc(-c3cnn(C)c3)cs2)c(-c2cc3c(=O)c(C(=O)O)cn(Cc4cn(C)cn4)c3cn2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2N LiOH (1 mL) was added to a mixture of ethyl 6-(6-(3-ethylureido)-4-(4-(1-methyl-1H-pyrazol-4-yl)thiazol-2-yl)pyridin-3-yl)-1-((1-methyl-1H-imidazol-4-yl)methyl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylate, 86.3 mg, 0.14 mmol) in MeOH (imp and THF (1 mL). The resulting solution was stirred at room temperature for two hours. The solvent was removed and the residue was diluted with water and acidified with 1N HCl. The precipitated product was collected by filtration and washed with water and dried (60 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][CH:25]=2)[CH2:18][NH2:19])=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH:17]([C:14]1[CH:13]=[CH:12][N:11]=[CH:16][CH:15]=1)[C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[N:24][CH:25]=1)=[O:6]
Reactant: NCC(c1ccncc1)c1ccc(C(F)(F)F)nc1
Reactant: O=C(O)c1ccccc1Cl
Product: O=C(NCC(c1ccncc1)c1ccc(C(F)(F)F)nc1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and 2-(pyridin-4-yl)-2-(2-(trifluoromethyl)pyridin-5-yl)ethanamine. LCMS (MH+): m/z=406.1, tR (minutes, Method F)=2.27
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:17][CH2:16][C@@H:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]2)(=O)=O)=CC=1.[CH2:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH3:27]>C(Cl)Cl>[CH2:26]([N:28]1[CH2:33][CH2:32][N:31]([CH2:12][C@H:13]2[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:14]2)[CH2:30][CH2:29]1)[CH3:27]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)C2)cc1
Reactant: CCN1CCNCC1
Solvent: ClCCl
Product: CCN1CCN(C[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)C2)CC1
Temperature: 0 °C
Yield: 71.2 %

Procedure:
To a stirred solution of ((1S,3R)-3-(tert-butoxycarbonylamino)cyclopentyl)methyl 4-methylbenzenesulfonate (Intermediate 18-step 2, about 0.5 g) in DCM (50 ml) potassium carbonate (about 0.3 g) was added at room temperature and cooled to about 0° C. After ten minutes, 1-ethyl piperazine (0.23 g) was added and stirred the reaction at room temperature for about 6 hours then completion of the reaction monitored by TLC. The reaction mixture was neutralized and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (0.3 g) as a pale yellow solid. 1H NMR (300 MHz, CDCl3: 1.09-1.24 (m, 3H); 1.39 (s, 9H); 2.29-2.60 (m, 4H); 2.79-2.80 (m, 10H); 3.06-3.18 (m, 6H); 3.70-3.73 (m, 1H); ES Mass: 312 (100%) [M+1].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[F:41][C:42]1([F:53])[CH2:46][CH2:45][N:44]([CH2:47][C@@H:48]([NH2:52])[CH:49]([CH3:51])[CH3:50])[CH2:43]1>CN(C=O)C>[F:53][C:42]1([F:41])[CH2:46][CH2:45][N:44]([CH2:47][C@@H:48]([NH:52][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([CH3:1])[CH:3]=2)[CH:49]([CH3:50])[CH3:51])[CH2:43]1
Reactant: CC(C)[C@H](N)CN1CCC(F)(F)C1
Reactant: Cc1ccc(C(=O)O)cc1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N[C@H](CN2CCC(F)(F)C2)C(C)C)cc1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 50.7 %

