Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]2[N:8]=[C:9]([C:13]([OH:15])=O)[CH:10]=[C:11]([CH3:12])[C:6]2=[N:5][N:4]=1.[CH2:16]([NH:18]CC)[CH3:17]>CN(C=O)C>[CH2:16]([NH:18][C:13]([C:9]1[CH:10]=[C:11]([CH3:12])[C:6]2[N:7]([C:3]([NH2:2])=[N:4][N:5]=2)[N:8]=1)=[O:15])[CH3:17]
Reactant: Cc1cc(C(=O)O)nn2c(N)nnc12
Reactant: CCNCC
Agent: Cl
Solvent: CN(C)C=O
Product: CCNC(=O)c1cc(C)c2nnc(N)n2n1
Reaction time: 2 h
Yield: 38.9 %

Procedure:
3-Amino-8-methyl-[1,2,4]triazolo[4,3-b]pyridazine-6-carboxylic acid hydrochloride (W1.141; 300 mg) was dissolved in DMF (6 ml) and admixed with 0-[(ethoxycarbonyl)-cyanomethyleneamino]-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TOTU; 429 mg) and diethylamine (573 mg). After 2 h, the DMF was drawn off and the residue was Purified using silica gel (24 g cartridge, dichloromethane/methanol gradient of 0-20% in 60 min). The product was taken up with water and freeze-dried. In order to remove residual diethylamine, the mixture was chromatographed using a short column (dichloromethane/methanol 95:5). 112 mg of the title compound were obtained, which was still contaminated with diethylamine.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([F:26])=[CH:10][N:11]3[C:16]([C:17]=2[CH3:18])=[C:15]([CH:19]2[CH2:21][CH2:20]2)[CH:14]=[C:13]([C:22]([OH:24])=[O:23])[C:12]3=[O:25])[CH2:4]1.C([O-])(=O)C.[Na+].CO[C:34]1(OC)[CH2:38][CH2:37][CH2:36]O1>C(OCC)(=O)C>[CH:19]1([C:15]2[CH:14]=[C:13]([C:22]([OH:24])=[O:23])[C:12](=[O:25])[N:11]3[C:16]=2[C:17]([CH3:18])=[C:8]([N:5]2[CH2:6][CH2:7][C@H:3]([N:2]4[CH:34]=[CH:38][CH:37]=[CH:36]4)[CH2:4]2)[C:9]([F:26])=[CH:10]3)[CH2:20][CH2:21]1
Reactant: COC1(OC)CCCO1
Reactant: Cc1c(N2CC[C@H](N)C2)c(F)cn2c(=O)c(C(=O)O)cc(C3CC3)c12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1c(N2CC[C@H](n3cccc3)C2)c(F)cn2c(=O)c(C(=O)O)cc(C3CC3)c12
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
A mixture of 25 mg 8-(3(S)-aminopyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride (from Example 257) and 40 mg of sodium acetate in 0.7 mL of ethyl acetate was heated to 100° C. To this solution was added 0.009 mL of dimethoxytetrahydrofuran dropwise, and the reaction was stirred at 110° C. for 5 min, then quenched by addition of water. The mixture was extracted twice with methylene chloride, and the extract was washed with water, dried over MgSO4 and concentrated. The residue was purified by preparative TLC, eluting with 100:10 chloroform:methanol, to give 13.6 mg of the title product as a yellow solid after removal of the solvent. MS 395 (M-Cl)+. 1H NMR (CDCl3) δ: 0.67 (m, 2H), 1.00 (m, 2H), 2.20 (m, 1H), 2.46 (m, 1H), 2.56 (m, 1H), 2.66 (s, 3H), 3.89 (m, 1H), 3.99 (m, 2H0, 4.15 (m, 1H), 4.86 (m, 1H), 6.23 (t, 2H, J=2 Hz), 6.79 (t, 2H, J=2 hz), 8.32 (s, 1H), 9.15 (d, 1H, J=10 Hz), 13.83 (br, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C@H:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[NH:5][C:6](=[O:21])[C@H:7]([CH2:19][OH:20])[NH:8]C(OCC1C=CC=CC=1)=O.CO.[ClH:33].O>[Pd].O1CCCC1>[ClH:33].[CH3:1][O:2][C:3](=[O:30])[C@H:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[NH:5][C:6](=[O:21])[C@H:7]([CH2:19][OH:20])[NH2:8]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)CO

