Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24](N)=[O:25])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:31][C:32]1[CH:33]=[C:34]([NH:39][C:40](=[O:45])[CH2:41][N:42]([CH3:44])[CH3:43])[CH:35]=[CH:36][C:37]=1[CH3:38].[I-].[K+].Cl.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:43][N:42]([CH3:44])[CH2:41][C:40]([NH:39][C:34]1[CH:35]=[CH:36][C:37]([CH3:38])=[C:32]([NH:31][C:2]2[N:3]3[C:4](=[N:21][C:22]4[C:23]([C:24]3=[O:25])=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:5]3[CH:10]=[CH:9][N:8]([S:11]([C:14]4[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=4)(=[O:12])=[O:13])[C:6]=3[N:7]=2)[CH:33]=1)=[O:45]
Reactant: Cc1ccc(NC(=O)CN(C)C)cc1N
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccccc4C(N)=O)nc(Cl)nc32)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c2nc(Nc2cc(NC(=O)CN(C)C)ccc2C)n2c(=O)c4ccccc4nc32)cc1
Yield: 823.8 %

Procedure:
To a pressurized vessel was added 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide (1.0 g, 2.27 mmol), N1-(3-amino-4-methylphenyl)-N2,N2-dimethylglycinamide (0.590 g, 2.83 mmol), potassium iodide (<10 mg) and hydrochloric acid as a 4.0M solution in dioxanes (ca 4 mL). The resulting suspension was stirred until all solids had completely dissolved (24 hr.) The reaction was poured into into saturated sodium bicarbonate and diluted with dichloromethane. The organic layer was dried over sodium sulfate, volatiles removed under reduced pressure, and the solids triturated with diethyl ether to afford N2,N2-dimethyl-N1-[4-methyl-3-({3-[(4-methylphenyl)sulfonyl]-7-oxo-3,7-dihydropyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-5-yl}amino)phenyl]glycinamide (1.11 g, 18.7 mmol, 82% yield) of sufficient purity for use in subsequent transformations. ESIMS (M+H)=596.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH:8](C#N)[C:9]2[CH:10]=[CH:11][C:12]([F:17])=[C:13]([CH:16]=2)[C:14]#[N:15])=[C:4]([CH3:20])[C:3]=1[CH3:21].Cl.O>C(O)(=O)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([F:17])=[C:13]([CH:16]=2)[C:14]#[N:15])=[C:4]([CH3:20])[C:3]=1[CH3:21]
Reactant: Cc1c(Cl)nnc(C(C#N)c2ccc(F)c(C#N)c2)c1C
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(Cl)nnc(Cc2ccc(F)c(C#N)c2)c1C
Temperature: 25 °C

Procedure:
Intermediate B1 was suspended in a mixture of acetic acid, conc. aq. HCl and water (1:1:2, 0.07M). The suspension was stirred and heated at reflux for 75 min. The reaction mixture was cooled to RT and the solvents were removed under reduced pressure. To the residue was added saturated aq. NaHCO3 and the mixture was extracted with EtOAc. The organic phase was dried (Na2SO4), filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel, eluting with PE-EtOAc (10-80% EtOAc) to afford the title compound as a yellow solid. MS (ES) C14H11ClFN3 required: 275, found: 276 (M+H)+.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:18]=[CH:17][C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[N:10]=[C:11]([NH2:12])[C:5]=2[CH:4]=1.[CH2:19]([C@H:27]1[CH2:32]N[CH2:30][CH2:29][NH:28]1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.CS(C)=O>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:2][C:3]1[CH:18]=[CH:17][C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[N:10]=[C:11]([N:12]3[CH2:30][CH2:29][NH:28][C@@H:27]([CH2:19][CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:32]3)[C:5]=2[CH:4]=1
Reactant: Cc1ccc2c(c1)C(N)=Nc1ccccc1N2
Reactant: c1ccc(CC[C@H]2CNCCN2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(c1)C(N1CCN[C@@H](CCc3ccccc3)C1)=Nc1ccccc1N2
Temperature: 110 °C
Reaction time: 67 h
Yield: 70.6 %