Procedure:
3,4-Dimethylbenzoic acid (130 mg, 0.87 mmol) and TBTU (279 mg, 0.87 mmol) was mixed in DMF (1.5 mL). The mixture was cooled to 0° C. and NMM (0.287 mL, 2.61 mmol) was dropwise added. After 10 min at 0° C. was (S)-1-(3,3-difluoropyrrolidin-1-yl)-3-methylbutan-2-amine (Compound O) (167 mg, 0.87 mmol) added. The resultant mixture was stirred at rt over night. The mixture was concentrated and the residue dissolved in DCM (5 mL). The organic phase was washed with HCl (1M aq. solution, 5 mL), NaHCO3 (saturated, 2×5 mL) and brine (5 mL), and filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (143 mg, 51%). 1H NMR (400 MHz, DMSO-d6) δ 0.65-1.03, 1.61-1.92, 2.00-2.21, 2.23, 2.53-3.03, 3.66-4.22, 7.19, 7.55, 7.61, 7.87. Total no of protons: 26.
Reaction SMILES: [O-:1]I(=O)(=O)=O.[Na+].[CH3:7][C:8]([CH3:29])([Si:10]([CH3:28])([CH3:27])[O:11][CH2:12][CH2:13][CH2:14][S:15][CH2:16][CH2:17][CH2:18][O:19][Si:20]([CH3:26])([CH3:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH3:9]>O.CO>[CH3:9][C:8]([CH3:29])([Si:10]([CH3:28])([CH3:27])[O:11][CH2:12][CH2:13][CH2:14][S:15](=[O:1])[CH2:16][CH2:17][CH2:18][O:19][Si:20]([CH3:26])([CH3:25])[C:21]([CH3:22])([CH3:23])[CH3:24])[CH3:7]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC(C)(C)[Si](C)(C)OCCCSCCCO[Si](C)(C)C(C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCCS(=O)CCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of sodium (meta)periodate (7.751 g, 1.1 eq) in water (40 mL) was slowly poured into a solution of 2,2,3,3,13,13,14,14-octamethyl-4,12-dioxa-8-thia-3,13-disilapentadecane (12.32 g, 1 eq) in methanol (150 mL) at 0° C. and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then filtered through a pad of celite and silica gel which was washed with methanol. The filtrate was concentrated under reduced pressure at a temperature below 25° C. The residue was diluted with brine and extracted a couple of times with chloroform. All organic solvents were combined, dried with anhydrous sodium sulfate, and concentrated to give the title compound as a clear oil (12.84 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.[Cl:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([NH:20][NH2:21])=[O:19])=[CH:16][CH:15]=1.C(O)C>O1CCCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[N:21][NH:20][C:18](=[O:19])[C:17]2[CH:16]=[CH:15][C:14]([Cl:13])=[CH:23][CH:22]=2)=[CH:3][CH:2]=1
Reactant: NNC(=O)c1ccc(Cl)cc1
Reactant: O=Cc1ccnc2ccccc12
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(NN=Cc1ccnc2ccccc12)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
A mixture of 7.86 gm (0.05 mole) of 4-quinolinecarboxaldehyde, 8.53 gm (0.05 mole) of 4-chlorobenzhydrazide, 400 ml of ethanol and 100 ml of tetrahydrofuran is refluxed 2 hr. Thin layer chromatography of the reaction mixture establishes that the reaction is complete. The reaction mixture is concentrated to one-half the original volume and then cooled to room temperature. The solid which separates is collected, washed with ethanol and dried to give 13.18 gm (85%) of title compound, having a melting point of 232.6° C.
Reaction SMILES: C(O[C:6]([C:8]1[C:9]([OH:26])=[C:10]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[S:15][C:11]2=[C:12](O)[N:13]=1)=[O:7])CCC.C([O:31][C:32]([C:34]1[N:39]=C(O)C2C=C(C3C=CC(OC)=CC=3)SC=2C=1O)=[O:33])CCC>>[OH:26][C:9]1[C:8]([C:6]([NH:39][CH2:34][C:32]([OH:33])=[O:31])=[O:7])=[N:13][CH:12]=[C:11]2[S:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)=[CH:17][C:10]=12
Reactant: CCCCOC(=O)c1nc(O)c2cc(-c3ccc(OC)cc3)sc2c1O
Reactant: CCCCOC(=O)c1nc(O)c2sc(-c3ccc(OC)cc3)cc2c1O
Product: COc1ccc(-c2cc3c(O)c(C(=O)NCC(=O)O)ncc3s2)cc1