Procedure:
To a mixture of 8.328 g. of Nα -benzyloxycarbonyl-L-seryl-L-tyrosine methyl ester [cf. Fischer and Whetstone, J. Am. Chem. Soc., 76, 5076 (1954)] and 500 mg. of 20% palladium on carbon is added 70 ml. of methanol containing 6.67 ml. of 3N hydrogen chloride in tetrahydrofuran and the mixture stirred under hydrogen at one inch water pressure for three hours. The mixture is filtered to remove the catalyst and the filtrate is evaporated to dryness under reduced pressure to give a residue of L-seryl-L-tyrosine methyl ester hydrochloride which is suitable for use without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:18]([F:21])([F:20])[F:19])[C:5]([N:8]2[C:12]([OH:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[N:9]2)=[N:6][CH:7]=1.Br[CH2:23][N:24]1[C:28](=[O:29])[C:27]2[C:30]([CH:36]([CH3:38])[CH3:37])=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:26]=2[S:25]1(=[O:40])=[O:39]>CN(C=O)C>[C:36](=[C:30]1[CH:27]2[C:28](=[O:29])[N:24]([CH2:23][O:13][C:12]3[N:8]([C:5]4[C:4]([C:18]([F:19])([F:21])[F:20])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=4)[N:9]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:11]=3)[S:25](=[O:40])(=[O:39])[C:26]2=[CH:33][C:32]([O:34][CH3:35])=[CH:31]1)([CH3:38])[CH3:37]
Reactant: Oc1cc(C(F)(F)F)nn1-c1ncc(Cl)cc1C(F)(F)F
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Solvent: CN(C)C=O
Product: COC1=CC(=C(C)C)C2C(=O)N(COc3cc(C(F)(F)F)nn3-c3ncc(Cl)cc3C(F)(F)F)S(=O)(=O)C2=C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.2 %

Procedure:
To a mixture 1-(5-chloro-3-trifluoromethyl-2-pyridyl)-3-trifluoromethyl-5-hydroxypyrazole (440 mg; 1.30 mmol) in 8 ml of DMF was added under nitrogen KF (132 mg, 2.28 mmol) and the mixture was stirred at room temperature for 10 minutes. To the above mixture was added 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (400 mg, 1.14 mmol) and the resulting mixture was stirred at room temperature for one hour. The mixture was quenched with cold saturated ammonium chloride solution, diluted with water, and extracted with ether (3×). The combined organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue (an oil) was purified by flash chromatography (silica gel; 20% ethyl acetate in hexane) and recrystallized from ether/hexane to afford 343 mg (50%) of 4-isopropyyl-6-methoxy-2-[1-(5-chloro-3-trifluoromethyl-2-pyridyl)-3-trifluoromethylpyrazol-5-yl-oxymethyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =3-CF3 -5-Cl-2-pyridyl; R2 =CF3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3) as a white solid, m.p. 141°-142° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][CH2:8][CH:7]3[CH2:11][CH2:12][CH2:13][CH2:14][CH:6]3[C:5]=2[N:4]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[N:3]=1.Cl[CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.[H-].[Na+].[I-].[Na+]>CN(C=O)C.C(=O)(O)[O-].[Na+]>[CH3:1][C:2]1[C:10]2[CH2:9][CH2:8][CH:7]3[CH2:11][CH2:12][CH2:13][CH2:14][CH:6]3[C:5]=2[N:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:23][CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:17][CH:16]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(O)cc2)c2c1CCC1CCCCC21
Reactant: ClCCCN1CCCC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccc(OCCCN3CCCC3)cc2)c2c1CCC1CCCCC21
Temperature: 70 °C
Yield: 45.7 %