Procedure:
Combine 2-methyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride (600.0 mg, 2.31 mmol), (S)-2-phenethyl-piperazine (879.1 mg, 4.62 mmol), N,N-diisopropylethylamine (298.6 mg, 2.31 mmol), DMSO (1.0 ml), and toluene (4.0 ml). Stir and heat the mixture at 110° C. After 67 hours, cool the mixture to ambient temperature and then dilute it with ethyl acetate. Wash the organic layer with 0.1 N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using dichloromethane/methanol (90:10) to give 646.3 mg (71%) of a tan foam: mp 67°, dec; mass spectrum (ion spray): m/z=397.3 (M+1).
Reaction SMILES: Cl[C:2]1[N:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.Cl.[NH2:25][C@H:26]([C:28]([NH2:30])=[O:29])[CH3:27]>CN(C)C(=O)C>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[N:23][C:2]([NH:25][C@@H:26]([CH3:27])[C:28]([NH2:30])=[O:29])=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: C[C@H](N)C(N)=O
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N[C@@H](C)C(N)=O)cc1OCC2
Temperature: 90 °C
Yield: 7 %

Procedure:
A solution containing 9-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine 317 (0.1 g, 0.3 mmol), prepared according to Example 377, and L-alaninamide HCl (0.15 g, 1.21 mmol) in N,N-dimethylacetamide (1 mL) was heated at 90° C. for 16 h. The crude reaction mixture was directly purified by rp-HPLC to provide 8 mg (7% yield) of 392. MS (ESI+) m/z 383.1 (M+H+), calcd. 383.2. 1H NMR (400 MHz, DMSO) δ 8.99 (s, 1H), 7.88 (s, 1H), 7.81 (s, 1H), 7.30 (s, 1H), 6.90 (s, 1H), 6.81 (d, J=7.4 Hz, 1H), 6.12 (s, 1H), 5.92 (dt, J=13.1, 6.5 Hz, 1H), 4.47 (q, J=5.8 Hz, 4H), 4.37-4.21 (m, 1H), 1.47 (dd, J=6.6 Hz, 6H), 1.25 (d, J=7.0 Hz, 3H)
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:16])[NH:4][C:5](=[O:15])[N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:7]=1.I[CH3:18]>>[Br:1][C:2]1[C:3](=[O:16])[N:4]([CH3:18])[C:5](=[O:15])[N:6]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH:7]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)n1cc(Br)c(=O)[nH]c1=O
Product: Cn1c(=O)c(Br)cn(C(=O)OC(C)(C)C)c1=O
Reaction time: 1.5 h
Yield: 57 %

Procedure:
The title compound was obtained according to the procedure described for Example 16 (Step 1), starting from tert-butyl 5-bromo-2,4-dioxo-pyrimidine-1-carboxylate (1.43 g, 4.92 mmol); iodomethane was used herein and the reaction was stirred under nitrogen for 1.5 hrs. The crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 70:30) to afford the title compound (0.85 g, 57%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 1.62 (s, 9H), 3.40 (s, 3H), 8.18 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@@H:7]2[O:20][C@H:19]([CH2:21][O:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@@H:9]([O:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C@@H:8]2[F:31])[CH:5]=[N:4][C:3]=1[C:32](=[O:37])[CH2:33][N:34]=[N+]=[N-].Cl.CO.[H][H]>CO.[Pd]>[NH2:1][C:2]1[N:6]([C@@H:7]2[O:20][C@H:19]([CH2:21][O:22][C:23](=[O:30])[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@@H:9]([O:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C@@H:8]2[F:31])[CH:5]=[N:4][C:3]=1[C:32](=[O:37])[CH2:33][NH2:34]
Reactant: [N-]=[N+]=NCC(=O)c1ncn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@@H]2F)c1N
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCC(=O)c1ncn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@@H]2F)c1N

Procedure:
Compound (17) obtained in step (8) above (567 mg) was dissolved in methanol (23 ml), to which was then added a 2.2M hydrogen chloride-methanol solution (0.75 ml). The resulting solution was subjected to a catalytic reduction by blowing hydrogen into the solution at room temperature in the presence as catalyst of palladium black for 1 hour (for the reduction of the azido group). The reaction solution so obtained was filtered and the filtrate was concentrated to leave a solid, which was then washed with diethyl ether, to afford the titled compound (18) as a solid (508 mg) which was insoluble in ethyl ether.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[C:12]1([CH3:18])C=CC=C[CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+].B1(C2CC2)OC(=O)CN(C)CC(=O)O1>CC([O-])=O.CC([O-])=O.[Pd+2].O>[CH:18]1([C:2]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=2[NH2:4])[CH2:12][CH2:13]1
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Reactant: Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN1CC(=O)OB(C2CC2)OC(=O)C1
Solvent: O
Product: Nc1cc([N+](=O)[O-])ccc1C1CC1
Yield: 70 %