Procedure:
The title compound was prepared from a mixture of 4,7-dihydroxy-2-(4-methoxy-phenyl)-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester and 4,7-dihydroxy-2-(4-methoxy-phenyl)-thieno[3,2-c]pyridine-6-carboxylic acid butyl ester, example 3-b, under conditions analogous to experimental example 1-f. MS: (+) m/z 390.24, 392.19 (M+1, 35Cl/37Cl).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][N:13]=[C:14]2[NH2:17])=[CH:9][CH:8]=1.N>ClCCl>[NH2:17][C:14]1[C:15]2[C:10](=[CH:9][CH:8]=[C:7]([OH:6])[CH:16]=2)[CH:11]=[CH:12][N:13]=1
Reactant: COc1ccc2ccnc(N)c2c1
Agent: BrB(Br)Br
Agent: N
Solvent: ClCCl
Product: Nc1nccc2ccc(O)cc12
Temperature: 25 °C
Reaction time: 96 h
Yield: 97.2 %

Procedure:
Boron tribromide (35 mL) in 50 mL of dichloromethane was added dropwise to a stirred solution of 7-methoxy-isoquinoline-1ylamine (21.6 g) in 70 mL of dichloromethane at 10° C. After stirring for 4 d at ambient temperature the reaction mixture was poured on ice and the pH adjusted to pH 9 by adding concentrated aqueous ammonia. The precipitated material was collected by filtration and dried in vacuo to give 19.3 g (97%) of the title compound as a light brownish solid. M.p. 260° C. (decomp.); El-MS: 160 (M+).
Reaction SMILES: [CH2:1]([N:9]1[C:13](=[O:14])[CH:12]([Cl:15])[CH:11]([Cl:16])[S:10]1=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].ClC1C=CC=C(C(OO)=[O:26])C=1>C(Cl)(Cl)Cl>[CH2:1]([N:9]1[C:13](=[O:14])[CH:12]([Cl:15])[CH:11]([Cl:16])[S:10]1(=[O:26])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN1C(=O)C(Cl)C(Cl)S1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCN1C(=O)C(Cl)C(Cl)S1(=O)=O
Temperature: 50 °C
Reaction time: 72 h

Procedure:
To a solution of 2.84g. (0.01 mole) of 2-octyl-4,5-dichloro-3-isothiazolidinone 1-oxide in 20 ml. of chloroform at 0° C. is added a solution of 5.4g. (0.025 mole) of 81% pure m-chloroperbenzoic acid in 100 ml. of chloroform. The mixture is stirred for three days at 50° C. The reaction mixture is filtered and the filtrate is washed with a dilute sodium bicarbonate solution. The chloroform layer is dried over magnesium sulfate and evaporated to give the crude product.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH:9]([OH:12])CO.O1CCC(OCC2CC[N:24]([C:27]3[CH:28]=[CH:29][C:30]4[N:31]([C:33]([C:36]([F:39])([F:38])[F:37])=[N:34][N:35]=4)[N:32]=3)[CH2:23][CH2:22]2)CC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[F:38][C:36]([F:37])([F:39])[C:33]1[N:31]2[N:32]=[C:27]([N:24]3[CH2:5][CH2:6][CH:7]([CH2:8][O:3][CH2:4][CH2:9][OH:12])[CH2:22][CH2:23]3)[CH:28]=[CH:29][C:30]2=[N:35][N:34]=1
Reactant: OCC(O)C1CCCCO1
Reactant: FC(F)(F)c1nnc2ccc(N3CCC(COC4CCOCC4)CC3)nn12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: OCCOCC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 54.3 %