Procedure:
4-(3-Methyl-4,5,5a,6,7,8,9,9a-octahydrobenzo[g]indazol-1-yl)phenol (1.49 mmol) was dissolved in N,N′-dimethylformamide (6 mL), and 1-(3-chloropropyl)pyrrolidine (0.22 g, 1.49 mmol), sodium hydride (72 mg, 60% dispersion in mineral oil, 1.79 mmol) and a catalytic amount of sodium iodide were added. The reaction was heated at 70° C. for 3 hours. The solution was diluted with saturated sodium bicarbonate and extracted with ethyl acetate. The extracts were dried over MgSO4 and concentrated. SiO2 chromatography with 2% triethylamine/10% methanol/ethyl acetate gave 0.268 g of the desired product. LC-MS (C25H35N3O calc'd 393) m/z 394 (M+H). 1H NMR (300 MHz, CDCl3) 7.27 (d, J=8.7 Hz, 2H), 6.91 (d, J=9 Hz, 2H), 4.05 (t, J=6.3 Hz, 2H), 2.64 (t, J=7.2 Hz, 2H), 2.58-2.39 (m, 7H), 2.20 (s, 3H), 2.07-2.00 (m, 2H), 1.82-1.10 (m, 14H), 0.91-0.79 (m, 1H).
Reaction SMILES: C1(NN)C=CC=CC=1.[C:9]1([NH:15][N:16]=[C:17](OC)[CH3:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[O-:21][C:22]#[N:23].[Na+].C(O)(=O)C>CO.O>[CH3:18][C:17]1[NH:23][C:22](=[O:21])[N:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:16]=1
Reactant: N#C[O-]
Reactant: COC(C)=NNc1ccccc1
Agent: [Na+]
Solvent: CO
Solvent: NNc1ccccc1
Solvent: O
Product: Cc1nn(-c2ccccc2)c(=O)[nH]1
Temperature: 25 °C

Procedure:
A stirred solution of 2.0 grams (0.019 mole) of phenylhydrazine and 2.7 grams (0.022 mole-1.2 eq.) of TMOA in 20 mL of methanol is heated at reflux for about 1.5 hours, until the reaction to the intermediate N--phenyl--N'--(1-methoxyethylidene)hydrazine is complete. The progress of the reaction is monitored by gas chromatography (GC). After this time, the reaction mixture is cooled in an ice-water bath (0° C.) and 1.5 grams (0.022 mole-1.2 eq.) of sodium cyanate is added. Upon completion of addition, 1.3 grams (0.022 mole-1.2 eq.) of acetic acid is added dropwise. The reaction mixture is then stirred at the ice-water bath temperature for about 10 minutes, then it is allowed to warm to ambient temperature. After this time, two mL of water is added to the reaction mixture. Upon completion of addition, the reaction mixture is stirred at ambient temperature for about ten hours. The reaction mixture is concentrated under reduced pressure, yielding 4,5-dihydro-3-methyl-1-phenyl-1,2,4-triazol-5(1 H)-one.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].Cl[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](Cl)=[O:15])[N:9]=1)=[O:7].O.[CH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:15])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:9]=1)(=[O:7])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)n1
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=C(c1ccccc1)c1cccc(C(=O)c2ccccc2)n1
Temperature: 60 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
Aluminium trichloride (5.1 g, 3.18 mmol) was added to a suspension of 2,6-bis(chlorocarbonyl)pyridine (3.7 g, 18 mmol) in 200 ml of benzene. The reaction mixture was heated to 60° C. and kept at that temperature for 4 h and subsequently for 16 h at room temperature. The mixture was poured into water, the organic layer was separated and evaporated to dryness. The residue was dissolved in CH2Cl2 and filtered. Removal of CH2Cl2 in vacuum yielded 3.0 g (58%) of product.
Reaction SMILES: Cl[C:2]([C:4]1[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][C:10]#[N:11])=[CH:6][CH:5]=1)=[O:3].BrC1C=CC(C(O)=[O:20])=CC=1.C(#N)C=C.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:2]([C:4]1[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][C:10]#[N:11])=[CH:6][CH:5]=1)([OH:20])=[O:3]
Reactant: N#CC=Cc1ccc(C(=O)Cl)cc1
Reactant: O=C(O)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: C=CC#N
Solvent: CCN(CC)CC
Product: N#CC=Cc1ccc(C(=O)O)cc1
Yield: 35 %