Procedure:
In a 250 mL round bottom flask to a solution of 2-bromo 5-nitroaniline (2.30 g, 10.60 mmol) in toluene (90 mL) tricyclohexylphosphine (0.89 g, 3.18 mmol), Cs2CO3 (17.22 g, 52.99 mmol), cyclopropylboronic acid MIDA ester (2.92 g, 14.84 mmol) and 10 ml de-ionized water were added and the solution was degassed with nitrogen for 30 minutes. To the above solution Pd(OAc)2 (0.36 g, 1.59 mmol) was added under nitrogen and the reaction mixture was refluxed for 12 hours. LC MS analysis of the crude reaction indicated the completion of the reaction. The crude reaction mixture was filtered on celite pad and the volatiles were removed under reduced pressure. The dark brown oil was worked-up with 2×100 mL ethyl acetate and water (100 mL), dried on MgSO4 and ethyl acetate was evaporated under reduced pressure. The crude reaction mixture was separated by column chromatography to give Compound 13 in 70% yield.
Reaction SMILES: [NH2:1][C:2](=[N:13][NH:14][C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1)[CH2:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5]>C(O)C>[C:7]1([S:4]([CH2:3][C:2]2[N:1]=[C:15]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:14][N:13]=2)(=[O:6])=[O:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC(CS(=O)(=O)c1ccccc1)=NNC(=O)c1cccnc1
Solvent: CCO
Product: O=S(=O)(Cc1n[nH]c(-c2cccnc2)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
15.0 g (0.047 mol) nicotinic acid (1-amino-2-benzenesulfonyl-ethylidene)-hydrazide were heated at 220° C. for 20 minutes. The molten mass was then cooled, dissolved in 100 ml hot ethanol and stirred overnight at room temperature. The precipitated crystals were filtered off and dried to yield 13.6 g (96%)) 3-(5-benzenesulfonylmethyl-2H-[1,2,4]triazol-3-yl)-pyridine as white solid, MS m/e (%): 300 (M+, 8), 236(99), 159 (100), 105(43), 77(35).
Reaction SMILES: C([O:4][C@H:5]([CH2:10]Br)[CH2:6][C:7]([OH:9])=[O:8])(=O)C.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>O>[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13].[O:4]1[CH2:10][C@@H:5]1[CH2:6][C:7]([OH:9])=[O:8]
Reactant: CC(=O)O[C@H](CBr)CC(=O)O
Solvent: CC(C)(C)N
Solvent: O
Product: O=C(O)C[C@H]1CO1
Reaction time: 2 h

Procedure:
To a 2 l of three-necked flask equipped with thermometer, pH meter and mechanical stirrer were charged distilled water (1 l), (S)-3-acetoxy-4-bromobutyric acid (90 g, 0.4 mol) and t-butylamine (88 g, 1.2 mol). The reaction mixture was stirred at 0˜5° C. for 2 hours to afford (S)-3,4-epoxybutyric acid t-butylamine salt. Over 99% of conversion was detected by NMR.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]([O:17]CC)=[O:16])=[CH:12][C:11]=3[CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[OH-].[K+]>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]([OH:17])=[O:16])=[CH:12][C:11]=3[CH:20]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cc2cc(-c3ccccc3)ccc2o1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1cc2cc(-c3ccccc3)ccc2o1