Procedure:
Sodium hydride (60% dispersion in oil, 0.180 g, 4.5 mmol) was added to neat tetrahydropyranylethyleneglycol (3 g, 20.5 mmol). When the effervescence had subsided 6-[4-(methanesulfonyloxymethyl)piperidin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Example 294, preparation of starting materials) (1.138 g, 3 mmol) was added and the mixture was heated at 100° C. for 40 minutes. The reaction mixture was partitioned between DCM and water. The organic phase was washed with water and brine, dried over MgSO4 and evaporated. The crude intermediate was disolved in methanol (20 mL) and p-toluenesulfonic acid monohydrate (0.855 g, 4.5 mmol) was added. The solution was stirred for 1 hour and then evaporated. The reaction mixture was partitioned between DCM and water and the organic phase was washed with water and brine, dried over MgSO4 and evaporated. The product was isolated by MPLC silica chromatography, eluting with 5% methanol/DCM. The product containing fractions were evaporated giving a crystalline solid which was triturated with ether, giving 2-[[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]methoxy]ethanol (0.563 g, 54%)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]2[S:10][CH:11]=[CH:12][C:8]=2[C:7](=[CH:13][C:14]([OH:16])=[O:15])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[CH:4]=1>C(O)C>[CH3:1][O:2][C:3]1[C:9]2[S:10][CH:11]=[CH:12][C:8]=2/[C:7](=[CH:13]\[C:14]([OH:16])=[O:15])/[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[CH:4]=1
Reactant: COC1=Cc2ccccc2C(=CC(=O)O)c2ccsc21
Solvent: CCO
Product: COC1=Cc2ccccc2/C(=C/C(=O)O)c2ccsc21
Reaction time: 20 h

Procedure:
The isomer mixture product of example 2 is dissolved in 1 l boiling 95% ethanol, seeded with crystals of the pure (Z) isomer obtained in accordance with example (5a1) above and allowed to cool slowly with stirring. After standing for 20 hours the yellow crystal mass is filtered off and pressed. The pure (Z)-[10-methoxy-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ylidene]-acetic acid is obtained following re-crystallisation from ethanol: m.p.=184°-187° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([NH2:9])=[N:6][C:7]=1[Cl:8].C(=O)(O)[O-].[Na+].[C:18](Cl)(=[O:20])[CH3:19]>>[Cl:1][C:2]1[N:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([NH:9][C:18](=[O:20])[CH3:19])=[N:6][C:7]=1[Cl:8]
Reactant: CC(=O)Cl
Reactant: Nc1nc(Cl)c(Cl)nc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)Nc1nc(Cl)c(Cl)nc1[N+](=O)[O-]

Procedure:
To 1.0 g of 5,6-dichloro-3-nitropyrazinamine in 15 ml acetyl chloride under nitrogen atmosphere at room temperature is added 0.84 g anhydrous sodium bicarbonate. The reaction mixture is then stirred and heated at reflux for 4 days. Excess acetyl chloride is then removed in vacuo and the residue is chromatographed on silica gel. The desired product is eluted from the column with chloroform.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:60][CH:61]=[CH:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1.FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:60][CH:61]=[CH:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: N=C(OCC=Cc1ccccc1)C(Cl)(Cl)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC=Cc4ccccc4)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (100 mg in 3 ml 33% methylene chloride in cyclohexane), cinnamyl trichloroacetimidate (54 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 30 minutes the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×8 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (45 mg).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:19]2=[O:51])=[N:9]1)=O)(C)(C)C.Cl.C(OCC)C>O1CCOCC1>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:19]2=[O:51])=[N:9]1
Reactant: COc1ccccc1N(C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21)C(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1ccccc1N(C(=O)CN1C(=O)C(Cc2n[nH]c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-[3-(1-tert-butoxycarbonyl-1H-indazol-3-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(2-methoxy-phenyl) acetamide, prepared as in Intermediate 73, (260 mg, 0.377 mmol) and 4N HCl in dioxane (2 mL) is stirred at RT for 2 h. Diethyl ether (40 mL) is added and the resultant mixture stirred vigorously for 20 min. The solids were allowed to settle and the solvent is decanted. This procedure is repeated three times and the final gum dried by concentration in vacuo. Recrystallisation from 5% methanol in ethyl acetate afforded the title compound (126 mg) as a white powdery solid, which exists as 3:2 mixture of rotamers (major rotamer recorded): 1H NMR (300 MHz, CDCl3) δ7.98 (t, 1H, J=8.0), 7.70 (m, 1H), 7.61 (s, 1H), 7.40-6.90 (m, 15H), 5.05 (m, 1H, J=6.9), 4.45 (d, 2H, J=16.4), 4.25 (d, 1H, J=17.5), 4.07 (d, 1H, J=16.4), 3.74 (m, 5H), 1.16 (m, 6H); Low resolution MS (FAB) m/e 588 (M+); Tr =27.29 min (RP-HPLC, 100% A to 100% C, 30 min).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[C:9]1([NH:15]N)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(OC2C=CC=CC=2)C=CC=CC=1.C1C=CC=CC=1>[C:4]1(=[O:8])[C:3]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:15][C:2]=2[CH:7]=[CH:6][NH:5]1
Reactant: O=c1cc(O)cc[nH]1
Reactant: NNc1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccccc1
Product: O=c1[nH]ccc2[nH]c3ccccc3c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.3 %