Procedure:
The 4-chloroformylcinnamonitrile can be prepared as follows: 10.05 g (50 mmols) of 4-bromobenzoic acid, 3.31 g (62.5 mmols) of acrylonitrile, 12.6 g (125 mmols) of triethylamine, 0.112 g (0.5 mmol) of palladium acetate, 0.608 g (2 mmols) of tri-o-tolylphosphine and 20 ml of toluene are boiled under reflux for 6 hours. The reaction mixture is extracted by shaking with 100 ml of 2N hydrochloric acid and the crude product is filtered off and recrystallised from methanol. 3 g (35% of theory) of 4-carboxycinnamonitrile are obtained in the form of pale yellow crystals; melting point 281° C.
Reaction SMILES: [C:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([OH:26])[CH:20]([CH3:25])[CH2:21][C:22]([OH:24])=[O:23])=[CH:15][CH:14]=2)=[C:6]([CH2:29][CH2:30][CH3:31])[C:5]=1[OH:32])(=[O:3])[CH3:2].[OH-].[Na+].[CH2:35]1COCC1>CO>[C:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([OH:26])[CH:20]([CH3:25])[CH2:21][C:22]([O:24][CH3:35])=[O:23])=[CH:15][CH:14]=2)=[C:6]([CH2:29][CH2:30][CH3:31])[C:5]=1[OH:32])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCSc2ccc(C(O)C(C)CC(=O)O)cc2)ccc(C(C)=O)c1O
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCCSc2ccc(C(O)C(C)CC(=O)OC)cc2)ccc(C(C)=O)c1O
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To the 4-((3-(4-acetyl-3-hydroxy-2-propylphenoxy) propyl)thio)-beta-methyl-gamma-hydroxybenzene butanoic acid γlactone (8.84 g, 20 mM) described in EP 104,885 (Apr. 4, 1984) was added a mixture of 2N NaOH (12 ml, 24 mM), THF (50 ml) and MeOH (20 ml) and the mixture was stirred 12 hours under N2. The reaction mixture was evaporated to dryness and dissolved in water (75 ml) and cooled to 0° C.; 1N HCl was added drop wise until the PH was lower than 6 and the organic compound was extracted into EtOAc (200 ml). The organic layer was washed with brine (100 ml) and dried with Na2SO4. The solvent was removed in vacuo with no heating and the residue was dissolved in Et2O (100 ml) and cooled to 0° C. Diazomethane (in Et2O) was added in excess and the reaction mixture was evaporated to dryness with no heat and dried under high vacuum to yield the title compound as an oil slightly contaminated (by less than 10 percent of the starting lactone).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6]/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10]>CN(C=O)C>[N:1]([CH2:6]/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10])=[N+:2]=[N-:3]
Reactant: COC(=O)/C=C/CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C/CN=[N+]=[N-]
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
To the solution of NaN3 (2.80 g, 43.01 mmol) in 100 ml of DMF at −20° C. was added methyl 4-bromocrotonate (5.00 ml, 85%, 36.10 mmol). After stirred at −20° C. for 30 min, the mixture was stirred at 0° C. for 4 h, evaporated, suspended with EtAc/Hexane (1:1), filtered, evaporated and chromatographic purification on SiO2 column eluted with EtAc/Hexane (1:25 to 1:10) to afford HRMS for 4.08 g (80%) of the title product. 1H NMR (CDCl3) 6.88 (m, 1H), 6.06 (ddd, 1H, J−=1.7, 3.4, 15.6 Hz), 3.97 (dd, 2H, J=1.2, 4.96 Hz), 3.73 (s, 3H); 13C NMR 166.23, 140.86, 123.49, 51.95, 51.36; ESI MS m/z+ 182.5 (M+Na+H2O); HRMS m/z+ (C5H7N3O2+H2O+Na) calcd 182.0542, found 182.0548.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([O:15]C)=[O:14])=[N:4][C:5]([O:10][CH2:11][CH3:12])=[C:6]([Cl:9])[C:7]=1[Cl:8].[OH-].[Na+]>CO>[NH2:1][C:2]1[C:3]([C:13]([OH:15])=[O:14])=[N:4][C:5]([O:10][CH2:11][CH3:12])=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: CCOc1nc(C(=O)OC)c(N)c(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1nc(C(=O)O)c(N)c(Cl)c1Cl
Yield: 46.5 %

Procedure:
A solution of the compound prepared in Example 430 (0.025 g) in methanol (1 mL) was treated with sodium hydroxide (0.094 mL) and refluxed for 3 hours. This material was evaporated in vacuo and residue dissolved in water and acidified with 1 mol/L hydrochloric acid. The product was extracted with ethyl acetate, dried, and evaporated in vacuo to provide the title compound (0.011 g) with the following physical data.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:4]1[C@@H:7]([CH2:8][C:9](=[O:23])[C:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[N+]=[N-])[NH:6][C:5]1=[O:24])[CH3:3]>C1C=CC=CC=1.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[OH:1][C@@H:2]([C@H:4]1[C:5](=[O:24])[N:6]2[C@@H:7]1[CH2:8][C:9](=[O:23])[CH:10]2[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1CC(=O)C(=[N+]=[N-])C(=O)OCc1ccccc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccccc3)C(=O)C[C@H]12