Procedure:
A mixture of 1.3 g of Compound 1B and 50 ml of 10% alcoholic potassium hydroxide was refluxed for 4 hours. The solvent was evaporated under reduced pressure and the residue was washed with ether and dissolved in water. The basic solution was acidified with dilute hydrochloric acid and extracted with ether. The ether layer was extracted with dilute sodium bicarbonate solution. The aqueous solution was re-acidified with dilute hydrochloric acid and extracted with ether. The ether extract was dried (Na2SO4) and concentrated under reduced pressure. The residue was crystallized from ethanol to give 5-phenyl-2-benzofurancarboxylic acid (1C), as white solid, mp: 220°-221° C.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].ClOC(C)(C)C.[CH3:23][S:24][CH2:25][C:26](OCC)=[O:27].C(N(CC)CC)C>C(Cl)Cl>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]([C:3]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:2]=2[NH:1][C:26](=[O:27])[CH:25]3[S:24][CH3:23])=[O:5])=[CH:7][CH:8]=1
Reactant: CCOC(=O)CSC
Reactant: Nc1ccccc1C(=O)c1ccc(Cl)cc1
Agent: CC(C)(C)OCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSC1C(=O)Nc2c(C(=O)c3ccc(Cl)cc3)cccc21
Temperature: -65 °C
Reaction time: 0.25 h
Yield: 33 %

Procedure:
A solution of 23.1 g. (0.1 mole) of 2-amino-4'-chlorobenzophenone in 400 ml. of methylene chloride was cooled to -65° C. and treated dropwise with 12.4 g. (0.1 mole) of t-butyl hypochlorite. After 15 min., 13.4 g. of ethyl α-(methylthio)acetate (0.1 mole) was added dropwise maintaining -65° C. temperature. After 11/2 hr. 10.1 g. of triethylamine (0.1 mole) was added and the reaction mixture allowed to come to room temperature. The solution was then washed with water and stripped. The residue was taken into methanol and brought to reflux at which time 1N hydrochloric acid was added and the resulting mixture refluxed overnight. The mixture was cooled, resulting precipitate filtered off and recrystallized from toluene, giving 10 g. of a cream colored solid. The product (33% yield) melted at 186°-188° C.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=O)[CH:10]=2)[NH:5][N:4]=1)[CH3:2].[C:14](/[CH:16]=[C:17](\[O-:19])/[CH3:18])#[N:15].[Na+].C(O)(=O)C.N1CCCCC1>ClCCl>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](/[CH:12]=[C:16](/[C:17](=[O:19])[CH3:18])\[C:14]#[N:15])[CH:10]=2)[NH:5][N:4]=1)[CH3:2]
Reactant: CCc1n[nH]c2ccc(C=O)cc12
Reactant: C/C([O-])=C/C#N
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1n[nH]c2ccc(/C=C(\C#N)C(C)=O)cc12
Yield: 87.4 %

Procedure:
A mixture of 0.50 g (2.87 mmol) 3-ethyl-1H-indazole-5-carbaldehyde (Example 6A), 0.33 g (3.16 mmol) sodium (1Z)-1-cyanoprop-1-en-2-olate, 0.21 ml (3.6 mmol) acetic acid and 0.028 ml (0.29 mmol) piperidine in dry dichloromethane (25 ml) containing 4 Å molecular sieve was stirred under reflux for 16 h. Upon cooling, a precipitate was formed which was collected by filtration and washed with saturated aqueous sodium bicarbonate solution and water. The solid was dissolved in ethanol, and the molecular sieve was filtered off. The filtrate was concentrated under reduced pressure, and the residue was treated with ethyl acetate and saturated aqueous sodium carbonate solution. The organic layer was washed with water, dried, and concentrated under reduced pressure to afford the title compound (0.60 g, 88% of th.) as a pale yellow solid which was used in subsequent steps without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].C1N2CCN(CC2)C1.[CH3:25][N:26]([CH3:30])[C:27](Cl)=[S:28]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[C:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:27](=[S:28])[N:26]([CH3:30])[CH3:25])=[CH:13][CH:14]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Reactant: CN(C)C(=S)Cl
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OC(=S)N(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.9 %