Procedure:
4-Hydroxypyridin-2(1H)-one (3 g, 27 mmol) and phenylhydrazine (8.74 g, 81 mmol) in diphenyl ether (54 mL) were heated at 240° C. for 5 hours in a Dean Stark apparatus. The reaction mass was cooled to room temperature, diluted with benzene, stirred for 2 hours and filtered. The solid collected was dried under high vacuum and washed with ether to afford 3 g of the product (60% yield).
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)[CH3:2].S(Cl)([Cl:22])=O>>[CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([Cl:22])=[O:16])=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CC[C@H]1CC[C@H](CCc2ccc(C(=O)O)cc2)CC1
Reactant: O=S(Cl)Cl
Product: CC[C@H]1CC[C@H](CCc2ccc(C(=O)Cl)cc2)CC1
Yield: 100 %

Procedure:
4-[2-(trans-4-Ethylcyclohexyl)ethyl]-benzoic acid (10.5 gram, 40.38 m moles) prepared as in Example 2 was refluxed with thionyl chloride (60 ml) for 1 hour. The excess thionyl chloride was then distilled off to give 4-[2-(trans-4-ethylcyclohexyl)ethyl]benzoyl chloride (11.2 gram 100% of theory).
Reaction SMILES: [OH:1][CH:2]([C:6]1[C:7]([CH3:28])=[N:8][C:9]2[N:10]([N:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:21]=2)[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[C:3]([OH:5])=[O:4].[CH3:29]O>>[OH:1][CH:2]([C:6]1[C:7]([CH3:28])=[N:8][C:9]2[N:10]([N:19]=[C:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:21]=2)[C:11]=1[C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)[C:3]([O:5][CH3:29])=[O:4]
Reactant: Cc1ccc(-c2c(C(O)C(=O)O)c(C)nc3cc(-c4ccccc4)nn23)cc1
Reactant: CO
Product: COC(=O)C(O)c1c(C)nc2cc(-c3ccccc3)nn2c1-c1ccc(C)cc1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a solution of 2-hydroxy-2-(5-methyl-2-phenyl-7-p-tolylpyrazolo[1,5-a]pyrimidin-6-yl)acetic acid (6 mg, 0.016 mmol) in methanol (2 mL) was added thionyl chroride (0.0023 mL, 0.032 mmol). The reaction mixture was stirred at 40° C. for 16 hrs. The solvent was evaporated to give the title compound. The crude product was used directly for next step.
Reaction SMILES: [C:1]([P:5](=[O:17])([CH2:13][CH:14]([CH3:16])[CH3:15])C(OCC)OCC)([CH3:4])([CH3:3])[CH3:2]>Cl>[C:1]([PH:5](=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(OCC)P(=O)(CC(C)C)C(C)(C)C
Agent: Cl
Product: CC(C)C[PH](=O)C(C)(C)C
Temperature: 25 °C

Procedure:
A solution of 1.2 g (0.005 mol) of tertiary-butyl(iso-butyl)(diethoxymethyl)phosphine oxide in 10 ml of 5% hydrochloric acid is heated at 80° C. for 9 hours. After this the mixture is allowed to cool to room temperature, evaporated under reduced pressure and the crude product is extracted into chloroform and washed with water. The organic extract is dried and evaporated to give tertiary-butyl(iso-butyl)phosphine oxide as a pale yellow oil.