Procedure:
A suspension of (3S,4R)-3-[(R)-1-hydroxyethyl]-4-[3-benzyloxycarbonyl-2-oxo-3-diazopropyl] azetidin-2-one (50 mg, 0.15 mmol) and rhodium (II) acetate (0.1 mg) in dry benzene (3 mL) was deoxygenated by bubbling through nitrogen for 10 minutes. The mixture was then heated to 78° for 1 hour. During heating the solid starting material gradually went into solution. The mixture was then cooled, filtered to remove the catalyst, and the filtrate was concentrated in vacuo to yield (5R, 6S) benzyl 6-[(R)-1-hydroxyethyl]-1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate, 45 mg. (98%) as a colorless oil.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:10][C:11](=O)[CH2:12][C@@H:13]([OH:18])[CH2:14][C:15]([NH2:17])=[O:16].C(O)(=O)C(C(C(O)=O)O)O.N>ClCCl.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4].COC(C)(C)C>[CH2:1]([O:8][C:11](=[O:10])[CH2:12][C@@H:13]([OH:18])[CH2:14][C:15]([NH2:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: COC(=O)C[C@@H](O)CC(N)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: N
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: NC(=O)C[C@H](O)CC(=O)OCc1ccccc1
Temperature: 55 °C
Reaction time: 5 h

Procedure:
Mixture of Benzyl alcohol (131.0 g), (S)-methyl-3-hydroxyglutaramate (100 g) and Tetraisopropyl orthotitanate (17.5 g) are mixed in a flask. The mixture was stirred under vacuum at 50-60° C. for about 5 hrs. The reaction mixture was cooled and diluted with dichloromethane (500 ml). The reaction mixture was added to a stirred solution of Tartaric acid (37 g in 370 ml DM water) and 500 ml dichloromethane mixture. The reaction mixture was stirred and pH was adjusted to 7.0-8.0 by Aq ammonia solution. Layers were separated. The organic phase was removed and the aqueous phase was extracted with dichloromethane. Combined organic layer was washed with Aq ammonia and tartaric acid solution followed by brine wash. The organic phase was dried over anhydrous sodium sulphate and evaporated under reduced pressure to yield oil. To this oil tert-butyl methyl ether (800 ml) was added, stirred, cooled, filtered and dried to give (S)-Benzyl-3-hydroxyglutaramate.
Reaction SMILES: [NH2:1][C:2]1[C:12]([N+:13]([O-])=O)=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([O:16][CH2:17][CH:18]([F:20])[F:19])[CH:3]=1>[Ni].C1COCC1>[NH2:1][C:2]1[C:12]([NH2:13])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([O:16][CH2:17][CH:18]([F:19])[F:20])[CH:3]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(N)cc1OCC(F)F
Agent: [Ni]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(N)c(N)cc1OCC(F)F

Procedure:
The sub-title compound was prepared in accordance with Example 59 (g) using ethyl 4-amino-2-(2,2-difluoroethoxy)-5-nitrobenzoate (1.00 g; 3.44 mmol), Ra—Ni (1.0 g) and THF (50 mL). The sub-title compound was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].Cl.[OH:29][CH2:30]C1CNCC1O>>[Br:1][C:2]1[C:3]([N:22]2[CH2:26][C@@H:25]([CH2:30][OH:29])[C@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:19])([F:20])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: OCC1CNCC1O
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Agent: Cl
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2C[C@@H](CO)[C@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 12.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Example 35) and 4-(hydroxymethyl)pyrrolidin-3-ol hydrochloride to afford an off-white solid. UPLC-MS (Condition 3) tR=0.98 min, m/z=476.2/478.2 [M+H]+, m/z=474.0/476.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.11-2.23 (m, 1H) 3.25-3.34 (m, 2H) 3.39-3.49 (m, 1H) 3.50-3.62 (m, 2H) 3.83-3.96 (m, 2H) 4.04-4.12 (m, 1H) 4.70 (t, J=5.27 Hz, 1H) 5.07 (d, J=4.37 Hz, 1H) 7.33 (d, J=8.75 Hz, 2H) 7.83 (d, J=9.00 Hz, 2H) 8.32 (d, J=2.06 Hz, 1H) 8.66 (d, J=1.80 Hz, 1H) 10.21 (s, 1H).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9](=[O:12])[N:8]([CH3:13])[C:7]3[CH:14]=[N:15][C:16]([NH:18][C:19]4[CH:34]=[CH:33][C:22](C(NC5CCN(C)CC5)=O)=[CH:21][C:20]=4[O:35][CH3:36])=[N:17][C:6]2=3)[CH2:4][CH2:3][CH2:2]1.Cl>O.CO.C(#N)C>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9](=[O:12])[N:8]([CH3:13])[C:7]3[CH:14]=[N:15][C:16]([NH:18][C:19]4[CH:34]=[CH:33][CH:22]=[CH:21][C:20]=4[O:35][CH3:36])=[N:17][C:6]2=3)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCC1)CCC(=O)N2C
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CC#N
Product: COc1ccccc1Nc1ncc2c(n1)N(C1CCC1)CCC(=O)N2C
Reaction time: 0.25 h
Yield: 12.3 %