Procedure:
A DMF (100 mL) solution of 2-(4-hydroxyphenoxy)-2-methyl propionic acid ethyl ester (15.2 g, 67.7 mmol) and DABCO (15.2 g, 135.5 mmol) was charged dropwise with N,N-dimethylthiocarbamoyl chloride (16.7 g, 135.5 mmol) in 20 mL DMF over 15 min. The reaction was stirred at rt for 18 h and then quenched with water. The reaction was partitioned between water (1L) and EtOAc (500 mL) and the organic layer washed with 1N HCl (500 mL). After drying (MgSO4) and concentration, the crude product was obtained as a tan oil. Purification by flash chromatography (15% EtOAc/hexane) provided the product (15.8 g, 75%) as a pale yellow oil: 1H NMR (CDCl3) δ 1.32 (t, 3H), 1.65 (s, 6H), 3.37 (s, 3H), 3.50 (s, 3H), 4.30 (q, 2H), 6.93 (dd, 4H); MS (m/e) 312.
Reaction SMILES: [CH3:1][C:2]([NH:5][CH2:6][CH:7]([OH:29])[CH2:8][O:9][C:10]1[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=1[C:12]([NH:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](Cl)=[CH:18][NH:19]2)=[O:13])([CH3:4])[CH3:3].[OH-:30].[Na+]>C(O)C.Cl.O>[CH3:1][C:2]([NH:5][CH2:6][CH:7]([OH:29])[CH2:8][O:9][C:10]1[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=1[C:12]([NH:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][C:18](=[O:30])[NH:19]2)=[O:13])([CH3:4])[CH3:3]
Reactant: CC(C)(C)NCC(O)COc1ccccc1C(=O)Nc1cccc2[nH]cc(Cl)c12
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)NCC(O)COc1ccccc1C(=O)Nc1cccc2c1CC(=O)N2

Procedure:
2.5 g of the product of Step A in 35 ml of ethanol and 70 ml of 1N hydrochloric acid was refluxed for 1 hour and the reaction mixture was diluted with water, alkalinized with sodium hydroxide and extracted with ethyl acetate. After elimination of the solvent under reduced pressure, 2.5 g of crude product were obtained with crystallized spontaneously from a mixture of solvents: chloroform-ethyl acetate-triethylamine (6-3-1) to obtain 1.9 g of 2-[3[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-N-[2,3-dihydro-2-oxo-1H-indol-4-yl]benzamide melting at 160° C.
Reaction SMILES: Cl.[Si]([O:9][C:10]1([CH2:16][CH2:17][CH2:18][N:19]2[C:31]3[C:30]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[N:24]=[CH:23][C:22]=3[N:21]=[C:20]2[CH2:32][O:33][CH2:34][CH3:35])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)(C(C)(C)C)(C)C>CO>[CH2:34]([O:33][CH2:32][C:20]1[N:19]([CH2:18][CH2:17][CH2:16][C:10]2([OH:9])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[C:31]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[CH:23][C:22]=2[N:21]=1)[CH3:35]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCCC1(O[Si](C)(C)C(C)(C)C)CCCCC1
Agent: Cl
Solvent: CO
Product: CCOCc1nc2cnc3ccccc3c2n1CCCC1(O)CCCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 98.2 %

Procedure:
An aqueous solution of 3 M HCl (3.0 mL) was added to a solution of 1-[3-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)propyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline (prepared as described in part G, 3.16 mmol) in methanol (10 mL). A solid formed and additional methanol (10 mL) was added. The reaction was stirred at rt for 3 d and the solvent was removed in vacuo. The residue was dissolved in dichloromethane (40 mL) and saturated aqueous sodium bicarbonate (30 mL) was added so that the pH=8. The aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to yield 1-{3-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}cyclohexanol (1.14 g, 98%) as a brown gum.
Reaction SMILES: C1COCC1.C([O:8][C:9]([C:11]1[N:12]=[C:13]([C:16]2[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)[N:19]=[C:18]3[N:39]4[CH2:45][CH2:44][CH2:43][N:40]4[C:41](=[O:42])[C:17]=23)[O:14][CH:15]=1)=[O:10])C.[OH-].[Na+]>CCO>[CH2:25]([O:24][C:22]([C:21]1[C:16]([C:13]2[O:14][CH:15]=[C:11]([C:9]([OH:10])=[O:8])[N:12]=2)=[C:17]2[C:41](=[O:42])[N:40]3[CH2:43][CH2:44][CH2:45][N:39]3[C:18]2=[N:19][C:20]=1[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=1)=[O:23])[CH3:26]
Reactant: CCOC(=O)c1coc(-c2c(C(=O)OCC)c(CCc3ccc(C(F)(F)F)cc3)nc3c2c(=O)n2n3CCC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1c(CCc2ccc(C(F)(F)F)cc2)nc2c(c1-c1nc(C(=O)O)co1)c(=O)n1n2CCC1

Procedure:
A THF (4 mL) of ethyl 4-[4-(ethoxycarbonyl)-1,3-oxazol-2-yl]-5-oxo-2-{2-[4-(trifluoromethyl)phenyl]ethyl}-8,9-dihydro-5H,7H-pyrazolo[1′2′:1,2]pyrazolo[3,4-b]pyridine-3-carboxylate (0.400 g, 0.717 mmol), 0.717 mL of 1 N NaOH and EtOH (0.717 mL) was stirred for 6 h at ambient temperature and then concentrated. The residue was treated with 1 N HCl until acidic and the organics extracted with EtOAc (2×) and then dried (Na2SO4), filtered and concentrated to a yellowish-orange solid and used in the proceeded step with no further purification: 1H NMR (CDCl3, 400 MHz) δ 8.39 (s, 1H), 7.51 (d, J=8.1 Hz, 2H), 7.29 (d, J=7.9 Hz, 2H), 4.12–4.00 (m, 6H)), 3.18–3.08 (m, 4H), 2.81–2.74 (m, 2H), 1.00 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[C:9]([C:14]2[N:15]=[N:16][N:17]([CH2:19][CH3:20])[N:18]=2)[CH:10]=[CH:11][CH:12]=[O:13])=[CH:4][CH:3]=1.[C:28]([O:34][CH2:35][CH3:36])(=[O:33])[CH2:29][C:30]([CH3:32])=[O:31]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[C:9]([C:14]2[N:15]=[N:16][N:17]([CH2:19][CH3:20])[N:18]=2)[CH:10]=[CH:11][CH:12]([OH:13])[CH2:32][C:30](=[O:31])[CH2:29][C:28]([O:34][CH2:35][CH3:36])=[O:33])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: CCn1nnc(C(C=CC=O)=C(c2ccc(F)cc2)c2ccc(F)cc2)n1
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC(O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn(CC)n1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5,5-bis(4-fluorophenyl)-4-(2-ethyl-2H-tetrazol-5-yl)-2,4-pentadienal (2.0 g) in 20 mL of tetrahydrofuran at -40° C. was added 6.9 mL of 0.8M (5.5 mmoles) freshly prepared solution of ethyl acetoacetate dianion [described in Example 10]. The solution was stirred at -40° C. for 30 minutes and then allowed to warm to -10° C. After a total of one hour, the reaction was quenched with 1N HCl. The mixture was extracted with chloroform, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography to give 0.4 g of pure title compound. MS (EI): m/e=496 for M+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH2:3][NH:4][C:5]1[N:9]=[C:8](N)[S:7][N:6]=1.Cl.O1CCCCC1[O:20][CH2:21][C:22]([NH2:24])=[NH:23].[O-]CC.[Na+].[Na]>>[F:12][C:2]([F:1])([F:11])[CH2:3][N:4]=[C:5]([NH2:6])[NH:9][C:8]1[S:7][N:23]=[C:22]([CH2:21][OH:20])[N:24]=1
Reactant: N=C(N)COC1CCCCO1
Reactant: Nc1nc(NCC(F)(F)F)ns1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: NC(=NCC(F)(F)F)Nc1nc(CO)ns1
Reaction time: 4 h

Procedure:
3-(2,2,2-Trifluoroethyl)amino-5-amino-1,2,4-thiadiazole (2.0 g.) and tetrahydropyranyloxyacetamidine hydrochloride (2.0 g.) was added to a solution of sodium ethoxide prepared from sodium (0.46 g.) and alcohol (50 ml.). The resulting mixture was stirred at 20° for 4 hours then heated under reflux for 60 hours. Volatile material was evaporated in vacuo and the residue was shaken with 2N hydrochloric acid (30 ml.) and ethyl acetate (30 ml.). The aqueous layer was further extracted with ethyl acetate (3×30 ml.) then the pH was adjusted to 10 with 2N sodium hydroxide. The basified mixture was extracted with ethyl acetate (6×30 ml.) and the combined extracts were dried (MgSO4) and evaporated in vacuo to give the crude product as an oil. It would be purified by fractionation on a silica gel column eluted with ethyl acetate to give 5-[2-(2,2,2-trifluoroethyl)guanidino]-3-hydroxymethyl-1,2,4-thiadiazole, m.p. 123°-125°.