Procedure:
A mixture of 0.23 g (0.00085 mole) of 4-(9-cyclobutyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-24) and 3 mL of 1M hydrochloric acid was heated at 180 degree for 45 minutes in a microwave reactor. The cooled mixture was diluted with 2 mL of water, 3 mL of methanol and 2 mL of acetonitrile and then stirred for 15 minutes. The solids were removed by filtration and the aqueous solution was made basic (pH>10). The solid which formed was collected, washed with water, and then purified by C18 reverse phase silica gel chromatography, eluting with an acetonitrile-water gradient (10:90-100:0) to give 0.037 g of 9-cyclobutyl-2-(2-methoxy-phenylamino)-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (I-25)
Reaction SMILES: [C:1](OCC)(OCC)(OCC)[CH2:2][CH3:3].Cl.N1C=CC=CC=1.[NH2:20][C:21]1[CH:22]=[N:23][C:24]2[C:29]([C:30]=1[NH:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36])=[CH:28][CH:27]=[CH:26][CH:25]=2>N1C=CC=CC=1>[CH2:2]([C:3]1[N:31]([CH2:32][CH2:33][CH2:34][CH2:35][OH:36])[C:30]2[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:23]=[CH:22][C:21]=2[N:20]=1)[CH3:1]
Reactant: CCOC(CC)(OCC)OCC
Reactant: Nc1cnc2ccccc2c1NCCCCO
Agent: Cl
Solvent: c1ccncc1
Product: CCc1nc2cnc3ccccc3c2n1CCCCO

Procedure:
Triethyl orthopropionate (15.1 mL of 97%, 1.1 eq.) and a catalytic amount of pyridine hydrochloride were added to a solution of 4-[(3-aminoquinolin-4-yl)amino]butan-1-ol (16 g, 69 mmol, 1 eq.) in pyridine (150 mL). The reaction mixture was refluxed for 1 hour at which time analysis by TLC indicated that all of the starting material had been consumed. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water (300 mL). The resulting solid was isolated by filtration and then recrystallized from ethyl acetate to provide 8.2 g of 4-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol. A second crop (1.9 g) was obtained by reducing the volume of the mother liquor.
Reaction SMILES: Cl.[OH:2][C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1.[Cl-].[NH4+].[In]>CN1C(=O)CCC1.C(O)C.O>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([N:4]2[CH:5]=[CH:6][CH:7]=[N:8][C:3]2=[O:2])=[CH:13][CH:14]=1
Reactant: Oc1ncccn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCO
Product: Nc1ccc(-n2cccnc2=O)cc1
Reaction time: 8 h

Procedure:
2-Hydroxypyrimidine hydrogenchloride (2.1, 1.50 g, 11.3 mmol) was stirred in 20 mL dry NMP at RT. To it was added sodium hydride (60% in mineral oil, 0.95 g, 23.5 mmol) in small portions carefully. The mixture was stirred for 30 min before 4-fluoro-1-nitrobenzene (1.0 mL, 9.4 mmol) was added. The mixture was sent to 80° C. bath and stirred overnight. It was concentrated in vacuo and taken into acetonitrile. After vigorously stirring, the insoluble solid was collected, which was a mixture of leftover 2-hydroxypyrimidine and 1-(4-nitrophenyl)pyrimidin-2(1H)-one 2.2. MS found for C10H7N3O3 (M+H)+ 218.0. This solid (1.27 g, 5.8 mmol) was dissolved in 100 mL ethanol and 30 mL water. To it was added ammonium chloride (3.1 g, 58 mmol) and indium powder (2.6 g, 23 mmol). The mixture was refluxed for 6 hrs. It was concentrated in vacuo, filtered through celite. The solid cake was rinsed with water. The filtrate was concentrated and subjected to reverse phase prep HPLC to isolate 1-(4-aminophenyl)pyrimidin-2(1H)-one 2.3. MS found for C10H9N3O (M+H)+ 188.1.